bluuebunny/crossref_metadata_2025 huggingface dataset:
Protocol for a within-trial economic evaluation of a psychoeducational intervention tailored to people at high risk of developing a second or subsequent melanoma
Authors: Dieng M , Cust A E , Kasparian N A , Butow P , Costa D S J , Menzies S W , Mann G J , Morton R L
Published: October 2016

Introduction

Psychological support programmes are not currently funded for people with a history of melanoma. A major barrier to the implementation of effective psychological interventions in routine clinical care is a lack of cost-effectiveness data. This paper describes the planned economic evaluation alongside a randomised controlled trial of a psychoeducational intervention for people with a history of melanoma who are at high risk of developing new primary disease.

Method and analysis

The economic evaluation is a within-trial analysis to evaluate the incremental costs and health outcomes of a psychoeducational intervention compared to usual care from the perspective of the Australian healthcare system. Cost-effectiveness and cost-utility analyses will be conducted, providing estimates of the cost to reduce fear of melanoma recurrence and the cost per quality-adjusted life-year (QALY) gained. Fear of melanoma recurrence will be measured using the Fear of Cancer Recurrence Inventory and preference-based quality of life measured using the Assessment of Quality of Life—8 Dimensions (AQoL-8D) instrument. The AQoL-8D will provide utilities for estimation of QALYs in the cost-utility analysis. Unit costs of health services and medicines will be taken from the Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme national databases. Health outcomes, and health service and medication use will be collected at baseline, 6 and 12 months follow-up. The within-trial analysis will be conducted at 12 months, consistent with the end point of the trial.

Ethics and dissemination

Approval to conduct the study was granted by the Sydney Local Health District (RPAH zone) Ethics Review Committee (X13-0065 and HREC/13/RPAH/86), the Department of Health and Ageing Human Research Ethics Committee (21/2013), the University of Sydney Human Research Ethics Committee (2013/595), and the Australian Institute of Health and Welfare Ethics Committee (EO 2013/4/58).

Trial registration number

ACTRN12613000304730; Pre-results.
Discordance between patients' stated values and treatment preferences for end-of-life care: results of a multicentre survey
Authors: Heyland Daren K , Heyland Rebecca , Dodek Peter , You John J , Sinuff Tasnim , Hiebert Tim , Jiang Xuran , Day Andrew G
Published: October 2016

Background

Medical orders for the use of life-supports should be informed by patients' values and treatment preferences. The purpose of this study was to explore the internal consistency of patients' (or their family members') stated values, and the relationship between these values and expressed preferences.

Methods

We conducted a prospective study in 12 acute care hospitals in Canada. We administered a questionnaire to elderly patients and their family members about their values related to end-of-life (EOL) care, treatment preferences and decisional conflict.

Results

Of 513 patients and 366 family members approached, 278 patients (54%) and 225 family members (61%) consented to participate. Participants' most important stated values were to be comfortable and suffer as little as possible, to have more time with family, to avoid being attached to machines and tubes and that death not be prolonged. The least important stated value was that life be preserved. Based on prespecified expected associations between the various values measured, there were inconsistencies in participants' expressed value statements. With few exceptions, participants' expressed values were not associated with expected corresponding treatment preferences. Of the 109 (40%) patients and 95 (42%) family members who had made decisions about use of life-supports, 68 (56%) patients and 60 (59%) family members had decisional conflict.

Conclusions

Decision-making regarding medical treatments at the EOL is inadequate. To reduce decisional conflict, patients and their families need more support to clarify their values and ensure that their preferences are grounded in adequate understanding of their illness and treatment options.

Trial registration number

NCT01362855.
Circumscription of species of Hodophilus (Clavariaceae, Agaricales) in North America with naphthalene odours
Authors: Adamčík Slavomír , Looney Brian P. , Birkebak Joshua M. , Jančovičová Soňa , Adamčíková Katarína , Marhold Karol , Matheny P. Brandon
Published: October 2016

Five North American Hodophilus species with naphthalene-like odours are now recognized based on sequence and (or) morphological data and molecular annotation of type collections. Two well-supported eastern North American species do not match any of the studied types and are described here as new: Hodophilus hesleri and Hodophilus smithii. The previously described Hodophilus paupertinus is found to represent an autonomous species and appears restricted to western North America. Hodophilus subfuscescens is found to be an independent lineage in eastern North America. A morphological type study of Hodophilus peckianus shows that it is a distinct species and not represented among recent collections. Multilocus phylogenetic analyses of European and North American material of species with naphthalene odours reveal no species with transatlantic distributions. Overall, Hodophilus comprises two superclades (the Hodophilus foetens superclade and the Hodophilus micaceus superclade) and 16 terminal clades that correspond to phylogenetic species. This study introduces a new approach for morphological delimitation of agaricoid Clavariaceae combining shape and dimensions of particular elements in the pileipellis and caulocystidia. All previously described taxa included in this study, which were previously treated in the genera Hygrophorus, Camarophyllopsis, or Hygrotrama, are formally transferred to Hodophilus.
Weak solution of parabolic complex Monge–Ampère equation II
Authors: Son Do Hoang
Published: October 2016

