bluuebunny/crossref_metadata_2025 huggingface dataset:
Photophysicochemical properties and photodynamic therapy activity of chloroindium(III) tetraarylporphyrins and their gold nanoparticle conjugates
Authors: Soy Rodah C. , Babu Balaji , Oluwole David O. , Nwaji Njemuwa , Oyim James , Amuhaya Edith , Prinsloo Earl , Mack John , Nyokong Tebello
Published: January 2019

Novel chloroindium(III) complexes of tetra(4-methylthiophenyl)porphyrin (2a) and tetra-2-thienylporphyrin (2b) dyes have been synthesized and characterized. The main goal of the project was to identify fully symmetric porphyrin dyes with Q-band regions that lie partially in the therapeutic window that are suitable for use in photodynamic therapy (PDT). 2a and 2b were found to have fluorescence quantum yield values [Formula: see text] 0.01 and moderately high singlet oxygen quantum yields (0.54−0.73) due to heavy atom effects associated with the sulfur and indium atoms. The dark toxicity and PDT activity against epithelial breast cancer cells (MCF-7) were investigated over a dose range of 3.0−40 [Formula: see text]g [Formula: see text] mL[Formula: see text]. The in vitro dark cytotoxicity of 2a is significantly lower than that of 2b at [Formula: see text] 40 [Formula: see text]g [Formula: see text] mL[Formula: see text]. 2a was conjugated with gold nanoparticles (AuNPs) to form a nanoconjugate (2a-AuNPs), which exhibited a higher singlet oxygen quantum yield ([Formula: see text] value and PDT activity than was observed for 2a alone. The results suggest that the AuNPs nanoconjugates of readily synthesized fully symmetric porphyrin dyes are potentially suitable for PDT applications, if meso-aryl substituents that provide scope for nanoparticle conjugation can be introduced that shift the Q bands into the therapeutic window.
DIGITAL TRANSFORMATION IN THE NEW PRODUCT DEVELOPMENT PROCESS: THE ROLE OF IT-ENABLED PLM SYSTEMS FOR RELATIONAL, STRUCTURAL, AND NPD PERFORMANCE
Authors: SCHWEITZER FIONA MARIA , HANDRICH MATTHIAS , HEIDENREICH SVEN
Published: January 2019

Companies increasingly use digital product lifecycle management (PLM) systems with information technology (IT)-based workflow and product data management functions to assist new product development (NPD). However, empirical evidence on whether and how such digital transformation in PLM contributes to NPD performance is scarce. The objective of this paper is to fill this void. We use Assemblage Theory to develop a theoretical model that links the digital transformation in PLM to performance and focus on the extent to which IT-based data gathering and exchange occur in NPD. We carry out a quantitative survey among 216 key informants of manufacturing companies and use structural equation modelling on the resultant data to provide empirical evidence for our hypothesis. We find that the level of digital transformation in PLM positively influences structural and relational performance and, in effect, also enhances NPD performance. Our findings also show that organisational complexity positively moderates these relationships. For managers, our findings demonstrate the value of digital transformation for managing the NPD process, notably in larger, more complex organisations.
A Medium Model Leading to Analogy of Major Physics Laws
Authors: Yi Ting
Published: January 2019

The attempt of this paper is to suggest a new theoretical medium to support the efforts of building particle models as mechanical field structures. The medium model is based on two simple fundamental assumptions. All the properties of the medium, as counterparts in this medium of the well-known physics laws, including energy and momentum conservations, Lorentz transformation and special relativity, electromagnetic interaction, etc., are derived from these two assumptions. The governing equations are established based on the derived properties. Some steady solutions as well as the feasibility of interpreting these solutions as particles are also briefly discussed.
Evaluating GSD-Aware
Authors: Vizcaíno Aurora , García Félix , Guzmán Ignacio García Rodriguez De , Moraga M. Ángeles
Published: January 2019

Global Software Development (GSD) is currently a strong industry trend. This means that if computer science engineers are to be trained to deal with this model, it is very important to include the topic in software engineering courses, attempting to ensure that students learn about GSD and become familiar with its advantages and challenges. However, software engineering courses do not always consider including it in their curricula. It must also be recognized that it is difficult to find a suitable method to teach/develop the different skills needed for GSD. There is often a lot of content and not a great deal of time available to teach it. In this article, we propose the use of a serious game called GSD-Aware, with which students can “suffer” some of the typical challenges of GSD by interacting with avatars and by using several means of communication to solve a number of problems posed. The article focuses on the description of the game and on the empirical study conducted to analyze whether GSD-Aware helps students to be conscious of GSD challenges. It was discovered that after 50 minutes playing the game, the students were aware of the greater influence that the following factors can have: lack of coordination, lack of trust, cultural differences, lack of face-to-face and informal communication, time difference, and lack of team spirit. In their final analysis, students agreed that the serious game scenarios helped them to understand what GSD is and to grasp the importance of some GSD challenges.
Exploring and Expanding GSE Education with Open Source Software Development
Authors: Hjelsvold Rune , Mishra Deepti
Published: January 2019

