bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancement-mode CdS nanobelts field effect transistors and phototransistors with HfO2 passivation
Authors: Peng Meng , Wu Feng , Wang Zhen , Wang Peng , Gong Fan , Long Mingsheng , Chen Changqing , Dai Jiangnan , Hu Weida
Published: March 2019

As typical direct bandgap II–VI semiconductors, quasi-one dimensional CdS nanowires, nanobelts, and nanorods have shown great potential in electronic and optoelectronic applications. However, most nano-scale CdS Field Effect Transistors (FETs) work in the depletion-mode (D-mode) due to the high unintentional n-type doping concentration, which results in high power consumption under off-state. In addition, the large dark current limits to the specific detectivity when they are fabricated into phototransistors. Here, we have synthesized single crystal CdS nanobelts (NBs) on a SiO2/Si substrate via chemical vapor deposition. The CdS NB FETs were fabricated with HfO2 as a passivation layer. It is found that the working mode of the FETs was transformed from the D-mode to the enhancement-mode with the threshold voltage changing from −22.6 to 0.7 V due to the decrease in the defect density. The HfO2 passivated CdS NB phototransistor shows a responsivity of 4.7 × 104 A/W and an ultrahigh detectivity of 9.07 × 1014 Jones at the source-drain voltage of 1 V under an illumination wavelength of 450 nm. Our work demonstrates an effective way to achieve enhancement-mode CdS FETs and high performance phototransistors.
Collisional enhancement of energetic particle Alfvénic resonance width in tokamaks
Authors: White R. B. , Duarte V. N. , Gorelenkov N. N. , Meng G.
Published: March 2019

The phase-space structure of resonances between fast ions and an Alfvénic mode and the associated modification of density profiles in tokamaks are studied as a function of particle collisions. Guiding-center simulations in a realistic tokamak equilibrium are employed to address the resonance broadening parametric dependencies with respect to changes in the pitch-angle scattering rate. The rate of collisional replenishment, along with resonance strength, given by the combination of eigenmode and resonance structures and equilibrium parameters, determines saturation amplitudes for a given damping rate. As seen from the distribution function flattening, collisions have an effect of broadening the resonances, while the absolute value of δf decreases with increasing collisionality. It is observed that the collisional broadening can be comparable to the collisionless resonance width due to the mode amplitude alone. The resonance broadening coefficients are compared with the existing theory based on analytically expected saturation levels, showing fair agreement. The results can be useful in assisting reduced kinetic models, such as quasilinear models, when prescribing the effective resonance phase-space width, i.e., the mode-particle interaction platform, due to collisional or turbulent processes.
Defining the native and naturalised flora for the Australian continent
Authors: Fensham R. J. , Laffineur B.
Published: March 2019

