bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing competency using simulation: the SimZones approach
Authors: Roussin Christopher , Sawyer Taylor , Weinstock Peter
Published: September 2019

Introduction

Competency-based medical education (CBME) is a system of medical training that focuses on a structured approach to developing the clinical abilities of medical education graduates and practicing physicians. CBME requires a robust and multifaceted system of assessment in order to both measure and guide the progress of learners toward pre-established goals. Simulation has been proposed as one method for assessing competency in healthcare workers. However, a longitudinal framework for assessing competency using simulation has not been developed.

Methods

Conjecture mapping methodology was used to map Miller’s framework for competency assessment—‘knows’, ‘knows how’, ‘shows how’, and ‘does’—to the five SimZones described by Roussin and Weinstock. The SimZones describe a system of organising the development and delivery of simulation-based education and offer a foundation for both guiding and organising assessment in a simulation context.

Results

A conceptualised alignment of the SimZones with Miller’s pyramid of assessment was developed, as well as a detailed conjecture map. SimZone 0 (auto-feedback) and SimZone 1 (foundational instruction) mapped to ‘knows’ and ‘knows how’. SimZone 2 (acute care instruction) mapped to ‘shows how’. SimZone 3 (team and system development) mapped to ‘shows how’. SimZone 4 (real-life debriefing and development) mapped to ‘does’.

Conclusion

The SimZones system of competency assessment offers a robust, flexible, and multifaceted system to guide both formative and summative assessment in CBME. The SimZones approach adds to the many methods of competency assessment available to educators. Adding SimZones to the vocabulary of CBME may be helpful for the full deployment of CBME.
Do age, period or cohort effects explain circulatory disease mortality trends, Scotland 1974–2015?
Authors: Parkinson Jane , Minton Jon , Bouttell Janet , Lewsey James , Shah Anoop , McCartney Gerry
Published: September 2019

Objective

We aimed to explore whether age, period or cohort effects explain the trends and inequalities in ischaemic heart disease (IHD) and cerebrovascular disease (CeVD) mortality in Scotland.

Methods

We analysed IHD and CeVD deaths for 1974–2015 by sex, age and area deprivation, visually explored the data using heatmaps and dotplots and built regression models.

Results

CeVD mortality improved steadily over time while IHD mortality improved more rapidly from the late 1980s. Age effects were evident; both outcomes showed an exponential relationship with age for all except males for IHD in the 1980s and 1990s. The mortality profiles by age became older, although improvement was slower for those aged <50 years for IHD, especially for males, and faster for CeVD in females aged <65 years. Rates were higher, and inequalities greater, among males, especially for IHD. For IHD, increased risk for males over females reduced with age (incidence rate ratio for 41–50 year old males=4.28 (95% CI 4.12 to 4.44) and 1.17 (95% CI 1.16 to 1.18) for 71–80 year olds). Inequalities in IHD mortality by area deprivation persisted over time, increasing from around 10% to around 25% higher risk in the most deprived areas between 1974 and 1986 before declining in absolute terms from around 2000. Inequalities for CeVD increased after the late 1980s.

Conclusions

IHD and CeVD mortality in Scotland exhibit age but not recent distinct period or cohort effects. The improvements in mortality rates have been more sustained for CeVD and inequalities greater for IHD.
Cartilage-gut-microbiome axis: a new paradigm for novel therapeutic opportunities in osteoarthritis
Authors: Berthelot Jean-Marie , Sellam Jérémie , Maugars Yves , Berenbaum Francis
Published: September 2019

DNA of gut microbiota can be found in synovium of osteoarthritis and rheumatoid arthritis. This finding could result from the translocation of still alive bacteria from gut to joints through blood, since the diversified dormant microbiota of healthy human blood can be transiently resuscitated in vitro. The recent finding of gut microbiome in human cartilage, which differed between osteoarthritis and controls, suggests that a similar trafficking of dead or alive bacteria from gut microbiota physiologically occurs between gut and epiphysial bone marrow. Subchondral microbiota could enhance cartilage healing and transform components of deep cartilage matrix in metabolites with immunosuppressive properties. The differences of microbiome observed between hip and knee cartilage, either in osteoarthritis or controls, might be the counterpart of subtle differences in chondrocyte metabolism, themselves in line with differences in DNA methylation according to joints. Although bacteria theoretically cannot reach chondrocytes from the surface of intact cartilage, some bacteria enter the vascular channels of the epiphysial growth cartilage in young animals, whereas others can infect chondrocytes in vitro. In osteoarthritis, the early osteochondral plate angiogenesis may further enhance the ability of microbiota to locate close to the deeper layers of cartilage, and this might lead to focal dysbiosis, low-grade inflammation, cartilage degradation, epigenetic changes in chondrocytes and worsening of osteoarthritis. More studies on cartilage across different ethnic groups, weights, and according to age, are needed, to confirm the silent presence of gut microbiota close to human cartilage and better understand its physiologic and pathogenic significance.
Anthelmintic resistance in gastrointestinal nematodes in sheep raised under mountain farming conditions in Northern Italy
Authors: Lambertz Christian , Poulopoulou Ioanna , Wuthijaree Kunlayaphat , Gauly Matthias
Published: September 2019

