bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Quality of Medical Documentation at a University Teaching Hospital
Authors: Ridyard Edward , Street Elliot
Published: April 2015

A recent joint publication by the Royal College of Physicians and Royal College of Nursing raised concern regarding the variability in the organisation and quality of documentation during ward rounds [1]. The aim of the study was to evaluate the standard of medical documentation at a University Teaching Hospital. Retrospective manual analysis of patient’s paper and electronic paper records (EPR) from the different specialties. Inclusion criteria included in-patient stay of more than two days and admission after 1st July 2013. A VTE assessment was available in 100% of patients. The plan and postoperative instructions were available in 100% of patients. Notes were documented contemporaneously in 75% of cases which increased to 80% in the second following by 89.11% in the third cycle. If a consultant was present on the ward round this was documented in 80% of cases in the first cycle. This subsequently increased to 90% in the second cycle and 100% in the third cycle. Overall the quality of medical documentation was of a reasonable standard but could be improved even further if we continue to document contemporaneously and name every person present at each patient encounter.
Onyx embolization in distal dissecting posterior inferior cerebellar artery aneurysms
Authors: Puri Ajit S , Massari Francesco , Hou Samuel Y , Lozano Juan Diego , Howk Mary , Perras Mary , Brooks Christopher , Gounis Matthew J , Kan Peter , Wakhloo Ajay K
Published: April 2015

Background

Dissecting aneurysms located along the distal segments of the posterior inferior cerebellar artery (PICA) are extremely rare, accounting for only 0.5–0.7% of all intracranial aneurysms. Treatment of these aneurysms is challenging, both surgically and endovascularly. We present our preliminary experience and clinical data utilizing Onyx as an embolization agent in the treatment of these lesions with proximal parent artery preservation.

Methods

7 consecutive ruptured peripheral PICA aneurysms, in 7 patients, were treated with superselective Onyx embolization at our institutions. According to the anatomical classification of Listeret al, these aneurysms were located in the lateral medullary segment (n=1), tonsillomedullary segment (n=1), and the telovelotonsillary segment (n=5) of the PICA. Technical feasibility, procedure related complications, angiographic results, follow-up diagnostic imaging, and clinical outcome were evaluated.

Results

In all cases, endovascular treatment was successful, with complete occlusion of the aneurysm with proximal parent artery preservation at the final postprocedural angiogram. Procedure related complications were not observed. One patient with a poor clinical condition at admission died during the initial hospital stay due to extensive subarachnoid and intraventricular hemorrhage. No rebleeding or recanalization was noted during follow-up. Two patients had a residual moderate to severe disability at follow-up. Favorable outcomes, with no or mild disability, were observed in four of the surviving patients.

Conclusions

Angiographic, diagnostic imaging, and clinical results of our small series indicate that Onyx embolization of dissecting distal PICA aneurysms with parent artery preservation is an effective option with acceptable morbidity and mortality rate, in those cases in which surgical clipping or endovascular coiling of the aneurysmal sac is not suitable.
Trends in 30-day mortality rate and case mix for paediatric cardiac surgery in the UK between 2000 and 2010
Authors: Brown Katherine L , Crowe Sonya , Franklin Rodney , McLean Andrew , Cunningham David , Barron David , Tsang Victor , Pagel Christina , Utley Martin
Published: April 2015

Objectives

To explore changes over time in the 30-day mortality rate for paediatric cardiac surgery and to understand the role of attendant changes in the case mix.

Methods, setting and participants

Included were: all mandatory submissions to the National Institute of Cardiovascular Outcomes Research (NICOR) relating to UK cardiac surgery in patients aged <16 years. The χ2test for trend was used to retrospectively analyse the proportion of surgical episodes ending in 30-day mortality and with various case mix indicators, in 10 consecutive time periods, from 2000 to 2010. Comparisons were made between two 5-year eras of: 30-day mortality, period prevalence and mean age for 30 groups of specific operations.

Main outcome measure

30-day mortality for an episode of surgical management.

Results

Our analysis includes 36 641 surgical episodes with an increase from 2283 episodes in 2000 to 3939 in 2009 (p<0.01). The raw national 30-day mortality rate fell over the period of review from 4.3% (95% CI 3.5% to 5.1%) in 2000 to 2.6% (95% CI 2.2% to 3.0%) in 2009/2010 (p<0.01). The case mix became more complex in terms of the percentage of patients <2.5 kg (p=0.05), with functionally univentricular hearts (p<0.01) and higher risk diagnoses (p<0.01). In the later time era, there was significant improvement in 30-day mortality for arterial switch with ventricular septal defect (VSD) repair, patent ductus arteriosus ligation, Fontan-type operation, tetralogy of Fallot and VSD repair, and the mean age of patients fell for a range of operations performed in infancy.