The value of distinguishing between plant species regarded as ‘native’ and ‘alien’ has special relevance in the island continent of Australia, where European settlement was a springboard for human-assisted plant dispersal. The year of European settlement is proposed here as providing a distinction between a ‘native’ and ‘naturalised’ flora and is applied for the entire Australian flora of vascular plants. Herbarium collections and ecological criteria were employed to determine the status of 168 species of ambiguous origin. The date of 1788 proved to be a relatively straightforward criterion to assign native and naturalised status and the origin of only 27 plant species remains ambiguous. The dispersal of plants between continents is an ongoing process but European settlement of the Australian continent represents a very sharp biogeographic event for the Australian flora and provides a straightforward criterion for determining the ‘naturalised’ species.
Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis
Authors: Baragaña Beatriz , Forte Barbara , Choi Ryan , Nakazawa Hewitt Stephen , Bueren-Calabuig Juan A. , Pisco João Pedro , Peet Caroline , Dranow David M. , Robinson David A. , Jansen Chimed , Norcross Neil R. , Vinayak Sumiti , Anderson Mark , Brooks Carrie F. , Cooper Caitlin A. , Damerow Sebastian , Delves Michael , Dowers Karen , Duffy James , Edwards Thomas E. , Hallyburton Irene , Horst Benjamin G. , Hulverson Matthew A. , Ferguson Liam , Jiménez-Díaz María Belén , Jumani Rajiv S. , Lorimer Donald D. , Love Melissa S. , Maher Steven , Matthews Holly , McNamara Case W. , Miller Peter , O’Neill Sandra , Ojo Kayode K. , Osuna-Cabello Maria , Pinto Erika , Post John , Riley Jennifer , Rottmann Matthias , Sanz Laura M. , Scullion Paul , Sharma Arvind , Shepherd Sharon M. , Shishikura Yoko , Simeons Frederick R. C. , Stebbins Erin E. , Stojanovski Laste , Straschil Ursula , Tamaki Fabio K. , Tamjar Jevgenia , Torrie Leah S. , Vantaux Amélie , Witkowski Benoît , Wittlin Sergio , Yogavel Manickam , Zuccotto Fabio , Angulo-Barturen Iñigo , Sinden Robert , Baum Jake , Gamo Francisco-Javier , Mäser Pascal , Kyle Dennis E. , Winzeler Elizabeth A. , Myler Peter J. , Wyatt Paul G. , Floyd David , Matthews David , Sharma Amit , Striepen Boris , Huston Christopher D. , Gray David W. , Fairlamb Alan H. , Pisliakov Andrei V. , Walpole Chris , Read Kevin D. , Van Voorhis Wesley C. , Gilbert Ian H.
Published: March 2019

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage
Plasmodium falciparum
and
Cryptosporidium parvum
in cell-culture studies. Target deconvolution in
P. falciparum
has shown that cladosporin inhibits lysyl-tRNA synthetase (
Pf
KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both
Pf
KRS1 and
C. parvum
KRS (
Cp
KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED
90
= 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between
Pf
KRS1 and
Cp
KRS. This series of compounds inhibit
Cp
KRS and
C. parvum
and
Cryptosporidium hominis
in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for
Pf
KRS1 and
Cp
KRS vs. (human)
Hs
KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.
Strong triaxial coupling and anomalous Poisson effect in collagen networks
Authors: Ban Ehsan , Wang Hailong , Franklin J. Matthew , Liphardt Jan T. , Janmey Paul A. , Shenoy Vivek B.
Published: March 2019

Significance

Networks of collagen fibers are the primary mechanical component of the extracellular matrix of many soft tissues. In common pathological and physiological conditions, collagen networks experience a combination of multiaxial and shear deformation modes. Here, we show that the fibrous nature of the extracellular matrix leads to strong coupling between these modes due to bending, buckling, and stretching of the fibers. We have developed a 3D framework to describe the unusual nonlinear mechanics of these networks, in particular, the abnormally large lateral contraction and concomitant stiffening when stretched. Our model can guide improved design of engineered tissues for regenerative medicine and identify the mechanisms of pathological stiffening of extracellular matrices and their interactions with cells in cancer and fibrosis.
Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies
Authors: Raman Swetha , Beilschmidt Melissa , To Minh , Lin Kevin , Lui Francine , Jmeian Yazen , Ng Mark , Fernandez Minerva , Fu Ying , Mascall Keith , Duque Alejandro , Wang Xiaowei , Pan Guohua , Angers Stephane , Moffat Jason , Sidhu Sachdev S. , Magram Jeanne , Sinclair Angus M. , Fransson Johan , Julien Jean-Philippe
Published: March 2019

Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.
Thermo-metallo-mechanical modelling of heat treatment induced residual stress in Ti–6Al–4V alloy
Authors: Rae W.
Published: March 2019

Residual stress fields dynamically fluctuate throughout the manufacturing process of metallic components and are caused by local misfit of a thermal, mechanical or metallurgical nature. Recent advances have been made in the area of microstructure and residual stress prediction; yet few have considered dual-phase titanium alloys. The aim of the work presented was to carry out a review of the existing state-of-the-art in residual stress modelling with an intended application to industrial heat treatment of Ti–6Al–4V alloy. Four areas were evaluated: thermal, mechanical and metallurgical sub-models, and model validation via residual stress measurement. Recommendations for future research include further investigation of transformation induced plasticity and stress relaxation behaviour in Ti–6Al–4V.