Anthelmintic resistance (AR) in sheep raised under mountain farming conditions in South Tyrol (Northern Italy) was assessed on eight farms (n=99 animals). A faecal egg count reduction (FECR) test was done after routine anthelmintic treatments. Furthermore, on 27 farms (n=306 animals), a FECR test was conducted after oral formulations of a macrocyclic lactone (ML), benzimidazole (BZ) (partly in combination with salicylanilide (SA)) or a combination of imidazothiazole and SA were applied under controlled conditions on the same farm. Following routine treatments, three of five ML‐treated flocks showed an adequate efficacy, while the other two reached a FECR of only around 75 per cent. A wide range of gastrointestinal nematode genera were identified in one flock following the treatment. From the three BZ‐treated flocks, only one showed an adequate FECR, both other farms reached 68 per cent and 84 per cent, respectively. Under controlled conditions, FECR ranged between 77 per cent and 81 per cent indicating AR for all the applied anthelmintics. Trichostrongylus species, Teladorsagia species and Haemonchus species were identified after ML treatment, Teladorsagia species after BZ treatment and Trichostrongylus species and Haemonchus species after combined BZ and SA application. Taking into consideration that underdosing might have affected results of the routine treatments, a high prevalence of AR was found in sheep under mountain farming conditions.
Ethanolic extract and ethyl acetate fraction of Coutoubea spicata attenuate hyperglycemia, oxidative stress, and muscle damage in alloxan-induced diabetic rats subjected to resistance exercise training program
Authors: Santos Jymmys Lopes dos , Araújo Silvan Silva de , Silva Ana Mara de Oliveira e , Lima Clésio Andrade , Vieira Souza Lúcio Marques , Costa Rôas Araújo , Aidar Martins Felipe José , Voltarelli Fabrício Azevedo , Estevam Charles dos Santos , Marçal Anderson Carlos
Published: September 2019

Gentianaceae family (such as Coutoubea spicata) contains iridoids and flavonoids with antidiabetic properties. However, there is no information available about the antidiabetic effects of C. spicata when combined with resistance exercise training (RET). This study evaluated the effects of the ethanolic extract (EE) and ethyl acetate fraction (EAF) of C. spicata on biochemical markers, muscle damage, and oxidative stress in diabetic rats submitted to RET. Alloxan-induced diabetic rats were distributed into 4 groups (each group, n = 8) treated with distilled water (TD), EE, EAF, or metformin and submitted to RET. Two groups without the disease (each group, n = 8) (sedentary control and trained control), as well as a sedentary diabetic group (n = 8) were included. Body weight and glycemia were evaluated weekly. After 30 days, lipid/lipoprotein profile, aspartate aminotransferase, alanine aminotransferase, muscle damage ((creatine kinase (CK) and lactate dehydrogenase (LDH)), and oxidative stress (malondialdehyde (MDA), sulfhydryl groups (SH), and ferric reducing antioxidant power) were evaluated. MDA and SH for pancreas, liver, heart, and muscle were evaluated. C. spicata extract and fraction combined with RET recovered body weight and reduced glycemia, muscle damage (CK: 36.83% and 21.45%; LDH: 49.83% and 68.55%), and low-density lipoprotein cholesterol (70.63%; 59.18%) and improved redox status (MDA: 50.33%, 39.74%; and SH: 53.97%; 76.41%), respectively, when compared with the TD group. C. spicata plus RET promoted anti-hyperglycemic, lipid-reducing, and antioxidant effects in diabetic rats.

Novelty C. spicata presents anti-hyperglycemic and lipid-lowering effects potentiated by RET. C. spicata reduces muscle injury and increases antioxidant defense.
Constitutive expression of chrysanthemum CmBBX29 delays flowering time in transgenic Arabidopsis
Authors: Chen Hong , Huang Fei , Liu Yanan , Cheng Peilei , Guan Zhiyong , Fang Weimin , Chen Sumei , Chen Fadi , Jiang Jiafu
Published: September 2019

BBX transcription factors are known to regulate the flowering time and the plant response to various abiotic stresses, but their functions in chrysanthemum have yet to be thoroughly explored. Here, a chrysanthemum homolog of the Arabidopsis thaliana gene AtBBX29 was isolated and characterized. The gene was transcribed in various plant organs but most strongly in the root and in the ligulate flowers. Its temporal pattern of transcription mirrored that of CmCO, the chrysanthemum homolog of the key flowering regulator CONSTANS (CO). Its constitutive expression in A. thaliana induced a delay to flowering, suppressing the transcription of FLOWERING LOCUS T (FT), SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), LEAFY (LFY), and APETALA 1 (AP1), while promoting that of FLOWERING LOCUS C (FLC). Our results indicate that CmBBX29 can regulate flowering time in A. thaliana by the integration of FLC and the photoperiod pathway.
Analysis of the X(3842) as a D-wave charmonium meson
Authors: Yu Guo-Liang , Wang Zhi-Gang
Published: September 2019