We study the equation [Formula: see text] in [Formula: see text], where [Formula: see text] and [Formula: see text] is a bounded strictly pseudoconvex domain in [Formula: see text], with the boundary condition [Formula: see text] and the initial condition [Formula: see text]. In this paper, we consider the case, where [Formula: see text] is smooth and [Formula: see text] is an arbitrary plurisubharmonic function in a neighborhood of [Formula: see text] satisfying [Formula: see text].
ASEAN’s TRADE AND FOREIGN DIRECT INVESTMENT: LONG-TERM CHALLENGES FOR ECONOMIC INTEGRATION
Authors: KAWAI MASAHIRO , NAKNOI KANDA
Published: October 2016

This paper explores the long-term challenges for economic integration of the Association of Southeast Asian Nations (ASEAN) through trade and foreign direct investment (FDI). The region has emerged as an important production base for global multinational corporations by joining East Asia’s supply chains. While proceeding to establish the ASEAN Economic Community (AEC) by the end of 2015, ASEAN has also forged five major free trade agreements (FTAs) with its dialogue partners (China, India, Japan, Republic of Korea, and Australia–New Zealand) and is currently negotiating the Regional Comprehensive Economic Partnership. In addition, four ASEAN member states have completed Trans-Pacific Partnership negotiations. Econometric evidence suggests that (i) trade flows and inward FDI mutually reinforce each other, i.e., an increase in trade flows stimulates inward FDI and vice versa; (ii) a larger market tends to attract more inward FDI; (iii) FTAs tend to help stimulate inward FDI; and (iv) strong institutions, good physical infrastructure, and low costs of doing business are critical in boosting inward FDI. The paper suggests that in the long run it is ASEAN’s interest to further integrate itself with the rest of Asia and the world (through a Free Trade Area of the Asia-Pacific and an Asia–Europe FTA), while substantially deepening its internal integration (by moving from the AEC to a customs and economic union) and thereby maintaining ASEAN centrality.
A Self-Starting 70 mV-1 V, 65% Peak Efficient, TEG Energy Harvesting Chip with 5 ms Startup Time
Authors: Sinha Arun Kumar
Published: October 2016

This paper presents design and measurement results of a DC–DC converter, intended to harvest energy from a thermo-electric generator (TEG). The prototype chip was fabricated in 130[Formula: see text]nm CMOS technology. The designed converter can extract maximum power from a TEG, without using an input capacitor ([Formula: see text] or a closed loop maximum peak power tracking circuit to regulate the input voltage ([Formula: see text]. The converter uses a low voltage oscillator coupled with charge pump to directly power the auxiliary circuits; and auxiliary circuits drives two inductors in two half cycles of a clock pulse. The measurement has been performed by using a TEG, and a voltage source (50–200[Formula: see text]mV) with a series resistance of 5[Formula: see text]ohms. The result shows that the prototype can self-starts from 70[Formula: see text]mV with 5[Formula: see text]ms startup time and can work up to a minimum of 50[Formula: see text]mV; and can extract, 57.2% (at 50[Formula: see text]mV) to 65% (at 200[Formula: see text]mV), of the available power.
The Proper Location and Sizing of Multiple Distributed Generators for Maximizing Voltage Stability Using PSO
Authors: Muthulakshmi K. , Sasiraja R. M. , Suresh Kumar V.
Published: October 2016

Energy technologies and their efficient use plays a vital role in socio-economic development of any country. In the recent years, the restructuring of electricity market evolves some major improvements in the technologies of energy production and thus, it has paved the way for increasing the applications of Distributed Generation (DG) with renewable energy sources. In this research, the optimal placement and sizing of multiple DGs are achieved by a novel indicator United Bus and Line Voltage Firmness Factor (UBL_VFF). The objectives of this work are the minimization of system losses and maximization of voltage stability and they are achieved by identifying the weakest voltage bus due to the weakest link in the system. Particle Swarm Optimization (PSO) is used for solving this optimization problem. The effectiveness of this proposed approach is tested in 33 and 69 bus radial distribution test systems. The results of this proposed method is compared with the results reported in the contemporary literature. The results have proved to be robust in terms of reduction in system losses and maximization of bus and line voltage stability.
The power of weak-field GR gravity
Authors: Cooperstock F. I.
Published: October 2016