This review was submitted as part of the 2019 Materials Literature Review Prize of the Institute of Materials, Minerals and Mining run by the Editorial Board of MST. Sponsorship of the prize by TWI Ltd is gratefully acknowledged.
Propagation of longitudinal and bulk waves in shock-loaded transversally isotropic single crystals
Authors: Nikolaevna Krivosheina Marina , Viktorovich Kobenko Sergey , Vladimirovna Tuch Elena , Aleksandrovich Kashin Oleg , Ivanovich Lotkov Aleksander , Andreevich Khon Yurii
Published: March 2019

The paper is present 3D numerical simulation data on elastoplastic deformation in auxetic single crystals with account of anisotropic pressure. The use of anisotropic pressure allows us to demonstrate the absence of shock wave splitting into an elastic precursor and a plastic wave in a Zn single crystal in the loading direction [0001]. This effect in Zn single crystals is observed in full-scale experiments at any loading rate in the [0001] direction. It is shown that anisotropic pressure should be entered into mathematical models of materials whose elastic properties are characterised by five and more independent elastic constants and hence by bulk compression anisotropy. The use of isotropic pressure in simulating the deformation of such materials leads to nonphysical results.
Designing a rigorous microscopy experiment: Validating methods and avoiding bias
Authors: Jost Anna Payne-Tobin , Waters Jennifer C.
Published: March 2019

Images generated by a microscope are never a perfect representation of the biological specimen. Microscopes and specimen preparation methods are prone to error and can impart images with unintended attributes that might be misconstrued as belonging to the biological specimen. In addition, our brains are wired to quickly interpret what we see, and with an unconscious bias toward that which makes the most sense to us based on our current understanding. Unaddressed errors in microscopy images combined with the bias we bring to visual interpretation of images can lead to false conclusions and irreproducible imaging data. Here we review important aspects of designing a rigorous light microscopy experiment: validation of methods used to prepare samples and of imaging system performance, identification and correction of errors, and strategies for avoiding bias in the acquisition and analysis of images.
Topology optimization of self-sensing nanocomposite structures with designed boundary conditions
Authors: Seifert Ryan , Patil Mayuresh , Seidel Gary
Published: March 2019

Controlling volume fractions of nanoparticles in a matrix can have a substantial influence on composite performance. This paper presents a topology optimization algorithm that designs nanocomposite structures for objectives pertaining to stiffness and strain sensing. Local effective properties are obtained by controlling local volume fractions of carbon nanotubes (CNTs) in an epoxy matrix, which are assumed to be well dispersed and randomly oriented. The method is applied to the optimization of a plate with a hole structure. Several different allowable CNT volume fraction constraints are examined, and the results show a tradeoff in preferred CNT distributions for the two objectives. It is hypothesized that the electrode location plays an important role in the strain sensing performance, and a surrogate model is developed to incorporate the electrode boundary as a set of additional design variables. It is shown that optimizing the topology and boundary electrode location together leads to further improvements in resistance change.
Engineering tunable local loss in a synthetic lattice of momentum states
Authors: Lapp Samantha , Ang’ong’a Jackson , An Fangzhao Alex , Gadway Bryce
Published: March 2019