In this paper, we assign the newly reported state [Formula: see text] to be a [Formula: see text]-wave [Formula: see text] meson, and study its mass and decay constant with QCD sum rules by considering the contributions of vacuum condensates up to dimension-6 in the operator product expansion. The predicted mass [Formula: see text] GeV is in agreement with the experimental data [Formula: see text] MeV from the LHCb collaboration. This result supports assigning [Formula: see text] as the [Formula: see text] charmonium meson. In this case, its predicted strong decay width with the [Formula: see text] decay model is compatible with the experimental data.
Structures, electronic and magnetic properties of the MnnS and Mnn−1S2 (n = 1–6) clusters
Authors: Li Zhi , Zhao Zhen , Wang Qi , Shi Tong-Tong
Published: September 2019

To understand sulfide inclusions in the steel industry, the structures, stabilities, electronic and magnetic properties of the Mn[Formula: see text]S and Mn[Formula: see text]S2 (n=1–6) clusters are investigated by using first-principles. The results show that the S atoms prefer to occupy the outside surface center of the Mn[Formula: see text] (n = 3–6) clusters. Chiral isomers are occurred to the Mn5S2 isomers. The Mn2S, Mn2S2 clusters are more stable than their neighbors. However, the MnS, S2, and Mn5I2 clusters possess higher dynamic stability than their neighbors by the HOMO–LUMO gaps. The Mn[Formula: see text]S and Mn[Formula: see text]S2 (n = 1–6) clusters prefer to spontaneous generation by Gibbs free energy. A few 4s orbital electrons of Mn atoms transferred to the S atoms by Mülliken population analysis. For the other Mn[Formula: see text]S (n = 1–6) clusters, the spin density (17.256) of the ground-state Mn6S clusters is the largest. For the Mn[Formula: see text]S2 (n = 1–6) clusters, the total spin (9.604) of the ground-state Mn2S2 cluster is the largest.
High-order breathers, lumps and hybrid solutions to the (2+1)-dimensional fifth-order KdV equation
Authors: Li Wen-Tao , Zhang Zhao , Yang Xiang-Yu , Li Biao
Published: September 2019

In this paper, the (2+1)-dimensional fifth-order KdV equation is analytically investigated. By using Hirota’s bilinear method combined with perturbation expansion, the high-order breather solutions of the fifth-order KdV equation are generated. Then, the high-order lump solutions are also derived from the soliton solutions by a long-wave limit method and some suitable parameter constraints. Furthermore, we extend this method to obtain hybrid solutions by taking long-wave limit for partial soliton solutions. Finally, the dynamic behavior of these solutions is presented in the figures.
Influence of partial pressure of oxygen on thermochromic performance of VO2 thin films by RF magnetron sputtering
Authors: Guo Pengfei , Liu Caijuan , Liu Junhui , Li Ruoping , Huang Mingju
Published: September 2019

In order to obtain a material with high solar modulation ability [Formula: see text] and crystalline quality, [Formula: see text] films were prepared on quartz glass substrates using RF magnetron sputtering under various oxygen partial pressures. Their phase, surface, transmittance, and film sheet resistance properties were analyzed. As the oxygen partial pressure increased, the luminous transmittance [Formula: see text] of the film increased to as high as 55.6%, while the [Formula: see text] first increased to a maximum of 10.8% and then decreased. This paper is a meaningful aid in the application of [Formula: see text] films to smart windows.
Combinatorial Test Design Using Design-Time Decisions for Variability
Authors: Lee Jihyun , Hwang Sunmyung
Published: September 2019

Design-time artifacts such as module structures from the module view, component diagrams from the component-and-connector view, sequence diagrams, communication diagrams, activity diagrams, or state-machine diagrams from the behavioral view of software architecture can be used to generate effective test cases for fault detection at integration testing level. Various combinatorial test design (CTD) methods have been developed for generating valid and representative product configurations for a software product line, but these methods assume that all bindings for variabilities are performed at run time. Thus, these methods have a limitation in that they do not consider design decisions for variability represented in design-time artifacts. This paper aims to propose a CTD method that uses design-time variability, called the DesignTimeCTD method, considering variability-related decisions at design stage and investigating the effectiveness of reducing the number of tests. The DesignTimeCTD uses variability model, variation points in design-time artifacts, and variability implementation mechanisms used for implementation together in order to reduce the number of tests. As a result, the CTD method, which uses design-time decisions for variability, contributes to reducing the test case by approximately 14% by allowing test engineers to consider design-time variability-related decisions together.
Fast Fréchet Distance Between Curves with Long Edges
Authors: Gudmundsson Joachim , Mirzanezhad Majid , Mohades Ali , Wenk Carola
Published: September 2019

Computing the Fréchet distance between two polygonal curves takes roughly quadratic time. In this paper, we show that for a special class of curves the Fréchet distance computations become easier. Let [Formula: see text] and [Formula: see text] be two polygonal curves in [Formula: see text] with [Formula: see text] and [Formula: see text] vertices, respectively. We prove four results for the case when all edges of both curves are long compared to the Fréchet distance between them: (1) a linear-time algorithm for deciding the Fréchet distance between two curves, (2) an algorithm that computes the Fréchet distance in [Formula: see text] time, (3) a linear-time [Formula: see text]-approximation algorithm, and (4) a data structure that supports [Formula: see text]-time decision queries, where [Formula: see text] is the number of vertices of the query curve and [Formula: see text] the number of vertices of the preprocessed curve.
Bioconjugatable synthetic chlorins rendered water-soluble with three PEG-12 groups via click chemistry
Authors: Matsumoto Nobuyuki , Taniguchi Masahiko , Lindsey Jonathan S.
Published: September 2019