Global software engineering (GSE) courses traditionally require cooperation between at least two universities so as to provide a distributed development environment to the students. In this study, we explore an alternative way to organize a global software engineering course where students work on open source software development (OSSD) projects rather than in a multi-university collaboration setting. The results show that the new setup may provide core GSE challenges as well as challenges associated with software development outsourcing and challenges related to working on large open source software. The present article compares the experiences gained from running a combined GSE and OSSD course against the experiences gained from running a traditional GSE course. The two alternatives are compared in terms of students’ learning outcomes and course organization. The authors found that a combined GSE and OSSD course provides learning opportunities that are partly overlapping with, and partly complementary to, a traditional GSE course. The authors also found that the combined OSSD and GSE course was somewhat easier to organize because most of the activities took place in a single university setting. The authors used the extended GSE taxonomy for the comparison and found it to be a useful tool for this, although it had some limitations in expressive power. Therefore, two additional relationship dimensions are proposed that will further enrich the extended taxonomy in classifying GSE (and OSSD) projects.
Assessing Students’ IT Professional Values in a Global Project Setting
Authors: Frezza S. , Daniels M. , Wilkin A.
Published: January 2019

This research aimed at evaluating the development and use of low-cost affective domain assessment instruments, culminating with personal and group characterization of representative global information technology (IT) professional values. Values and valuing are a compelling component of Bloom's affective domain of learning for engineering education. In helping students develop professional engineering competencies, it is essential that they develop not just cognitive knowledge of something but also values related to that knowledge and the ability to express these values in professional action. However, even if some professional values are identified, understood, and expressed, assessing students’ values and valuing are difficult, and assessment instruments are often difficult to develop, particularly for assessing student learning in the context of a particular course.

This exploratory study aimed at examining assessment of dispositional knowledge in the context of global software engineering (GSE). It focused on the development and use of a set of instruments for assessing affective domain student learning of global IT/software engineering (SE) professional values. The project included making explicit the IT professional values of interest among the participating faculty in the form of actionable value statements. Following a process derived from Thurstone scale development, the project included validation of these statements with an expert panel as question roots, followed by the use of these questions to investigate student and alumni receiving, responding, and valuing of these professional values. The effort needed to generate questionnaires suitable for course use was relatively low; these questionnaires were deployed to students and alumni from an open-ended global software engineering project course. Students responding reported significant agreement when receiving these global values, but sent more mixed responses in responding to and valuing them. The effort helped identify several actionable IT professional values worth reinforcing in future course offerings.
Limit of Hardware Solutions for Self-Protecting Fault-Tolerant NoCs
Authors: Louri Ahmed , Collet Jacques , Karanth Avinash
Published: January 2019

We study the ultimate limits of hardware solutions for the self-protection strategies against permanent faults in networks on chips (NoCs). NoCs reliability is improved by replacing each base router by an augmented router which includes extra protection circuitry. We compare the protection achieved by the self-test and self-protect (STAP) architectures to that of triple modular redundancy with voting (TMR). Two STAP architectures are considered. In the first one, a defective router self-disconnects from the network, while it self-heals in the second one. In practice, none of the considered architectures (STAP or TMR) can tolerate all the permanent faults, especially faults in the extra-circuitry for protection or voting, and consequently, there will always be some unidentified defective augmented routers which are going to transmit errors in an unpredictable manner. This study consists of tackling this fundamental problem. Specifically, we study and determine the average percentage of residual unidentified defective routers (UDRs) and their impact on the overall reliability of the NoC in light of self-protection strategies. Our study shows that TMR is the most efficient solution to limit the average percentage of UDRs when there are typically less than a 0.1 percent of defective base routers. However, TMR is also the most cost prohibitive and the least power efficient. Above 1% of defective base routers, the STAP approaches are more efficient although the protection efficiency decreases inexorably in the very defective technologies (e.g. when there is 10% or more of defective base routers). For instance, if the chip includes 10% of defective base routers, our study shows that there will remain on the average 1% of UDRs, which causes a major challenge for NoC reliability.
Kernel Protection Against Just-In-Time Code Reuse
Authors: Pomonis Marios , Petsios Theofilos , Keromytis Angelos D. , Polychronakis Michalis , Kemerlis Vasileios P.
Published: January 2019

The abundance of memory corruption and disclosure vulnerabilities in kernel code necessitates the deployment of hardening techniques to prevent privilege escalation attacks. As stricter memory isolation mechanisms between the kernel and user space become commonplace, attackers increasingly rely on code reuse techniques to exploit kernel vulnerabilities. Contrary to similar attacks in more restrictive settings, as in web browsers, in kernel exploitation, non-privileged local adversaries have great flexibility in abusing memory disclosure vulnerabilities to dynamically discover, or infer, the location of code snippets in order to construct code-reuse payloads. Recent studies have shown that the coupling of code diversification with the enforcement of a “read XOR execute” (R
∧
X) memory safety policy is an effective defense against the exploitation of userland software, but so far this approach has not been applied for the protection of the kernel itself.