Dissipation can serve as a powerful resource for controlling the behavior of open quantum systems. Recently there has been a surge of interest in the influence of dissipative coupling on large quantum systems and, more specifically, how these processes can influence band topology and phenomena like many-body localization. Here, we explore the engineering of local, tunable dissipation in so-called synthetic lattices, arrays of quantum states that are parametrically coupled in a fashion analogous to quantum tunneling. Considering the specific case of momentum-state lattices, we investigate two distinct mechanisms for engineering controlled loss: one relying on an explicit form of dissipation by spontaneous emission, and another relying on reversible coupling to a large reservoir of unoccupied states. We experimentally implement the latter and demonstrate the ability to tune the local loss coefficient over a large range. The introduction of controlled loss to the synthetic lattice toolbox promises to pave the way for studying the interplay of dissipation with topology, disorder, and interactions.
An infinitely generated self-similar set with positive Lebesgue measure and empty interior
Authors: Baker Simon , Sidorov Nikita
Published: March 2019

In [Problems on self-similar sets and self-affine sets: An update, Birkhäuser, Basel, 2000] Peres and Solomyak ask the question: Do there exist self-similar sets with positive Lebesgue measure and empty interior? This question was answered in the affirmative by Csörnyei et al. in 2006. The authors of that paper gave a parameterised family of iterated function systems for which almost all of the corresponding self-similar sets satisfied the required properties. They did not however provide an explicit example. Motivated by a desire to construct an explicit example, we provide an explicit construction of an infinitely generated self-similar set with positive Lebesgue measure and empty interior.
Normalized solutions to the mixed dispersion nonlinear Schrödinger equation in the mass critical and supercritical regime
Authors: Bonheure Denis , Casteras Jean-Baptiste , Gou Tianxiang , Jeanjean Louis
Published: March 2019

In this paper, we study the existence of solutions to the mixed dispersion nonlinear Schrödinger equation
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="gamma normal upper Delta squared u minus normal upper Delta u plus alpha u equals StartAbsoluteValue u EndAbsoluteValue Superscript 2 sigma Baseline u comma u element-of upper H squared left-parenthesis double-struck upper R Superscript upper N Baseline right-parenthesis comma">

γ

Δ
2

u
−
Δ
u
+
α
u
=

|

u

|

2
σ

u
,

u
∈

H
2

(

R

N

)
,

\gamma \Delta ^2 u -\Delta u + \alpha u=|u|^{2 \sigma } u, \qquad u \in H^2({\mathbb {R}}^N),

\]
under the constraint
\[

∫

R

N

|

u

|

2

d
x
=
c
>
0.

\int _{{\mathbb {R}}^N}|u|^2 \, dx =c>0.

\]
We assume that
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="gamma greater-than 0 comma upper N greater-than-or-equal-to 1 comma 4 less-than-or-equal-to sigma upper N greater-than StartFraction 4 upper N Over left-parenthesis upper N minus 4 right-parenthesis Superscript plus Baseline EndFraction">

γ
>
0
,
N
≥
1
,
4
≤
σ
N
>

4
N

(
N
−
4

)
+

\gamma >0, N \geq 1, 4 \leq \sigma N > \frac {4N}{(N-4)^+}

, whereas the parameter

α
∈

R

\alpha \in {\mathbb {R}}

will appear as a Lagrange multiplier. Given

c
∈

R

+

c \in {\mathbb {R}}^+

, we consider several questions including the existence of ground states and of positive solutions and the multiplicity of radial solutions. We also discuss the stability of the standing waves of the associated dispersive equation.
Drosophila p53 directs nonapoptotic programs in postmitotic tissue
Authors: Kurtz Paula , Jones Amanda E. , Tiwari Bhavana , Link Nichole , Wylie Annika , Tracy Charles , Krämer Helmut , Abrams John M.
Published: March 2019