Chlorins provide many ideal features for use as red-region fluorophores but require molecular tailoring for solubilization in aqueous solution. A chlorin building-block bearing 18,18-dimethyl, 15-bromo and 10-[2,4,6-tris(propargyloxy)phenyl] substituents has been transformed via click chemistry with CH3(OCH2CH[Formula: see text]-N3 followed by Suzuki coupling with 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid, thereby installing a water-solubilization motif and a bioconjugatable handle, respectively. In toluene, [Formula: see text]-dimethylformamide (DMF) or water, the resulting facially encumbered free base chlorin exhibits characteristic chlorin absorption ([Formula: see text] [Formula: see text]412, 643 nm) and fluorescence ([Formula: see text] [Formula: see text]645 nm) spectra with only modest variation in fluorescence quantum yield ([Formula: see text] values (0.24, 0.25 and 0.19, respectively). The zinc chlorin derived therefrom exhibits similar spectral constancy ([Formula: see text] [Formula: see text]414 and 613 nm, [Formula: see text] [Formula: see text]616 nm) and [Formula: see text] 0.094, 0.10 and 0.086 in the three solvents. The results together indicate the viability of the molecular design and synthetic methodology to create red-region fluorophores for use in diverse applications.
Research on China’s Regional Economic Linkages: Based on the Analyses of Carbon Emission Transfers and Labor Mobility
Authors: QI Yawei , XU Zhiqin
Published: September 2019

In the face of the dual challenges of coordinated development of regional economy and sustainable development, strengthening the regional economic linkages is critical to realizing the coordinated development of the regional economy based on the reasonable transfer of carbon emissions. Under the background of industrial transfer, the authors used the inter-regional input–output model to measure the carbon emissions and labor transfers among 30 provinces in 2002, 2007 and 2010, analyzed the relationship between labor mobility and the spatial transfer of carbon emissions and introduced their scales and directions into a gravity model to measure the economic relations among regions. The results show that the embodied carbon emission tends to transfer from western and northeastern China to central and eastern China, which is consistent with the direction of labor mobility, and both of them show the feature of spatial clustering. Under the effects of carbon emission transfers and labor mobility, the radiation effects of the central node provinces in China such as Guangdong, Zhejiang, Hebei, Beijing, Henan and Gansu have given rise to the integrated regional spatial organizations of Beijing–Tianjin–Hebei, Yangtze River Delta Pan-Pearl River Delta and northwestern China, among which Yangtze River Delta and Pan-Pearl River Delta enjoy a relatively stable structure.
Measuring Conditional Independence by Independent Residuals for Causal Discovery
Authors: Zhang Hao , Zhou Shuigeng , Guan Jihong , Huan Jun (Luke)
Published: September 2019

We investigate the relationship between conditional independence (CI)
x
⫫
y
|
Z
and the independence of two residuals
x
−E(
x
|
Z
)⫫
y
−E(
y
|
Z
), where
x
and
y
are two random variables and
Z
is a set of random variables. We show that if
x
,
y
, and
Z
are generated by following linear structural equation models and all external influences follow joint Gaussian distribution, then
x
⫫
y
|
Z
if and only if
x
−E(
x
|
Z
)⫫
y
−E(
y
|
Z
). That is, the test of
x
⫫
y
|
Z
can be relaxed to a simpler unconditional independence test of
x
−E(
x
|
Z
)⫫
y
−E(
y
|
Z
). Furthermore, testing
x
−E(
x
|
Z
)⫫
y
−E(
y
|
Z
) can be simplified by testing
x
−E(
x
|
Z
)⫫
y
or
y
−E(
y
|
Z
)⫫
x
. On the other side, if all these external influences follow non-Gaussian distributions and the model satisfies structural faithfulness condition, then we have
x
⫫
y
|
Z
⇔
x
−E(
x
|
Z
)⫫
y
−E(
y
|
Z
).

We apply the results above to the causal discovery problem, where the causal directions are generally determined by a set of
V
-structures and their consistent propagations, so CI test-based methods can return a set of Markov equivalence classes. We show that in the linear non-Gaussian context, in many cases
x
−E(
x
|
Z
)⫫
z
or
y
−E(
y
|
Z
)⫫
z
(∀
z
∈
Z
and
Z
is a minimal
d
-separator) is satisfied when
x
−E(
x
|
Z
)⫫
y
−E(
y
|
Z
), which implies
z
causes
x
(or
y
) if
z
directly connects to
x
(or
y
). Therefore, we conclude that CIs have useful information for distinguishing Markov equivalence classes.

