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Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment, but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ-modified mRNA (D1-modRNA), and D1-modRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an up-regulation of Stat1 and RnaseL, and increased systemic inflammation. This result correlated with significantly reduced antigen-specific antibody responses and reduced protection against influenza virus infection compared with D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material.

Self-amplifying mRNA (saRNA) represents a promising platform for nucleic acid delivery of vaccine immunogens. Unlike plasmid DNA, saRNA does not require entry into the nucleus of target cells for expression, having the capacity to drive higher protein expression compared to mRNA as it replicates within the cytoplasm. In this study, we examined the potential of stabilized native-like HIV-1 Envelope glycoprotein (Env) trimers to elicit immune responses when delivered by saRNA polyplexes (PLXs), assembled with linear polyethylenimine. We showed that Venezuelan equine encephalitis virus (VEEV) saRNA induces a stronger humoral immune response to the encoded transgene compared to Semliki Forest virus saRNA. Moreover, we characterized the immunogenicity of the soluble and membrane-bound ConSOSL.UFO Env design in mice and showed a faster humoral kinetic and an immunoglobulin G (IgG)2a skew using a membrane-bound design. The immune response generated by PLX VEEV saRNA encoding the membrane-bound Env was then evaluated in larger animal models including macaques, in which low doses induced high IgG responses. Our data demonstrated that the VEEV saRNA PLX nanoparticle formulation represents a suitable platform for the delivery of stabilized HIV-1 Env and has the potential to be used in a variety of vaccine regimens.

Focusing T cell responses on the most vulnerable parts of HIV-1, the functionally conserved regions of HIV-1 proteins, is likely a key prerequisite for vaccine success. For a T cell vaccine to efficiently control HIV-1 replication, the vaccine-elicited individual CD8+ T cells and as a population have to display a number of critical traits. If any one of these traits is suboptimal, the vaccine is likely to fail. Fine-tuning of individual protective characteristics of T cells will require iterative stepwise improvements in clinical trials. Although the second-generation tHIVconsvX immunogens direct CD8+ T cells to predominantly protective and conserved epitopes, in the present work, we have used formulated self-amplifying mRNA (saRNA) to deliver tHIVconsvX to the immune system. We demonstrated in BALB/c and outbred mice that regimens employing saRNA vaccines induced broadly specific, plurifunctional CD8+ and CD4+ T cells, which displayed structured memory subpopulations and were maintained at relatively high frequencies over at least 22 weeks post-administration. This is one of the first thorough analyses of mRNA vaccine-elicited T cell responses. The combination of tHIVconsvX immunogens and the highly versatile and easily manufacturable saRNA platform may provide a long-awaited opportunity to define and optimize induction of truly protective CD8+ T cell parameters in human volunteers. Keywords: RNA vaccine, HIV vaccine, conserved regions, tHIVconsvX, simian adenovirus, MVA, T cell vaccine, heterologous prime-boost, in vivo killing, T cells

Summary: Chemiluminescence and fluorescence have revolutionized the study of chemical and biological processes. However, unlike fluorescence, spatiotemporal control of chemiluminescence is challenging, and the technically simple solution of converting chemical energy into light energy only at specific sites defined by a clean, easy-to-deliver focused light stimulus is not yet a viable option. Here, we demonstrate the spatial and temporal control of a chemiluminescent reaction by photoinduced oxidative hotspots on a silicon surface. The excitation light is not required to pass through the liquid sample; hence, the light stimulus can excite a luminescent dye under effectively dark conditions. This provides a strategy for removing light-induced sample damages, photobleaching, and autofluorescence.

Background: In patients with low-gradient aortic stenosis (AS) and low transvalvular flow, dobutamine stress echocardiography (DSE) is recommended to determine AS severity, whereas the degree of aortic valve calcification (AVC) supposedly correlates with AS severity according to current European and American guidelines., Objectives: The purpose of this study was to assess the relationship between AVC and AS severity as determined using echocardiography and DSE in patients with aortic valve area <1 cm 2 and peak aortic valve velocity <4.0 m/s., Methods: All patients underwent DSE to determine AS severity and multislice computed tomography to quantify AVC. Receiver-operating characteristics curve analysis was used to assess the diagnostic value of AVC for AS severity grading as determined using echocardiography and DSE in men and women., Results: A total of 214 patients were included. Median age was 78 years (25th-75th percentile: 71-84 years) and 25% were women. Left ventricular ejection fraction was reduced (<50%) in 197 (92.1%) patients. Severe AS was diagnosed in 106 patients (49.5%). Moderate AS was diagnosed in 108 patients (50.5%; in 77 based on resting transthoracic echocardiography, in 31 confirmed using DSE). AVC score was high (≥2,000 for men or ≥1,200 for women) in 47 (44.3%) patients with severe AS and in 47 (43.5%) patients with moderate AS. AVC sensitivity was 44.3%, specificity was 56.5%, and positive and negative predictive values for severe AS were 50.0% and 50.8%, respectively. Area under the receiver-operating characteristics curve was 0.508 for men and 0.524 for women., Conclusions: Multi-slice computed tomography-derived AVC scores showed poor discrimination between grades of AS severity using DSE and cannot replace DSE in the diagnostic work-up of low-gradient severe AS., Competing Interests: Funding Support and Author Disclosures Dr Van Mieghem has received grant support/research contracts from Abbott Vascular, Boston Scientific, Medtronic, Edwards Lifesciences, Daiichy Sankyo, AstraZeneca, and PulseCath BV; and has received consulting/speaker fees from Abbot Vascular, Boston Scientific Corporation, Medtronic, Daiichy Sankyo, PulseCath BV, JenaValve, and Amgen. Dr Mehran has received grant support/research contracts from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena Pharmaceuticals, AstraZeneca, Atricure Inc, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, Cytsorbents, Daiichy-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen Pharmaceuticals, Magenta, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave Medical, Vivasure, and Zoll; has received consulting/speaker fees from AstraZeneca, E.R. Squibb and Sons LLC, Esperion Science/Innovativa Biopharma, Ionis Pharmaceuticals, IQVIA, J-Calc, McVeigh Global, Novartis, Novo Nordisk, Overcome, Primer Healthcare of New Jersey, Radcliffe, SL Solutions, TARSUS Cardiology, Vectura, and WebMD; and she has equity in Applied Therapeutics, Elixir, and STEL. Dr Mehran’s spouse has equity in ControlRad. Dr Kodali has received grant support/research contracts from Admedus, Dura Biotech, Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and JenaValve; has received consulting/speaker fees from Admedus, Dura Biotech, TriCares, X-Dot, Tioga, Helix Valve Repair, and Moray Medical; and has equity in Dura Biotech, Microinterventional Devices, Thubrika Aortic Valve Inc, Supira, Admedus, Triflo, and Adona. Dr Hahn has received consulting/speaker fees from Abbott Structural, Medtronic, Edwards Lifesciences, Boston Scientific, Baylis Medical, Navigate, Philips Healthcare, Siemens Healthcare, and 3mensio; and has equity in Navigate. Dr Bax has received grant support/research contracts from Biotronic, Boston Scientific, Medtronic, Bayer AG, and Edwards Lifesciences; and has received consulting/speaker fees from Abbott Vascular and Edwards Lifesciences. Drs Veulemans and Zeus have received consulting fees, travel expenses, or study honoraria from Medtronic, Edwards Lifesciences, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The risks of prefrail and frail women undergoing transcatheter aortic valve replacement (TAVR) have not been fully examined. The aim of the analysis was to assess the prognostic impact of prefrailty and frailty in women undergoing TAVR., Methods: Women at intermediate or high surgical risk with severe aortic stenosis undergoing TAVR from the prospective multicentre WIN-TAVI (Women's International Transcatheter Aortic Valve Implantation) registry were stratified based on the number of Fried frailty criteria (weight loss, exhaustion, low physical activity, slow gait, weakness) met: nonfrail (no criteria), prefrail (1 or 2 criteria), or frail (3 or more criteria). The primary outcome at 1 year was the Valve Academic Research Consortium 2 (VARC-2) efficacy end point, a composite of mortality, stroke, myocardial infarction, hospitalisation for valve-related symptoms or heart failure, and valve-related dysfunction; secondary outcomes included the composite of VARC-2 life-threatening or major bleeding., Results: Out of 1019 women, 297 (29.1%) met at least 1 frailty criterion: 264 (25.9%) had prefrailty and 33 (3.2%) frailty. The 1-year risk of the primary outcome was significantly higher in prefrail and frail (20.2%) than in nonfrail (14.9%) women (adjusted hazard ratio [aHR] 1.51, 95% confidence interval [CI] 1.07-2.12). The risk of VARC-2 life-threatening or major bleeding was higher in prefrail or frail (19.9%) than in nonfrail (10.0%) women (aHR 2.06, 95% CI 1.42-2.97). These risks were consistently increased in the prefrail and frail groups assessed separately., Conclusions: In women undergoing TAVR, the presence of prefrailty or frailty conferred an increased risk of the VARC-2 efficacy end point and of VARC-2 life-threatening or major