A Complicated Course of Brain Tumor Resection in a Patient with a Left Ventricular Assist Device

Left ventricular assist devices (LVAD) are mechanical pumps that have become a standard treatment for end-stage heart failure. As patients with LVAD are living longer, the number of noncardiac surgeries performed in these patients is rising. However, these patients present a unique set of risk factors, some of which include acquired coagulopathies, anticoagulation status, and hemodynamic instability. Thus, performing noncardiac surgeries in patients with an LVAD requires a precise and complex surgical strategy with optimal communication among the surgical team. Therefore, knowledge of best perioperative approaches for patients with LVAD is urgently needed. Here, we present a detailed perioperative surgical approach in the case of a brain tumor resection for a 62-year-old patient with an LVAD whose course was complicated with a brain hematoma. Critical details include key aspects of monitoring patient hemodynamic stability and handling of anesthesia, patient positioning, and antiplatelet and anticoagulation drug therapy. This case highlights the importance for anesthesiologists to be well informed about perioperative LVAD management, as well as common complications that they may encounter

Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis.

Ciliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information, it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography, we show that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermostability of the second C2 domain by targeting residues that point toward its hydrophobic core. Genome-engineered cells homozygous for these mutations have largely normal centriole numbers but show reduced CEP120 levels, compromised recruitment of distal centriole markers, and deficient cilia formation. Our results provide insight into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B, and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles

Transcriptional silencing of long noncoding RNA GNG12-AS1 uncouples its transcriptional and product-related functions.

Long noncoding RNAs (lncRNAs) regulate gene expression via their RNA product or through transcriptional interference, yet a strategy to differentiate these two processes is lacking. To address this, we used multiple small interfering RNAs (siRNAs) to silence GNG12-AS1, a nuclear lncRNA transcribed in an antisense orientation to the tumour-suppressor DIRAS3. Here we show that while most siRNAs silence GNG12-AS1 post-transcriptionally, siRNA complementary to exon 1 of GNG12-AS1 suppresses its transcription by recruiting Argonaute 2 and inhibiting RNA polymerase II binding. Transcriptional, but not post-transcriptional, silencing of GNG12-AS1 causes concomitant upregulation of DIRAS3, indicating a function in transcriptional interference. This change in DIRAS3 expression is sufficient to impair cell cycle progression. In addition, the reduction in GNG12-AS1 transcripts alters MET signalling and cell migration, but these are independent of DIRAS3. Thus, differential siRNA targeting of a lncRNA allows dissection of the functions related to the process and products of its transcription.The authors acknowledge all the members of Murrell, Rinn, Odom and Gergely laboratory as well as Massimiliano di Pietro, Klaas Mulder, Anna Git, Jason Carroll in Cambridge and Laurence Hurst (University of Bath) for reading and providing helpful comments on the manuscript. We also thank the Genomics, Microscopy and Bioinformatics core facilities at the Cambridge Institute for support, Christina Ernst for thumbnail image design, Ezgi Hacisuleyman for the design of the negative control vector, Cole Trapnell and David Hendrickson for providing us with lincExpress vector, Arjun Raj with the RNA FISH and Alaisdair Russell with the lentiviral work. This research was supported by The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. The authors have no conflicting financial interests.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1040

Elective Total Knee Replacement in a Patient With a Left Ventricular Assist Device-Navigating the Challenges With Spinal Anesthesia.

Elective joint surgery in a patient with a left ventricular assist device (LVAD) may become increasingly common as these devices become entrenched in the management of patients with heart failure. Furthermore, regional techniques may be reasonable anesthetic options in this challenging population. This case conference discusses a spinal anesthetic for an elderly female with an LVAD who presented for an elective left total knee arthroplasty. The expert case commentaries that follow the case discussion further explore the anesthetic issues in light of the existing literature

Mitotic spindle association of TACC3 requires Aurora-A-dependent stabilization of a cryptic α-helix.

Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation. The helix extends into a third, adjacent motif that is recognized by a helical-repeat region of CHC, not a recognized phospho-reader domain. This potentially widespread mechanism of phospho-recognition provides greater flexibility to tune the molecular details of the interaction than canonical recognition motifs that are dominated by phosphate binding

A Composite Metric for Benchmarking Site Performance in TAVR: Results from the STS/ACC TVT Registry

Background: Transcatheter aortic valve replacement (TAVR) is a transformative therapy for aortic stenosis. Despite rapid improvements in technology and techniques, serious complications remain relatively common and are not well described by single outcome measures. The purpose of this study was to determine if there is site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. Methods: We performed a retrospective cohort study using data from the STS/ACC TVT Registry to develop a novel ranked composite performance measure that incorporates mortality and serious complications. The selection and rank order of the complications for the composite was determined by their adjusted association with 1-year outcomes. Sites whose risk-adjusted outcomes were significantly more or less frequent than the national average based on a 95% probability interval were classified as performing worse or better than expected. Results: The development cohort consisted of 52,561 patients who underwent TAVR between January 1, 2015 and December 31, 2017. Based on the associations with 1-year risk-adjusted mortality and health status, we identified four periprocedural complications to include in the composite risk model in addition to mortality. Ranked empirically according to severity, these included stroke, major, life-threatening or disabling bleeding, stage III acute kidney injury, and moderate or severe peri-valvular regurgitation. Based on these ranked outcomes, we found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better than expected site performance was observed in 25/301 (8%) of sites; performance as expected was observed in 242/301 sites (80%); and worse than expected performance was observed in 34/301 (11%) of sites. Thirty-day mortality, stroke, major, life-threatening or disabling bleeding, and moderate or severe peri-valvular leak were each substantially more common in sites with worse than expected performance as compared with other sites. There was good aggregate reliability of the model. Conclusions: There are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine structural, process-related, and technical factors associated with high- and low-performing sites

Patients with type A acute aortic dissection presenting with major brain injury: Should we operate on them?

none20siopenDi Eusanio, Marco*; Patel, Himanshu J.; Nienaber, Christoph A.; Montgomery, Daniel M.; Korach, Amit; Sundt, Thoralf M.; Devincentiis, Carlo; Voehringer, Matthias; Peterson, Mark D.; Myrmel, Truls; Folesani, Gianluca; Larsen, Magnus; Desai, Nimesh D.; Bavaria, Joseph E.; Appoo, Jehangir J.; Kieser, Teresa M.; Fattori, Rossella; Eagle, Kim; Di Bartolomeo, Roberto; Trimarchi, SantiDi Eusanio, Marco; Patel, Himanshu J.; Nienaber, Christoph A.; Montgomery, Daniel M.; Korach, Amit; Sundt, Thoralf M.; Devincentiis, Carlo; Voehringer, Matthias; Peterson, Mark D.; Myrmel, Truls; Folesani, Gianluca; Larsen, Magnus; Desai, Nimesh D.; Bavaria, Joseph E.; Appoo, Jehangir J.; Kieser, Teresa M.; Fattori, Rossella; Eagle, Kim; Di Bartolomeo, Roberto; Trimarchi, Sant

Studying Black Holes on Horizon Scales with VLBI Ground Arrays

High-resolution imaging of supermassive black holes is now possible, with new applications to testing general relativity and horizon-scale accretion and relativistic jet formation processes. Over the coming decade, the EHT will propose to add new strategically placed VLBI elements operating at 1.3mm and 0.87mm wavelength. In parallel, development of next-generation backend instrumentation, coupled with high throughput correlation architectures, will boost sensitivity, allowing the new stations to be of modest collecting area while still improving imaging fidelity and angular resolution. The goal of these efforts is to move from imaging static horizon scale structure to dynamic reconstructions that capture the processes of accretion and jet launching in near real time