Conclusions

The raw 30-day mortality rate for paediatric cardiac surgery fell over a decade despite a rise in the national case mix complexity, and compares well with international benchmarks. Definitive repair is now more likely at a younger age for selected infants with congenital heart defects.
Effects of a 12-day maximal shuttle-run shock microcycle in hypoxia on soccer specific performance and oxidative stress
Authors: Gatterer Hannes , Klarod Kultida , Heinrich Dieter , Schlemmer Philipp , Dilitz Stefan , Burtscher Martin
Published: April 2015

The purpose of this study was to investigate the effect of a maximal shuttle-run shock microcycle in hypoxia on repeated sprint ability (RSA, 6 × 40-m (6 × 20 m back and forth, 20″ rest in between)), Yo-Yo-intermittent-recovery (YYIR) test performance, and redox-status. Fourteen soccer players (age: 23.9 ± 2.1 years), randomly assigned to hypoxia (∼3300 m) or normoxia training, performed 8 maximal shuttle-run training sessions within 12 days. YYIR test performance and RSA fatigue-slope improved independently of the hypoxia stimulus (p < 0.05). Training reduced the oxidative stress level (−7.9%, p < 0.05), and the reduction was associated with performance improvements (r = 0.761, ΔRSA; r = −0.575, ΔYYIR, p < 0.05).
Comparative analysis of genetic variation in kava (Piper methysticum) assessed by SSR and DArT reveals zygotic foundation and clonal diversification
Authors: Vandenbroucke Henri , Mournet Pierre , Malapa Roger , Glaszmann Jean-Christophe , Chaïr Hana , Lebot Vincent
Published: April 2015

Kava (Piper methysticum) is a major cash crop in the Pacific. The aim of this study was to assess genetic variation among 103 accessions of kava using SSRs and DArTs. Genetic structure was determined using clustering analyses (WPGMA) and principal coordinate analyses (PCA). Thirteen SSR primers and 75 DArT markers were found polymorphic, and the two types of markers generated similar clustering patterns. Genetic distances ranged from 0 to 0.65 with an average of 0.24 using SSRs and from 0 to 0.64 with an average of 0.24 using DArT. Eleven genotypes were identified with SSR while 28 genotypes were identified with DArT markers. By combining the two sets of markers, a total of only 30 distinct genotypes were observed. In the Vanuatu archipelago, noble cultivars originating from different islands clustered together within a very narrow genetic base despite their diversity of morphotypes. SSR and DArT fingerprints allowed the identification of kava cultivars unsuitable for consumption, so called two-days, and clearly differentiated the wild types classified as P. methysticum var. wichmannii from the cultivars as var. methysticum. Molecular data reveals that all noble cultivars evolved by the predominance of clonal selection. Although they are represented by clearly distinct morphotypes, these cultivars are genetically vulnerable and their potential to adapt to forthcoming changes is limited. These newly developed markers provide high resolution and will be useful for kava diversity analyses and quality assessment.
Real-Time System for Driver Fatigue Detection by RGB-D Camera
Authors: Zhang Liyan , Liu Fan , Tang Jinhui
Published: April 2015

Drowsy driving is one of the major causes of fatal traffic accidents. In this article, we propose a real-time system that utilizes RGB-D cameras to automatically detect driver fatigue and generate alerts to drivers. By introducing RGB-D cameras, the depth data can be obtained, which provides extra evidence to benefit the task of head detection and head pose estimation. In this system, two important visual cues (head pose and eye state) for driver fatigue detection are extracted and leveraged simultaneously. We first present a real-time 3D head pose estimation method by leveraging RGB and depth data. Then we introduce a novel method to predict eye states employing the WLBP feature, which is a powerful local image descriptor that is robust to noise and illumination variations. Finally, we integrate the results from both head pose and eye states to generate the overall conclusion. The combination and collaboration of the two types of visual cues can reduce the uncertainties and resolve the ambiguity that a single cue may induce. The experiments were performed using an inside-car environment during the day and night, and theyfully demonstrate the effectiveness and robustness of our system as well as the proposed methods of predicting head pose and eye states.
Fusing Multiple Features for Depth-Based Action Recognition
Authors: Zhu Yu , Chen Wenbin , Guo Guodong
Published: April 2015

Human action recognition is a very active research topic in computer vision and pattern recognition. Recently, it has shown a great potential for human action recognition using the three-dimensional (3D) depth data captured by the emerging RGB-D sensors. Several features and/or algorithms have been proposed for depth-based action recognition. A question is raised: Can we find some complementary features and combine them to improve the accuracy significantly for depth-based action recognition? To address the question and have a better understanding of the problem, we study the fusion of different features for depth-based action recognition. Although data fusion has shown great success in other areas, it has not been well studied yet on 3D action recognition. Some issues need to be addressed, for example, whether the fusion is helpful or not for depth-based action recognition, and how to do the fusion properly. In this article, we study different fusion schemes comprehensively, using diverse features for action characterization in depth videos. Two different levels of fusion schemes are investigated, that is, feature level and decision level. Various methods are explored at each fusion level. Four different features are considered to characterize the depth action patterns from different aspects. The experiments are conducted on four challenging depth action databases, in order to evaluate and find the best fusion methods generally. Our experimental results show that the four different features investigated in the article can complement each other, and appropriate fusion methods can improve the recognition accuracies significantly over each individual feature. More importantly, our fusion-based action recognition outperforms the state-of-the-art approaches on these challenging databases.
A Combined Approach Toward Consistent Reconstructions of Indoor Spaces Based on 6D RGB-D Odometry and KinectFusion
Authors: Figueroa Nadia , Dong Haiwei , Saddik Abdulmotaleb El
Published: April 2015