bleeding., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Markers of systemic inflammation, such as high-sensitivity C-reactive protein (hsCRP), have been associated with the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). Whether this risk varies according to the presence of high bleeding risk (HBR) conditions is unclear., Objectives: The aim of this study was to evaluate the impact of systemic inflammation, as measured by hsCRP levels and cardiovascular outcomes in patients stratified by HBR status following PCI., Methods: Consecutive patients undergoing PCI between 2012 and 2019 with baseline hsCRP levels were included. High hsCRP was defined as >3 mg/L, and HBR was defined per the Academic Research Consortium HBR criteria. The primary outcome was MACCE, including all-cause death, myocardial infarction, or stroke at 1 year. All bleeding was assessed as a secondary outcome., Results: A total of 15,150 patients were included, and 40.4% (n = 6,125) qualified as HBR. The adjusted risk for MACCE was consistently higher in patients with high hsCRP in both HBR (adjusted HR [aHR]: 1.49; 95% CI: 1.18-1.87) and non-HBR (aHR: 1.87; 95% CI: 1.31-2.66) subgroups, with no interaction between HBR status and hsCRP level (P interaction  = 0.26). Conversely, although bleeding risk was higher in the HBR cohort, hsCRP did not predict the occurrence of bleeding in either the HBR (aHR: 1.04; 95% CI: 0.82-1.31) or the non-HBR (aHR: 0.99; 95% CI: 0.71-1.39) subgroup (P interaction  = 0.539)., Conclusions: Elevated hsCRP at the time of PCI is associated with a higher risk for ischemic but not bleeding events, irrespective of HBR status., Competing Interests: Funding Support and Author Disclosures Dr Dangas has received institutional research grants from Abbott Laboratories, AstraZeneca, Bayer, Boston Scientific, Medtronic, and Daiichi Sankyo; has received consultant fees from Biosensors International and Boston Scientific; and has received speaker honoraria from Chiesi. Dr Sharma has received consulting fees or honoraria from Abbott, Boston Scientific, Abiomed, and Cardiovascular Systems. Dr Mehran has received institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Cardiawave, CellAegis Devices, the European Cardiovascular Research Center, Chiesi, Concept Medical, CSL Behring, Data Sciences International, Insel Gruppe, Medtronic, OrbusNeich, Philips, Transverse Medical, and Zoll; has received personal fees from the American College of Cardiology, Boston Scientific, the California Institute for Regenerative Medicine, CineMed, Janssen, WebMD, and the Society for Cardiovascular Angiography and Interventions; has received consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Cardiawave, CeloNova BioSciences, Chiesi, Concept Medical, CSL Behring, Data Sciences International, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, and Philips; holds equity (<1%) in Applied Therapeutics, Elixir Medical, STEL, and ControlRad (spouse); is a scientific advisory board member for the American Medical Association and Biosensors International (spouse); and is a faculty member at the Cardiovascular Research Foundation (no fee). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients on long-term oral anticoagulation (OAC) therapy is still uncertain., Objectives: The aim of this analysis was to assess the effects of 1- vs 3-month DAPT in patients with and those without concomitant OAC included in the XIENCE Short DAPT program., Methods: The XIENCE Short DAPT program enrolled patients with high bleeding risk who underwent successful PCI with a cobalt-chromium everolimus-eluting stent. DAPT was discontinued at 1 or 3 months in patients free from ischemic events and adherent to treatment. The effect of 1- vs 3-month DAPT was compared in patients with and those without OAC using propensity score stratification. The primary endpoint was all-cause death or any myocardial infarction (MI). The key secondary endpoint was Bleeding Academic Research Consortium (BARC) types 2 to 5 bleeding. Outcomes were assessed from 1 to 12 months after index PCI., Results: Among 3,364 event-free patients, 1,462 (43%) were on OAC. Among OAC patients, the risk for death or MI was similar between 1- and 3-month DAPT (7.4% vs 8.8%; adjusted HR: 0.74; 95% CI: 0.49-1.11; P = 0.139), whereas BARC types 2 to 5 bleeding was lower with 1-month DAPT (adjusted HR: 0.71; 95% CI: 0.51-0.99; P = 0.046). These effects were consistent in patients with and those without OAC (P for interaction = NS)., Conclusions: Between 1 and 12 months after PCI, 1-month compared with 3-month DAPT was associated with similar rates of all-cause death or MI and a reduced rate of BARC types 2 to 5 bleeding, irrespective of OAC treatment., Competing Interests: Funding Support and Author Disclosures The study was sponsored by Abbott. Dr Valgimigli has received personal fees from AstraZeneca, Alvimedica/CID, Abbott Vascular, Daiichi Sankyo, Opsens, Bayer, CoreFlow, Idorsia Pharmaceuticals, Universität Basel | Departement Klinische Forschung, Vifor, Bristol Myers Squibb, iVascular, and Medscape; and has received grants and personal fees from Terumo, outside the submitted work. Dr Spirito has received a research grant from the Swiss National Science Foundation. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Ventura, outside the submitted work; and has received research grants to his institution from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. Dr Bangalore has received consulting fees or has been an advisory board member for Abbott Vascular, Boston Scientific, Biotronik, Amgen, Pfizer, Merck, Viatris, and REATA. Dr Vranckx has received personal fees from Daiichi Sankyo, Bayer, Pfizer/Bristol Myers Squibb, Novartis, and CSL Behring, not related to this research. Dr Bhatt has served on advisory boards for AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; has served on boards of directors for AngioWave, the Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, the Society of Cardiovascular Patient Care, and TobeSoft; has stock or stock options with AngioWave, Bristol Myers Squibb, and DRS.LINQ; has served as inaugural chair of the American Heart Association Quality Oversight Committee; has been a consultant for Broadview Ventures; has served on data monitoring committees for Acesion Pharma, Assistance Publique–Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly the Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), the Cleveland Clinic (including for the ExCEED trial, funded by Edwards Lifesciences), Contego Medical (chair, PERFORMANCE 2 trial), the Duke Clinical Research Institute, the Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo, and for the ABILITY-DM trial, funded by Concept Medical), Novartis, the Population Health Research Institute, and Rutgers University (for the National Institutes of Health–funded MINT trial); has received honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org, and chair of the American College of Cardiology Accreditation Oversight Committee), the law firm of Arnold and Porter (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), the Baim Institute for Clinical Research (formerly the Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee, funded by Boehringer Ingelheim; AEGIS-II executive committee, funded by CSL Boehringer), Belvoir Publications (editor-in-chief, Harvard Heart Letter), the Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen & Company, the Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), the Journal of the American College of Cardiology (guest editor, associate editor), K2P (cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (continuing medical education steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, the Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention), the Society of Cardiovascular Patient Care (secretary and treasurer), WebMD (continuing medical education steering committees), and John Wiley (steering committee); has other relationships with Clinical Cardiology (deputy editor), the NCDR-ACTION Registry Steering Committee (chair), and the VA CART Research and Publications Committee (chair); has been named on a patent for sotagliflozin, assigned to Brigham and Women’s Hospital, which assigned to Lexicon (neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); has received research funding from 89Bio, Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, Myo-Kardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, the Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and Youngene; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has been a site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has been a trustee for the American College of Cardiology; and has performed unfunded research for FlowCo andTakeda. Dr Campo has received institutional research grants outside the submitted work. Dr Neumann has received grants or fees from Amgen, Bayer Health Care, Biotronik, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Ferrer, Pfizer, Novartis, GlaxoSmithKline, Abbott Vascular, and Medtronic. Dr Toelg has received speaker honoraria from Boston Scientific, Abbott Vascular, and Biotronik. Dr Windecker has received research, travel, or educational grants to the institution from Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, Infraredx, Janssen-Cilag, Johnson & Johnson, Medicure, Medtronic, Merck Sharp & Dohme, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pfizer, Polares, Regeneron, Sanofi, Servier, Sinomed, Terumo, Vifor, and V-Wave; serves as an advisory board member and/or a member of the steering or executive groups of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, Janssen, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, V-Wave, and Xeltis, with payments to the institution but no personal payments; and is a member of the steering or executive committee groups of several investigator-initiated trials that receive funding from industry, without impact on his personal remuneration. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, Atricure, Bayer, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, CSL Behring, Cytosorbents, Daiichi Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi-Cardia, PLx Pharma, RenalPro, RM Global, Shockwave, Vivasure, and Zoll; has received personal fees from Cine-Med Research, Novartis, and WebMD; holds equity (<1%) in Applied Therapeutics, Elixir Medical, Stel, and ControlRad (spouse); is a scientific advisory board member for the American Medical Association, the American College of Cardiology (Board of Trustees member), and the Society for Cardiovascular Angiography and Interventions (Women in Innovations Committee member); is an associate editor for JAMA; and is a faculty member for the Cardiovascular Research Foundation (no fee). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Nearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases., Objectives: The authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI)., Methods: In the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables., Results: The incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566)., Conclusions: In the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence., Competing Interests: Funding Support and Author Disclosures This work was supported by an investigator-initiated grant from AstraZeneca. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and has received institutional research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and Scott R. MacKenzie Foundation. Dr Baber has received honoraria from AstraZeneca and Boston Scientific. Dr Dangas has received consulting fees from AstraZeneca and Biosensors; has received advisory board fees from AstraZeneca; and has held stock in Medtronic. Dr Cohen has received institutional grant support and consulting fees from AstraZeneca, Medtronic, Abbott Vascular, and Boston Scientific. Dr Gibson has received grant support from Angel Medical, Bayer, CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson, and Portola Pharmaceuticals; has received consulting fees from Angel Medical, Bayer, CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson, Portola Pharmaceuticals, The Medicines Company, Eli Lilly, Gilead Sciences, Novo Nordisk, WebMD, UpToDate Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi, Somahlution, Verreseon Corporation, Boston Scientific, Impact Bio, MedImmume, Medtelligence, MicroPort, PERT Consortium, and GE Healthcare; holds equity in inference; and serves as chief executive officer of Baim Institute, receiving grant support, paid to Baim Institute, from Bristol Myers Squibb and AstraZeneca. Dr Huber has received lecture fees from AstraZeneca and Bayer. Dr Mehta has received grant support from and serves on an executive committee and as site investigator for AstraZeneca. Dr Ohman has received consulting fees from 3D Communications, Abiomed, ACI Clinical, Biotie, Cara Therapeutics, Cardinal Health, Faculty Connection, Imbria, Impulse Medical, Janssen Pharmaceuticals, Medscape, Milestone Pharmaceuticals, and XyloCor; and has received grant support from Abiomed, Chiesi, and Portola. Dr Escaned has received consulting fees from Abbott, Philips, Boston Scientific, and Medtronic; and has received lecture fees from Abbott, Philips, Boston Scientific, Medtronic, Abiomed, Terumo, and Biosensors. Dr Steg has received consulting fees from Sanofi, Amarin, Amgen, Bristol Myers Squibb, Novartis, Regeneron, Eli Lilly, Novo Nordisk, and AstraZeneca; has received grant support from Bayer/Janssen, Merck, Sanofi, Amarin, and Servier; has received lecture fees from Merck, Bristol Myers Squibb, Sanofi, Amgen, and AstraZeneca; has received fees for serving on steering, critical event, or data monitoring committees from Bayer/Janssen, Amarin, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Servier, and Idorsia; and has received fees for serving as cochair of trials from Sanofi and chair of a registry from Servier. Dr Mehran has received institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, Zoll; personal fees from ACC, Boston Scientific, California Institute for Regenerative Medicine (CIRM), Cine-Med Research, Janssen, WebMD, SCAI; institutional consulting fees from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, DSI, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, Philips; and holds equity <1% in Applied Therapeutics, Elixir Medical, STEL, CONTROLRAD (spouse); and has served on a scientific advisory board for AMA and Biosensors (spouse). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiorenal syndrome is a condition where is a bidirectional and mutually detrimental relationship between the heart and kidneys. The mechanisms underlying cardiorenal syndrome are multifactorial and complex. Patients with kidney disease exhibit increased cardiovascular risk, presenting as coronary and peripheral artery disease, structural heart disease, arrhythmias, heart failure, and sudden cardiac death, largely occurring because of a systemic proinflammatory state, causing myocardial and vascular remodeling, manifesting as atherosclerotic lesions, vascular and valvular calcification, and myocardial fibrosis, particularly among those with advanced disease. This review summarizes the current understanding and clinical implications of kidney disease in patients with cardiovascular disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Data on the prognostic value of high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) are limited., Methods: Patients undergoing PCI at a tertiary center from January 2012 to December 2019 were included. CKD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73m 2 and elevated hs-CRP was defined as >3 mg/L. Acute myocardial infarction (MI), acute heart failure, neoplastic disease, patients undergoing hemodialysis, or hs-CRP >10 mg/L were exclusion criteria. The primary outcome was major adverse cardiac events (MACE), a composite of all-cause death, MI, and target vessel revascularization at 1-year after PCI., Results: Out of 12,410 patients, 3029 (24.4 %) had CKD. Elevated hs-CRP levels were found in 31.8 % of CKD and 25.8 % of no-CKD patients. At 1 year, MACE occurred in 87 (11.0 %) CKD patients with elevated hs-CRP and 163 (9.5 %) with low hs-CRP (adj. HR 1.26, 95 % CI 0.94-1.68); among no-CKD patients, in 200 (10 %) and 470 (8.1 %), respectively (adj. HR 1.21, 95 % CI 1.00-1.45). Hs-CRP was associated with an increased risk of all-cause death in both CKD (Adj. HR 1.92, 95 % CI 1.07-3.44) and no-CKD patients (adj. HR 3.02, 95 % CI 1.74-5.22). There was no interaction between hs-CRP and CKD status., Conclusions: Among patients undergoing PCI without acute MI, elevated hs-CRP values were not associated with a higher risk of MACE at 1 year, but with increased mortality hazards consistently in patients with or without CKD., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: Declaration of Competing Interest All authors have no conflict of interest to report.

Introduction: The Seattle Angina Questionnaire (SAQ-7) quantifies the impact of angina on patient functionality and quality of life. There is scarce data on the impact of social determinants and comorbidities on SAQ-7 in patients undergoing percutaneous coronary intervention (PCI) with planned staged PCI., Methods: Patients completed a SAQ-7 before each PCI. Multivariable regression analysis was performed to study the impact of social determinants, comorbidities, and procedural characteristics on SAQ-7 scores at index PCI and at the time of the staged PCI., Results: 531 patients were studied. Female sex, non-White race, coronary artery bypass graft history (CABG), and chronic lung disease were associated with lower baseline SAQ-7 scores. Overall, SAQ-7 increased between index procedure and staged PCI (11.9 ± 23.4). Body mass index (BMI) and the treatment of bifurcation lesions were independently associated with improvement of SAQ-7 between PCIs. Post-intervention, neither sex nor race was independently associated with changes in SAQ-7 scores., Conclusion: Different disparities and comorbid factors affect SAQ-7 before and after PCI. After revascularization, sex and race were not independent predictors of SAQ-7 improvement., Competing Interests: Declaration of competing interest Our conflicts of interest are as follows: George Dangas: Consulting: Albany Medical Center, CERC, Piedmont Liability Trust, University at Albany – SUNY; Equity: Elixir Medical Corporation, STEL, ControlRad; Other Activities: ACT 1 Torrance CA, Asan University South Korea, Gaffney Events, John Wiley and Sons, Inc., Samin Sharma Foundation; Scientific Advisory Board: Society for Cardiovascular Angiography and Interventions (SCAI). Annapoorna Kini: Industry-Sponsored Lectures: Miscellaneous teaching and lectures at academic institutions. Roxana Mehran: Consulting: Witt Kieffer; Equity: Elixir Medical Corporation, STEL, ControlRad; Industry-Sponsored Lectures: Asan University South Korea, Brazilian Cardiology Society, COLOMBIA webinar, China Cardiology Conference, Europa Group, Gaffney Events, India Webinar, India Webinar Mumbai, Samin Sharma Foundation, Society for Cardiovascular Angiography and Interventions (SCAI), St. Francis Hospital, Taiwan Cardiology Conference, Tarsus, University of Florence, University of Purchase, WebMD, Webinar APSCJCS; Scientific Advisory Board: American College of Cardiology. Samin K. Sharma: Equity: Eternal Heart Care Centre and Research Institute Private Limited (EHCRI); Industry-Sponsored Lectures: Abbott Laboratories, Boston Scientific Corporation, Cardiovascular Systems, Inc. (CSI), miscellaneous teaching and lectures at academic institutions. All other authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve implantation (TAVI) has become an accepted treatment for patients with severe aortic stenosis (AS). Predicting which patients are at risk for adverse clinical outcomes after TAVI remains difficult, especially in women., Aim: To identify predictors of adverse events in the WIN-TAVI cohort., Methods: The WIN-TAVI study is an observational registry