In summary, comparing with the existing discretization-based and kernel-based CI testing methods, the proposed method provides a simpler way to measure CI, which needs only one unconditional independence test and two regression operations. When being applied to causal discovery, it can find more causal relationships, which is extensively validated by experiments.
On the importance of the nonuniform aortic stiffening in the hemodynamics of physiological aging
Authors: Pagoulatou Stamatia Z. , Bikia Vasiliki , Trachet Bram , Papaioannou Theodore G. , Protogerou Athanase D. , Stergiopulos Nikolaos
Published: September 2019

Mathematical models of the arterial tree constitute a valuable tool to investigate the hemodynamics of aging and pathology. Rendering such models as patient specific could allow for the assessment of central hemodynamic variables of clinical interest. However, this task is challenging, particularly with respect to the tuning of the local area compliance that varies significantly along the arterial tree. Accordingly, in this study, we demonstrate the importance of taking into account the differential effects of aging on the stiffness of central and peripheral arteries when simulating a person’s hemodynamic profile. More specifically, we propose a simple method for effectively adapting the properties of a generic one-dimensional model of the arterial tree based on the subject’s age and noninvasive measurements of aortic flow and brachial pressure. A key element for the success of the method is the implementation of different mechanisms of arterial stiffening for young and old individuals. The designed methodology was tested and validated against in vivo data from a population of n = 20 adults. Carotid-to-femoral pulse wave velocity was accurately predicted by the model (mean error = 0.14 m/s, SD = 0.77 m/s), with the greatest deviations being observed for older subjects. In regard to aortic pressure, model-derived systolic blood pressure and augmentation index were both in good agreement (mean difference of 2.3 mmHg and 4.25%, respectively) with the predictions of a widely used commercial device (Mobil-O-Graph). These preliminary results encourage us to further validate the method in larger samples and consider its potential as a noninvasive tool for hemodynamic monitoring.

NEW & NOTEWORTHY We propose a technique for adapting the parameters of a validated one-dimensional model of the arterial tree using noninvasive measurements of aortic flow and brachial pressure. Emphasis is given on the adjustment of the arterial tree distensibility, which incorporates the nonuniform effects of aging on central and peripheral vessel elasticity. Our method could find application in the derivation of important hemodynamic indices, paving the way for novel diagnostic tools.
Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases
Authors: Schalkwijk C. G. , Stehouwer C. D. A.
Published: September 2019

The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer, and disorders of the central nervous system. MGO is mainly formed as a byproduct of glycolysis and, under physiological circumstances, detoxified by the glyoxalase system. MGO is the major precursor of nonenzymatic glycation of proteins and DNA, subsequently leading to the formation of advanced glycation end products (AGEs). MGO and MGO-derived AGEs can impact on organs and tissues affecting their functions and structure. In this review we summarize the formation of MGO, the detoxification of MGO by the glyoxalase system, and the biochemical pathways through which MGO is linked to the development of diabetes, vascular complications of diabetes, and other age-related diseases. Although interventions to treat MGO-associated complications are not yet available in the clinical setting, several strategies to lower MGO have been developed over the years. We will summarize several new directions to target MGO stress including glyoxalase inducers and MGO scavengers. Targeting MGO burden may provide new therapeutic applications to mitigate diseases in which MGO plays a crucial role.
Stem Cells and the Differentiation Hierarchy in Mammary Gland Development
Authors: Fu Nai Yang , Nolan Emma , Lindeman Geoffrey J. , Visvader Jane E.
Published: September 2019

The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor cells. Both short- and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging diversity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.
Mechanisms and Antitumor Activity of a Binary EGFR/DNA–Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide
Authors: Sharifi Zeinab , Abdulkarim Bassam , Meehan Brian , Rak Janusz , Daniel Paul , Schmitt Julie , Lauzon Nidia , Eppert Kolja , Duncan Heather M. , Petrecca Kevin , Guiot Marie-Christine , Jean-Claude Bertrand , Sabri Siham
Published: September 2019

Purpose:

Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM.

Experimental Design:

ZR2002 is a “combi-molecule” designed to inflict DNA damage through its chlorethyl moiety and induce irreversible EGFR tyrosine kinase inhibition. We assessed its in vitro efficacy in temozolomide-resistant patient-derived GSCs, mesenchymal temozolomide-sensitive and resistant in vivo–derived GSC sublines, and U87/EGFR isogenic cell lines stably expressing EGFR/wild-type or variant III (EGFRvIII). We evaluated its antitumor activity in mice harboring orthotopic EGFRvIII or mesenchymal TMZ-resistant GSC tumors.

Results:

ZR2002 induced submicromolar antiproliferative effects and inhibited neurosphere formation of all GSCs with marginal effects on normal human astrocytes. ZR2002 inhibited EGF-induced autophosphorylation of EGFR, downstream Erk1/2 phosphorylation, increased DNA strand breaks, and induced activation of wild-type p53; the latter was required for its cytotoxicity through p53-dependent mechanism. ZR2002 induced similar effects on U87/EGFR cell lines and its oral administration significantly increased survival in an orthotopic EGFRvIII mouse model. ZR2002 improved survival of mice harboring intracranial mesenchymal temozolomide-resistant GSC line, decreased EGFR, Erk1/2, and AKT phosphorylation and was detected in tumor brain tissue by MALDI imaging mass spectrometry.