We propose a 6D RGB-D odometry approach that finds the relative camera pose between consecutive RGB-D frames by keypoint extraction and feature matching both on the RGB and depth image planes. Furthermore, we feed the estimated pose to the highly accurate KinectFusion algorithm, which uses a fast ICP (Iterative Closest Point) to fine-tune the frame-to-frame relative pose and fuse the depth data into a global implicit surface. We evaluate our method on a publicly available RGB-D SLAM benchmark dataset by Sturm et al. The experimental results show that our proposed reconstruction method solely based on visual odometry and KinectFusion outperforms the state-of-the-art RGB-D SLAM system accuracy. Moreover, our algorithm outputs a ready-to-use polygon mesh (highly suitable for creating 3D virtual worlds) without any postprocessing steps.
Exploring Spatial Correlation for Visual Object Retrieval
Authors: Shi Miaojing , Sun Xinghai , Tao Dacheng , Xu Chao , Baciu George , Liu Hong
Published: April 2015

Bag-of-visual-words (BOVW)-based image representation has received intense attention in recent years and has improved content-based image retrieval (CBIR) significantly. BOVW does not consider the spatial correlation between visual words in natural images and thus biases the generated visual words toward noise when the corresponding visual features are not stable. This article outlines the construction of a visual word co-occurrence matrix by exploring visual word co-occurrence extracted from small affine-invariant regions in a large collection of natural images. Based on this co-occurrence matrix, we first present a novel high-order predictor to accelerate the generation of spatially correlated visual words and a penalty tree (PTree) to continue generating the words after the prediction. Subsequently, we propose two methods of co-occurrence weighting similarity measure for image ranking: Co-Cosine and Co-TFIDF. These two new schemes down-weight the contributions of the words that are less discriminative because of frequent co-occurrences with other words. We conduct experiments on
Oxford
and
Paris Building
datasets, in which the
ImageNet
dataset is used to implement a large-scale evaluation. Cross-dataset evaluations between the
Oxford
and
Paris
datasets and
Oxford
and
Holidays
datasets are also provided. Thorough experimental results suggest that our method outperforms the state of the art without adding much additional cost to the BOVW model.
A Case Study of Data Quality in Text Mining Clinical Progress Notes
Authors: Berndt Donald J. , McCart James A. , Finch Dezon K. , Luther Stephen L.
Published: April 2015

Text analytic methods are often aimed at extracting useful information from the vast array of unstructured, free format text documents that are created by almost all organizational processes. The success of any text mining application rests on the quality of the underlying data being analyzed, including both predictive features and outcome labels. In this case study, some focused experiments regarding data quality are used to assess the robustness of Statistical Text Mining (STM) algorithms when applied to clinical progress notes. In particular, the experiments consider the impacts of task complexity (by removing signals), training set size, and target outcome quality. While this research is conducted using a dataset drawn from the medical domain, the data quality issues explored are of more general interest.
User-Constrained Multimodal Route Planning
Authors: Dibbelt Julian , Pajor Thomas , Wagner Dorothea
Published: April 2015

In the multimodal route planning problem, we are given multiple transportation networks (e.g., pedestrian, road, public transit) and ask for a best
integrated
journey between two points. The main challenge is that a seemingly optimal journey may have changes between networks that do not reflect the user’s modal preferences. In fact, quickly computing reasonable multimodal routes remains a challenging problem: previous approaches either suffer from poor query performance or their available choices of modal preferences during query time is limited. In this work, we focus on computing exact multimodal journeys that can be restricted by specifying
arbitrary
modal sequences at query time. For example, a user can say whether he or she wants to only use public transit, prefers to also use a taxi or walking at the beginning or end of the journey, or has no restrictions at all. By carefully adapting node contraction, a common ingredient to many speedup techniques on road networks, we are able to compute point-to-point queries on a continental network combined of cars, railroads, and flights several orders of magnitude faster than Dijkstra’s algorithm. Thereby, we require little space overhead and obtain fast preprocessing times.
Pairwised Specific Distance Learning from Physical Linkages
Authors: Hu Juhua , Zhan De-Chuan , Wu Xintao , Jiang Yuan , Zhou Zhi-Hua
Published: April 2015

In real tasks, usually a good classification performance can only be obtained when a good distance metric is obtained; therefore, distance metric learning has attracted significant attention in the past few years. Typical studies of distance metric learning evaluate how to construct an appropriate distance metric that is able to separate training data points from different classes or satisfy a set of constraints (e.g., must-links and/or cannot-links). It is noteworthy that this task becomes challenging when there are only limited labeled training data points and no constraints are given explicitly. Moreover, most existing approaches aim to construct a global distance metric that is applicable to all data points. However, different data points may have different properties and may require different distance metrics. We notice that data points in real tasks are often connected by physical links (e.g., people are linked with each other in social networks; personal webpages are often connected to other webpages, including nonpersonal webpages), but the linkage information has not been exploited in distance metric learning. In this article, we develop a pairwised specific distance (PSD) approach that exploits the structures of physical linkages and in particular captures the key observations that nonmetric and clique linkages imply the appearance of different or unique semantics, respectively. It is noteworthy that, rather than generating a global distance, PSD generates different distances for different pairs of data points; this property is desired in applications involving complicated data semantics. We mainly present PSD for multi-class learning and further extend it to multi-label learning. Experimental results validate the effectiveness of PSD, especially in the scenarios in which there are very limited labeled training data points and no explicit constraints are given.
Renegotiation in Service Level Agreement Management for a Cloud-Based System
Authors: Hani Ahmad Fadzil M. , Paputungan Irving Vitra , Hassan Mohd Fadzil
Published: April 2015