of 1019 women undergoing TAVI for severe symptomatic AS. Follow-up was 1 year. The primary outcome was defined according to VARC-2: a composite of mortality, stroke, myocardial infarction or hospitalization for valve-related symptoms or heart failure. The secondary outcome was a composite of cardiovascular mortality or hospitalization for valve-related symptoms or heart failure., Results: We included 1019 women with severe AS (mean age of 82.5 ± 6.3 years). At 1 year, 16.4% of the patients experienced the primary endpoint and 12.6% the secondary endpoint. The use of oral anticoagulants (OAC) was the strongest independent predictor of the primary outcome (adjusted hazard ratio [aHR] 1.51, 95% confidence interval [CI] 1.079-2.106, p = 0.016). Independent predictors of the secondary endpoint were age (aHR 1.04 per year, 95% CI 1.01-1.074, p = 0.016) and use of OAC (aHR: 1.79, 95% CI 1.24-2.60, p = 0.002). OAC use was not associated with higher bleeding risk., Conclusion: Pre-procedural use of OAC was the strongest predictor of adverse outcomes during 1-year follow-up, likely reflecting a combination of high-risk factors and comorbidities, but was not related to increased bleeding risk., Competing Interests: Declaration of Competing Interest Dr. Petronio received consultancy fees from Medtronic, Abbott, Boston Scientific, and funds from Boston Scientific and Abbott. Dr. Lefèvre received consultancy fees from Edwards, Boston Scientific and Abbot. Dr. Van Mieghem received research grants from Abbott, Boston Scientific, Edwards Lifesciences, Medtronic, Abiomed, PulseCath BV, Daiichi Sankyo, Pie Medical. Dr. Morice is CEO and shareholder of CERC, a CRO not involved in this trial. Dr. Dangas received a research grant to institution form Daiichi-Sankyo. Dr. Chieffo received consultancy fees from Abiomed, Biosensor, Edwards and Shockwave Medical and payments for lecturs from Boston Scientific and Abbot Vascular. Dr. Mehran received research grants to the institution from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Applied Therapeutics, Arena, AstraZeneca, BAIM, Bayer, Beth Israel Deaconess, Biosensors, Biotronik, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Cytosorbents, DSI, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe AG, Magenta, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, RenalPro, Shockwave, Vivasure, Zoll, consulting fees from Cine-Med Research, WebMD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: COMBO (OrbusNeich Medical, Hong Kong) is a dual-therapy coronary stent featuring sirolimus as antiproliferative drug and an anti-CD34+ antibody coating to attract endothelial progenitor cells favoring rapid stent re-endothelization. The Mega COMBO collaboration aimed to evaluate the performance of the COMBO stent in a large contemporary cohort of patients undergoing percutaneous coronary intervention (PCI)., Methods: Patient-level data of subjects undergoing PCI with the COMBO stent from the REMEDEE-Trial, REMEDEE-OCT, HARMONEE, REDUCE, SORT OUT X, REMEDEE-Registry and MASCOT studies were pooled together. The primary endpoint was 1-year target lesion failure (TLF), a composite of cardiovascular death, target vessel myocardial infarction (TV-MI) or clinically driven target lesion revascularization (CD-TLR). Secondary outcomes were the individual components of the primary endpoint and stent thrombosis (ST). Endpoints were evaluated against performance goals based on the EAPCI (the European Association of Percutaneous Coronary Intervention) recommendations for new drug-eluting stents., Results: A total of 6753 patients (mean age 63.7 ± 11.4 years, 23% women) were included. At 1-year follow-up, TLF occurred in 303 (4.6%) patients. The rates of cardiovascular death, TV-MI, and CD-TLR were 1.3%, 1.8%, and 2.5%, respectively. The rate of definite/probable ST was 0.73%, early ST (<1 month) was 0.48%, while late ST (1-12 months) was 0.26%. The performance goals were met for all of the evaluated endpoints., Conclusions: This large patient-level pooled analysis provides a comprehensive outline of the performance of the dual-therapy COMBO stent. The low rates of primary and secondary endpoints suggest that this stent technology may be a good alternative to other contemporary drug eluting coronary stent platforms., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Cardiovascular disease is the leading cause of death in women. Decades of grassroots campaigns have helped to raise awareness about the impact of cardiovascular disease in women, and positive changes affecting women and their health have gained momentum. Despite these efforts, there has been stagnation in the overall reduction of cardiovascular disease burden for women in the past decade. Cardiovascular disease in women remains understudied, under-recognised, underdiagnosed, and undertreated. This Commission summarises existing evidence and identifies knowledge gaps in research, prevention, treatment, and access to care for women. Recommendations from an international team of experts and leaders in the field have been generated with a clear focus to reduce the global burden of cardiovascular disease in women by 2030. This Commission represents the first effort of its kind to connect stakeholders, to ignite global awareness of sex-related and gender-related disparities in cardiovascular disease, and to provide a springboard for future research., Competing Interests: Declaration of interests MA reports personal fees from Bayer, Boehringer, Tecnofarma, and Axon, and non-financial support from Boehringer, outside the submitted work. YA reports grants from the Dutch Heart Foundation and has a patent image guided plaque ablation (USP 945593 licenced). CNBM reports grants from US National Institutes of Health (NIH) Study Section, Peer Review Medical Research Program Cardiovascular Health for the Department of Defense Congressionally Directed Medical Research Program, US National Heart, Lung, and Blood Institute (NHLBI) subcontract to Research Triangle Institute International, NHLBI R01, US National Institute on Aging U54, and Women's Ischemia Syndrome Evaluation HFpEF; consulting fees from the US Food and Drug Administration Renal Advisory Panel; and consulting fees or honoraria from iRhythm, Abbott Diagnostics, and Sanofi Vascular. AC reports personal fees from Abbott Vascular, Magenta, Biosensor, Abiomed, and Cardional Health. GAF reports grants from the Australian National Health and Medical Research Council and Abbott Diagnostics; and personal fees from CSL Behring and Janssen. VK reports personal fees from honoraria and for speaking from Bayer, Daichii Sankyo, Amgen, AstraZeneca, and Abbott, outside the submitted work. CSPL reports grants from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; personal fees from Abbott Diagnostics, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Biofourmis, Boehringer Ingelheim, Boston Scientific, Corvia Medical, Cytokinetics, Darma, Us2.ai, JanaCare, Janssen Research & Development, Medtronic, Menarini Group, Merck, MyoKardia, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, Stealth BioTherapeutics, The Corpus, Vifor Pharma, and WebMD Global; and has a patent pending (PCT/SG2016/050217), and a patent issued (16/216,929). JEP reports grants from BIOTRONIK and AtriCure. JS reports grants from the Canadian Institutes of Health Research, Heart & Stroke Foundation of Canada, Michael Smith Foundation of Health Research, and NIH; and consulting fees from Abbott Vascular, Boston Scientific, Gore, Baylis, and Abiomed. RM reports grants from Abbott Laboratories, Abiomed, Applied Therapeutics, AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Cerecor, Chiesi, Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich, and Zoll; personal fees from Boston Scientific, Cine-Med Research, Janssen Scientific Affairs, Medscape/WebMD, American College of Cardiology, and American Medical Association; non-financial support from Regeneron Pharmaceuticals; consultancy or advisory board fees paid to her institution from Abbott Laboratories, Beth Israel Deaconess, Bristol Myers Squibb, Chiesi, Concept Medical, Daiichi Sankyo, Medtronic, Novartis, CardiaWave, Duke University, Idorsia, Spectranetics/Philips/Volcano Corp; consultant fees paid to the institution of her spouse from Abiomed, Bayer; <1% equity in Applied Therapeutics, Elixir Medical, and STEL; and spouse's <1% equity in ControlRad. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive-aged women and leads to hyperandrogenism, anovulation, and infertility. PCOS has been associated with elevated serum homocysteine as well as altered methylation status; however, characterization of one-carbon metabolism (OCM) in PCOS remains incomplete., Objectives: The aim of our research was to assess OCM in a letrozole-induced Sprague Dawley rat model of PCOS., Methods: Five-week-old female rats (n = 36) were randomly assigned to letrozole [0.9 mg/kg body weight (BW)] treatment or vehicle (carboxymethylcellulose) control that was administered via subcutaneously implanted slow-release pellets every 30 d. For both treatment groups, 12 rats were randomly assigned to be euthanized during proestrus at one of the following time points: 8, 16, or 24 wk of age. Daily BW was measured and estrous cyclicity was monitored during the last 30 d of the experimental period. Ovaries were collected to assess mRNA and protein abundance of OCM enzymes., Results: Letrozole-induced rats exhibited 1.9-fold higher cumulative BW gain compared with control rats across all age groups (P < 0.0001). Letrozole reduced the time spent at proestrus (P = 0.0001) and increased time in metestrus (P < 0.0001) of the estrous cycle. Cystathionine β-synthase (Cbs) mRNA abundance was reduced in the letrozole-induced rats at 16 (59%; P < 0.05) and 24 (77%; P < 0.01) wk of age. In addition, CBS protein abundance was 32% lower in 8-wk-old letrozole-induced rats (P = 0.02). Interestingly, betaine-homocysteine S-methyltransferase mRNA abundance increased as a function of age in letrozole-induced rats (P = 0.03)., Conclusion: These data demonstrate that letrozole-induced PCOS Sprague Dawley rats temporally decrease the ovarian abundance of Cbs mRNA and protein in the early stages of PCOS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Although the number of complex percutaneous coronary intervention (CPCI) procedures is increasing, data regarding sex-related outcomes following CPCI are scarce., Methods: We retrospectively analyzed data of patients enrolled in a single-center registry between 2009 and 2017. Patients were divided into two groups (CPCI and non-CPCI) stratified by sex. CPCI was defined as any PCI procedure with ≥1 of the following characteristics: ≥3 target vessels/lesions, ≥3 stents implanted, bifurcation with ≥2 stents, stent length > 60 mm, or chronic total occlusion. The primary outcome was major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), and target vessel revascularization, at oneon-year follow-up., Results: Among 20,419 patients, 5004 (24.5%) underwent CPCI of whom 25.6% (n = 1281) women and 74.4% (n = 3723) men. Women presented with more comorbidities yet less complex coronary anatomy than men (syntax score: 19.5 ± 10.3 vs. 20.6 ± 10.7, p = 0.009). Moreover, women were more likely to fulfill a single rather than multiple CPCI criteria. At one year, a higher rate of MACE occurred in women (14.0% vs. 11.6%, p = 0.02). After multivariable adjustment for confounders, the risk of MACE at one year was similar among both sexes (HR:1.04, 95% CI [0.85-1.26], p = 0.71), without significant interaction between the complexity of the procedure and sex (p-interaction = 0.96). Nonetheless, the risk of MI was significantly higher in women than men undergoing CPCI (HR:1.63, 95% CI [1.12-2.38], p = 0.01)., Conclusions: Despite presenting with less challenging lesions than men, women had a higher rate of MI at one year following CPCI, even after adjusting for potential confounders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Patients undergoing percutaneous coronary intervention (PCI) have an increased risk of both ischemic events and bleeding complications resulting from antithrombotic therapy. These events are particularly common in patients with a concomitant indication for oral anticoagulation, such as those with atrial fibrillation, and are associated with a substantial healthcare resource burden. Advances in procedural aspects of PCI have led to marked improvements in outcomes and a consequent reduction in the costs resulting from PCI-associated complications. Furthermore, recent randomized clinical trials have investigated the optimal antithrombotic strategy in the specific case of patients with atrial fibrillation undergoing PCI, leading to a shift toward the tailoring of antithrombotic therapy according to the patient's individual stroke and bleeding risks. Here we review these recent advances, with a particular focus on the improvements in antithrombotic strategies offered by the non-vitamin K antagonist oral anticoagulants., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Pediatric asthma exacerbations are a frequent reason for emergency care. Early administration of oral systemic corticosteroids (OCS) in the emergency department (ED) decreases hospitalization rates and ED length-of-stay (LOS). However, it is unknown whether even earlier OCS administration by emergency medical services (EMS) in the prehospital setting further improves outcomes., Purpose: To describe the background and methods of a type 1 hybrid effectiveness-implementation trial of EMS-administered OCS for pediatric asthma patients incorporating a stepped wedge design and the RE-AIM framework., Methods: The study employs a non-randomized stepped wedge design where multiple EMS agencies adopt OCS as a treatment for pediatric asthma exacerbations at varying times. This design accommodates ethical considerations of studying pediatric subjects in the prehospital setting where informed consent is not feasible. We will compare hospitalization rates, ED LOS, and short-term healthcare costs between pediatric asthma patients who do and do not receive OCS from EMS. Using geographic information systems (GIS), we will measure how differences in outcomes scale with increasing EMS transport time. We will use the RE-AIM framework to guide a mixed methods analysis of barriers and enablers to EMS administration of OCS for pediatric asthma patients, including quantitative measures of adoption and uptake and qualitative EMS provider focus group data., Conclusion: This trial will determine if earlier EMS administration of OCS to pediatric asthma patients decreases hospitalizations, ED LOS, and short-term healthcare costs, and if those outcomes scale with longer EMS transport times. We will identify barriers and enablers to implementing EMS-administered OCS for pediatric asthma patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The COMBO drug-eluting stent combines sirolimus-elution from a biodegradable polymer with an anti-CD34+ antibody coating for early endothelialization., Objective: We investigated for geographical differences in outcomes after percutaneous coronary intervention (PCI) with the COMBO stent among Asians and Europeans., Methods: The COMBO Collaboration is a pooled patient-level analysis of the MASCOT and REMEDEE registries of all-comers undergoing attempted COMBO stent PCI. The primary outcome was 1-year target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TV-MI) and target lesion revascularization (TLR)., Results: This study included 604 Asians (17.9%) and 2775 Europeans (82.1%). Asians were younger and included fewer females, with a higher prevalence of diabetes mellitus but lower prevalence of other comorbidities than Europeans. Asians had a higher prevalence of ACC/AHA C type lesions and received longer stent lengths. More Asians than Europeans were discharged on clopidogrel (86.5% vs 62.8%) rather than potent P2Y 12  inhibitors. One-year TLF occurred in 4.0% Asians and 4.1% of Europeans, p = 0.93. The incidence of cardiac death was higher in Asians (2.8% vs. 1.3%, p = 0.007) with similar rates of TV-MI (1.5% vs. 1.2%, p = 0.54) and definite stent thrombosis (0.3% vs. 0.5%, p = 0.84) and lower incidence of TLR than Europeans (1.0% vs. 2.5%, p = 0.025). After adjustment, differences for cardiac death and TLR were no longer significant., Conclusions: In the COMBO collaboration, although 1-year TLF was similar regardless of geography, Asians experienced higher rates of cardiac death and lower TLR than Europeans, while incidence of TV-MI and ST was similar in both regions. Adjusted differences did not reach statistical significance. CLINICALTRIAL., Gov Identifier-Numbers: NCT01874002 (REMEDEE Registry), NCT02183454 (MASCOT registry)., Competing Interests: Declaration of competing interest Dr. Mehran has received institutional research grant support from Eli Lilly/Daiichi-Sankyo Inc., AstraZeneca, The Medicines Company, Bristol-Myers Squibb, OrbusNeich, Beth Israel Deaconess, and Bayer; has served as a consultant for Boston Scientific, Cardiovascular Systems Inc., Medscape, and Shanghai BraccoSine Pharmaceutical; has received institutional advisory board funding from Bristol-Myers Squibb; has received institutional funding from Claret Medical; owns equity in Claret Medical and Elixir Medical; has served on the executive committee for Janssen Pharmaceuticals and Osprey Medical; has served on the data safety monitoring board for Watermark Research Partners; and has a spouse who has served as a consultant for Abiomed and the Medicines Company. Dr. Kala has served as a consultant for Boston Scientific; has received research support from AstraZeneca, Novartis, Zoll; has served on advisory board for Astra Zeneca, Bayer, Medtronic and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Coronary revascularization, either percutaneous by stent implantation or surgical, has been established as the treatment of choice for patients with significant coronary stenosis. One of the main targets of coronary revascularization - especially in patients with stable disease - is to alleviate symptoms and thereby improve quality of life. Residual angina after successful coronary revascularization is not uncommon and indeed frustrating for the patient as much as for the treating physician. Several studies have shown worse outcomes in females with regard to post-revascularization morbidity and mortality in percutaneous as well as surgical coronary procedures. Although none of the studies has specifically looked at sex-related differences in residual angina after revascularization, some studies have found that female compared to male sex was a predictor of post-revascularization angina. This review article aims to summarize the results of these studies as well as to discuss the potential underlying mechanisms of these findings., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to examine the association between dual-antiplatelet therapy (DAPT) cessation and cardiovascular risk after percutaneous coronary intervention in relation to age., Background: Examination of outcomes by age after percutaneous coronary intervention is relevant given the aging population., Methods: Two-year clinical outcomes, incidence, and effect of DAPT cessation on outcomes were compared by ages ≤55, 56 to 74, and ≥75 years from the PARIS (Patterns of Non-Adherence to Antiplatelet Regimens in Stented Patients) registry. DAPT cessation included physician-recommended discontinuation, interruption for surgery, and disruption (from noncompliance or bleeding). Clinical endpoints were major adverse cardiac events (MACE) (a composite of cardiac death, definite or probable stent thrombosis, spontaneous myocardial infarction, or clinically indicated target lesion revascularization), a secondary restrictive definition of MACE (MACE2) excluding target lesion revascularization, and bleeding., Results: A total of 1,192 patients (24%) were ≤55 years, 2,869 (57%) were 56 to 74 years, and 957 (19%) were ≥75 years of age. Patients ≥75 years of age