TP53 is the most frequently mutated gene in human cancers, and despite intensive research efforts, genome-scale studies of p53 function in whole animal models are rare. The need for such in vivo studies is underscored by recent challenges to established paradigms, indicating that unappreciated p53 functions contribute to cancer prevention. Here we leveraged the Drosophila system to interrogate p53 function in a postmitotic context. In the developing embryo, p53 robustly activates important apoptotic genes in response to radiation-induced DNA damage. We recently showed that a p53 enhancer (p53RErpr) near the cell death gene reaper forms chromatin contacts and enables p53 target activation across long genomic distances. Interestingly, we found that this canonical p53 apoptotic program fails to activate in adult heads. Moreover, this failure to exhibit apoptotic responses was not associated with altered chromatin contacts. Instead, we determined that p53 does not occupy the p53RErpr enhancer in this postmitotic tissue as it does in embryos. Through comparative RNA-seq and chromatin immunoprecipitation–seq studies of developing and postmitotic tissues, we further determined that p53 regulates distinct transcriptional programs in adult heads, including DNA repair, metabolism, and proteolysis genes. Strikingly, in the postmitotic context, p53-binding landscapes were poorly correlated with nearby transcriptional effects, raising the possibility that p53 enhancers could be generally acting through long distances.
Diastolic Reverse Dipping Pattern Is the Predictor for the Echocardiographic Changes in the Untreated Masked Hypertensive Patients
Authors: Li Jianhao , Cao Yalin , Liu Chen , Li Jiayong , Yao Fengjuan , Dong Yugang , Huang Huiling
Published: March 2019

BACKGROUND

The prognostic value of the dipping categories of diastolic blood pressure (DBP) is unknown. This study aimed to investigate the association between DBP dipping categories of diastolic blood pressure and echocardiographic changes in untreated masked hypertension (MH) patients.

METHODS

This retrospective study included 721 untreated MH patients between June 2006 and June 2016. Nocturnal dipping categories were defined according to the percentage decrease in nocturnal blood pressure (BP) compared to daytime BP as follows: non-dipping: decrease 0% to <10%, dipping: decrease 10% to 20%, reverse dipping: decrease <0%, and extreme dipping: decrease >20%. The echocardiographic findings were analyzed.

RESULTS

The 4 echocardiographic parameters (left atrium [LA] dimension, interventricular septum [IVS] thickness, linear left ventricular end-diastolic dimension [LVEDD], and left ventricular [LV] mass) were significantly different among the 4 DBP dipping categories. Multivariate linear regression analysis showed that DBP reverse dipping pattern was associated with higher IVS thickness (B: 0.53, 95% CI: 0.24 to 0.82; P < 0.001) and LV mass (B: 12.36, 95% CI: 2.38 to 22.35; P = 0.015), whereas DBP extreme dipping was associated with lower LVEDD (B: −7.05, 95% CI: −11.30 to −2.80; P = 0.001).The nocturnal systolic hypertension was associated with higher IVS thickness (B: 0.42, 95% CI: 0.14 to 0.71; P = 0.003) and LV mass (B:14.21, 95% CI: 4.54 to 23.88; P = 0.004). The nocturnal systolic blood pressure was associated with LA dimension, IVS thickness, left ventricular posterior wall thickness, and LV mass (all Ps < 0.05).

CONCLUSIONS

These results suggest that specific DBP dipping categories and nocturnal systolic hypertension were the predictive factors for the echocardiographic changes in untreated MH patients.
Gatekeeping Stories of Dissent and Mobility
Authors: Pérez-Torres Rafael
Published: March 2019

Three new studies consider the significance of storytelling in a Latinx and hemispheric American context around the turn of the millennium. Where neoliberal policies seem to position ethnoracial subjectivities in realms of social abjection or racial containment, these studies contribute to interdisciplinary conversations about racial affiliation, economic aspiration, and political dissent in literature. Each considers writers either engaging complex negotiations between racial and class affiliations, challenging social expectations for cultural products in an ethnic marketplace, or speaking against repressive governmental regimes. Each weighs a hope for transformative social change against the efficient, impersonal, even brutal management of modern ethnoracial otherness. Elda Román analyzes stories about upward mobility for racially or ethnically identified characters who strive to maintain a critical sense of racial affiliation while seeking greater social and class mobility. Since forms like magical realism often mark the ethnic identification of an author, Christopher González considers how unexpected or challenging narrations break down restrictive perceptions of what Latinx literature can be. Theresa Longo, deliberating over a radical Latin American literature of dissent distributed to US audiences by small publishing houses, sketches an intellectual history of radical thought in the Americas that has informed a dominant strain of US Latinx criticism.
An Examination of Semantic Impairment in Amnestic MCI and AD: What Can We Learn From Verbal Fluency?
Authors: Chasles M -J , Tremblay A , Escudier F , Lajeunesse A , Benoit S , Langlois R , Joubert S , Rouleau I
Published: March 2019