Conclusions:

These findings provide the molecular basis of binary EGFR/DNA targeting and uncover the oral bioavailability, blood–brain barrier permeability, and antitumor activity of ZR2002 supporting potential evaluation of this first-in-class drug in recurrent GBM.
The Zinc-Finger AN1-Type Domain 2a Gene Acts as a Regulator of Cell Survival in Human Melanoma: Role of E3-Ligase cIAP2
Authors: Pizzato Scomazzon Sofia , Riccio Anna , Santopolo Silvia , Lanzilli Giulia , Coccia Marta , Rossi Antonio , Santoro M. Gabriella
Published: September 2019

The zinc-finger AN1-type domain-2a gene, also known as AIRAP (arsenite-inducible RNA-associated protein), was initially described as an arsenite-inducible gene in Caenorhabditis elegans and mammalian cells. Differently from the AIRAP worm homologue, aip-1, a gene known to play an important role in preserving animal lifespan and buffering arsenic-induced proteotoxicity, mammals have a second, constitutively expressed, AIRAP-like gene (AIRAPL), recently implicated in myeloid transformation. We have identified human AIRAP as a canonical heat-shock gene, whose expression, differently from AIRAPL, is strictly dependent on the proteotoxic-stress regulator heat-shock factor 1 (HSF1). AIRAP function is still not well defined and there is no information on AIRAP in cancer. Herein we show that bortezomib and next-generation proteasome inhibitors ixazomib and carfilzomib markedly induce AIRAP expression in human melanoma at concentrations comparable to plasma-levels in treated patients. AIRAP-downregulation leads to bortezomib sensitization, whereas AIRAP-overexpression protects melanoma cells from the drug, identifying AIRAP as a novel HSF1-regulated marker of chemotherapy resistance. More importantly, this study unexpectedly revealed that, also in the absence of drugs, AIRAP-silencing hinders melanoma clonogenic potential and spheroid growth, promoting caspase activation and apoptotic cell death, an effect independent of AIRAPL and linked to downregulation of the antiapoptotic protein cIAP2. Interestingly, AIRAP was found to interact with cIAP2, regulating its stability in melanoma. Taken together, the results identify AIRAP as a novel HSF1-dependent regulator of prosurvival networks in melanoma cells, opening new therapeutic perspectives in chemoresistant melanoma treatment.

Implications:

The findings identify ZFAND2A/AIRAP as a novel stress-regulated survival factor implicated in the stabilization of the antiapoptotic protein cIAP2 and as a new potential therapeutic target in melanoma.
Aflibercept Treatment for Macular Edema following Branch Retinal Vein Occlusion: Age-Based Responses
Authors: Sırakaya Ender , Küçük Bekir , Ağadayı Alperen
Published: September 2019

Purpose: The aim of this study was to compare responses to aflibercept treatment in age-based groups of patients with macular edema following branch retinal vein occlusion (BRVO). Methods: Eighty-five patients with macular edema following BRVO were divided into 4 groups according to their age: Group I (i.e., 45- to 54-year-olds), Group II (i.e., 55- to 64-year-olds), Group III (i.e., 65- to 74-year-olds), and Group IV (i.e., 75- to 84-year-olds). Each patient received a loading dose of 3 monthly intravitreal aflibercept injections. The treatment response was evaluated with visual acuity (VA) and optical coherence tomography measurements of the central foveal thickness (CFT), outer nuclear layer thickness (ONLT), and photoreceptor layer thickness (PRLT) before treatment and 1 month after the first and third injections. Results: In Group I (n = 19), Group II (n = 25), Group III (n = 23), and Group IV (n = 18), the mean values of VA, CFT, ONLT, and PRLT improved significantly 3 months after treatment. Whereas VA improved the most in Group I, its improvement significantly decreased in each progressively older age group, as did the reduction of the CFT, ONLT, and PRLT values, all of which were greater in groups I and II. Furthermore, age significantly correlated with changes in VA, CFT, ONLT, and PRLT across all groups. Conclusion: The efficacy and effectiveness of aflibercept treatment decrease in patients with macular edema following BRVO as they age, most likely due to age-related changes in posterior ocular structures.
Executive Function, Eating Behavior, and Preoperative Weight Loss in Bariatric Surgery Candidates: An Observational Study
Authors: Walø-Syversen Gro , Kvalem Ingela L. , Kristinsson Jon , Eribe Inger L. , Rø Øyvind , Dahlgren Camilla Lindvall
Published: September 2019