had higher DAPT cessation rates and increased risk for MACE2, death, cardiac death, and bleeding compared with younger patients. Discontinuation and interruption were not associated with increased cardiovascular risk across age groups, whereas disruption was associated with increased risk for MACE and MACE2 in younger patients but not in patients ≥75 years of age (p for trend <0.05)., Conclusions: Nonadherence and outcomes vary by age, with patients ≥75 years having the highest DAPT cessation rates. We observed no association between outcomes and DAPT cessation in patients ≥75 years, whereas discontinuation was associated with lower MACE rates and disruption with increased MACE rates in patients <75 years., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Clinical trial data studies suggest superiority of prasugrel over clopidogrel in patients with diabetes. However, the use, safety and efficacy profile of prasugrel in unselected diabetic patients presenting with acute coronary syndromes (ACS) remain unclear., Methods: PROMETHEUS was a prospective multicenter observational study of 19,919 ACS PCI patients enrolled between 2010 and 2013. The primary endpoint was 90-day major adverse cardiovascular events (MACE), comprising all-cause death, myocardial infarction, stroke or unplanned revascularization. The safety endpoint was bleeding requiring hospitalization., Results: We identified 7580 (38%) subjects with and 12,329 (62%) without diabetes. Diabetic patients were older and had significantly higher rates of cardiovascular risk factors. However, they were less likely to receive prasugrel (18.2% vs. 21.7%). Use of prasugrel did not increase with the severity of clinical presentation in diabetics, whereas, among non-diabetics, prescription of prasugrel was higher in NSTEMI and STEMI compared to unstable angina. The 90-day and 1-year adjusted risk of MACE was greater in diabetics (at 1 year: 22.7% vs. 16.5%; HR 1.22 [1.14-1.33], p < 0.001). At 1 year, the risk of bleeding was also higher in diabetics (4.9% vs. 4.1%, HR 1.19 [1.01-1.39], p = 0.035). After multivariable adjustment, use of prasugrel was associated with a lower risk of death in diabetic patients both at 90 days and 1 year., Conclusions: Use of prasugrel in diabetic patients with PCI-treated ACS was lower than in non-diabetics despite their high-risk profile and the severity of their clinical presentation. In diabetics, prasugrel was associated with a lower adjusted risk of 90-day death compared with clopidogrel., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: This study sought to investigate the outcome of high-risk and inoperable patients with severe symptomatic aortic stenosis undergoing transfemoral transcatheter aortic valve replacement (TAVR) in hospitals with (iOSCS) versus without institutional on-site cardiac surgery (no-iOSCS)., Background: Current guidelines recommend the use of TAVR only in institutions with a department for cardiac surgery on site., Methods: In this analysis of the prospective multicenter Austrian TAVI registry, 1,822 consecutive high-risk patients with severe symptomatic aortic stenosis undergoing transfemoral TAVR were evaluated. A total of 290 (15.9%) underwent TAVR at no-iOSCS centers (no-iOSCS group), whereas the remaining 1,532 patients (84.1%) were treated in iOSCS centers (iOSCS group)., Results: Patients of the no-iOSCS group had a higher perioperative risk defined by the logistic EuroSCORE (20.9% vs. 14.2%; p < 0.001) compared with patients treated in hospitals with iOSCS. Procedural survival was 96.9% in no-iOSCS centers and 98.6% in iOSCS centers (p = 0.034), whereas 30-day survival was 93.1% versus 96.0% (p = 0.039) and 1-year survival was 80.9% versus 86.1% (p = 0.017), respectively. After propensity score matching for confounders procedural survival was 96.9% versus 98.6% (p = 0.162), 93.1% versus 93.8% (p = 0.719) at 30 days, and 80.9% versus 83.4% (p = 0.402) at 1 year., Conclusions: Patients undergoing transfemoral TAVR in hospitals without iOSCS had a significantly higher baseline risk profile. After propensity score matching short- and long-term mortality was similar between centers with and without iOSCS., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the rate of access to primary and preventive care and emergency department (ED) reliance for foster youth as well as the impact of a transition from fee-for-service (FFS) Medicaid to managed care (MC) on this access., Methods: Secondary administrative data were obtained from Medicaid programs in one state that transitioned foster youth from an FFS to an MC (Texas) and another state, comparable in population size and racial/ethnic diversity, which continuously enrolled foster youth in an FFS system (Florida). Eligible participants were foster youth (aged 0-18 years) enrolled in these states between 2006 and 2010 (n = 126,714). A Puhani approach to difference-in-difference was used to identify the effect of transition after adjusting for race/ethnicity, gender, and health status. Data were used to calculate access to primary and preventive care as well as ED reliance. ED reliance was operationalized as the number of ED visits relative to the number of total ambulatory visits; high ED reliance was defined as ≥33%., Results: The transition to MC was associated with a 6% to 13% increase in access to primary care. Preventive care visits were 10% to 13% higher among foster youth in MC compared to those in FFS. ED reliance declined for the intervention group but to a lesser extent than did the control group, yielding a positive mean percentage change., Conclusions: Foster youth access to care may benefit from a Medicaid MC delivery system, particularly as the plans used are designed with the unique needs of this vulnerable population., (Copyright © 2018 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Potent P2Y 12 inhibitors might offer enhanced benefit against thrombotic events in complex percutaneous coronary intervention (PCI). We examined prasugrel use and outcomes according to PCI complexity, as well as analyzing treatment effects according to thienopyridine type., Methods: PROMETHEUS was a multicentre observational study that compared clopidogrel vs prasugrel in acute coronary syndrome patients who underwent PCI (n = 19,914). Complex PCI was defined as PCI of the left main, bifurcation lesion, moderate-severely calcified lesion, or total stent length ≥ 30 mm. Major adverse cardiac events (MACE) were a composite of death, myocardial infarction, stroke, or unplanned revascularization. Outcomes were adjusted using multivariable Cox regression for effect of PCI complexity and propensity-stratified analysis for effect of thienopyridine type., Results: The study cohort included 48.9% (n = 9735) complex and 51.1% (n = 10,179) noncomplex patients. Second generation drug-eluting stents were used in 70.1% complex and 66.2% noncomplex PCI patients (P < 0.0001). Complex PCI was associated with greater adjusted risk of 1-year MACE (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.20-1.39; P < 0.001). Prasugrel was prescribed in 20.7% of complex and 20.1% of noncomplex PCI patients (P = 0.30). Compared with clopidogrel, prasugrel significantly decreased adjusted risk for 1-year MACE in complex PCI (HR, 0.79; 95% CI, 0.68-0.92) but not noncomplex PCI (HR, 0.91; 95% CI, 0.77-1.08), albeit there was no evidence of interaction (P interaction = 0.281)., Conclusions: Despite the use of contemporary techniques, acute coronary syndrome patients who undergo complex PCI had significantly higher rates of 1-year MACE. Adjusted magnitude of treatment effects with prasugrel vs clopidogrel were consistent in complex and noncomplex PCI without evidence of interaction., (Copyright © 2018. Published by Elsevier Inc.)

Objectives: The aim of this study was to examine whether stent length per patient and stent length per lesion are negative markers for 3-year outcomes in women following percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES)., Background: In the era of advanced stent technologies, whether stent length remains a correlate of adverse outcomes is unclear., Methods: Women treated with new-generation DES in 14 randomized trials from the WIN-DES (Women in Innovation and Drug-Eluting Stents) pooled database were evaluated. Total stent length per patient, which was available in 5,403 women (quartile 1, 8 to 18 mm; quartile 2, 18 to 24 mm; quartile 3, 24 to 36 mm; quartile 4, ≥36 mm), and stent length per lesion, which was available in 5,232 women (quartile 1, 8 to 18 mm; quartile 2, 18 to 20 mm; quartile 3, 20 to 27 mm; quartile 4, ≥27 mm) were analyzed in quartiles. The primary endpoint was 3-year major adverse cardiovascular events (MACE), defined as a composite of all-cause death, myocardial infarction, or target lesion revascularization., Results: In the per-patient analysis, a stepwise increase was observed with increasing stent length in the adjusted risk for 3-year MACE (p for trend <0.0001), myocardial infarction (p for trend <0.001), cardiac death (p for trend = 0.038), and target lesion revascularization (p for trend = 0.011) but not definite or probable stent thrombosis (p for trend = 0.673). In the per-lesion analysis, an increase was observed in the adjusted risk for 3-year MACE (p for trend = 0.002) and myocardial infarction (p for trend <0.0001) but not other individual endpoints. On landmark analysis for late event rates between 1 and 3 years, stent length per patient demonstrated weak associations with target lesion revascularization (p = 0.0131) and MACE (p = 0.0499), whereas stent length per lesion was not associated with higher risk for any late events, suggesting that risk was established early within the first year after PCI., Conclusions: In this pooled analysis of women undergoing PCI with new-generation DES, increasing stent length per patient and per lesion were independent predictors of 3-year MACE but were not associated with definite or probable stent thrombosis., (Copyright © 2018. Published by Elsevier Inc.)

