Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Combined Application of a Novel Robotic System and Exoscope for Microsurgical Anastomoses: Preclinical Performance

Background The concept of robotic microsurgery is becoming increasingly known as several robotic systems tailored to the specific needs of microsurgery are being introduced. Training with these devices is essential to draw conclusions about their potential clinical utility. This study describes the training and learning curve of experienced microsurgeons and complete novices using such a robotic surgical system in combination with an exoscope

Preclinical Performance of the Combined Application of Two Robotic Systems in Microsurgery: A Two-center Study

Background:. Recent advancements in the development of robotic devices increasingly draw the attention toward the concept of robotic microsurgery, as several systems tailored to open microsurgery are being introduced. This study describes the combined application of a novel microsurgical robot, the Symani, with a novel robotic microscope, the RoboticScope, for the performance of microvascular anastomoses in a two-center preclinical trial. Methods:. Six novices, residents, and experienced microsurgeons (n = 18) performed five anastomoses on 1.0-mm-diameter silicone vessels with a conventional versus combined robotic approach, resulting in 180 anastomoses. Microsurgical performance was evaluated, analyzing surgical time, subjective satisfaction with the anastomosis and robotic setup, anastomosis quality using the anastomosis lapse index score, microsurgical skills using the Structured Assessment of Microsurgery Skills score, and surgical ergonomics using the Rapid Entire Body Assessment score. Results:. All participants significantly improved their performance during the trial and quickly adapted to the novel systems. Surgical time significantly decreased, whereas satisfaction with the anastomosis and setup improved over time. The use of robotic systems was associated with fewer microsurgical errors and enhanced anastomosis quality. Especially novices demonstrated accelerated skill acquisition upon robotic assistance compared with conventional microsurgery. Moreover, upper extremity positioning was significantly improved. Overall, the robotic approach was subjectively preferred by participants. Conclusions:. The concept of robotic microsurgery holds great potential to improve precision and ergonomics in microsurgery. This two-center trial provides promising evidence for a steep learning curve upon introduction of robotic microsurgery systems, suggesting further pursuit of their clinical integration

Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis

Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source