Background: Individual differences in executive function may influence eating behavior, weight loss (WL), and WL maintenance in obesity treatment. Executive function, which designates top-down cognitive control processes, has been related to eating behaviors which may impact weight, and has been found to be predictive of WL in both behavioral WL programs and after bariatric surgery. Currently, we lack knowledge on the role of executive function in the period before bariatric surgery. If executive function impacts eating behavior and WL in the preoperative period, it may be a target for clinical attention in this stage. Objectives: We aimed to examine the relationship between objective performance-based measures of executive function, eating patterns, and WL in the preoperative period. Method: Baseline data in an ongoing observational longitudinal study of bariatric surgery patients were used. Eighty patients completed neuropsychological testing and self-report questionnaires 4 weeks prior to surgery. Results: We found that working memory predicted WL before surgery and inhibitory control predicted adherence to dietary recommendations. Conclusion: Our study indicates that executive function may play a role in short-term WL and dietary adherence prior to surgery, suggesting that executive function in the preoperative period deserves an extended research focus.
Comparative Chromosome Painting in Two Brazilian Stork Species with Different Diploid Numbers
Authors: Seligmann Igor C.A. , Furo Ivanete O. , dos Santos Michelly S. , Tagliarini Marcella M. , Araujo Cristiane C.D. , O''Brien Patricia C.M. , Ferguson-Smith Malcolm A. , de Oliveira Edivaldo H.C.
Published: September 2019

Despite the variation observed in the diploid chromosome number of storks (Ciconiiformes, Ciconiidae), from 2n = 52 to 2n = 78, most reports have relied solely on analyses by conventional staining. As most species have similar macrochromosomes, some authors propose that karyotype evolution involves mainly fusions between microchromosomes, which are highly variable in species with different diploid numbers. In order to verify this hypothesis, in this study, the karyotypes of 2 species of storks from South America with different diploid numbers, the jabiru (Jabiru mycteria, 2n = 56) and the maguary stork (Ciconia maguary, 2n = 72), were analyzed by chromosome painting using whole chromosome probes from the macrochromosomes of Gallus gallus (GGA) and Leucopternis albicollis (LAL). The results revealed that J. mycteria and C. maguary share synteny within chromosome pairs 1-9 and Z. The syntenies to the macrochromosomes of G. gallus are conserved, except for GGA4, which is homologous to 2 different pairs, as in most species of birds. A fusion of GGA8 and GGA9 was observed in both species. Additionally, chromosomes corresponding to GGA4p and GGA6 are fused to other segments that did not hybridize to any of the macrochromosome probes used, suggesting that these segments correspond to microchromosomes. Hence, our data corroborate the proposed hypothesis that karyotype evolution is based on fusions involving microchromosomes. In view of the morphological constancy of the macrochromosome pairs in most Ciconiidae, we propose a putative ancestral karyotype for the family, including the GGA8/GGA9 fusion, and a diploid number of 2n = 78. The use of probes for microchromosome pairs should be the next step in identifying other synapomorphies that may help to clarify the phylogeny of this family.
Readmissions After Acute Myocardial Infarction: How Often Do Patients Return to the Discharging Hospital?
Authors: Rymer Jennifer A. , Chen Anita Y. , Thomas Laine , Fonarow Gregg C. , Peterson Eric D. , Wang Tracy Y.
Published: September 2019

Background

When patients require readmission after a recent myocardial infarction (
MI
), returning to the discharging (index) hospital may be associated with better outcomes as a result of greater continuity in care. However, little evidence exists to answer this frequent patient question.

Methods and Results

Among Medicare patients aged ≥65 years discharged home alive post‐
MI
from 491
US
hospitals in the ACTION (Acute Coronary Treatment Intervention Outcomes Network) Registry, we compared reason for readmission, duration of rehospitalization, and 30‐day mortality between patients readmitted to the index versus nonindex hospital within 30 days of index
MI
discharge. Among 53 471
MI
patients, 7715 (14%) were readmitted within 30 days, and most readmitted patients (73%) returned to the discharging hospital. Reason for readmission was not significantly associated with location of readmission. In multivariable modeling, the strongest factors associated with readmission to a nonindex hospital were distance from the discharging hospital, transfer‐in during the index
MI
hospitalization, and frequency of nonindex hospital admissions in the year preceding to the index
MI
. Duration of rehospitalization did not differ significantly between patients readmitted to the index versus nonindex hospital (median, 4 versus 3 days;
P
=0.17). Mortality risk was also not significantly different between patients readmitted to the index versus nonindex hospital overall (7.4 versus 7.7%; adjusted odds ratio, 0.89; 95%
CI
, 0.73–1.10) and when stratified by reason for readmission (
P
for interaction=0.61).

Conclusions

Post‐
MI
readmissions did not differ in reason for readmission, duration of rehospitalization, or associated mortality when compared between patients who returned to the discharging hospital and those who sought care elsewhere.
Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction
Authors: Vorasayan Pongpat , Bevers Matthew B. , Beslow Lauren A. , Sze Gordon , Molyneaux Bradley J. , Hinson Holly E. , Simard J. Marc , von Kummer Rüdiger , Sheth Kevin N. , Kimberly W. Taylor
Published: September 2019

Background and Purpose—

Prior studies have shown a linear relationship between computed tomography (CT)–derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke).

Methods—

This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU.

Results—

A median of 3 CT scans (interquartile range, 2–4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20–0.26;
P
<0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (β=−2.80; 95% CI, −5.07 to −0.53;
P
=0.016) and reduced MLS (β=−1.50; 95% CI, −2.71 to −0.28;
P
=0.016). Treatment with intravenous glibenclamide reduced both gray and white matter water uptake. In mediation analysis, gray matter NWU (β=0.15; 95% CI, 0.11–0.20;
P
<0.001) contributed to a greater proportion of MLS mass effect, as compared with white matter NWU (β=0.08; 95% CI, 0.03–0.13;
P
=0.001).