In this article, we fill this gap by presenting kR
∧
X: a kernel-hardening scheme based on execute-only memory and code diversification. We study a previously unexplored point in the design space, where a hypervisor or a super-privileged component is not required. Implemented mostly as a set of GCC plugins, kR
∧
X is readily applicable to x86 Linux kernels (both 32b and 64b) and can benefit from hardware support (segmentation on x86, MPX on x86-64) to optimize performance. In full protection mode, kR
∧
X incurs a low runtime overhead of 4.04%, which drops to 2.32% when MPX is available, and 1.32% when memory segmentation is in use.
Optimal Choice of When to Garbage Collect
Authors: Jacek Nicholas , Chiu Meng-Chieh , Marlin Benjamin M. , Moss J. Eliot B.
Published: January 2019

We consider the ultimate limits of program-specific garbage collector (GC) performance for real programs. We first characterize the GC schedule optimization problem. Based on this characterization, we develop a linear-time dynamic programming solution that, given a program run and heap size, computes an
optimal
schedule of collections for a non-generational collector. Using an analysis of a heap object graph of the program, we compute a property of heap objects that we call their
pre-birth
time. This information enables us to extend the non-generational GC schedule problem to the generational GC case in a way that also admits a dynamic programming solution with cost quadratic in the length of the trace (number of objects allocated). This improves our previously reported approximately optimal result. We further extend the two-generation dynamic program to any number of generations, allowing other generalizations as well. Our experimental results for two generations on traces from Java programs of the DaCapo benchmark suite show that there is considerable promise to reduce garbage collection costs for some programs by developing program-specific collection policies. For a given space budget, optimal schedules often obtain modest but useful time savings, and for a given time budget, optimal schedules can obtain considerable space savings.
A Higher-Order Calculus of Computational Fields
Authors: Audrito Giorgio , Viroli Mirko , Damiani Ferruccio , Pianini Danilo , Beal Jacob
Published: January 2019

The complexity of large-scale distributed systems, particularly when deployed in physical space, calls for new mechanisms to address composability and reusability of collective adaptive behaviour. Computational fields have been proposed as an effective abstraction to fill the gap between the macro-level of such systems (specifying a system’s collective behaviour) and the micro-level (individual devices’ actions of computation and interaction to implement that collective specification), thereby providing a basis to better facilitate the engineering of collective APIs and complex systems at higher levels of abstraction. This article proposes a full formal foundation for field computations, in terms of a core (higher-order) calculus of computational fields containing a few key syntactic constructs, and equipped with typing, denotational and operational semantics. Critically, this allows formal establishment of a link between the micro- and macro-levels of collective adaptive systems by a result of computational adequacy and abstraction for the (aggregate) denotational semantics with respect to the (per-device) operational semantics.
An Autotuning Protocol to Rapidly Build Autotuners
Authors: Liu Junhong , Tan Guangming , Luo Yulong , Li Jiajia , Mo Zeyao , Sun Ninghui
Published: January 2019

Automatic performance tuning (Autotuning) is an increasingly critical tuning technique for the high portable performance of Exascale applications. However, constructing an autotuner from scratch remains a challenge, even for domain experts. In this work, we propose a performance tuning and knowledge management suite (PAK) to help rapidly build autotuners. In order to accommodate existing autotuning techniques, we present an autotuning protocol that is composed of an extractor, producer, optimizer, evaluator, and learner. To achieve modularity and reusability, we also define programming interfaces for each protocol component as the fundamental infrastructure, which provides a customizable mechanism to deploy knowledge mining in the performance database. PAK’s usability is demonstrated by studying two important computational kernels: stencil computation and sparse matrix-vector multiplication (SpMV). Our proposed autotuner based on PAK shows comparable performance and higher productivity than traditional autotuners by writing just a few tens of code using our autotuning protocol.
An Active Learning Approach for Improving the Accuracy of Automated Domain Model Extraction
Authors: Arora Chetan , Sabetzadeh Mehrdad , Nejati Shiva , Briand Lionel
Published: January 2019

Domain models are a useful vehicle for making the interpretation and elaboration of natural-language requirements more precise. Advances in natural-language processing (NLP) have made it possible to automatically extract from requirements most of the information that is relevant to domain model construction. However, alongside the relevant information, NLP extracts from requirements a significant amount of information that is superfluous (not relevant to the domain model). Our objective in this article is to develop automated assistance for filtering the superfluous information extracted by NLP during domain model extraction. To this end, we devise an active-learning-based approach that iteratively learns from analysts’ feedback over the relevance and superfluousness of the extracted domain model elements and uses this feedback to provide recommendations for filtering superfluous elements. We empirically evaluate our approach over three industrial case studies. Our results indicate that, once trained, our approach automatically detects an average of ≈ 45% of the superfluous elements with a precision of ≈ 96%. Since precision is very high, the automatic recommendations made by our approach are trustworthy. Consequently, analysts can dispose of a considerable fraction – nearly half – of the superfluous elements with minimal manual work. The results are particularly promising, as they should be considered in light of the non-negligible subjectivity that is inherently tied to the notion of relevance.
Impact of cardiovascular embryology animations on short-term learning
Authors: Upson-Taboas Charity F. , Montoya Ruben , O’Loughlin Valerie Dean
Published: January 2019