Introduction

The Verbal Fluency Test (VF) is commonly used in neuropsychology. Some studies have demonstrated a marked impairment of semantic VF compared to phonemic VF in Alzheimer’s disease (AD). Since amnestic Mild Cognitive Impairment (aMCI) is associated with increased risk of conversion to incident AD, it is relevant to examine whether a similar impairment is observed in this population. The objective of the present empirical study is to compare VF performance of aMCI patients to those of AD and elderly controls matched one-to-one for age and education.

Method

Ninety-six participants divided into three equal groups (N = 32: AD, aMCI and Controls) were included in this study. Participants in each group were, on average, 76 years of age and had 13 years of education. A repeated measures ANOVA with the Group (AD, aMCI, NC) as between-subject factor and the Fluency condition (“P” and “animals”) as within-subject factor was performed. T-tests and simple ANOVAs were also conducted to examine the interaction.

Results

There was a significant interaction between the groups and the verbal fluency condition. In AD, significantly fewer words were produced in both conditions. In contrast, participants with aMCI demonstrated a pattern similar to controls in the phonemic condition, but generated significantly fewer words in the semantic condition.

Conclusion

These results indicate a semantic memory impairment in aMCI revealed by a simple, commonly-used neuropsychological test. Future studies are needed to investigate if semantic fluency deficits can help predict future conversion to AD.
Microfluidic devices for embryonic and larval zebrafish studies
Authors: Khalili Arezoo , Rezai Pouya
Published: March 2019

Zebrafish or Danio rerio is an established model organism for studying the genetic, neuronal and behavioral bases of diseases and for toxicology and drug screening. The embryonic and larval stages of zebrafish have been used extensively in fundamental and applied research due to advantages offered such as body transparency, small size, low cost of cultivation and high genetic homology with humans. However, the manual experimental methods used for handling and investigating this organism are limited due to their low throughput, labor intensiveness and inaccuracy in delivering external stimuli to the zebrafish while quantifying various neuronal and behavioral responses. Microfluidic and lab-on-a-chip devices have emerged as ideal technologies to overcome these challenges. In this review paper, the current microfluidic approaches for investigation of behavior and neurobiology of zebrafish at embryonic and larval stages will be reviewed. Our focus will be to provide an overview of the microfluidic methods used to manipulate (deliver and orient), immobilize and expose or inject zebrafish embryos or larvae, followed by quantification of their responses in terms of neuron activities and movement. We will also provide our opinion in terms of the direction that the field of zebrafish microfluidics is heading toward in the area of biomedical engineering.
Dissecting differential signals in high-throughput data from complex tissues
Authors: Li Ziyi , Wu Zhijin , Jin Peng , Wu Hao
Published: March 2019

Motivation

Samples from clinical practices are often mixtures of different cell types. The high-throughput data obtained from these samples are thus mixed signals. The cell mixture brings complications to data analysis, and will lead to biased results if not properly accounted for.

Results

We develop a method to model the high-throughput data from mixed, heterogeneous samples, and to detect differential signals. Our method allows flexible statistical inference for detecting a variety of cell-type specific changes. Extensive simulation studies and analyses of two real datasets demonstrate the favorable performance of our proposed method compared with existing ones serving similar purpose.

Availability and implementation

The proposed method is implemented as an R package and is freely available on GitHub (https://github.com/ziyili20/TOAST).