Conclusions—

In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01794182.
Blood Pressure Variability and Cardiovascular Outcomes in Patients With Prior Stroke
Authors: de Havenon Adam , Fino Nora F. , Johnson Brian , Wong Ka-Ho , Majersik Jennifer J. , Tirschwell David , Rost Natalia
Published: September 2019

Background and Purpose—

Every year in the United States, almost 185 000 ischemic strokes occur in patients with a prior stroke. Recurrent stroke has significantly higher morbidity and mortality. Among modifiable risk factors for recurrent stroke, hypertension is the most prevalent. Reducing systolic blood pressure is standard of care for secondary stroke prevention. Recent literature suggests that increased blood pressure variability (BPV) is associated with primary stroke, although studies have not convincingly shown that it is associated with recurrent stroke, which was the goal of this analysis.

Methods—

We conducted a secondary analysis of 17 916 patients in the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial, which is the largest trial of patients with potential recurrent stroke. We calculated BPV and evaluated its effect on recurrent stroke (composite and stratified by ischemic or hemorrhagic stroke), major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure), and all-cause death.

Results—

Both systolic and diastolic BPV were associated with recurrent stroke, major cardiovascular events, and all-cause death. The association with stroke was significant for ischemic, but not hemorrhagic, stroke. For every 10-point increase in BPV (systolic SD, range =0–54.2), the hazard ratio for a recurrent ischemic stroke was 1.15 (95% CI, 1.02–1.32;
P
=0.02), for major cardiovascular events was 1.19 (95% CI, 1.09–1.31;
P
<0.001), and for all-cause death was 1.24 (95% CI, 1.10–1.39;
P
<0.001).

Conclusions—

Our study adds to the growing body of literature suggesting that BPV is an important and potentially modifiable risk factor for ischemic stroke, cardiovascular events, and all-cause death. Specifically, it is the first study to demonstrate that increased BPV is associated with recurrent ischemic stroke and that diastolic BPV can be as important as systolic BPV. Future work should focus on evaluating whether actively reducing BPV, using widely available and inexpensive antihypertensive medications, reduces the risk of cardiovascular disease.
Algorithmic Spatialization Using Object-Based Audio and Indoor Positioning System
Authors: Fan Yuan-Yi
Published: September 2019

The author presents a novel compositional framework to guide designing interplay between moving listeners and sound objects in space. Demonstrated by a case study of interactive octophonic installation, the presented framework offers new ways to articulate and analyze artistic interplay using real-world location context as a spatial composition canvas.
B. Yoma 35b: Some Observations Concerning Divine Mediators and Rabbis
Authors: Basser Herbert W.
Published: September 2019

The familiar “Hillel-meets-his-teachers” tradition (B. Yoma 35b) reveals a deeper story that features mystical, apocalyptic images representing none other than the beloved masters of early rabbinic culture. Here we find the image of a heavenly being enthroned on high that was identified in non-rabbinic circles with God’s demiurge (Enoch, Yehoel, Metatron). This provides evidence that rabbis defused the mystical stories that were leading to two-power challenges to rabbinic authority and to the increasingly antinomian positions of Jews inside and outside of Christian churches. We can therefore appreciate the Rabbis’ portrayal of Torah scholars as embodying true Enochian power.
Cisterns, Waterways, and Rabbis: a Rabbinic Lens into Conflict Avoidance in the Riparian World
Authors: Wachs Meir
Published: September 2019

In the liminal spaces between concretized biblical law and a world in which “every man did what was right in his own eyes” (Judg. 17:6), the Rabbinic tradition developed enactments toward the pursuit of harmony and to minimize conflict. This paper delves into the role of one such mechanism, found throughout the primary sources, in an area of irrigation policy. The article seeks to understand the topic’s contours in the arena of rhetoric vs. reality. I argue that, contrary to initial appearances, the enactment of peace under discussion has every indication of being rooted in its social, legal and natural milieus.
Revolutionary Law Abidance: Kachin Rebel Governance and the Adoption of ihl in Resistance to Myanmar State Violence
Authors: de la Cour Venning Alicia
Published: September 2019

Although armed opposition actors are increasingly prevalent within contemporary conflicts, ethnographies seeking to understand and explain their relationship with international law are scarce. While scholars highlight the state-centric nature of international law, discussing at length how it privileges state over non-state actors, few examine the way rebels perceive and relate to the international legal system. Drawing on seven months of field research among Kachin civil society and the Kachin Independence Organisation / Army (kio/A), this article demonstrates how the kio/A’s nascent engagement with international law is being strategically pursued as part of a broader rebel governance project. Ethnographic research exposes the oft neglected rebel perspective. It reveals how rebels interact with international humanitarian norms as a means to facilitate and mediate relations with both local and international actors, in an attempt to promote nation building aspirations and thereby strengthen resistance to state violence.