Long-Term Outcomes After Revascularization for Stable Ischemic Heart Disease: An Individual Patient-Level Pooled Analysis of 19 Randomized Coronary Stent Trials.

Background: Whether revascularization improves prognosis in stable ischemic heart disease is controversial.

Methods: Individual patient-level data from 19 prospective, randomized stent trials were pooled. Rates of 5-year major adverse cardiovascular events (MACE; a composite of cardiac death, myocardial infarction, or ischemia-driven target lesion revascularization) were assessed and compared after percutaneous coronary intervention with bare-metal stents (BMS) and first-generation and second-generation drug-eluting stents (DES1 and DES2, respectively).

Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients: The PARTNER 3 Trial.

Background: This study aimed to compare echocardiographic findings in low-risk patients with severe aortic stenosis after surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR).

Methods: The PARTNER 3 trial (Placement of Aortic Transcatheter Valves) randomized 1000 patients with severe aortic stenosis and low surgical risk to undergo either transfemoral TAVR with the balloon-expandable SAPIEN 3 valve or SAVR. Transthoracic echocardiograms obtained at baseline and at 30 days and 1 year after the procedure were analyzed by a consortium of 2 echocardiography core laboratories.

Rapid and site-specific deep phosphoproteome profiling by data-independent acquisition without the need for spectral libraries.

Quantitative phosphoproteomics has transformed investigations of cell signaling, but it remains challenging to scale the technology for high-throughput analyses. Here we report a rapid and reproducible approach to analyze hundreds of phosphoproteomes using data-independent acquisition (DIA) with an accurate site localization score incorporated into Spectronaut. DIA-based phosphoproteomics achieves an order of magnitude broader dynamic range, higher reproducibility of identification, and improved sensitivity and accuracy of quantification compared to state-of-the-art data-dependent acquisition (DDA)-based phosphoproteomics.

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

Background: There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk.

Methods: We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.

Trends in Usage and Clinical Outcomes of Coronary Atherectomy: A Report From the National Cardiovascular Data Registry CathPCI Registry.

Background: Adjunctive coronary atherectomy (CA) can be utilized in treating severely calcified coronary lesions; however, the temporal trends, patient selection, and variation in use of CA have not been well described. We sought to assess the trends in usage, interhospital variability, and outcomes with CA among patients undergoing percutaneous coronary intervention (PCI).

Methods: All patients undergoing PCI in the National Cardiovascular Data Registry CathPCI Registry from July 1, 2009 to December 31, 2016 (N=3 864 377) were analyzed based on utilization of either rotational or orbital CA.

Identification, preclinical profile, and clinical proof of concept of an orally bioavailable pro-drug of miridesap.

Background And Purpose: Miridesap, a depleter of serum amyloid P component (SAP), forms an essential component of a novel approach to remove systemic amyloid deposits; low oral bioavailability necessitates that it is given parenterally. We sought to identify and clinically characterise a pro-drug that preserves the pharmacological properties of miridesap while having adequate oral bioavailability and physical stability.

Experimental Approach: We utilised a preclinical screening cascade focused on appropriate physicochemical properties, physical and gut stability, and conversion to miridesap in liver microsomes and blood.

R-From-T as a Common Mechanism of Arrhythmia Initiation in Long QT Syndromes.

Background: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood.

Methods: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS.

Predicting In Vivo Efficacy from In Vitro Data: Quantitative Systems Pharmacology Modeling for an Epigenetic Modifier Drug in Cancer.

Reliably predicting in vivo efficacy from in vitro data would facilitate drug development by reducing animal usage and guiding drug dosing in human clinical trials. However, such prediction remains challenging. Here, we built a quantitative pharmacokinetic/pharmacodynamic (PK/PD) mathematical model capable of predicting in vivo efficacy in animal xenograft models of tumor growth while trained almost exclusively on in vitro cell culture data sets.

Prosthetic Valve Endocarditis After TAVR and SAVR: Insights From the PARTNER Trials.

Background: Prosthetic valve endocarditis (PVE) is a rare but critical mechanism of valve failure and death after transcatheter and surgical aortic valve replacement (TAVR, SAVR) warranting further analysis in modern aortic valve replacement experience. We characterize the incidence, risk factors, microbiological profile and outcomes of PVE from the PARTNER trials and registries (Placement of Aortic Transcatheter Valve).

Methods: We analyzed a pooled cohort of all patients in PARTNER 1 and PARTNER 2 trials and registries.