An understanding of human embryology is essential for students to better understand the subjects of human anatomy and physiology. However, human embryology is a challenging subject for many, since they must learn how anatomic structures and physiological processes develop over a period of time. Embryology texts typically use static, two-dimensional images to illustrate the dynamic three-dimensional developmental processes, making it difficult for a student to understand spatial relationships and sequential steps. To help students conceptualize these series of complex dynamic developmental events that occur over time, two of the authors and a graphic artist developed six web-based cardiovascular embryology animations and housed them on an Indiana University website. This research study examines knowledge gains and user satisfaction of students, faculty, and laypeople around the world who accessed these six website animations. Data collection spanned 6 yr, and pretest/posttest assessments (ranging from 4 to 7 multiple-choice questions each) were used to determine immediate knowledge gains of cardiovascular embryology. The total number of completed pretest/posttest assessments ranged from 555 to 1,449 per animation. The number of correct posttest scores was significantly improved over matched pretest scores (confidence interval range 1.3–3.2, depending on the animation, P < 0.001), suggesting the animations are useful for embryology learning (at least in the short term). Demographic and user satisfaction information was gathered with an anonymous survey at the end of each animation. Survey data from all animations indicated participants found the animations easy to use and very effective for their learning. This research highlights the positive impacts of web-based animations on learning complicated events of cardiovascular embryology.
Top 100 Most Influential Articles in the Field of Myeloid Neoplasms: A Bibliometric Study
Authors: Iqbal Unzela , Rehan Aiman , Akmal Manahil , Jamali Momal , Iqbal Abiha , Khan Bilal Ahmed , Wasif Khawaja Uzair , Rivera Erika , Khan Maliha
Published: January 2019

Background: Bibliometric analyses are a tool employed by researchers and funding agencies to establish the most important areas of research in a particular field, and to determine which foci need increased research attention. Such analyses have been published in a variety of clinical specialties; however, a detailed literature search showed that no such study has been done for “myeloid neoplasms.” In order to bridge this gap, we conducted a citation analysis of the 100 most influential articles on myeloid neoplasms. Methods: Two independent researchers extracted relevant articles from the Scopus database. These articles were then ranked in descending order of citations and a list of the top 100 original articles was made. A further, more detailed list was created containing significant discriminating characteristics. Results: The top cited articles were published over a period of 47 years, with most of them being published in the 5-year interval of 2001–2005. The citations ranged from 636 to 4,039. The articles originated from 28 different countries. Most of the articles were published in high-impact journals. Conclusion: Our analysis sheds light on the quality of work and driving trends, listing the most cited and impactful guideline articles within this field and aiding clinicians.
Health Economic Evaluations of Digital Health Interventions for Secondary Prevention in Stroke Patients: A Systematic Review
Authors: Valenzuela Espinoza Alexis  , Steurbaut Stephane , Dupont Alain , Cornu Pieter , van Hooff Robbert-Jan , Brouns Raf , Putman Koen
Published: January 2019

Background: In the first 5 years after their stroke, about a quarter of patients will suffer from a recurrent stroke. Digital health interventions facilitating interactions between a caregiver and a patient from a distance are a promising approach to improve patient adherence to lifestyle changes proposed by secondary prevention guidelines. Many of these interventions are not implemented in daily practice, even though efficacy has been shown. One of the reasons can be the lack of clear economic incentives for implementation. We propose to map all health economic evidence regarding digital health interventions for secondary stroke prevention. Summary: We performed a systematic search according to PRISMA-P guidelines and searched on PubMed, Web of Science, Cochrane, and National Institute for Health Research Economic Evaluation Database. Only digital health interventions for secondary prevention in stroke patients were included and all study designs and health economic outcomes were accepted. We combined the terms “Stroke OR Cardiovascular,” “Secondary prevention,” “Digital health interventions,” and “Cost” in one search string using the AND operator. The search performed on April 20, 2017 yielded 163 records of which 26 duplicates were removed. After abstract screening, 20 articles were retained for full-text analysis, of which none reported any health economic evidence that could be included for analysis or discussion. Key Messages: There is a lack of evidence on health economic outcomes on digital health interventions for secondary stroke prevention. Future research in this area should take health economics into consideration when designing a trial and there is a clear need for health economic evidence and models.
Visitando a trajetória ou (re)produzindo o passado do Condephaat
Authors:  Wolff Silvia Ferreira Santos
Published: January 2019

Trata-se de rememoração da trajetória do Conselho de Defesa do Patrimônio Histórico, Arqueológico, Artístico e Turístico  (Condephaat), órgão oficial de preservação do patrimônio cultural em São Paulo, a partir dos anos 1980, com ênfase na avaliação dos efeitos da ampliação de seus quadros técnicos e renovação dos conceitos de preservação naquela década.
Imagens de um certo Brasil e redes de significância na tradução para o português de Là où les tigres sont chez eux, de Jean-Marie Blas de Roblès: emergência do exótico?
Authors: Camargo Raquel Peixoto do Amaral
Published: January 2019

Neste artigo nos ateremos a imagens do Brasil e a redes de significância (Berman 1995) que aparecem no romance Là où les tigres sont chez eux, de Jean-Marie Blas de Roblès, e observaremos suas refrações na tradução para o português, Lá onde os tigres se sentem em casa, de Mauro Pinheiro e Maria de Fátima do Coutto. É nosso objetivo perceber como se dá a criação de um Brasil exótico no romance e como esse exótico emerge e se reconfigura na tradução. Inicialmente, observaremos o processo criativo do autor que, mediante um movimento de reversão de expectativas, engendra a construção de redes de significância e de imagens do Brasil. Voltaremos, em seguida, o olhar para o texto traduzido, no intuito de perceber diferenças que reiterem ou enfraqueçam as redes de significância do original. Apontaremos, por fim, algumas consequências advindas das diferenças encontradas.
Brachial Artery Echogenicity and Grayscale Texture Changes in HIV-Infected Individuals Receiving Low-Dose Methotrexate
Authors: Stein James H. , Yeh Eunice , Weber Joanne M. , Korcarz Claudia , Ridker Paul M , Tawakol Ahmed , Hsue Priscilla Y. , Currier Judith S. , Ribaudo Heather , Mitchell Carol K.C.
Published: January 2019

Objective—

We evaluated the biological effects of low-dose methotrexate on 3 novel brachial artery grayscale ultrasound measures that may indicate subclinical arterial injury.