Managing Service Level Agreement (SLA) within a cloud-based system is important to maintain service continuity and improve trust due to cloud flexibility and scalability. We conduct a general review on cloud-based systems to understand how service continuity and trust are addressed in cloud SLA management. The review shows that SLA renegotiation is necessary to improve trust and maintain service continuity; however, research on SLA renegotiation is limited. Of the two key approaches in renegotiation, namely bargaining-based negotiation and offer generation--based negotiation, the latter approach is the most promising due to its ability to generate optimized multiple-offer SLA parameters within one round during renegotiation.
Cloud Computing
Authors: Chhabra Shruti , Dixit V. S.
Published: April 2015

Cloud Computing is the fastest growing technology in the IT industry. It helps in providing services and resources with the help of internet. Resources are always provided by the Cloud Service Provider. Resources may be servers, storage, applications and networks. Keeping Resources in the cloud environment can be helpful in saving infrastructure cost and time for the user. Transferring the entire information of the enterprise onto the cloud contains lots of security issues and threats. This paper focuses on the various concepts related to cloud computing, its various business and service models and its entities along with several issues and challenges related to it.
An Empirical Evaluation of Iterative Maintenance Life Cycle Using XP
Authors: Choudhari Jitender , Suman Ugrasen
Published: April 2015

Maintainability of a software product affects its maintenance cost and operational life. Maintainability of legacy systems, which have been developed through non-XP methodologies, has become a challenging issue for its maintenance. The iterative maintenance life cycle using extreme programming is an effective process for software maintenance [2]. This paper describes a controlled experiment that examines maintainability during maintenance of academic projects. The experiment was conducted with postgraduate students in a project course. The maintenance of each application was allocated to a couple of project teams; one team has used XP-based approach and yet another team has employed a traditional waterfall-based approach of maintenance. On measuring internal quality metrics of projects, it is observed that XP-based approach produces more maintainable code than traditional approach. The productivity of XP-based team is observed higher and at the same time, XP-based maintenance team was more confident about the code, and also reported higher confidence in future changes to their product. The iterative maintenance life cycle using XP has improved the maintainability of a software.
Fortran 2008 coarrays
Authors: Shterenlikht Anton , Margetts Lee , Cebamanos Luis , Henty David
Published: April 2015

Coarrays are a Fortran 2008 standard feature intended for SIMD type parallel programming. The runtime environment starts a number of identical executable images of the coarray program, on multiple processors, which could be actual physical processors or threads. Each image has a unique number and its private address space. Ordinary variables are private to an image. Coarray variables are available for read/write access from any other image. Coarray communications are of "single sided" type, i.e. a remote call from imageA to image B does not need to be accompanied by a corresponding call in image B. This feature makes coarray programming a lot simpler than MPI. The standard provides synchronisation intrinsics to help avoid race conditions or deadlocks. Any ordinary variable can be made into a coarray - scalars, arrays, intrinsic or derived data types, pointers, allocatables are all allowed. Coarrays can be declared in, and passed to, procedures. Coarrays are thus very flexible and can be used for a number of purposes. For example a collection of coarrays from all or some images can be thought of as a large single array. This is precisely the inverse of the model partitioning logic, typical in MPI programs. A coarray program can exploit functional parallelism too, by delegating dis- tinct tasks to separate images or teams of images. Coarray collectives are expected to become a part of the next version of the Fortran standard. A major unresolved problem of coarray programming is the lack of standard parallel I/O facility in Fortran. In this paper several simple complete coarray programs are shown and compared to alternative parallel technologies - OpenMP, MPI and Fortran 2008 intrinsic "do concurrent". Inter image communication patterns and data transfer are illustrated. An example of a materials microstructure simulation coarray program scaled up to 32k cores is shown. Problems with coarray I/O at this scale are highlighted and addressed with the use of MPI-I/O. A hybrid MPI/coarray programming is discussed and illustrated with a finite element/cellular automata (CAFÉ) multi-scale model. The paper completes with a description of the new coarray language features, expected in the 2015 Fortran standard, and with a brief list of coarray resources
Magma Fragmentation
Authors: Gonnermann Helge M.
Published: April 2015