Supplementary information

Supplementary data are available at Bioinformatics online.
Modeling Regional Transmission and Containment of a Healthcare-associated Multidrug-resistant Organism
Authors: Paul Prabasaj , Slayton Rachel B , Kallen Alexander J , Walters Maroya S , Jernigan John A
Published: March 2019

Background

The Centers for Disease Control and Prevention (CDC) recently published interim guidance for a public health response to contain novel or targeted multidrug-resistant organisms (MDROs). We assessed the impact of implementing the strategy in a US state using a mathematical model.

Methods

We used a deterministic compartmental model, parametrized via a novel analysis of carbapenem-resistant Enterobacteriaceae data reported to the National Healthcare Safety Network and patient transfer data from the Centers for Medicare and Medicaid Services. The simulations assumed that after the importation of the MDRO and its initial detection by clinical culture at an index hospital, fortnightly prevalence surveys for colonization and additional infection control interventions were implemented at the index facility; similar surveys were then also implemented at those facilities known to be connected most strongly to it as measured by patient transfer data; and prevalence surveys were discontinued after 2 consecutive negative surveys.

Results

If additional infection-control interventions are assumed to lead to a 20% reduction in transmissibility in intervention facilities, prevalent case count in the state 3 years after importation would be reduced by 76% (interquartile range: 73–77%). During the third year, these additional infection-control measures would be applied in facilities accounting for 42% (37–46%) of inpatient days.

Conclusions

CDC guidance for containing MDROs, when used in combination with information on transfer of patients among hospitals, is predicted to be effective, enabling targeted and efficient use of prevention resources during an outbreak response. Even modestly effective infection-control measures may lead to a substantial reduction in transmission events.
Clinical Correlates of Human Immunodeficiency Virus–1 (HIV-1) DNA and Inducible HIV-1 RNA Reservoirs in Peripheral Blood in Children With Perinatally Acquired HIV-1 Infection With Sustained Virologic Suppression for at Least 5 Years
Authors: Bitnun Ari , Ransy Doris G , Brophy Jason , Kakkar Fatima , Hawkes Michael , Samson Lindy , Annabi Bayader , Pagliuzza Amélie , Morand Jacob-Adams , Sauve Laura , Chomont Nicolas , Lavoie Stephanie , Kim John , Sandstrom Paul , Wender Paul A , Lee Terry , Singer Joel , Read Stanley E , Soudeyns Hugo ,   Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) Research Group, Ariane Alimenti , Petronela Ancuta , Ari Bitnun , Jason Brophy , Jared Bullard , Tae-Wook Chun , Hélène C F Côté , Joanne Embree , Michael T Hawkes , Fatima Kakkar , Christos Karatzios , Rupert Kaul , John Kim , Valérie Lamarre , Normand Lapointe , Pascal Lavoie , Terry Lee , Deborah M Money , Dorothy Moore , Stanley Read , Robert Reinhard , Lindy Samson , Paul Sandstorm , Laura Sauve , Sandra Seigel , Joel Singer , Hugo Soudeyns , Ben Tan , Wendy Vaudry
Published: March 2019

Background

The Early Pediatric Initiation Canada Child Cure Cohort (EPIC4) study is a prospective, multicenter, Canadian cohort study investigating human immunodeficiency virus–1 (HIV-1) reservoirs, chronic inflammation, and immune responses in children with perinatally acquired HIV-1 infection. The focus of this report is HIV-1 reservoirs and correlates in the peripheral blood of children who achieved sustained virologic suppression (SVS) for ≥5 years.

Methods

HIV-1 reservoirs were determined by measuring HIV-1 DNA in peripheral blood mononuclear cells and inducible cell-free HIV-1 RNA in CD4+ T-cells by a prostratin analogue stimulation assay. HIV serology was quantified by signal-to-cutoff ratio (S/CO).