Approach and Results—

Exploratory analysis from a clinical trial of people with HIV infection at increased cardiovascular disease risk who were randomly assigned to low-dose methotrexate (target dose 15 mg/wk) or placebo. Brachial artery ultrasound grayscale median, gray level difference statistic texture–contrast (GLDS-CON), and gray level texture entropy were measured at baseline and after 24 weeks of intervention. Findings from the intention-to-treat (N=148) and adequately-dosed (N=118) populations were consistent, so the adequately-dosed population results are presented. Participants were a median (Q1, Q3) age of 54 (50, 60) years. After 24 weeks, the low-dose methotrexate intervention was associated with a 25.4% (−18.1, 58.6;
P
=0.007) increase in GLDS-CON compared with 1.3% (−29.1, 44.7;
P
=0.97) with placebo (
P
=0.05) and a 0.10 u (−0.06, 0.23;
P
=0.026) increase in entropy compared with 0.02 u (−0.11, 0.14;
P
=0.54) with placebo (
P
=0.14). At week 24, changes in CD4+ T cells correlated inversely with changes in GLDS-CON (ρ=−0.20;
P
=0.031), and entropy (ρ=−0.21;
P
=0.023). Changes in D-dimer levels, but no other inflammatory biomarkers, also correlated inversely with changes in GLDS-CON (ρ=−0.23;
P
=0.014) and entropy (ρ=−0.26;
P
=0.005).

Conclusions—

Brachial artery GLDS-CON and entropy increased after 24 weeks of low-dose methotrexate, though the latter was not significantly different from placebo. Grayscale changes were associated with decreases in CD4+ T-cell and D-dimer concentrations and may indicate favorable arterial structure changes.
Safety of Sports for Young Patients With Implantable Cardioverter-Defibrillators
Authors: Saarel Elizabeth Vickers , Law Ian , Berul Charles I. , Ackerman Michael J. , Kanter Ronald J. , Sanatani Shubhayan , Cohen Mitchell I. , Berger Stuart , Fischbach Peter S. , Burton David A. , Dziura James , Brandt Cynthia , Simone Laura , Li Fangyong , Olshansky Brian , Cannom David S. , Lampert Rachel J.
Published: January 2019

Background:

Despite safety concerns, many young patients with implantable cardioverter-defibrillators (ICDs) participate in sports. We undertook a prospective, multinational registry to determine the incidence of serious adverse events because of sports participation. The primary end points were death or resuscitated arrest during sports or injury during sports because of arrhythmia or shock. Secondary end points included system malfunction and incidence of ventricular arrhythmias requiring multiple shocks for termination.

Methods:

Athletes with ICDs aged ≤21 years were included in this post hoc subanalysis of the ICD Sports Registry. Data on sports and clinical outcomes were obtained by phone interview and medical records review. ICD shocks and clinical details of lead malfunction were classified by 2 electrophysiologists.

Results:

A total of 129 young athletes participating in competitive (n=117) or dangerous (n=12) sports were enrolled. The mean age was 16 years (range, 10–21; 40% female; 92% white). The most common diagnoses were long QT syndrome (n=49), hypertrophic cardiomyopathy (n=30), and congenital heart disease (n=16). The most common sports were basketball and soccer, including 79 varsity/junior varsity high school and college athletes. During a median follow-up of 42 months, 35 athletes (27%) received 38 shocks. There were no occurrences of death, arrest, or injury related to arrhythmia, during sports. There was 1 ventricular tachycardia/ventricular fibrillation storm during competition. Freedom from lead malfunction was 92.3% at 5 years and 79.6% at 10 years.

Conclusions:

Although shocks related to competition/practice are not uncommon, there were no serious adverse sequelae. Lead malfunction rates were similar to previously reported in unselected pediatric ICD populations.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00637754.
High-Throughput Functional Evaluation of
KCNQ1
Decrypts Variants of Unknown Significance
Authors: Vanoye Carlos G. , Desai Reshma R. , Fabre Katarina L. , Gallagher Shannon L. , Potet Franck , DeKeyser Jean-Marc , Macaya Daniela , Meiler Jens , Sanders Charles R. , George Alfred L.
Published: January 2019

Background:

The explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that have implications for diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels as in congenital arrhythmia syndromes, in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost, time, and labor intensive.

Methods:

We implemented a strategy for performing high-throughput functional evaluations of ion channel variants that repurposed an automated electrophysiological recording platform developed previously for drug discovery.

Results:

We demonstrated the success of this approach by evaluating 78 variants in
KCNQ1
, a major gene involved in genetic disorders of cardiac arrhythmia susceptibility. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. This strategy also enabled studies of dominant-negative behavior of variants exhibiting severe loss-of-function. Overall, our results provided functional data useful for reclassifying >65% of the studied
KCNQ1
variants.