Magma fragmentation is the breakup of a continuous volume of molten rock into discrete pieces, called pyroclasts. Because magma contains bubbles of compressible magmatic volatiles, decompression of low-viscosity magma leads to rapid expansion. The magma is torn into fragments, as it is stretched into hydrodynamically unstable sheets and filaments. If the magma is highly viscous, resistance to bubble growth will instead lead to excess gas pressure and the magma will deform viscoelastically by fracturing like a glassy solid, resulting in the formation of a violently expanding gas-pyroclast mixture. In either case, fragmentation represents the conversion of potential energy into the surface energy of the newly created fragments and the kinetic energy of the expanding gas-pyroclast mixture. If magma comes into contact with external water, the conversion of thermal energy will vaporize water and quench magma at the melt-water interface, thus creating dynamic stresses that cause fragmentation and the release of kinetic energy. Lastly, shear deformation of highly viscous magma may cause brittle fractures and release seismic energy.
Media and Politics
Authors: Strömberg David
Published: April 2015

This article provides a review of recent literature in economics on the effect of mass media on politics. The focus is on the welfare effects of mass media. I also discuss the likely implications of existing behavioral theories of media effects, developed outside of economics.
Tunable Exfoliation of Synthetic Clays
Authors: Stöter Matthias , Rosenfeldt Sabine , Breu Josef
Published: April 2015

The large hydration enthalpy of inorganic interlayer cations sandwiched between moderately negatively charged silicate layers endows to smectites (e.g., hectorite) remarkably rich intracrystalline reactivity compared with most other layered materials. Moreover, they are transparent and inert in most potential suspension media. Upon suspension in water, smectites readily swell. For homogeneous, melt-synthesized smectites, the degree of swelling can be tuned by choice of interlayer cation and charge density of the layer. Because swelling renders the clay stacks more shear labile, the efficiency of exfoliation by applying shearing forces can in turn be adjusted. Certain smectites even spontaneously delaminate into clay platelets of uniform thickness of 1 nm by progressive osmotic swelling. Osmotic swelling can also be applied to produce well-defined double stacks when one starts with ordered, interstratified heterostructures. Nanocomposites made with high-aspect-ratio fillers obtained this way show superior mechanical, flame retardancy, and permeability properties.
High dietary sodium reduces brachial artery flow-mediated dilation in humans with salt-sensitive and salt-resistant blood pressure
Authors: Matthews Evan L. , Brian Michael S. , Ramick Meghan G. , Lennon-Edwards Shannon , Edwards David G. , Farquhar William B.
Published: April 2015

Recent studies demonstrate that high dietary sodium (HS) impairs endothelial function in those with salt-resistant (SR) blood pressure (BP). The effect of HS on endothelial function in those with salt-sensitive (SS) BP is not currently known. We hypothesized that HS would impair brachial artery flow-mediated dilation (FMD) to a greater extent in SS compared with SR adults. Ten SR (age 42 ± 5 yr, 5 men, 5 women) and 10 SS (age 39 ± 5 yr, 5 men, 5 women) healthy, normotensive participants were enrolled in a controlled feeding study consisting of a run-in diet followed by a 7-day low dietary sodium (LS) (20 mmol/day) and a 7-day HS (300 mmol/day) diet in random order. Brachial artery FMD and 24-h BP were assessed on the last day of each diet. SS BP was individually assessed and defined as a change in 24-h mean arterial pressure (MAP) of >5 mmHg between the LS and HS diets (ΔMAP: SR −0.6 ± 1.2, SS 7.7 ± 0.4 mmHg). Brachial artery FMD was lower in both SS and SR individuals during the HS diet ( P < 0.001), and did not differ between groups ( P > 0.05) (FMD: SR LS 10.6 ± 1.3%, SR HS 7.2 ± 1.5%, SS LS 12.5 ± 1.7%, SS HS 7.8 ± 1.4%). These data indicate that an HS diet impairs brachial artery FMD to a similar extent in adults with SS BP and SR BP.
Right ventricular dysfunction in children and adolescents conceived by assisted reproductive technologies
Authors: von Arx Robert , Allemann Yves , Sartori Claudio , Rexhaj Emrush , Cerny David , de Marchi Stefano F. , Soria Rodrigo , Germond Marc , Scherrer Urs , Rimoldi Stefano F.
Published: April 2015

Assisted reproductive technologies (ART) predispose the offspring to vascular dysfunction, arterial hypertension, and hypoxic pulmonary hypertension. Recently, cardiac remodeling and dysfunction during fetal and early postnatal life have been reported in offspring of ART, but it is not known whether these cardiac alterations persist later in life and whether confounding factors contribute to this problem. We, therefore, assessed cardiac function and pulmonary artery pressure by echocardiography in 54 healthy children conceived by ART (mean age 11.5 ± 2.4 yr) and 54 age-matched (12.2 ± 2.3 yr) and sex-matched control children. Because ART is often associated with low birth weight and prematurity, two potential confounders associated with cardiac dysfunction, only singletons born with normal birth weight at term were studied. Moreover, because cardiac remodeling in infants conceived by ART was observed in utero, a situation associated with increased right heart load, we also assessed cardiac function during high-altitude exposure, a condition associated with hypoxic pulmonary hypertension-induced right ventricular overload. We found that, while at low altitude cardiac morphometry and function was not different between children conceived by ART and control children, under the stressful conditions of high-altitude-induced pressure overload and hypoxia, larger right ventricular end-diastolic area and diastolic dysfunction (evidenced by lower E-wave tissue Doppler velocity and A-wave tissue Doppler velocity of the lateral tricuspid annulus) were detectable in children and adolescents conceived by ART. In conclusion, right ventricular dysfunction persists in children and adolescents conceived by ART. These cardiac alterations appear to be related to ART per se rather than to low birth weight or prematurity.
Molecular Pathways: Leveraging the BCL-2 Interactome to Kill Cancer Cells—Mitochondrial Outer Membrane Permeabilization and Beyond
Authors: Brahmbhatt Hetal , Oppermann Sina , Osterlund Elizabeth J. , Leber Brian , Andrews David W.
Published: April 2015