While general relativity (GR) is our premier theory of gravity, galactic dynamics from the outset has been studied with Newtonian gravity (NG), guided by the long-held belief in the idea of the “Newtonian-limit” of GR. This maintains that when the gravitational field is weak and the velocities are nonrelativistic, NG is the appropriate theory, apart from small corrections at best (such as in GPS tracking). However, there are simple examples of phenomena where there is no NG counterpart. We present a particularly simple new example of the stark difference that NG and weak-field GR exhibit for a modified van Stockum source, which speaks to the flat galactic rotation curve problem. We note that the linear GR compatibility equation in the literature is incomplete. Its completion is vital for our case, leading to a stark contrast between GR and NG for totally flat van Stockum rotation curves.
A conservative assessment of the current constraints on dark matter annihilation from cosmic rays and CMB observations
Authors: Masi Nicolò , Ballardini Mario
Published: October 2016

In view of the current interest in combining different observations to constraint annihilating weakly interacting massive particle (WIMP) dark matter (DM), we examine the relation between the Sommerfeld effect at the recombination epoch and in the galactic halo. By considering an up-to-date collection of interpolations of cosmic rays (CRs) lepton data (AMS-02 2014, Fermi and PAMELA), as DM annihilation signals, we show that current CRs measurements and recent Planck 2015 constraints from CMB anisotropies almost overlap for DM masses of the order of few TeV, although great theoretical uncertainties afflict CRs and DM descriptions. Combining CRs fits we obtain proper minimal regions allowed by CMB observations, especially for [Formula: see text] and [Formula: see text] annihilation channels, once assumed viable values of the efficiency factor for energy absorption at recombination: the results are consistent with those obtained by the Planck collaboration but allow a slightly larger overlap between CRs constraints from the lepton sector and CMB. Incoming AMS-02 measurements of CRs antiprotons will help to clarify the conundrum.
Zeros, factorizations and least common multiples of quaternion polynomials
Authors: Bolotnikov Vladimir
Published: October 2016

It is known that quaternion polynomials may have spherical zeros and isolated left and right zeros. These zeros along with appropriately defined multiplicities form the zero structure of a polynomial which can be alternatively described in terms of left and right spherical divisors of a polynomial as well as in terms of its left and right indecomposable divisors. These alternative descriptions are used to construct a polynomial with prescribed zero structure and more generally, to construct the least common multiple of given polynomials. Similar questions are discussed in the context of quaternion power series and particularly, finite Blaschke products.
McCoy property and nilpotent elements of skew generalized power series rings
Authors: Paykan Kamal , Moussavi Ahmad
Published: October 2016

Let [Formula: see text] be a ring, [Formula: see text] a strictly ordered monoid and [Formula: see text] a monoid homomorphism. The skew generalized power series ring [Formula: see text] is a common generalization of (skew) polynomial rings, (skew) power series rings, (skew) Laurent polynomial rings, (skew) group rings, and Mal’cev–Neumann Laurent series rings. In this paper, we consider the problem of determining when [Formula: see text] is nilpotent in [Formula: see text]. We study various annihilator properties and a variety of conditions and related properties that the skew generalized power series [Formula: see text] inherits from [Formula: see text]. We also introduce and study the [Formula: see text]-McCoy condition on [Formula: see text], a generalization of the standard McCoy condition from polynomials to skew generalized power series. We resolve the structure of [Formula: see text]-McCoy rings and obtain various necessary or sufficient conditions for a ring to be [Formula: see text]-McCoy. As particular cases of our general results we obtain several new theorems on the McCoy condition. Moreover various examples of [Formula: see text]-McCoy rings are provided.
INVERSION RECOVERY GRADIENT ECHO PULSE SEQUENCE PROGRAM ON A 0.7 TESLA OPEN SUPERCONDUCTING MAGNETIC RESONANCE IMAGING PLATFORM
Authors: LI SHUO , ZHU YANCHUN , YANG JIE , XIE YAOQIN , GAO SONG
Published: October 2016

The newly developed open superconducting magnetic resonance imaging (MRI) system, which combines the advantages of the high magnetic fields of superconducting MRI systems and open characteristics of permanent MRI systems, has great potential in clinical and research applications. However, few pulse sequences are applicable to this system. In addition, further testing on this system is needed. Therefore, in this paper, an inversion recovery gradient echo (IR-GE) pulse sequence was developed based on the features of the 0.7 Tesla open superconducting MRI system. An MR Solutions spectrometer was used to control the IR-GE pulse sequence. The developed IR-GE pulse sequence was applied to a pure water phantom using different inversion recovery times (TI). The results of the theoretical analysis and experiments indicate that the developed IR-GE pulse sequence could be effectively applied to the 0.7 Tesla open superconducting MRI system.
A PARAMETRIC MODEL OF THE PELVIC MOTION OF MIDDLE-AGED AND ELDERLY LOCOMOTION ON THE GROUND
Authors: ZHANG LIXUN , SONG DA , ZHANG XU , LI LAILU
Published: October 2016