Conclusions:

Our results illustrate an efficient and high-throughput paradigm linking genotype to function for a human cardiac ion channel that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.
Clinical Utility and Prognostic Value of Right Atrial Function in Pulmonary Hypertension
Authors: Alenezi Fawaz , Mandawat Aditya , Il’Giovine Zachary J. , Shaw Linda K. , Siddiqui Irfan , Tapson Victor F. , Arges Kristine , Rivera Danny , Romano Minna M.D. , Velazquez Eric J. , Douglas Pamela S. , Samad Zainab , Rajagopal Sudarshan
Published: January 2019

Background

Although right atrial (RA) enlargement is an established marker for adverse outcomes, the prognostic importance of RA dysfunction independent of RA size in pulmonary arterial hypertension is not known.

Methods and Results

Study subjects with pulmonary arterial hypertension were prospectively enrolled from 2010 to 2014. RA function was measured using RA speckle-tracking longitudinal strain and strain rate (SR) during each phase of the cardiac cycle: (1) RA reservoir (peak longitudinal strain, peak systolic SR), (2) RA conduit (peak early diastolic SR), and (3) RA active contraction (peak active contraction strain, peak contraction SR). The primary outcome was a composite of time to hospitalization or death assessed on follow-up. A total of 63 subjects had complete echocardiographic data. Of these, 91% were females, and the mean age was 58±12 years. During the follow-up period (range: 1–58 months), 39 were hospitalized or had died. After multivariable adjustment for age, sex, and left atrial size, peak longitudinal strain, peak active contraction strain, and peak early diastolic SR were significantly associated with increased risk of the composite outcome (
P
=0.0005,
P
=0.0167, and
P
=0.0054, respectively).

Conclusions

RA dysfunction independently predicts mortality and hospitalizations in patients with pulmonary arterial hypertension.
Transcarotid Compared With Other Alternative Access Routes for Transcatheter Aortic Valve Replacement
Authors: Chamandi Chekrallah , Abi-Akar Ramzi , Rodés-Cabau Josep , Blanchard Didier , Dumont Eric , Spaulding Christian , Doyle Daniel , Pagny Jean-Yves , DeLarochellière Robert , Lafont Antoine , Paradis Jean-Michel , Puri Rishi , Karam Nicole , Maes Frédéric , Rodriguez-Gabella Tania , Chassaing Stéphan , Le Page Olivier , Kalavrouziotis Dimitri , Mohammadi Siamak
Published: January 2019

Background

The optimal access for patients undergoing transcatheter aortic valve replacement (TAVR) who are not candidates for a transfemoral approach has not been elucidated. The purpose of this study was to compare the safety, feasibility, and early clinical outcomes of transcarotid TAVR compared with thoracic approaches.

Methods and Results

From a multicenter consecutive cohort of 329 alternative-access TAVR patients (2012–2017), we identified 101 patients who underwent transcarotid TAVR and 228 patients who underwent a transapical or transaortic TAVR. Preprocedural success and 30-day clinical outcomes were compared using multivariable propensity score analysis to account for between-group differences in baseline characteristics. All transcarotid cases were performed under general anesthesia, mainly using the left common carotid artery (97%). Propensity-matched groups had similar rates of 30-day all-cause mortality (2.1% versus 4.6%;
P
=0.37), stroke (2.1% versus 3.5%;
P
=0.67; transcarotid versus transapical/transaortic, respectively), new pacemaker implantation, and major vascular complications. Transcarotid TAVR was associated with significantly less new-onset atrial fibrillation (3.2% versus 19.0%;
P
=0.002), major or life-threatening bleeding (4.3% versus 19.9%;
P
=0.002), acute kidney injury (none versus 12.1%;
P
=0.002), and shorter median length of hospital stay (6 versus 8 days;
P
<0.001).

Conclusions

Transcarotid vascular access for TAVR is safe and feasible and is associated with encouraging short-term clinical outcomes. Our data suggest a clinical benefit of transcarotid TAVR with respect to atrial fibrillation, major bleeding, acute kidney injury, and length of stay compared with the more invasive transapical or transaortic strategies. Randomized studies are required to ascertain whether transcarotid TAVR yields equivalent results to other alternative vascular access routes.
Outcomes Following Percutaneous Coronary Intervention in Non–ST-Segment–Elevation Myocardial Infarction Patients With Coronary Artery Bypass Grafts
Authors: Shoaib Ahmad , Kinnaird Tim , Curzen Nick , Kontopantelis Evangelos , Ludman Peter , de Belder Mark , Rashid Muhammad , Kwok Chun Shing , Nolan James , Zaman Azfar , Mamas Mamas A. ,   On behalf of the British Cardiovascular Intervention Society (BCIS) and the National Institute for Cardiovascular Outcomes Research (NICOR)
Published: January 2019

Background

There are limited data on outcomes of patients with previous coronary artery bypass graft (CABG) presenting with non–ST-segment–elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compare clinical characteristics and outcomes in non–ST-segment–elevation myocardial infarction patients undergoing PCI with or without prior CABG surgery in a national cohort.