Objectives: This study sought to compare clinical outcomes in a contemporary acute coronary syndrome (ACS) percutaneous coronary intervention (PCI) cohort stratified by chronic kidney disease (CKD) status., Background: Patients with CKD exhibit high risks for both thrombotic and bleeding events, thus complicating decision making regarding antiplatelet therapy in the setting of ACS., Methods: The PROMETHEUS study was a multicenter observational study comparing outcomes with prasugrel versus clopidogrel in ACS PCI patients. Major adverse cardiac events (MACE) at 90 days and at 1 year were defined as a composite of death, myocardial infarction, stroke, or unplanned revascularization. Clinically significant bleeding was defined as bleeding requiring transfusion or hospitalization. Cox regression multivariable analysis was performed for adjusted associations between CKD status and clinical outcomes. Hazard ratios for prasugrel versus clopidogrel treatment were generated using propensity score stratification., Results: The total cohort included 19,832 patients, 28.3% with and 71.7% without CKD. CKD patients were older with greater comorbidities including diabetes and multivessel disease. Prasugrel was less often prescribed to CKD versus non-CKD patients (11.0% vs. 24.0%, respectively; p < 0.001). At 1 year, CKD was associated with higher adjusted risk of MACE (1.27; 95% confidence interval: 1.18 to 1.37) and bleeding (1.46; 95% confidence interval: 1.24 to 1.73). Although unadjusted rates of 1-year MACE were lower with prasugrel versus clopidogrel in both CKD (18.3% vs. 26.5%; p < 0.001) and non-CKD (10.9% vs. 17.9%; p < 0.001) patients, associations were attenuated after propensity stratification. Similarly, unadjusted differences in 1-year bleeding with prasugrel versus clopidogrel (6.0% vs. 7.4%; p = 0.18 in CKD patients; 2.6% vs. 3.5%; p = 0.008 in non-CKD patients) were not significant after propensity score adjustment., Conclusions: Although risks for 1-year MACE were significantly higher in ACS PCI patients with versus without CKD, prasugrel use was 50% lower in patients with renal impairment. Irrespective of CKD status, outcomes associated with prasugrel use were not significant after propensity adjustment. These data highlight the need for randomized studies evaluating the optimal antiplatelet therapy in CKD patients with ACS., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Percutaneous coronary intervention (PCI) of the left main (LM) or proximal left anterior descending artery (pLAD) is considered high-risk as these segments subtend substantial left ventricular myocardial area. We assessed the patterns and associations between dual antiplatelet therapy (DAPT) cessation and 2-year outcomes in LM/pLAD vs. other PCI from the all-comer PARIS registry., Methods: Two-year major adverse cardiovascular events (MACE) were a composite of cardiac death, myocardial infarction, definite/probable stent thrombosis or target lesion revascularization. DAPT cessation was predefined as physician-guided permanent discontinuation, temporary interruption, or non-recommended disruption due to non-compliance or bleeding., Results: Of the study population (n=5018), 25.0% (n=1252) underwent LM/pLAD PCI and 75.0% (n=3766) PCI to other segments. Compared to others, LM/pLAD patients presented with fewer comorbidities, less frequent acute coronary syndromes but more multivessel and bifurcation disease treated with greater stent lengths. Two-year adjusted risk of MACE (11.4% vs. 11.6%; HR 1.10, 95% CI 0.90-1.34, p=0.36) was similar between LM/pLAD vs. other patients. DAPT discontinuation was significantly higher (43.3% vs. 39.4%, p=0.01) in LM/pLAD patients with borderline significance for lower disruption (10.0% vs. 14.7%, p=0.059) compared to other patients. DAPT discontinuation was not associated with higher risk of MACE in LM/pLAD (HR 0.65, 95% CI 0.34-1.25) or other PCI groups (HR 0.67, 95% CI 0.47-0.95)., Conclusions: LM/pLAD PCI was not an independent predictor of 2-year MACE. Compared to other PCI, patients undergoing LM/pLAD PCI had higher rates of physician recommended DAPT discontinuation, however, discontinuation did not result in greater adverse events., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to examine the frequency and clinical impact of different cessation patterns of dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents among patients with and those without diabetes mellitus (DM)., Background: Early DAPT suspension after percutaneous coronary intervention increases the risk for major adverse cardiac events. However, temporal variability in risk and relation to DAPT cessation patterns among patients with DM remain unclear., Methods: Using data from the PARIS (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) registry, 1,430 patients with DM (34%) and 2,777 without DM (66%) treated with drug-eluting stents were identified. DAPT cessation modes were classified as temporary interruption (<14 days), disruption because of bleeding or poor compliance, and physician-recommended discontinuation., Results: During 2-year follow-up, DM was associated with an increased risk for thrombotic events but a similar risk for bleeding. The cumulative incidence of DAPT cessation was significantly lower in patients with versus those without DM (50.1% vs. 55.4%; p < 0.01), driven largely by less frequent physician-guided discontinuation beyond 1 year. In contrast, 2-year rates of interruption and disruption were similar between groups. When DAPT was interrupted or discontinued under physician guidance, the risk for major adverse cardiac events was unchanged compared with patients with DM on uninterrupted DAPT. Conversely, when DAPT was disrupted, the risk for major adverse cardiac events increased compared with uninterrupted DAPT, regardless of diabetic status, with no evidence of statistical interaction., Conclusions: DAPT cessation patterns vary according to diabetic status, with less frequent physician-guided discontinuation among patients with DM. The presence of DM does not emerge as a modifier of cardiovascular risk after DAPT cessation., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Catheter-based renal sympathetic denervation (RDN) can reduce blood pressure (BP) and sympathetic activity in certain patients with uncontrolled hypertension. Less is known about the impact of renal anatomy and procedural parameters on subsequent BP response., Methods/materials: A total of 564 patients with resistant hypertension underwent bilateral RDN in 9 centers in Europe and Australia using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). Anatomical criteria such as prevalence of accessory renal arteries (ARA), presence of renal artery disease (RAD), length, and diameter were analyzed blinded to patient's characteristics., Results: ARA was present in 171 patients (30%), and RAD was documented in 71 patients (13%). On average 11±2.7 complete 120-s ablations were performed, equally distributed on both sides. After 6months, BP was reduced by 19/8mmHg (p<0.001 for both). Change of systolic blood pressure (SBP) was not related to the presence of ARA (-18 vs. -20mmHg; p=NS) or RAD (-16 vs. -20mmHg; p=NS). Patients with a bilateral diameter≤4mm had a more pronounced reduction of SBP compared to patients with a unilateral diameter≤4mm or a bilateral diameter>4mm (-29 vs. -26 vs. -17mmHg; p<0.001). Neither the length of the renal artery nor the number of RF ablations influenced BP reduction after 6months., Conclusions: The diameter of renal arteries correlated with SBP change after RDN at 6-month follow-up. Change of SBP was not related to the lengths of the renal artery, presence of ARA, RAD, or the number of RF ablations delivered by a mono-electrode catheter., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The long known toxicity of free chromatin mediated by histones regained attention after discovery of neutrophil extracellular traps (NETs). Free histones from necrotic cells or NETs can damage prokaryotic and eukaryotic cells and are responsible for the aggravation of a growing list of diseases. DNases degrade the toxic chromatin polymer to nucleosomes and efficiently reduce local high histone concentrations. Therefore, DNase activity as a biomarker is of growing interest in basic and clinical research. Here a detailed one-step protocol is presented that allows rapid and sensitive detection of DNases down to 400 fg/μl per reaction based on the detection of fluorescent ethidium bromide/DNA complexes in a 96-well plate reader. The flexible protocol uses an internal standard for background correction and allows convenient and reliable data analysis using common laboratory equipment and chemicals without elaborate preparations. The DNase activity of a sample is clearly defined by substrate amount, incubation time, and (if appropriate) a DNase standard for absolute quantification in Kunitz units per milligram sample protein. Quantitative kinetic determination is possible within less than 1h down to 5 pg DNases/μl per reaction., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: In 2002 the ACC/AHA guidelines for the management of patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) were updated. We aimed to answer whether the implementation of updated guidelines was capable of influencing short- and long-term mortality in these patients., Methods: We analyzed data on 812 consecutive patients who were admitted with either UA or NSTEMI between 2001 and 2004. Patients admitted in the two years before the implementation of updated guidelines (UA(01/02) group and NSTEMI(01/02) group) were compared to patients admitted in the two years thereafter (UA(03/04) group and NSTEMI(03/04) group). Yearly follow-up concerning all-cause mortality was obtained up to four years., Results: The rate of revascularizations, the percentage of procedures performed within 48 h of admission, and the administration of clopidogrel increased significantly. However, still many - especially high-risk - patients did not receive revascularization. Patients of both UA groups had an identical in-hospital mortality rate. Differences in mortality between groups gained statistical significance over time (four-year mortality; 15.1% for the UA(03/04) group vs. 26.5% for the UA(01/02) group, p=0.014; HR 0.49 95% CI 0.28-0.87). In patients with NSTEMI in-hospital mortality decreased from 18.4% in the NSTEMI(01/02) group to 9.6% in the NSTEMI(03/04) group (p=0.011; HR 0.47 95% CI 0.26-0.84), and 1-year mortality from 34.7% to 25.1% (p=0.038; HR 0.63 95% CI 0.41-0.98), respectively. Mortality rates beyond one year were still lower in the NSTEMI(03/04) group as compared to the NSTEMI(01/02) group but it did not reach statistical significance. Multivariate Cox-regression analysis revealed furthermore that also patients with higher age and/or renal dysfunction benefit from an early invasive strategy., Conclusion: The implementation of updated guidelines for NSTE-ACS had significant impact on short- and long-term mortality. However, an early invasive strategy is still withheld to a significant number of high-risk patients, who would benefit from an invasive treatment., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Urologists, regardless of whether they practice in the community or in an academic institution, make decisions not only about their individual patients but also about hospital and health care policy by providing input to various committees that influence the adoption of new diagnostic and therapeutic technology. In an era of increasing awareness of healthcare costs, economic analyses that consider not only the potential benefit and harm of a given intervention but also the costs of the intervention, are increasingly important. This review article introduces a framework to critically appraise an economic analysis for its validity, impact, and applicability to patient care using an example from the urologic literature., (Published by Elsevier Inc.)