In order to study the movement characteristics of three rotational freedoms of pelvic motion during walking on the ground for middle-aged and elderly people, a mathematical model of pelvis motion was established according to the data measured. Pelvic motion parameters were studied by the Assessment of Biomechanics Functional (FAB) for 21 participants when walking at slow, normal, and fast speeds. In the experiment, multiple trajectories of the pelvis in three directions were measured, and the data were statistically analyzed with respect to the different conditions of height and walking speed. A mathematical model was established to fit the curve associated with walking speed and height. This mathematical model has practical significance for rehabilitation equipment and evaluation.
A NOVEL MULTI-DOF EXOSKELETON ROBOT FOR UPPER LIMB REHABILITATION
Authors: LIU LIN , SHI YUN-YONG , XIE LE
Published: October 2016

Patients who suffer from stroke have motion function disorders. They need rehabilitation training guided by doctors and trainers. Nowadays, robots have been introduced to help the patients regain their motion function in rehabilitation training. In this paper, a novel multi degree of freedom (DOF) exoskeleton robot, with light weight, including (6[Formula: see text]1) DOFs, named as Rehab-Arm, is proposed and developed for upper limb rehabilitation. The joints of the robot are equipped with micro motors which are capable of actuating each DOF respectively and simultaneously. The medial/lateral rotation of shoulder is realized by a semi-circle guide mechanism for convenience consideration and safety. The robot is used in sitting posture which is attached to a custom made chair. Hence, the robot can be used to assist patients in passive movement with 7 DOFs of the upper limb for rehabilitation. Five adult healthy male subjects participated in the experiment to test the joint movement accuracy of the robot. Finally, subjects can wear Rehab-Arm and move their upper limb, led by micro motors of the robot, to perform task assigned with specific trajectory.
SUPPRESSION OF ACTION TREMOR BY SENSORY ELECTRICAL STIMULATION IN PATIENTS WITH ESSENTIAL TREMOR
Authors: HEO JAE-HOON , KWON YURI , JEON HYEONG-MIN , KWON DO-YOUNG , LEE CHAN-NYEONG , PARK KEON-WOO , MANTO MARIO , KIM JI-WON , EOM GWANG-MOON
Published: October 2016

Essential tremor (ET) is the most common movement disorder that includes postural tremor and action tremor. This study investigates whether sensory electrical stimulation (SES) is effective on the action tremor in patients with ET. One task in the clinical testing of action tremor, “Archimedes spiral drawing”, was performed in 18 patients for three sessions, which were named as pre-stimulation (PRE), stimulation on (ON), and 5[Formula: see text]min after stimulation (POST). SES (sub-motor threshold) was applied on the muscles of the elbow and wrist only at ON session. Three-dimensional (3D) angular velocities were measured on three segments (index finger, hand, and forearm) from which movements of metacarpophalangeal (MP) and wrist joints were derived. Average tremor intensity in each session was represented by root mean square of the vector sum of 3D angular velocities. Tremor intensities in ON session were smaller than in PRE session in one segment (finger) and two joints (MP and wrist) ([Formula: see text]). Tremor intensities in POST session were even smaller than in ON session in all segments and one joint (wrist) ([Formula: see text]). The results indicate that SES suppresses action tremor and the effect continues and even improves 5[Formula: see text]min after the termination of stimulation. The findings of this study may contribute to the improvement of the quality of life in patients with ET.
Spatial Variation of Mechanical Properties of ZnO Thin Films RF-Sputtered in Various Gas Environment
Authors: Malapati V. , Singh R.
Published: October 2016

ZnO thin films were deposited on quartz substrates by RF sputtering under argon, oxygen and nitrogen gas environment. The as deposited films showed hexagonal wurtzite structure with (002) orientation along c-axis. The mechanical properties of films with thickness ranging from 842[Formula: see text]nm to 1067[Formula: see text]nm and grain size 94–124[Formula: see text]nm were studied using nanoindentation technique. The Young’s modulus and hardness of the films were in the range 76–257[Formula: see text]GPa and 5–18[Formula: see text]GPa, respectively. Both parameters decreased with increase in indentation depth of the films. The spatial distribution of these parameters were strongly dependent on the gas environment used for film deposition.
Regional gas transport in the heterogeneous lung during oscillatory ventilation
Authors: Herrmann Jacob , Tawhai Merryn H. , Kaczka David W.
Published: October 2016

Regional ventilation in the injured lung is heterogeneous and frequency dependent, making it difficult to predict how an oscillatory flow waveform at a specified frequency will be distributed throughout the periphery. To predict the impact of mechanical heterogeneity on regional ventilation distribution and gas transport, we developed a computational model of distributed gas flow and CO2 elimination during oscillatory ventilation from 0.1 to 30 Hz. The model consists of a three-dimensional airway network of a canine lung, with heterogeneous parenchymal tissues to mimic effects of gravity and injury. Model CO2 elimination during single frequency oscillation was validated against previously published experimental data (Venegas JG, Hales CA, Strieder DJ, J Appl Physiol 60: 1025–1030, 1986). Simulations of gas transport demonstrated a critical transition in flow distribution at the resonant frequency, where the reactive components of mechanical impedance due to airway inertia and parenchymal elastance were equal. For frequencies above resonance, the distribution of ventilation became spatially clustered and frequency dependent. These results highlight the importance of oscillatory frequency in managing the regional distribution of ventilation and gas exchange in the heterogeneous lung.
Reactive oxygen species and bacterial biofilms in diabetic wound healing
Authors: Nouvong Aksone , Ambrus Aaron M. , Zhang Ellen R. , Hultman Lucas , Coller Hilary A.
Published: October 2016

