Vancouver General Hospital

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a widespread modification in metazoans. Cumulative evidence has revealed the altered A-to-I editing profiles in cancers, but the underlying mechanism remains unclear. Here, we discover the well-known histone lysine methyltransferase enhancer of zeste homologue 2 (EZH2) as an unexplored ADAR interactor and editing regulator in prostate cancer (PCa). Through competing with interleukin enhancer binding factor 2 (ILF2) for ADAR1 binding, EZH2 reshapes the substrate selectivity of ADAR1 and thus exhibits a bidirectional role in editing regulation. Moreover, EZH2 depletion induces the translational repression of transportin-1 (TRN1), which further results in the accumulation of cytoplasmic ADAR1p110 isoform to protect many oncogenic transcripts from degradation. Consistently, depletion of ADAR1 dramatically enhances the sensitivity of cancer cells and tumors to EZH2 selective degraders. Collectively, our study sheds new light on a link between two layers of epigenetic regulations at histone modification and RNA editing levels, demonstrates a previously uncharacterized role of EZH2 in RNA editing and mRNA stability independently of its lysine methyltransferase activity, and reveals the significance of EZH2-ADAR1 cascade in governing RNA editing and mRNA stability, which may provide additional perspectives for the advancement of EZH2-targeting cancer therapies.

This age-based sub-group analysis was conducted within the investigator-initiated PRECISE trial, developed by academic leadership with funding and participation from HeartFlow Inc. The overall trial protocol and interpretation of results were reviewed and approved by the steering committee independently of the sponsor. Trial conduct followed the study protocol and was overseen by an independent data and safety monitoring board and the PRECISE steering committee. Operations were managed jointly by HeartFlow Inc. and the Duke Clinical Research Institute. Outcome assessments, including data and safety monitoring, event adjudication, and core lab functions, were performed independently of the sponsor. Academic authors drafted and revised the manuscript with input from HeartFlow Inc., which assisted in study conduct and data collection but did not influence outcome assessments or interpretation. The sponsor reviewed but did not prepare or approve the manuscript. The decision to publish was made independently by the lead authors and the steering committee. M.D. Kelsey: Advisory board for Bayer; Consultant/Speaker for Heartflow Inc. S. Vemulapalli: National Institutes of Health, Food and Drug Administration, American College of Cardiology, Cytokinetics, Edwards Lifesciences, Abbott Vascular; Consulting/Advisory: Astra Zeneca, Boehringer-Ingelheim, Cytokinetics, Edwards Lifesciences, Medtronic, Total CME, Ikon, Veralox Therapeutics. D.B. Mark: grant support from HeartFlow Inc. during the conduct of this study; grant support from Merck and Novo Nordisk outside the submitted work; grants or research support from NIH/NHLBI and American Heart Association; consulting fees from CeleCor, Novartis, and Boehringer Ingelheim outside the submitted work; honoraria from Elsevier outside the submitted work. C. Rogers: Employee and shareholder of HeartFlow. S. Mullen: Employee & shareholder of HeartFlow. W. Huey: Employee & shareholder of HeartFlow. A. Caune: Employee & shareholder of HeartFlow. J.A. Leipsic: Dr. Leipsic provides institutional CT core laboratory support to Edwards Lifesciences, Medtronic, Abbott Vascular, and Boston Scientific but takes no personal compensation and is a consultant to HeartFlow and Circle CVI. R.A. Byrne: Professor Robert A. Byrne does not accept direct or personal payments from the medical device or pharmaceutical industry, reports research funding to the institution from Abbott Vascular, Biosensors, Boston Scientific, and Translumina without impact on personal remuneration. N. Ng: Employee & stock options in HeartFlow. J.E. Udelson: Dr. Udelson has received personal fees from scPharmaceuticals, Merck, Alleviant, Reprieve CV, and Cardurion. P.S. Douglas: Dr. Douglas reports relevant research support to her institution from HeartFlow and as a consultant for Cleerly. M.G. Nanna: Dr. Nanna reports consulting for Heartflow, Merck, and Novo Nordisk as well as research support from the American College of Cardiology Foundation supported by the George F. and Ann Harris Bellows Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the Yale Claude D. Pepper Older Americans Independence Center (P30AG021342), and the National Institute on Aging (K76AG088428). E. Vemmou, K. Chiswell, R.M. Clare, E. Yow, K. Pier declare no conflicts of interest. Table S1: Cardiac Catheterization Rates Among Those with Positive and Negative Testing Stratified By Population Definition, Age, and Testing Strategy. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Background: Health care accounts for 4.6% of Canada's greenhouse gas (GHG) emissions, 25% of which comes from medications. Antimicrobials with high bioavailability offer no additional benefit when given intravenously, except when oral (PO) administration is not feasible. Intravenous (IV) formulations have a higher carbon footprint than their PO counterparts. IV-to-PO switch strategies benefit patients and the health care system by reducing line-related adverse events, nursing time, length of hospital stay, and costs and can also reduce carbon emissions. Objectives: Our primary objective was to quantify IV use of bioequivalent antimicrobials when PO administration is feasible. Secondary objectives were to determine GHG emissions and antimicrobial costs associated with unnecessary IV use of bioequivalent antimicrobials. Methods: We performed a retrospective, cross-sectional study of hospitalized adults who received IV azithromycin, ciprofloxacin, clindamycin, cotrimoxazole, fluconazole, levofloxacin, linezolid, metronidazole, moxifloxacin, or voriconazole at Vancouver General Hospital on five dates. We determined the proportion of patients receiving these antimicrobials who met criteria for PO administration. We also applied a life cycle assessment (LCA) to assess the GHG emissions of the antimicrobial drug delivery systems using OpenLCA with the Ecoinvent database. Using these data, we calculated the GHG emissions and costs associated with unnecessary IV use. Results: In total, 128 patients were identified. Seventy-eight (61%) met IV-to-PO switch criteria on the audit dates. Most eligible patients were admitted to general surgery, internal medicine, or critical care. The antimicrobial with the highest IV-to-PO switch eligibility was metronidazole (51%), most often prescribed for intra-abdominal infections. Over the five study dates, potential GHG savings were ∼80,000 gCO 2 -eq. Potential annual cost savings were ∼$59,000. Conclusion: Over 60% of patients receiving highly bioavailable IV antimicrobials were eligible for PO therapy, highlighting an opportunity to optimize prescribing. Promoting an IV-to-PO switch can improve patient outcomes and reduce environmental impact, supporting both patient-centred care and planetary health.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are influenced by age, which may influence the diagnostic performance of this peptide. Machine learning approaches incorporating NT-proBNP and age as continuous measures may have improved diagnostic performance. We pooled individual patient-level data for 10 369 patients [median age 73 years (25th-75th percentile: 59-82)] with suspected acute heart failure across fourteen studies. The diagnostic performance of guideline-recommended NT-proBNP thresholds (uniform rule-out threshold of 300 pg/mL and age-stratified rule-in thresholds of 450, 900, and 1800 pg/mL for patients <50, 50-75, and >75 years, respectively) and the Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF) machine learning model were evaluated using random effects meta-analysis across age groups. Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure. The negative predictive value (NPV) of the rule-out threshold of 300 pg/mL was lower in older patients [NPV 88.7% (confidence interval (CI) 84.2-92.1%) in patients ≥80 years vs 98.9% (97.6-99.5%) <50 years]. Conversely, the positive predictive value (PPV) of age-stratified rule-in thresholds was lower in younger patients [PPV 62.0% (56.2-67.5%) in those <50 years vs 79.6% (70.7-86.3%) ≥80 years]. CoDE-HF was more accurate than guideline-recommended thresholds across all age groups, with NPV and PPV ranging from 96.4% to 99.5% (93.8-99.8% CIs) and 81.1% to 84.2% (74.7-90.4% CIs), respectively. The diagnostic performance of guideline-recommended thresholds of NT-proBNP varies significantly with age. A decision-support tool incorporating NT-proBNP with age as a continuous variable provides a more consistent and accurate approach.