The inhibition of apoptosis enables the survival and proliferation of tumors and contributes to resistance to conventional chemotherapy agents and is therefore a very promising avenue for the development of new agents that will enhance current cancer therapies. The BCL-2 family proteins orchestrate apoptosis at the mitochondria and endoplasmic reticulum and are involved in other processes such as autophagy and unfolded protein response (UPR) that lead to different types of cell death. Over the past decade, significant efforts have been made to restore apoptosis using small molecules that modulate the activity of BCL-2 family proteins. The small molecule ABT-199, which antagonizes the activity of BCL-2, is currently the furthest in clinical trials and shows promising activity in many lymphoid malignancies as a single agent and in combination with conventional chemotherapy agents. Here, we discuss strategies to improve the specificity of pharmacologically modulating various antiapoptotic BCL-2 family proteins, review additional BCL-2 family protein interactions that can be exploited for the improvement of conventional anticancer therapies, and highlight important points of consideration for assessing the activity of small-molecule BCL-2 family protein modulators. Clin Cancer Res; 21(12); 2671–6. ©2015 AACR.
Intratumoral Heterogeneity: From Diversity Comes Resistance
Authors: Pribluda Ariel , de la Cruz Cecile C. , Jackson Erica L.
Published: April 2015

Tumors consist of a heterogeneous mixture of functionally distinct cancer cells. These functional differences can be caused by varying levels of receptor activity, differentiation, and distinct metabolic and epigenetic states. Intratumoral heterogeneity can lead to interdependence among different subpopulations of cells for sustained tumor growth. In addition, subpopulations can vary widely in their responses to therapeutic agents. As such, it is believed that intratumoral heterogeneity may underlie incomplete treatment responses, acquired and innate resistance, and disease relapse observed in the clinic in response to conventional chemotherapy and targeted agents. Clin Cancer Res; 21(13); 2916–23. ©2015 AACR.
Eribulin Mesylate: Mechanism of Action of a Unique Microtubule-Targeting Agent
Authors: Dybdal-Hargreaves Nicholas F. , Risinger April L. , Mooberry Susan L.
Published: April 2015

Eribulin mesylate (eribulin), an analogue of the marine natural product halichondrin B, is a microtubule-depolymerizing drug that has utility in the treatment of patients with breast cancer. Clinical trial results have demonstrated that eribulin treatment provides a survival advantage to patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane. Furthermore, a pooled analysis of two pivotal phase III trials has demonstrated that eribulin also improves overall survival in several patient subgroups, including in women with HER2-negative disease and triple-negative breast cancer. This review covers the preclinical research that led to the clinical testing and approval of eribulin, as well as subsequent research that was prompted by distinct and unexpected effects of eribulin in the clinic. Initial studies with halichondrin B demonstrated unique effects on tubulin binding that resulted in distinct microtubule-dependent events and antitumor actions. Consistent with the actions of the natural product, eribulin has potent microtubule-depolymerizing activities and properties that distinguish it from other microtubule-targeting agents. Here, we review new results that further differentiate the effects of eribulin from other agents on peripheral nerves, angiogenesis, vascular remodeling, and epithelial-to-mesenchymal transition. Together, these data highlight the distinct properties of eribulin and begin to delineate the mechanisms behind the increased survival benefit provided by eribulin for patients. Clin Cancer Res; 21(11); 2445–52. ©2015 AACR.
Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas
Authors: Lee Misu , Wiedemann Tobias , Gross Claudia , Leinhäuser Ines , Roncaroli Federico , Braren Rickmer , Pellegata Natalia S.
Published: April 2015

Purpose: Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPA), given their high relapse rate. Here, we evaluated the antitumor efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats).

Experimental Design: Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, and PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored noninvasively by diffusion weighted-magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, and PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene-expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells.

Results: NVP-BEZ235 showed antiproliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP-BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition.