Chronic wounds are a common and debilitating complication for the diabetic population. It is challenging to study the development of chronic wounds in human patients; by the time it is clear that a wound is chronic, the early phases of wound healing have passed and can no longer be studied. Because of this limitation, mouse models have been employed to better understand the early phases of chronic wound formation. In the past few years, a series of reports have highlighted the importance of reactive oxygen species and bacterial biofilms in the development of chronic wounds in diabetics. We review these recent findings and discuss mouse models that are being utilized to enhance our understanding of these potentially important contributors to chronic wound formation in diabetic patients.
Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process
Authors: Ohba Shigeo , Mukherjee Joydeep , Johannessen Tor-Christian , Mancini Andrew , Chow Tracy T. , Wood Matthew , Jones Lindsey , Mazor Tali , Marshall Roxanne E. , Viswanath Pavithra , Walsh Kyle M. , Perry Arie , Bell Robert J.A. , Phillips Joanna J. , Costello Joseph F. , Ronen Sabrina M. , Pieper Russell O.
Published: October 2016

Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo. Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680–9. ©2016 AACR.
Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation
Authors: Wang Yan , Hsu Jung-Mao , Kang Ya'an , Wei Yongkun , Lee Pei-Chih , Chang Shing-Jyh , Hsu Yi-Hsin , Hsu Jennifer L. , Wang Hung-Ling , Chang Wei-Chao , Li Chia-Wei , Liao Hsin-Wei , Chang Shih-Shin , Xia Weiya , Ko How-Wen , Chou Chao-Kai , Fleming Jason B. , Wang Huamin , Hwang Rosa F. , Chen Yue , Qin Jun , Hung Mien-Chie
Published: October 2016

The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway, which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). Although TGFβ and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understood how Gli1 functional activity is regulated. Here, we report the identification of Gli1 as a substrate for the protein arginine N-methyltransferase PRMT1 in PDAC. We found that PRMT1 methylates Gli1 at R597, promoting its transcriptional activity by enhancing the binding of Gli1 to its target gene promoters. Interruption of Gli1 methylation attenuates oncogenic functions of Gli1 and sensitizes PDAC cells to gemcitabine treatment. In human PDAC specimens, the levels of both total Gli1 and methylated Gli1 were correlated positively with PRMT1 protein levels. Notably, PRMT1 regulated Gli1 independently of the canonical Hh pathway as well as the TGFβ/Kras-mediated noncanonical Hh pathway, thereby signifying a novel regulatory mechanism for Gli1 transcriptional activity. Taken together, our results identified a new posttranslational modification of Gli1 that underlies its pivotal oncogenic functions in PDAC. Cancer Res; 76(23); 7049–58. ©2016 AACR.
TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione
Authors: De Logu Francesco , Tonello Raquel , Materazzi Serena , Nassini Romina , Fusi Camilla , Coppi Elisabetta , Li Puma Simone , Marone Ilaria M. , Sadofsky Laura R. , Morice Alyn H. , Susini Tommaso , Terreni Alessandro , Moneti Gloriano , Di Tommaso Mariarosaria , Geppetti Pierangelo , Benemei Silvia
Published: October 2016

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024–35. ©2016 AACR.
First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation Therapy in Patients with Locally Advanced Soft Tissue Sarcomas
Authors: Bonvalot Sylvie , Le Pechoux Cécile , De Baere Thierry , Kantor Guy , Buy Xavier , Stoeckle Eberhard , Terrier Philippe , Sargos Paul , Coindre Jean Michel , Lassau Nathalie , Ait Sarkouh Rafik , Dimitriu Mikaela , Borghi Elsa , Levy Laurent , Deutsch Eric , Soria Jean-Charles
Published: October 2016

Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS).

Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion.

Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6–40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%–90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible.

Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908–17. ©2016 AACR.
Severe Acute Subdural Hemorrhages in a Patient with Glutaric Acidemia Type 1 under Recommended Treatment
Authors: Ishige Mika , Fuchigami Tatsuo , Ogawa Erika , Usui Hiromi , Kohira Ryutaro , Watanabe Yoriko , Takahashi Shori
Published: October 2016

Glutaric acidemia type 1 is a rare autosomal recessive disease caused by a deficiency of glutaryl-CoA dehydrogenase. Previous studies have reported subdural hemorrhage in untreated patients with glutaric acidemia type 1. However, there is only one report of severe acute subdural hemorrhage after minor head trauma in a patient with glutaric acidemia type 1 under guideline-recommended treatment. We report a second case of life-threatening severe acute subdural hemorrhage after a minor head trauma in a patient with glutaric acidemia type 1. This patient was previously diagnosed by newborn screening, and treatment began at 25 days of age. Early diagnosis and guideline-recommended treatment produce better outcomes for patients with glutaric acidemia type 1, although the risk of subdural hemorrhage remains.
Gamma Knife Surgery for Recurrent or Residual Supratentorial Primitive Neuroectodermal Tumors
Authors: Se Young-Bem , Kim Dong Gyu , Kim Sung Kwon , Kim Jin Wook , Kim Yong Hwy , Park Chul-Kee , Chung Hyun-Tai , Paek Sun-Ha
Published: October 2016

Background: Supratentorial primitive neuroectodermal tumors (PNETs) are highly malignant and rare tumors of the central nervous system. Objectives: The aim of this study was to determine the role of Gamma Knife surgery (GKS) as a salvage treatment option for patients with recurrent or residual supratentorial PNETs. Methods: Between 1998 and 2014, 11 patients with supratentorial PNETs were retrospectively analyzed. This series consisted of 7 male and 4 female patients. The median age was 17 years. All patients received surgical resection followed by adjuvant therapy. The median time from operation to the first GKS treatment was 72.5 months. The median tumor volume was 17.5 cm3, and the median marginal dose was 11.5 Gy. Results: 15 (65%) of the 23 tumors had been controlled. The actuarial local tumor control rate was 91% at 3 months, 73% at 6 months, and 44% at 12 months. At the time of analysis, 9 (82%) of the patients had died. The median survival time after the first GKS session was 17 months. The median survival time from the initial diagnosis was 65 months. No adverse radiation effect after GKS treatment occurred in any patient. Conclusions: GKS treatment might be an effective salvage treatment option for recurrent or residual supratentorial PNETs after multimodal treatment.
High Levels of Soluble Endoglin Induce a Proinflammatory and Oxidative-Stress Phenotype Associated with Preserved NO-Dependent Vasodilatation in Aortas from Mice Fed a High-Fat Diet
Authors: Jezkova Katerina , Rathouska Jana , Nemeckova Ivana , Fikrova Petra , Dolezelova Eva , Varejckova Michala , Vitverova Barbora , Tysonova Kristyna , Serwadczak Agnieszka , Buczek Elzbieta , Bernabeu Carmelo , Lopez-Novoa Jose M. , Chlopicki Stefan , Nachtigal Petr
Published: October 2016

Aims: A soluble form of endoglin (sEng) was proposed to participate in the induction of endothelial dysfunction in small blood vessels. Here, we tested the hypothesis that high levels of sEng combined with a high-fat diet induce endothelial dysfunction in an atherosclerosis-prone aorta. Methods and Results: Six-month-old female and male transgenic mice overexpressing human sEng (Sol-Eng+) with low (Sol-Eng+low) or high (Sol-Eng+high) levels of plasma sEng were fed a high-fat rodent diet containing 1.25% cholesterol and 40% fat for 3 months. The plasma cholesterol and mouse sEng levels did not differ in the Sol-Eng+high and Sol-Eng+low mice. The expression of proinflammatory (P-selectin, ICAM-1, pNFκB and COX-2) and oxidative-stress-related markers (HO-1, NOX-1 and NOX-2) in the aortas of Sol-Eng+high female mice was significantly higher than in Sol-Eng+low female mice. Endothelium-dependent vasodilatation induced by acetylcholine was preserved better in the Sol-Eng+ high female mice than in the Sol-Eng+low female mice. Conclusion: These results suggest that high concentrations of sEng in plasma in combination with a high-fat diet induce the simultaneous activation of proinflammatory, pro-oxidative and vasoprotective mechanisms in mice aorta and the balance of these biological processes determines whether the final endothelial phenotype is adaptive or maladaptive.
Analysis of the Relationship between the Month of Birth and Risk of Multiple Sclerosis in a Spanish Population
Authors: Villar-Quiles Rocío N. , Matías-Guiu Jordi A. , Ortega Gloria , González-Suárez Inés , Oreja-Guevara Celia , Matías-Guiu Jorge
Published: October 2016