Objectives: This study sought to evaluate whether left ventricular (LV) lead position in cardiac resynchronization therapy (CRT) can be determined by myocardial deformation imaging during LV pacing and to compare imaging techniques for analysis of LV lead position., Background: LV lead position has a significant impact on effectiveness of CRT, but clinically applicable methods to determine LV lead position are less defined., Methods: In 56 patients (53 +/- 5 years, 34 men) undergoing CRT, fluoroscopy and 2 myocardial deformation imaging-based approaches were applied to determine the LV lead position. Myocardial deformation imaging-based techniques were used to determine 1) the segment with maximal temporal difference of peak circumferential strain before and while on biventricular CRT; and 2) the segment with earliest peak systolic circumferential strain during pure LV pacing. Twelve-month echocardiography was performed to determine LV remodeling and improvement in function. Optimal LV lead position was defined as concordance or immediate neighboring of the determined LV lead position to the segment with latest systolic strain prior to CRT., Results: LV lead position determined during LV pacing correlated to the position determined by fluoroscopy (kappa = 0.761). Patients with optimal LV lead position had greater improvement in LV ejection fraction and decrease in end-diastolic volume than those with nonoptimal LV lead position (12 +/- 4% vs. 7 +/- 3%, p < 0.001, and 28 +/- 13 ml vs. 14 +/- 8 ml, p < 0.001, respectively). Determination of the LV lead position based on myocardial deformation imaging during LV pacing showed greater discriminatory power for improvement of ejection fraction (difference optimal vs. nonoptimal lead position group: 4.64 +/- 1.01 ml; p < 0.001) than deformation imaging with biventricular pacing (3.03 +/- 1.08 ml; p = 0.007) and fluoroscopy (2.22 +/- 1.12 ml; p = 0.053)., Conclusions: Myocardial deformation imaging during LV pacing allows determination of the LV lead position in CRT. Improvement in LV function and remodeling as indicators of optimal LV lead position can be best predicted by LV lead position analysis during LV pacing. (Left Ventricular Lead Position in Cardiac Resynchronization Therapy; NCT00748735)., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Due to lack of families suitable for linkage analysis and positional cloning most of the genetic causes of human dilated cardiomyopathy (DCM) are still unknown. To facilitate rapid identification and validation of novel DCM disease genes appropriate animal models are needed. To assess here for the first time whether the zebrafish is a suitable model organism to validate DCM candidate genes using antisense knock-down strategies, we inactivated in zebrafish known human DCM disease genes and then evaluated the resulting cardiac phenotypes. Consistently, knock-down of the here selected human DCM genes leads to severe heart failure with impairment of systolic cardiac function in zebrafish. Furthermore, gene-specific differences which are also seen in human DCM can be reliably reproduced in the zebrafish model. Our results indicate that the zebrafish is a suitable model organism to rapidly evaluate novel DCM disease genes in-vivo.

Background: Missing data are widespread in the medical sciences. Given their prevalence, researchers must be prepared to address problems that arise when data are missing., Objectives: The objectives were to (1) provide an estimate of bias for each imputation technique with known values from data engineered to be missing completely at random; (2) determine whether different Center for Epidemiologic Studies Depression (CES-D) Scale scores were obtained from item-mean, person-mean, regression, and hot-deck imputation techniques and whether they differed from the CES-D score obtained from complete cases; and (3) determine whether the variables that predicted the CES-D scores were the same for the complete cases and each of the 4 imputation techniques., Methods: Depressive symptoms were assessed in patients (N=2,317) in an international clinical trial comparing high blood pressure treatments between April 1, 1999, and October 31, 1999. Patients were mailed surveys after randomization. Depressive symptoms were measured using the CES-D Scale. Respondents who completed all 20 items were compared with those who did not complete all 20 items, using independent t tests and chi-square. Z scores were used to determine CES-D mean differences, and multiple regression models were used to predict the CES-D scores for the 4 imputation techniques and the complete case data., Results: Imputed CES-D mean scores ranged from 14.58 to 14.68. The 4 imputed CES-D mean scores were consistently, but not significantly, higher than the complete case CES-D mean of 14.06. Imputed mean scores were similar to each other and the complete case mean score. Four regression models predicting the imputed CES-D scores yielded similar predictions. With the exception of sex, the same variables predicted the complete case CES-D and the imputed CES-D scores., Conclusions: All the imputed means were similar to the complete case mean, with the exception of the regression imputation. Imputing missing data did not significantly alter the conclusions regarding which factors were associated with variations in CES-D scores. Since imputation has the potential to increase statistical power, researchers dealing with missing CES-D scores should consider imputing missing data.

Purpose: To examine a nested model that predicts adolescent risky behavior, health care use, and health care expenditures from individual characteristics, such as age and gender, and community characteristics such as social capital and community-level risky behavior rates., Methods: Claims and encounter data were used to classify adolescents enrolled in Florida's Healthy Kids Program into two groups: those who engaged in risky behavior (ARB) and those who did not (NRB). Hierarchical linear modeling techniques were used to predict the odds of risky behavior, the odds of health care use, and health care expenditures based on individual and community characteristics., Results: ARB consumed significantly more health care services than NRB, and their higher use and charges were attributable not only to individual level factors (i.e., age, gender, presence of special health care need, metropolitan residence status), but also to community level factors (i.e., social capital, risky behavior rates, violence, and ethnic/racial composition) as well. In particular, community investment in social capital predicted lower levels of risky behavior as well as lower health care expenditures., Conclusions: This information is important in terms of policy efforts at providing health care for this vulnerable group of individuals, as well as in developing prevention and intervention programs that can be delivered through the health care system and via links to community supports.

Background: In planning lung cancer therapy, the possibility of mediastinal invasion merits attention. The results of CT and MRI in this respect are unsatisfactory, especially in determining aortic involvement., Study Objectives: To determine the validity of transesophageal echography in proving the invasion of lung cancer into the aortic wall., Patients: Two hundred one patients with lung cancer abutting against the aorta were examined using transesophageal echography and CT. In 97 patients, the results of both imaging techniques were compared with the surgical/pathologic results., Results: In a vast majority, transesophageal echography leads to a definitive result while CT remains equivocal. Controlled by surgical/pathologic results in 97 patients, transesophageal echography yielded a diagnostic accuracy of 91.8%., Conclusions: In lung cancer abutting against the aorta, the diagnostic procedure should be complemented by transesophageal echography if the therapeutic management depends on whether the aortic wall is invaded by the tumor or not.

Eighty-six osteolytic lesions of the rib cage were examined by means of conventional radiography and ultrasonography. The ultrasonographic criteria of osteolysis are described. Only 1 rib metastasis was missed by ultrasonography while 13 lesions were not detected by x-ray film. Of 63 ultrasonographically guided biopsies, 62 resulted in the final diagnosis; complications were not observed. The results recommend ultrasonographic examination combined with guided biopsy as the first diagnostic step, if a metastasis of the rib cage is suspected after physical examination or after a pathologic bone scan.

Survival of infants with greater than 80 per cent body surface area burns has not been well documented. Survival of a 4-month-old infant with 80 per cent full skin thickness flame injury is reported. Data from the National Burn Information Exchange showed that there were 2266 infants under 8 months of age treated for burns in reporting hospitals. Only four children of the 2266 were treated for full skin thickness thermal injury covering more than 80 per cent TBSA and none survived except for the child reported here. It was felt that early aggressive excision of the burn eschar was an important factor leading to the survival of this infant. Complex rehabilitation issues related to developmental issues as well as physical and psychosocial needs were identified and addressed throughout her time in hospital by a multidisciplinary team to ensure the best possible quality of life.