Conclusions: Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival. Clin Cancer Res; 21(14); 3204–15. ©2015 AACR.
Advanced Gastric Cancer with Liver and Lymph Node Metastases Successfully Resected after Induction Chemotherapy with Docetaxel, Cisplatin and 5-Fluorouracil
Authors: Cavanna Luigi , Bodini Flavio Cesare , Stroppa Elisa Maria , Banchini Filippo , Michieletti Emanuele , Capelli Patrizio , Zangrandi Adriano , Anselmi Elisa
Published: April 2015

Background: At diagnosis, about 35% of patients with gastric cancer present with distant metastases, and most patients with gastric cancer and liver metastases are excluded from curative surgery. Case: We report a case of human epidermal growth factor receptor-2 (HER2)-negative gastric cancer with metastases to the liver and perigastric lymph nodes. The patient (a 60-year-old man) was considered unresectable at diagnosis and was treated with palliative chemotherapy (docetaxel plus cisplatin and 5-fluorouracil by continuous intravenous infusion over 5 days every 3 weeks). However, after 6 courses of chemotherapy, a computed tomography scan showed a reduction of the liver metastasis and the disappearance of the enlarged perigastric lymph nodes. The patient then underwent a curative gastrectomy, lymphadenectomy and liver resection. After surgery, the patient was treated with 6 courses of FOLFOX-4 regimen as adjuvant chemotherapy. With a follow-up of 26 months after surgery, the patient is alive and disease free. Conclusion: In patients with metastatic gastric cancer, the prognosis is poor with a median overall survival of 11 months since curative treatments are excluded; however, this case illustrated that a personalized treatment with chemotherapy and surgery can allow a curative strategy in selected patients with HER2-negative advanced gastric cancer.
Extramedullary Hematopoiesis: Cytomorphologic, Histologic, and Radiologic Findings in Sixteen Cases
Authors: Sheikh Umer , Rodic Nemanja , Maleki Zahra
Published: April 2015

Background: We report a case series of extramedullary hematopoiesis (EMH) diagnosed from the fine needle aspiration (FNA) procedure. Unanticipated EMH is a markedly rare diagnosis that typically presents as a solitary mass of undetermined significance. As such, knowledge of cytopathologic characteristics as well as clinical and radiologic correlates of EMH is paramount. Method and Material: A total of 16 EMH cytopathologic cases were seen at the Johns Hopkins Hospital in the past 22 years. Results: Median age at diagnosis was 61 years and there was no gender bias (male-to-female ratio: 1:1). Presenting signs and symptoms varied widely, from incidental radiographic findings to hemiparesis. Likewise, presumptive clinical diagnoses in 11 of the 16 cases were benign and the other 5 were considered malignant prior to the diagnostic FNA. The most common anatomic site for EMH was the liver, followed by the presacral soft tissue and pleura. While most EMH nodules were singular, a few presented with as many as three radiographically distinct nodules. The average EMH nodule measured 2.8 cm; the EMH liver nodules were larger and measured 4.3 cm on average (p = 0.0043). Conclusion: We share here the salient clinical and radiologic findings and the diagnostic cytopathologic features of EMH in an effort to familiarize the pathologist/cytotechnologist community with this fascinating albeit rare entity.
Hyaluronic Acid Filler in HIV-Associated Facial Lipoatrophy: Evaluation of Tissue Distribution and Morphology with MRI
Authors: Becker Minerva , Balagué Nicolas , Montet Xavier , Calmy Alexandra , Salomon Denis , Toutous-Trellu Laurence ,   LIPO and Metabolism Group
Published: April 2015

Objective: This prospective observational study evaluated magnetic resonance imaging (MRI) findings of hyaluronic acid (HA) injections used for the correction of HIV-associated facial lipoatrophy. Methods: Ten consecutive males underwent subdermal HA injection (mean 1.3 ± 0.6 ml per side) and MRI examinations prior to and then 1, 6 and 12 months after injection. Two radiologists blinded to the clinical data assessed morphologic and quantitative changes. Results: MRI revealed HA deposition in the subdermal and deep fat compartments. A significant HA volume increase was observed 1 month after injection (mean increase 331%, p < 0.0001) as compared to the injected amount. No volume reduction occurred at 12 months (p = 0.9961). The measured bound water content did not change (p > 0.9991), whereas skin thickness and tissue vascularization increased during the first 6 months (p = 0.01). Conclusion: Our data show that the cosmetic results of HA injections are caused by water binding in the deep facial fat and by a transient increase in vascularization and skin thickness.
Noninvasive Molecular Ultrasound Monitoring of Vessel Healing After Intravascular Surgical Procedures in a Preclinical Setup
Authors: Curaj Adelina , Wu Zhuojun , Fokong Stanley , Liehn Elisa A. , Weber Christian , Burlacu Alexandrina , Lammers Twan , van Zandvoort Marc , Kiessling Fabian
Published: April 2015

Objective—

Cardiovascular interventions induce damage to the vessel wall making antithrombotic therapy inevitable until complete endothelial recovery. Without a method to accurately determine the endothelial status, many patients undergo prolonged anticoagulation therapy, denying them any invasive medical procedures, such as surgical operations and dental interventions. Therefore, we aim to introduce molecular ultrasound imaging of the vascular cell adhesion molecule (VCAM)-1 using targeted poly-
n
-butylcyanoacrylate microbubbles (MB
VCAM-1
) as an easy accessible method to monitor accurately the reendothelialization of vessels.