Background: Some studies have suggested an association between the month of birth and risk of multiple sclerosis (MS), related to environmental factors, mainly sun exposure and maternal vitamin D levels. Few studies have been conducted in Southern Europe countries. Madrid has a continental climate with considerable variation of sun hours between winter and summer, so it may be relevant to study this relationship. Methods: MS patients, born between 1932 and 2003, 1,335 of them from our database between 2004 and 2015, were analysed. The weighted average number of births per month in Madrid from 1996 and 2012 (n = 1,098,774) was considered the control population. The month and season of birth were analysed using chi-square, Hewitt's and Roberson's seasonality tests. Results: Birth rate increased in June, July, and September, and decreased in November, January, and February. Births were 29% more frequent in summer (July-September) than in winter (January-March), with a ratio of 0.79. Hewitt's test for seasonality gave a rank sum of 53 between May and October (p = 0.12). Rogerson's variation was applied to 3-, 4-, and 5-month periods. Substantial differences were noted in the 5-month periods (k = 5), although the largest rank sum (June-October) was not significant (p = 0.09). Conclusion: Our analysis seemed to suggest that pre-natal sun exposure may have an influence on the incidence of MS, most likely in combination with other environmental or genetic factors.
Improved Left Ventricular Structure and Function After Successful Kidney Transplantation
Authors: Hewing Bernd , Dehn Anna Maria , Staeck Oliver , Knebel Fabian , Spethmann Sebastian , Stangl Karl , Baumann Gert , Dreger Henryk , Budde Klemens , Halleck Fabian
Published: October 2016

Background/Aims: Cardiac changes observed in chronic kidney disease patients are of multifactorial origin including chronic uremia, hemodynamics or inflammation. Restoration of renal function by kidney transplantation (KTX) may reverse cardiac changes. Novel echocardiographic methods such as speckle tracking echocardiography (STE) allow early and sensitive detection of subtle changes of cardiac parameters. We evaluated changes of cardiac structure and function after KTX by advanced echocardiographic modalities. Methods: Thirty-one KTX recipients (female n=11) were evaluated by medical examination, laboratory testing and echocardiography before and after KTX (median follow-up 19 months). Left ventricular (LV) and right ventricular (RV) diameters and function were assessed by echocardiographic standard parameters. Longitudinal 2D strain of the LV (GLPS) and left atrium (LA) was determined by 2D STE. Results: After KTX, median serum creatinine level was 1.3 mg/dl (IQR, 1.2-1.5). Systolic blood pressure decreased significantly after KTX. Echocardiography showed a significant reduction in LV end-diastolic septal and posterior wall thickness and LV mass index after KTX, which was accompanied by an improvement of GLPS. There were no relevant changes in parameters of LA (reservoir, conduit or contractile) function, LV diastolic or RV function after KTX. Conclusion: LV hypertrophy reversed after successful KTX and was accompanied by an improvement in longitudinal LV function as assessed by STE. Diastolic function and STE-derived LA function parameters did not change significantly after KTX.
High ABCD2 Scores and In-Hospital Interventions following Transient Ischemic Attack
Authors: Cutting Shawna , Regan Elizabeth , Lee Vivien H. , Prabhakaran Shyam
Published: October 2016

Background and Purpose: Following transient ischemic attack (TIA), there is increased risk for ischemic stroke. The American Heart Association recommends admission of patients with ABCD2 scores ≥3 for observation, rapid performance of diagnostic tests, and potential acute intervention. We aimed to determine if there is a relationship between ABCD2 scores, in-hospital ischemic events, and in-hospital treatments after TIA admission. Methods: We reviewed consecutive patients admitted between 2006 and 2011 following a TIA, defined as transient focal neurological symptoms attributed to a specific vascular distribution and lasting <24 h. Three interventions were prespecified: anticoagulation for atrial fibrillation, carotid or intracranial revascularization, and intravenous or intra-arterial reperfusion therapies. We compared rates of in-hospital recurrent TIA or ischemic stroke and the receipt of interventions among patients with low (<3) versus high (≥3) ABCD2 scores. Results: Of 249 patients, 11 patients (4.4%) had recurrent TIAs or strokes during their stay (8 TIAs, 3 strokes). All 11 had ABCD2 scores ≥3, and no neurological events occurred in patients with lower scores (5.1 vs. 0%; p = 0.37). Twelve patients (4.8%) underwent revascularization for large artery stenosis, 16 (6.4%) were started on anticoagulants, and no patient received intravenous or intra-arterial reperfusion therapy. The ABCD2 score was not associated with anticoagulation (p = 0.59) or revascularization (p = 0.20). Conclusions: Higher ABCD2 scores may predict early ischemic events after TIA but do not predict the need for intervention. Outpatient evaluation for those with scores <3 would potentially have delayed revascularization or anticoagulant treatment in nearly one-fifth of ‘low-risk' patients.
CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction
Authors: Bischoff Joyce , Casanovas Guillem , Wylie-Sears Jill , Kim Dae-Hee , Bartko Philipp E. , Guerrero J. Luis , Dal-Bianco Jacob P. , Beaudoin Jonathan , Garcia Michael L. , Sullivan Suzanne M. , Seybolt Margo M. , Morris Brittan A. , Keegan Joshua , Irvin Whitney S. , Aikawa Elena , Levine Robert A.
Published: October 2016

Rationale

: Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation.

Objective

: Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro.