Methods and Results

We identified 205 039 patients with non–ST-segment–elevation myocardial infarction who underwent PCI between 2007 and 2014 in the British Cardiovascular Intervention Society database. Clinical, demographic, procedural, and outcome data were analyzed by dividing into 3 groups: group 1, PCI in native coronary arteries and no prior CABG (n=186 670); group 2, PCI in native arteries with prior CABG (n=8825); group 3, PCI in grafts (n=9544). Patients in group 2 and 3 were older and had more comorbidities and higher mortality at 30 days (group 2, 2.6% and group 3, 1.9%) and 1 year (group 2, 8.29% and group 3, 7.08%) as compared with group 1 (1.7% and 4.87%). After multivariable analysis, no significant difference in outcomes was observed in 30-days mortality (odds ratio; group 2=0.87 [CI, 0.69–1.80;
P
=0.20], group 3=0.91 [CI, 0.71–1.17;
P
=0.46]), in-hospital major adverse cardiovascular event (odds ratio: group 2=1.08 [CI, 0.88–1.34;
P
=0.45], group 3=0.97 [CI=0.77–1.23;
P
=0.82]), and in-hospital stroke (odds ratio: group 2=1.37 [CI, 0.71–2.69;
P
=0.35], group 3=1.13 [CI, 0.55–2.34;
P
=0.73]; group 1=reference).

Conclusions

Patients with prior CABG are presenting with non–ST-segment–elevation myocardial infarction and treated with PCI had more comorbid illnesses, but once these differences were adjusted for, prior CABG did not independently confer additional risk of mortality and major adverse cardiovascular event.
Drug-Eluting Stents Versus Bare-Metal Stents in Saphenous Vein Graft Intervention
Authors: Patel Nileshkumar J. , Bavishi Chirag , Atti Varunsiri , Tripathi Avnish , Nalluri Nikhil , Cohen Mauricio G. , Kini Annapoorna S. , Sharma Samin K. , Dangas George , Bhatt Deepak L.
Published: January 2019

Background

Percutaneous coronary intervention with drug-eluting stents (DES) has been increasingly used for revascularization of saphenous vein graft stenosis without strong clinical evidence favoring their use. Randomized controlled trials comparing DES versus bare-metal stents (BMS) in saphenous vein graft–percutaneous coronary intervention have been inconclusive.

Methods and Results

We performed a comprehensive literature search through May 15, 2018, for all eligible studies comparing DES versus BMS in patients with saphenous vein graft stenosis in PubMed, EMBASE, SCOPUS, Google Scholar, and ClinicalTrials.gov. Clinical outcomes included all-cause mortality, cardiovascular mortality, major adverse cardiovascular events, myocardial infarction, stent thrombosis, and target vessel revascularization. Six randomized controlled trials were eligible and included 1582 patients, of whom 797 received DES and 785 received BMS. The follow-up period ranged from 18 months to 60 months. There was no statistically significant difference between DES and BMS for all-cause mortality (risk ratio [RR],1.11; 95% CI, 0.0.77–1.62;
P
=0.57), cardiovascular mortality (RR, 1.00; 95% CI, 0.64–1.57;
P
=0.99), major adverse cardiovascular events (RR, 0.83; 95% CI, 0.63–1.10;
P
=20), target vessel revascularization (RR, 0.73; 95% CI, 0.48–1.11;
P
=0.14), myocardial infarction (RR, 0.74; 95% CI, 0.48–1.16;
P
=0.19), or stent thrombosis (RR, 1.06; 95% CI, 0.42–2.65;
P
=0.90).

Conclusions

In patients undergoing percutaneous coronary intervention for saphenous vein graft lesions, our results showed that there was no significant difference between DES and BMS for mortality, major adverse cardiovascular events, target vessel revascularization, myocardial infarction, or stent thrombosis.
Surgical Atrioventricular Valve Replacement With Melody Valve in Infants and Children
Authors: Pluchinotta Francesca R. , Piekarski Breanna L. , Milani Valentina , Kretschmar Oliver , Burch Phillip T. , Hakami Lale , Meyer David B. , Jacques Frederic , Ghez Olivier , Trezzi Matteo , Carotti Adriano , Qureshi Shakeel A. , Michel-Behnke Ina , Hammel James M. , Chai Paul , McMullan David , Mettler Bret , Ferrer Queralt , Carminati Mario , Emani Sitaram M.
Published: January 2019

Background

Pediatric patients with atrioventricular valve disease have limited options for prosthetic valve replacement in sizes <15 mm. Based on successful experience with the stented bovine jugular vein graft (Melody valve) in the right ventricular outflow tract, the prosthesis has been modified for surgical valve replacement in pediatric patients with atrioventricular dysfunction with the intention of subsequent valve expansion in the catheterization laboratory as the child grows.

Methods and Results

A multicenter, retrospective cohort study was performed among patients who underwent atrioventricular valve replacement with Melody valve at 17 participating sites from North America and Europe, including 68 patients with either mitral (n=59) or tricuspid (n=9) replacement at a median age of 8 months (range, 3 days to 13 years). The median size at implantation was 14 mm (range, 9–24 mm). Immediately postoperatively, the valve was competent with low gradients in all patients. Fifteen patients died; 3 patients underwent transplantation. Nineteen patients required reoperation for adverse outcomes, including valve explantation (n=16), left ventricular outflow tract obstruction (n=1), permanent pacemaker implantation (n=1), and paravalvular leak repair (n=1). Twenty-five patients underwent 41 episodes of catheter-based balloon expansion, exhibiting a significant decrease in median gradient (
P
<0.001) with no significant increase in grade of regurgitation. Twelve months after implantation, cumulative incidence analysis indicated that 55% of the patients would be expected to be free from death, heart transplantation, structural valve deterioration, or valve replacement.