Approach and Results—

ApoE
−/−
mice were fed with an atherogenic diet for 1 and 12 weeks and subsequently, endothelial denudation was performed in the carotid arteries using a guidewire. Molecular ultrasound imaging was performed at different time points after denudation (1, 3, 7, and 14 days). An increased MB
VCAM-1
binding after 1 day, a peak after 3 days, and a decrease after 7 days was found. After 12 weeks of diet, MB
VCAM-1
binding also peaked after 3 days but remained high until 7 days, indicating a delay in endothelial recovery. Two-photon laser scanning microscopy imaging of double fluorescence staining confirmed the exposure of VCAM-1 on the superficial layer after arterial injury only during the healing phase. After complete reendothelialization, VCAM-1 expression persisted in the subendothelial layer but was not reachable for the MB
VCAM-1
anymore.

Conclusion—

Molecular ultrasound imaging with MB
VCAM-1
is promising to assess vascular damage and to monitor endothelial recovery after arterial interventions. Thus, it may become an important diagnostic tool supporting the development of adequate therapeutic strategies to personalize anticoagulant and anti-inflammatory therapy after cardiovascular intervention.
Cellular Cholesterol Accumulation Facilitates Ubiquitination and Lysosomal Degradation of Cell Surface–Resident ABCA1
Authors: Mizuno Tadahaya , Hayashi Hisamitsu , Kusuhara Hiroyuki
Published: April 2015

Objective—

By excreting cellular cholesterol to apolipoprotein A-I, ATP-binding cassette transporter A1 (ABCA1) mediates the biogenesis of high-density lipoprotein in hepatocytes and prevents foam cell formation from macrophages. We recently showed that cell surface–resident ABCA1 (csABCA1) undergoes ubiquitination and later lysosomal degradation through the endosomal sorting complex required for transport system. Herein, we investigated the relevance of this degradation pathway to the turnover of csABCA1 in hypercholesterolemia.

Approach and Results—

Immunoprecipitation and cell surface-biotinylation studies with HepG2 cells and mouse peritoneal macrophages showed that the ubiquitination level and degradation of csABCA1 were facilitated by treatment with a liver X receptor (LXR) agonist and acetylated low-density lipoprotein. The effects of an LXR agonist and acetylated low-density lipoprotein on the degradation of csABCA1 were repressed completely by treatment with bafilomycin, an inhibitor of lysosomal degradation, and by depletion of tumor susceptibility gene 101, a major component of endosomal sorting complex required for transport-I. RNAi analysis indicated that LXRβ inhibited the accelerated lysosomal degradation of csABCA1 by the LXR agonist, regardless of its transcriptional activity. Cell surface coimmunoprecipitation with COS1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that LXRβ interacted with csABCA1 and inhibited the ubiquitination of csABCA1. Immunoprecipitates with anti-ABCA1 antibodies from the liver plasma membranes showed less LXRβ and a higher ubiquitination level of ABCA1 in high-fat diet–fed mice than in normal chow-fed mice.

Conclusions—

Under conditions of high cellular cholesterol content, csABCA1 became susceptible to ubiquitination by dissociation of LXRβ from csABCA1, which facilitated the lysosomal degradation of csABCA1 through the endosomal sorting complex required for transport system.
Depressive Symptoms in Younger Women and Men With Acute Myocardial Infarction: Insights From the VIRGO Study
Authors: Smolderen Kim G. , Strait Kelly M. , Dreyer Rachel P. , D'Onofrio Gail , Zhou Shengfan , Lichtman Judith H. , Geda Mary , Bueno Héctor , Beltrame John , Safdar Basmah , Krumholz Harlan M. , Spertus John A.
Published: April 2015

Background

Depression was recently recognized as a risk factor for adverse medical outcomes in patients with acute myocardial infarction (
AMI
). The degree to which depression is present among younger patients with an AMI, the patient profile associated with being a young
AMI
patient with depressive symptoms, and whether relevant sex differences exist are currently unknown.

Methods and Results

The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study enrolled 3572 patients with
AMI
(67.1% women; 2:1 ratio for women to men) between 2008 and 2012 (at 103 hospitals in the United States, 24 in Spain, and 3 in Australia). Information about lifetime history of depression and depressive symptoms experienced over the past 2 weeks (Patient Health Questionnaire; a cutoff score ≥10 was used for depression screening) was collected during index
AMI
admission. Information on demographics, socioeconomic status, cardiovascular risk,
AMI
severity, perceived stress (14‐item Perceived Stress Scale), and health status (Seattle Angina Questionnaire, EuroQoL 5D) was obtained through interviews and chart abstraction. Nearly half (48%) of the women reported a lifetime history of depression versus 1 in 4 in men (24%;
P
<0.0001). At the time of admission for AMI, more women than men experienced depressive symptoms (39% versus 22%,
P
<0.0001; adjusted odds ratio 1.64; 95%
CI
1.36 to 1.98). Patients with more depressive symptoms had higher levels of stress and worse quality of life (
P
<0.001). Depressive symptoms were more prevalent among patients with lower socioeconomic profiles (eg, lower education, uninsured) and with more cardiovascular risk factors (eg, diabetes, smoking).

Conclusions

A high rate of lifetime history of depression and depressive symptoms at the time of an
AMI
was observed among younger women compared with men. Depressive symptoms affected those with more vulnerable socioeconomic and clinical profiles.