Insights into the perception that research ethics committees are a barrier to research with seriously ill children: A study of committee minutes and correspondence with researchers studying seriously ill children.

Background: Research ethics committees are commonly perceived as a 'barrier' to research involving seriously ill children. Researchers studying seriously ill children often feel that committees view their applications more harshly compared to applications for research with other populations. Whether or not this is the case in practice is unknown.

Effect of Baseline Left Ventricular Ejection Fraction on 2-Year Outcomes After Transcatheter Aortic Valve Replacement: Analysis of the PARTNER 2 Trials.

Background: Impaired left ventricular function is associated with worse prognosis among patients with aortic stenosis treated medically or with surgical aortic valve replacement. It is unclear whether reduced left ventricular ejection fraction (LVEF) is an independent predictor of adverse outcomes after transcatheter aortic valve replacement.

Methods And Results: Patients who underwent transcatheter aortic valve replacement in the PARTNER 2 trials (Placement of Aortic Transcatheter Valves) and registries were stratified according to presence of reduced LVEF (<50%) at baseline, and 2-year risk of cardiovascular mortality was compared using Kaplan-Meier methods and multivariable Cox proportional hazards regression.

Clinical Relevance of Collagen Protein Degradation Markers C3M and C4M in the Serum of Breast Cancer Patients Treated with Neoadjuvant Therapy in the GeparQuinto Trial.

: Remodeling of extracellular matrix through collagen degradation is a crucial step in the metastatic cascade. The aim of this study was to evaluate the potential clinical relevance of the serum collagen degradation markers (CDM) C3M and C4M during neoadjuvant chemotherapy for breast cancer. : Patients from the GeparQuinto phase 3 trial with untreated HER2-positive operable or locally advanced breast cancer were enrolled between 7 November 2007, and 9 July 2010, and randomly assigned to receive neoadjuvant treatment with EC/docetaxel with either trastuzumab or lapatinib.

2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth.

The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease and have thus become an attractive therapeutic target for many types of invasive cancers. Following our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold.

Molecular Subtype Classification in Lower-Grade Glioma with Accelerated DTI.

Background And Purpose: Image-based classification of lower-grade glioma molecular subtypes has substantial prognostic value. Diffusion tensor imaging has shown promise in lower-grade glioma subtyping but currently requires lengthy, nonstandard acquisitions. Our goal was to investigate lower-grade glioma classification using a machine learning technique that estimates fractional anisotropy from accelerated diffusion MR imaging scans containing only 3 diffusion-encoding directions.

Atherosclerosis in Chronic Kidney Disease: More, Less, or Just Different?

Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter.

Developing a Newborn Resuscitation Telemedicine Program: A Follow-Up Study Comparing Two Technologies.

Early work has demonstrated that newborn resuscitation telemedicine programs (NRTPs) are feasible and improve the quality of high-risk newborn resuscitations in community settings. Research evaluating the telemedicine technology requirements for NRTPs is limited. To compare the quality and reliability of two telemedicine technologies for providing NRTP consults.

Impact of Diabetes Mellitus in Women Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents.

Background: Data examining the impact of diabetes mellitus (DM) on ischemic risk after percutaneous coronary intervention in women are limited as most clinical trial participants are male. We evaluated (1) the impact of DM on ischemic outcomes in women undergoing drug-eluting stent (DES) implantation and (2) whether the outcomes of new- versus early-generation DES vary by DM status.

Methods And Results: We pooled patient-level data of 10 448 women undergoing percutaneous coronary intervention with DES from 26 randomized trials.

Extent of Surgical Resection in Lower-Grade Gliomas: Differential Impact Based on Molecular Subtype.

Background And Purpose: Diffuse lower-grade gliomas are classified into prognostically meaningful molecular subtypes. We aimed to determine the impact of surgical resection on overall survival in lower-grade glioma molecular subtypes.

Materials And Methods: For 172 patients with lower-grade gliomas (World Health Organization grade II or III), pre- and postsurgical glioma volumes were determined using a semiautomated segmentation software based on FLAIR or T2-weighted MR imaging sequences.

Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary Intervention.

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018.

Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships.

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy, and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold.

Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update.

Purpose: To update the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.

Methods: PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs in patients with cancer published from January 31, 2010, through May 14, 2018. For biosimilar ESAs, the literature search was expanded to include meta-analyses and RCTs in patients with cancer or chronic kidney disease and cohort studies in patients with cancer due to limited RCT evidence in the cancer setting.