Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy

Objectives.This study of hypertensive left ventricular hypertrophy 1) assessed myocardial shortening in both the circumferential and long-axis planes, and 2) investigated the relation between geometry and systolic function.Background.In hypertensive left ventricular hypertrophy, whole-heart studies have suggested normal systolic function on the basis of ejection fraction-systolic stress relations. By contrast, isolated muscle data show that contractility is depressed. It occurred to us that this discrepancy could be related to geometric factors (relative wall thickness).Methods.We studied 43 patients with hypertensive left ventricular hypertrophy and normal ejection fraction (mean ± SD 69 ± 13%) and 50 clinically normal subjects. By echocardiography, percent myocardial shortening was measured in two orthogonal planes; circumferential shortening was measured at the endocardium and at the midwall, and long-axis shortening was derived from mitral annular motion (apical four-chamber view). Circumferential shortening was related to end-systolic circumferential stress and long-axis shortening to meridional stress.Results.Endocardial circumferential shortening was higher than normal (42 ± 10% vs. 37 ± 5%, p < 0.01) and midwall circumferential shortening lower than normal in the left ventricular hypertrophy group (18 ± 3% vs. 21 ± 3%, p < 0.01). Differences between endocardial and midwall circumferential shortening are directly related to differences in relative wall thickness. Long-axis shortening was also depressed in the left ventricular hypertrophy group (18 ± 6% in the left ventricular hypertrophy group, 21 ± 5% in control subjects, p < 0.05). Midwall circumferential shortening and end-systolic circumferential stress relations in the normal group showed the expected inverse relation; those for ∼33% of the left ventricular hypertrophy group were >2 SD of normal relations, indicating depressed myocardial function. There was no significant relation between long-axis shortening and meridional stress, indicating that factors other than afterload influence shortening in this plane.Conclusions.High relative wall thickness allows preserved ejection fraction and normal circumferential shortening at the endocardium despite depressed myocardial shortening in two orthogonal planes

Administration of a Glycoprotein IIb/IIIa Receptor Blocker with a Thienopyridine Derivative Does Not Increase the Risk of Thrombocytopenia

Author Institution: Akron Cardiology Consulltants, OHAuthor Institution: Dept. of Educational Foundations & Leadership, University of Akron, OHAuthor Institution: Summa Health System, University of Akron, OHAuthor Institution: Dept. of Medicine, Northeast Ohio Universities College of Medicine, Rootstown, OHAuthor Institution: Cardiac Rehabilitation Institute, Summa Health Syste, University of Akron, OHThe combination of aspirin, a thienopyridine derivative, and a glycoprotein IIb/IIIa receptor inhibitor has become standard therapy for patients undergoing percutaneous coronary intervention (PCI). Recent studies have shown an increased incidence of thrombocytopenia in those patients receiving a high loading dose of clopidogrel (thienopyridine) with abciximab (IIb/IIIa receptor inhibitor) prior to coronary intervention. We reviewed the records of 504 patients who underwent PCI at a large tertiary care hospital and noted an incidence of thrombocytopenia of 4.8%, comparable to published historical controls who received abciximab without clopidogrel. In patients undergoing PCI, there was no difference in thrombocytopenia or bleeding complications between patients receiving a high or a low dose of a thienopyridine. We conclude that a high loading dose of a thienopyridine derivative prior to PCI may be administered safely and efficaciously in the setting of concomitant administration of abciximab without an undue risk of thrombocytopenia

Unsupervised Paraphrasing via Deep Reinforcement Learning

Paraphrasing is expressing the meaning of an input sentence in different wording while maintaining fluency (i.e., grammatical and syntactical correctness). Most existing work on paraphrasing use supervised models that are limited to specific domains (e.g., image captions). Such models can neither be straightforwardly transferred to other domains nor generalize well, and creating labeled training data for new domains is expensive and laborious. The need for paraphrasing across different domains and the scarcity of labeled training data in many such domains call for exploring unsupervised paraphrase generation methods. We propose Progressive Unsupervised Paraphrasing (PUP): a novel unsupervised paraphrase generation method based on deep reinforcement learning (DRL). PUP uses a variational autoencoder (trained using a non-parallel corpus) to generate a seed paraphrase that warm-starts the DRL model. Then, PUP progressively tunes the seed paraphrase guided by our novel reward function which combines semantic adequacy, language fluency, and expression diversity measures to quantify the quality of the generated paraphrases in each iteration without needing parallel sentences. Our extensive experimental evaluation shows that PUP outperforms unsupervised state-of-the-art paraphrasing techniques in terms of both automatic metrics and user studies on four real datasets. We also show that PUP outperforms domain-adapted supervised algorithms on several datasets. Our evaluation also shows that PUP achieves a great trade-off between semantic similarity and diversity of expression

A prospective randomized trial of content expertise versus process expertise in small group teaching

Article deposited according to agreement with BMC, December 6, 2010.YesFunding provided by the Open Access Authors Fund

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

SCN5A encodes the alpha-subunit (Na(v)1.5) of the principle Na(+) channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Na(v)1.5 channel. Pharmacological targeting of mutation-altered Na(+) channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+) channel blockers flecainide and mexiletine. Our goal was to determine the Na(+) channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+) channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+) channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+) channel defects and suggest that both genetic background and age are particularly important in developing a mutation-specific therapeutic personalized approach to manage disorders in the young

Setting our sights on infectious diseases

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings

Evolution of structures and fabrics in the Barbados Accretionary Prism ; Insights from Leg 110 of the Ocean Drilling Program

The microstructures and crystal fabrics associated with the development of an amphibolite facies quartzo-feldspathic mylonitic shear zone (Torridon, NW Scotland) have been investigated using SEM electron channelling. Our results illustrate a variety of microstructures and fabrics which attest to a complex shear zone deformation history. Microstructural variation is particularly pronounced at low shear strains: significant intragranular deformation occurs via a domino-faulting style process, whilst mechanical incompatibilities between individual grains result in characteristic grain boundary deformation accommodation microstructures. A sudden reduction in grain size defines the transition to medium shear strains, but many of the boundaries inherited from the original and low shear strain regions can still be recognized and define distinctive bands oriented at low angles to the shear zone margin. Grains within these bands have somewhat steeper preferred dimensional orientations. These domains persist into the high shear strain mylonitic region, where they are oriented subparallel to the shear zone margin and consist of sub-20 μm grains. The microstructures suggest that the principal deformation mechanism was intracrystalline plasticity (with contributions from grain size reduction via dynamic recrystallization, grain boundary migration and grain boundary sliding). Crystal fabrics measured from the shear zone vary with position depending on the shear strain involved, and are consistent with the operation of several crystal slip systems (e.g. prism, basal, rhomb and acute rhomb planes) in a consistent direction (probably parallel to a and/or m). They also reveal the presence of Dauphine twinning and suggest that this may be a significant process in quartz deformation. A single crystal fabric evolution path linking the shear zone margin fabric with the mylonitic fabric was not observed. Rather, the mylonitic fabric reflects the instantaneous fabric which developed at a particular location for a particular shear strain and original parental grain orientation. The mature shear zone therefore consists of a series of deformed original grains stacked on top of each other in a manner which preserves original grain boundaries and intragranular features which develop during shear zone evolution. The stability of some microstructures to higher shear strains, the exploitation of others at lower shear strains, and a continuously evolving crystal fabric, mean that the strain gradient observed across many shear zones is unlikely to be equivalent to a time gradient

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701