Conclusions

The Melody valve is a feasible option for surgical atrioventricular valve replacement in patients with hypoplastic annuli. The prosthesis shows acceptable short-term function and is amenable to catheter-based enlargement as the child grows. However, patients remain at risk for mortality and structural valve deterioration, despite adequate early valvular function. Device design and implantation techniques must be refined to reduce complications and extend durability.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov.
Unique identifier: NCT02505074.
Periprocedural Stroke and Myocardial Infarction as Risks for Long-Term Mortality in CREST
Authors: Jones Michael R. , Howard George , Roubin Gary S. , Blackshear Joseph L. , Cohen David J. , Cutlip Donald E. , Leimgruber Pierre P. , Rhodes David , Prineas Ronald J. , Glasser Stephen P. , Lal Brajesh K. , Voeks Jenifer H. , Brott Thomas G. ,   for the CREST Investigators
Published: January 2019

Background:

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) previously reported increased mortality in patients who sustained a periprocedural stroke or cardiac event (myocardial infarction [MI] or biomarker only) in follow-up to 4 years. We now extend these observations to 10 years.

Methods and Results:

CREST is a randomized controlled trial designed to compare the outcomes of carotid stenting versus carotid endarterectomy. Proportional hazards models were used to assess the association between mortality and periprocedural stroke, MI, or biomarker-only events. For 10-year follow-up, patients with periprocedural stroke were at 1.74× the risk of death compared with those without stroke (adjusted hazard ratio [HR]=1.74; 95% CI, 1.21–2.50;
P
<0.003). This increased risk was driven by increased early (between 0 and 90 days) mortality (adjusted HR=14.41; 95% CI, 5.33–38.94;
P
<0.0001), with no significant increase in late (between 91 days and 10 years) mortality (adjusted HR=1.40; 95% CI, 0.93–2.10;
P
=0.11). Patients with a protocol MI were at 3.61× increased risk of death compared with those without MI (adjusted HR=3.61; 95% CI, 2.28–5.73;
P
<0.0001), with an increased hazard both early (adjusted HR=8.20; 95% CI, 1.86–36.2;
P
=0.006) and late (adjusted HR=3.40; 95% CI, 2.09–5.53;
P
<0.0001). Patients with a biomarker-only event were at 2.04× increased risk overall (adjusted HR=2.04; 95% CI, 1.09–3.84;
P
=0.03) than those without MI, with an increased early hazard (adjusted HR=8.44; 95% CI, 1.09–65.5;
P
=0.04) and a suggestive but nonsignificant association toward higher 91-day to 10-year risk (1.88; 95% CI, 0.97–3.64;
P
=0.062) contributing to the increased risk.

Conclusions:

In the CREST trial, patients with periprocedural events demonstrate a substantial increase in future mortality to 10 years. For stroke, this risk is largely confined to an early time frame while periprocedural MI or biomarker-only events confer a continuous increased mortality for 10 years. Strategies to reduce periprocedural events and to optimize the evaluation and management of patients with cardiac events should be considered in efforts to reduce not only early but also long-term mortality.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00004732.
Impact of High Deductible Health Plans on Cardiovascular Medication Adherence and Health Disparities
Authors: Lewey Jennifer , Gagne Joshua J. , Franklin Jessica , Lauffenburger Julie C. , Brill Gregory , Choudhry Niteesh K.
Published: January 2019

Background:

High deductible health plans (HDHP) are associated with high levels of patient cost-sharing and are becoming increasingly used in the United Status as a means of reducing healthcare utilization and spending. Our objective is to determine whether HDHP enrollment is associated with a change in adherence to evidence-based medications to treat cardiovascular risk factors and whether such changes vary based on race/ethnicity or socioeconomic status.

Methods and Results:

We conducted a retrospective cohort study using an interrupted time series with concurrent control group design among beneficiaries of Aetna—a national commercial insurer. We included 14 866 patients who filled prescriptions for medications to treat hypertension, high cholesterol, or diabetes mellitus between 2009 and 2014 and who switched from a traditional plan into an HDHP and 14 866 controls who did not switch to an HDHP matched based on calendar time, medication class, race/ethnicity, socioeconomic status, and propensity score. We were specifically interested in evaluating 4 prespecified subgroups based on race/ethnicity (white versus nonwhite) and socioeconomic status (higher versus lower). The main outcome was medication adherence as measured by proportion of days covered. The overall cohort had an average age of 53 years, and 44% were women. Baseline adherence was the lowest in the nonwhite patient group. Switching to an HDHP was associated with a decrease in the level of adherence of 5 percentage points across all 4 subgroups (change in level, −5.0%; 95% CI, −5.9% to −4.0%;
P
<0.0001).

Conclusions:

HDHP enrollment was associated with a reduction in adherence to medications to treat cardiovascular risk factors. The magnitude of this effect did not vary based on race/ethnicity or socioeconomic status. Because racial/ethnic minorities have lower rates of medication adherence, future studies should evaluate whether HDHP-associated changes in adherence have greater clinical consequences for these patients.