Deficits in human trisomy 21 iPSCs and neurons.

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.

Increased Aseptic Tibial Failures in Patients With a BMI ≥35 and Well-Aligned Total Knee Arthroplasties.

The purpose of this study was to calculate the risk of revision secondary to aseptic tibial loosening correlated with increased BMI in 5088 primary TKAs. The mean age was 69 years, with a mean follow-up of 7 years. Fifty-two (1.0%) revision TKAs were performed due to aseptic tibial loosening, with the 15-year risk being 2.7%. Patients with a BMI ≥35 kg/m(2) were significantly more likely to undergo revision due to aseptic tibial failure (HR=1.9; P<0.05). Coronal alignment was equivalent between those who did and did not experience tibial loosening. Given that the risk of revision TKA due to aseptic tibial component failure is 2-fold greater in those with a BMI of ≥35 kg/m(2), consideration should be given to additional fixation. Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.

Near-peer driven dissection selective: A primer to the medical school anatomy course.

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.

Hemorrhagic complications of cutaneous surgery for patients taking antithrombotic therapy: a systematic review and meta-analysis.

Cutaneous operations are generally safe procedures with minimal major risks. Excessive bleeding occasionally occurs, especially for patients taking antithrombotic medications. Conversely, stopping these medications before cutaneous surgery may increase the risk of a thromboembolic event. We aimed to synthesize the evidence regarding the risk of hemorrhage and thromboembolic events for patients undergoing cutaneous surgery while taking antithrombotic therapy. We performed a comprehensive search to identify randomized controlled trials and cohort studies that compared rates of hemorrhage and/or thromboembolic events between patients receiving antithrombotic therapy at cutaneous surgery and patients not receiving it. Odds ratio (OR) and risk difference for complications were calculated with random-effects models. Of 9214 patients taking anticoagulant or antiplatelet medications, 323 (3.5%) had hemorrhagic complications; of 21,696 control patients, 265 (1.2%) had hemorrhagic complications. Patients taking antithrombotic therapy had increased bleeding risk relative to control patients (OR 2.63 [95% CI 1.90-3.63]; P < 0.001) and an increased but less clinically important risk difference (OR 0.02 [95% CI 0.01-0.03]; P < 0.001) with high heterogeneity. No difference was observed in hemorrhage rates among patients whose antithrombotic therapy was stopped vs continued (OR 1.16 [95% CI 0.73-1.83]; P = 0.54). No difference was seen in rates of thromboembolic events among patients taking antithrombotic therapy vs control patients. However, two serious thromboembolic events were noted in a cohort of 59 patients whose antithrombotic therapy was stopped. Because of potentially devastating effects of thromboembolic events, the current accepted practice is indicated for continuation of antithrombotic therapy for patients undergoing cutaneous surgery.

Vascular Malformations and Health-Related Quality of Life: A Systematic Review and Meta-analysis.

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 Measures: The 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; I2 = 92%; P = .02) and mental health (mean difference, -6.04; 95% CI, -11.55 to -0.52; I2 = 83%; P = .03) compared with the US general population. Conclusions and Relevance: Patients 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.

Single-cell gene expression patterns in lupus monocytes independently indicate disease activity, interferon and therapy.

OBJECTIVES: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. METHODS: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. RESULTS: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. CONCLUSIONS: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.

Gene Expression Studies on Human Trisomy 21 iPSCs and Neurons: Towards Mechanisms Underlying Down's Syndrome and Early Alzheimer's Disease-Like Pathologies.

The cause of Alzheimer disease (AD) is not well understood and there is no cure. Our ability to understand the early events in the course of AD is severely limited by the difficulty of identifying individuals who are in the early, preclinical stage of this disease. Most individuals with Down's syndrome (DS, trisomy 21) will predictably develop AD and that they will do so at a young age makes them an ideal population in which to study the early stages of AD. Several recent studies have exploited induced pluripotent stem cells (iPSCs) generated from individuals with familial AD, spontaneous AD and DS to attempt to identify early events and discover novel biomarkers of disease progression in AD. Here, we summarize the progress and limitations of these iPSC studies with a focus on iPSC-derived neurons. Further, we outline the methodology and results for comparing gene expression between AD and DS iPSC-derived neurons. We highlight differences and commonalities in these data that may implicate underlying genes and pathways that are causative for AD.

Metal in Total Hip Arthroplasty: Wear Particles, Biology, and Diagnosis.

Total hip arthroplasty (THA) has been performed for nearly 50 years. Between 2006 and 2012, more than 600,000 metal-on-metal THA procedures were performed in the United States. This article reviews the production of metal wear debris in a metal-on-metal articulation and the interaction of cobalt and chromium ions that ultimately led to a dramatic decline in the use of metal-on-metal THA articulations. Additionally, the article reviews mechanisms of metal wear, the biologic reaction to cobalt and chromium ions, the clinical presentation of failing metal-on-metal articulations, and current diagnostic strategies. Further, the article discusses the use of inflammatory markers, metal ion levels, radiographs, metal artifact reduction sequence magnetic resonance imaging, and ultrasound for failed metal-on-metal THA procedures. When adopting new technologies, orthopedic surgeons must weigh the potential increased benefits against the possibility of new mechanisms of failure. Metal-on-metal bearings are a prime example of the give and take between innovation and clinical results, especially in the setting of an already successful procedure such as THA. [Orthopedics. 2016; 39(6):371-379.].