In 1954 Godman and Churg published an article in the Archives of Pathology & Laboratory Medicine entitled "Wegener's Granulomatosis" (now replaced by "granulomatosis with polyangiitis" [GPA]) and linked various forms of what is currently recognized as pauci-immune small-vessel vasculitis. To put the 1954 article by Godman and Churg into context and review current ideas of GPA. Published literature. Godman and Churg proposed the name Wegener's granulomatosis and defined the essential features as granulomatous inflammation and necrotizing vasculitis involving, typically, the upper respiratory tract, lung, and kidney. They suggested that GPA, allergic angiitis, and granulomatosis (later known as Churg-Strauss syndrome, now "eosinophilic granulomatosis with polyangiitis" [EGPA]), and what were referred to as "microscopic forms of periarteritis nodosa," now "microscopic polyangiitis," were related entities producing small-vessel vasculitis. We currently recognize these diseases as the spectrum of pauci-immune ANCA (anti-neutrophil cytoplasmic antibody)-associated small-vessel vasculitis, in contrast to small-vessel vasculitis characterized by immune complex deposits. ANCAs are antibodies directed against the neutrophil proteins proteinase 3 (PR3, usually associated with GPA) and myeloperoxidase (MPO, usually associated with microscopic polyangiitis and EGPA). A modern definition of GPA discloses that it can affect any organ in the body, characteristically with upper respiratory tract involvement. In the lung it is associated with necrotizing nodules and/or capillaritis with hemorrhage. It has been proposed that these forms of vasculitis should in the future be primarily classified by using ANCA specificity-that is, PR3 or MPO-as a disease definition, based on observations that the type of ANCA is what determines the location/pattern of organ involvement.

Sudden sensorineural hearing loss (SSNHL) is an acquired idiopathic hearing loss in which recent studies have suggested that microRNAs (miRNAs) have a pathogenetic role. We assessed six specific miRNAs linked to SSNHL in serum samples drawn from 11 SSNHL patients and 11 age and sex matched controls. Quantitative real-time PCR Cycle threshold (Ct) values were normalized to an internal control to determine relative miRNA levels. Inter-group mean age, sex, mean or median normalized Ct values were compared using Independent Sample t, Chi-squared or Mann-Whitney U tests. The relative expression (ΔΔCt) of miR-210-3p, miR-23a-2p, miR18b-5p -2.75, -3.33, and − 1.29, corresponded to statistically different ΔCt values (Students T-test, p = 0.006; Mann-Whitney U, p = 0.001 and 0.02) and fold changes of 6.73, 10.87, and 2.45, respectively, in SSNHL patients compared with controls. No significant difference in the expression levels of miR-15a-5p, miR-143-3p, or miR-183-5p was found. This study supports consistent dysregulation of miR-210-3p/-23a-3p and − 18b-5p across different populations of SSNHL patients, suggesting that they play a key role in the pathogenesis of SSNHL.