Methods and Results

: Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45
+
endothelial cells (VE-cadherin
+
/CD45
+
/α-smooth muscle actin [SMA]
+
and VE-cadherin
+
/CD45
+
/αSMA− cells) and possible fibrocytes (VE-cadherin
−
/CD45
+
/αSMA
+
) in inferior MI compared with sham-operated and normal sheep. CD45
+
cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin
+
/CD45
+
/αSMA
+
cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1–treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells.

Conclusions

: MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45
+
endothelial cells to MV adaptation and fibrosis post MI warrants investigation.
Shorter Hospital Stays and Lower Costs for Rivaroxaban Compared With Warfarin for Venous Thrombosis Admissions
Authors: Margolis Jay M. , Deitelzweig Steven , Kline Jeffrey , Tran Oth , Smith David M. , Bookhart Brahim , Crivera Concetta , Schein Jeff
Published: October 2016

Background

Venous thromboembolism, including deep vein thrombosis and pulmonary embolism, results in a substantial healthcare system burden. This retrospective observational study compared hospital length of stay (
LOS
) and hospitalization costs for patients with venous thromboembolism treated with rivaroxaban versus those treated with warfarin.

Methods and Results

Hospitalizations for adult patients with a primary diagnosis of deep vein thrombosis or pulmonary embolism who were initiated on rivaroxaban or warfarin were selected from MarketScan's Hospital Drug Database between November 1, 2012, and December 31, 2013. Patients treated with warfarin were matched 1:1 to patients treated with rivaroxaban using exact and propensity score matching. Hospital
LOS
, time from first dose to discharge, and hospitalization costs were reported descriptively and with generalized linear models (
GLM
s). The final study cohorts each included 1223 patients (751 with pulmonary embolism and 472 with deep vein thrombosis). Cohorts were well matched for demographic and clinical characteristics. Mean (±
SD
)
LOS
was 3.7±3.1 days for patients taking rivaroxaban and 5.2±3.7 days for patients taking warfarin, confirmed by
GLM
‐adjusted results (rivaroxaban 3.7 days, warfarin 5.3 days,
P
<0.001). Patients with provoked venous thromboembolism admissions showed longer
LOSs
(rivaroxaban 5.1±4.5 days, warfarin 6.5±5.6 days,
P
<0.001) than those with unprovoked venous thromboembolism (rivaroxaban 3.3±2.4 days, warfarin 4.8±2.8 days,
P
<0.001). Days from first dose to discharge were 2.4±1.7 for patients treated with rivaroxaban and 3.9±3.7 for patients treated with warfarin when initiated with parenteral anticoagulants (
P
<0.001), and 2.7±1.7 and 3.7±2.1, respectively, when initiated without parenteral anticoagulants (
P
<0.001). Patients initiated on rivaroxaban incurred significantly lower mean total hospitalization costs ($8688±$9927 versus $9823±$9319,
P
=0.004), confirmed by modeling (rivaroxaban $8387 [95% confidence interval, $8035–$8739]; warfarin $10 275 [95% confidence interval, $9842–$10 708]).

Conclusions

Rivaroxaban was associated with significantly shorter hospital
LOS
and lower hospitalization costs compared with warfarin.
Socioeconomic Status and the Quality of Acute Stroke Care
Authors: Pan Yuesong , Chen Ruoling , Li Zixiao , Li Hao , Zhao Xingquan , Liu Liping , Wang Chunxue , Wang Yilong , Wang Yongjun
Published: October 2016

Background and Purpose—

The association of socioeconomic status (SES) with quality of stroke care is not well understood, and few studies have examined the association with different indicators of SES simultaneously. We assessed the impacts of low levels of education, occupation, and income on the quality of stroke care.

Methods—

We examined data from the China National Stroke Registry recording consecutive stroke patients between September 2007 and August 2008. Baseline low SES was measured using educational level <6 years, occupation as manual workers or no job, and average family income per capita at ≤¥1000 per month. Compliance with 11 performances was summarized in a composite score defined as the proportion of all needed care given. Poor quality of care was defined as having a composite score of 0.71 or less.

Results—

Among 12 270 patients with ischemic stroke, 38.6% had <6 educational years, 37.6% had manual workers/no job, and 34.7% had income ≤¥1000 per month. There was an increased chance of receiving poor quality of care in patients with low education (adjusted odds ratio 1.15, 95% confidence interval 1.03–1.28), low occupation (adjusted odds ratio 1.16, 95% confidence interval 1.01–1.32), and low income (adjusted odds ratio 1.18, 95% confidence interval 1.06–1.30), respectively. People with low SES had poor performances on some aspects of care quality. Combined effects existed among these SES indicators; those with low SES from all 3 indicators had the poorest quality of care.

Conclusions—

There was a social gradient in the quality of stroke care. Continuous efforts of socioeconomic improvement will increase the quality of acute stroke care.