Practice Patterns and Trends in the Use of Medical Therapy in Patients Undergoing Percutaneous Coronary Intervention in Ontario

Background Clinical guidelines emphasize medical therapy as the initial approach to the management of patients with stable coronary artery disease (CAD). However, the extent to which medical therapy is applied before and after percutaneous coronary intervention (PCI) in contemporary clinical practice is uncertain. We evaluated medication use for patients with stable CAD undergoing PCI, and assessed whether the COURAGE study altered medication use in the Canadian healthcare system. Methods and Results A population‐based cohort of 23 680 older patients \u3e65 years old) with stable CAD undergoing PCI in Ontario between 2003 and 2010 was assembled. Optimal medical therapy (OMT) was defined as prescription for a β‐blocker, statin, and either angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker in the 90 days before PCI, and the same medications plus thienopyridine 90 days following PCI. Prior to PCI, 8023 (33.9%) patients were receiving OMT, 11 891 (50.2%) were on suboptimal therapy, and 3766 (15.9%) were not prescribed any medications of interest. There was significant improvement in medical therapy following PCI (OMT: 11 149 [47.1%], suboptimal therapy: 11 591 [48.9%], and none: 940 [4.0%], PPP\u3c0.001). Conclusions OMT was prescribed in about 1 in 3 patients prior to PCI and less than half after PCI. In contrast to the anticipated impact of COURAGE, we found lower rates of medication use in PCI patients after its publication

Peer-to-Peer Grids

We describe Peer-to-Peer Grids built around Integration of technologies from the peer-to-peer and Grid fields. We focus on the role of Web services linked by a powerful event service using uniform XML interfaces and application level routing. We describe how a rich synchronous and asynchronous collaboration environment can support virtual communities built on top of such infrastructure. Universal access mechanisms are discussed

Cell-Autonomous Death of Cerebellar Purkinje Neurons with Autophagy in Niemann-Pick Type C Disease

Niemann-Pick type C is a neurodegenerative lysosomal storage disorder caused by mutations in either of two genes, npc1 and npc2. Cells lacking Npc1, which is a transmembrane protein related to the Hedgehog receptor Patched, or Npc2, which is a secreted cholesterol-binding protein, have aberrant organelle trafficking and accumulate large quantities of cholesterol and other lipids. Though the Npc proteins are produced by all cells, cerebellar Purkinje neurons are especially sensitive to loss of Npc function. Since Niemann-Pick type C disease involves circulating molecules such as sterols and steroids and a robust inflammatory response within the brain parenchyma, it is crucial to determine whether external factors affect the survival of Purkinje cells (PCs). We investigated the basis of neurodegeneration in chimeric mice that have functional npc1 in only some cells. Death of mutant npc1 cells was not prevented by neighboring wild-type cells, and wild-type PCs were not poisoned by surrounding mutant npc1 cells. PCs undergoing cell-autonomous degeneration have features consistent with autophagic cell death. Chimeric mice exhibited a remarkable delay and reduction of wasting and ataxia despite their substantial amount of mutant tissue and dying cells, revealing a robust mechanism that partially compensates for massive PC death

A real-time PCR assay for quantification of parasite burden in murine models of leishmaniasis

Eukaryotic parasites in the genus Leishmania place approximately 350 million people per year at risk of disease. In addition to their global health significance, Leishmania spp. have served as an important model for delineating basic concepts in immunology such as T-helper cell polarization. There have been many qPCR-based assays reported for measuring parasite burden in humans and animals. However, these are largely optimized for use in clinical diagnosis and not specifically for animal models. This has led several of these assays to have suboptimal characteristics for use in animal models. For example, multi-copy number genes have been frequently used to increase sensitivity but are subject to greater plasticity within the genome and thus may confound effects of experimental manipulations in animal models. In this study, we developed a sybr-green based quantitative touchdown PCR assay for a highly conserved and single-copy putative RNA-binding protein, DRBD3. With primers that share greater than 90% sequence identity across all sequenced Leishmania spp., we demonstrate that this assay has a lower limit of detection of 100 fg of parasite DNA for Leishmania major, L. donovani, L. venezuelensis, and L. panamensis. Using C57BL6/J mice, we used this assay to monitor parasite burden over 1 month of infection with two strains of L. major (Seidman and Friedlin), and L. venezeuelensis. These characteristics rival the sensitivity of previously reported qPCR based methods of parasite quantitation while amplifying a stable, single copy gene. Use of this protocol in the future will lead to improved accuracy in animal based models and help to tease apart differences in biology of host-parasite interactions

A Suppressor/Enhancer Screen in Drosophila Reveals a Role for Wnt-Mediated Lipid Metabolism in Primordial Germ Cell Migration

Wnt proteins comprise a large family of secreted ligands implicated in a wide variety of biological roles. WntD has previously been shown to inhibit the nuclear accumulation of Dorsal/NF-κB protein during embryonic dorsal/ventral patterning and the adult innate immune response, independent of the well-studied Armadillo/β-catenin pathway. In this paper, we present a novel phenotype for WntD mutant embryos, suggesting that this gene is involved in migration of primordial germ cells (PGC) to the embryonic gonad. Additionally, we describe a genetic suppressor/enhancer screen aimed at identifying genes required for WntD signal transduction, based on the previous observation that maternal overexpression of WntD results in lethally dorsalized embryos. Using an algorithm to narrow down our hits from the screen, we found two novel WntD signaling components: Fz4, a member of the Frizzled family, and the Drosophila Ceramide Kinase homolog, Dcerk. We show here that Dcerk and Dmulk (Drosophila Multi-substrate lipid kinase) redundantly mediate PGC migration. Our data are consistent with a model in which the activity of lipid phosphate phosphatases shapes a concentration gradient of ceramide-1-phosphate (C1P), the product of Dcerk, allowing proper PGC migration

Comparing Trajectory of Surgical Aortic Valve Replacement in the Early vs. Late Transcatheter Aortic Valve Replacement Era

Background: Traditionally, the only effective treatment for aortic stenosis was surgical aortic valve replacement (SAVR). Transcatheter aortic valve replacement (TAVR) was approved in the United States in late 2011 and provided a critical alternative therapy. Our aims were to investigate the trends in the utilization of SAVR in the early vs. late TAVR era and to assess SAVR and TAVR outcomes.Methods: Using the 2011–2017 National Inpatient Sample database, we identified hospitalizations for patients with a most responsible diagnosis of aortic stenosis during which an aortic valve replacement (AVR) was performed, either SAVR or TAVR. Patients' sociodemographic and clinical characteristics, procedure complications, length of stay, and mortality were analyzed. Multivariable analyses were performed to identify predictors of in-hospital mortality. Piecewise regression analyses were performed to assess temporal trends in SAVR and TAVR utilization.Results: A total of 542,734 AVR procedures were analyzed. The utilization of SAVR was steady until 2014 with a significant downward trend in the following years 2015–2017 (P = 0.026). In contrast, a steady upward trend was observed in the TAVR procedure with a significant increase during the years 2015–2017 (P = 0.006). Higher in-hospital mortality was observed in SAVR patients. The mortality rate declined from 2011 to 2017 in a significantly higher proportion in the TAVR compared with the SAVR group.Conclusion: Utilization of SAVR showed a downward trend during the late TAVR era (2015–2017), and TAVR utilization demonstrated a steady upward trend during the years 2011–2017. Higher in-hospital mortality was recorded in patients who underwent SAVR