Results

Of 228 enrolled participants, 69 achieved SVS for ≥5 years. HIV-1 DNA, inducible cell-free HIV-1 RNA, and S/COs correlated directly with the age of effective combination antiretroviral therapy (cART) initiation (P < .001, P = .036, and P < .001, respectively) and age when SVS was achieved (P = .002, P = .038, and P < .001, respectively) and inversely with the proportion of life spent on effective cART (P < .001, P = .01, and P < .001, respectively) and proportion of life spent with SVS (P < .001, P = .079, and P < .001, respectively). Inducible cell-free HIV-1 RNA correlated with HIV-1 DNA, most particularly in children with SVS, without virologic blips, that was achieved with the first cART regimen initiated prior to 6 months of age (rho = 0.74; P = .037) or later (rho = 0.87; P < .001). S/COs correlated with HIV-1 DNA (P = .003), but less so with inducible cell-free HIV-1 RNA (P = .09).

Conclusions

The prostratin analogue stimulation assay, with its lower blood volume requirement, could be a valuable method for evaluating inducible HIV-1 reservoirs in children. Standard commercial HIV serology may be a practical initial indirect measure of reservoir size in the peripheral blood of children with perinatally acquired HIV-1 infection.
The prevalence and role of coping strategies in the nutritional intake of children born with esophageal atresia: a condition-specific approach
Authors: Dellenmark-Blom M , Chaplin J E , Quitmann J H , Jönsson L , Gatzinsky V , Dingemann J , Abrahamsson K
Published: March 2019

This study describes results of a condition-specific approach to the assessment of coping strategies in nutritional intake situations used by children with esophageal atresia. One hundred three families of children 2–17 years old with esophageal atresia participated (94% response rate). Following standardized focus groups with 30 families, nine coping items were developed, reflecting nine different coping strategies in nutritional intake situations. The coping items were pilot tested by 73 new families and evaluated for feasibility, validity, and reliability. The families also completed a validated condition-specific quality-of-life questionnaire for children with esophageal atresia, which included the scale Eating-Quality-of-life. Data were analyzed using descriptives, between-group analysis, and Spearman's rho (P < 0.05). Altogether, the coping items were feasible, valid, and reliable. Items reflecting problem-focused strategies revealed that 89% of 2–17 years old ‘recognized their responsibility’ and managed nutritional intake problems on their own, 79% ‘tried to solve their feeding problems’ testing different solutions, 79% took a ‘confronting approach’ to do what peers did in eating situations, and 54% ‘sought other people's support’. Items reflecting emotion-focused strategies showed that 86% of the children ‘accepted’ their feeding difficulties, 68% ‘reappraised feeding difficulties into positive outcomes’ such as to eat only when food tasted good. Moreover, 63% of the children ‘avoided’ nutritional intake situations, 29% ‘expressed worry or fear’ when faced with these situations, while 25% ‘distanced’ themselves from eating problems by hiding or throwing away food. The children's use of coping strategies were mostly related to the existence of digestive symptoms (P < 0.05). Positive and negative coping strategies were identified. Of particular note was a correlation cluster of the so-called disengagement strategies ‘avoidance’, ‘expression of emotional concerns’ and ‘distancing’. These strategies were negatively correlated with Eating-Quality-of-Life. Conversely, taking a ‘confronting approach’ correlated positively with Eating-Quality-of-life (P < 0.05). Hence, most children with esophageal atresia employ various coping strategies in nutritional intake situations. A good Eating-Quality-of-life may be positively affected by treating digestive morbidity and encouraging children to take an active approach to their eating problems rather than using disengagement coping.
A simple scoring system to predict early recurrence of Bismuth–Corlette type IV perihilar cholangiocarcinoma
Authors: Peng Ding-Zhong , Lu Jiong , Li Bei , Hu Hai-Jie , Ye Xi-Wen , Xiong Xian-Ze , Cheng Nan-Sheng
Published: March 2019

Background

Early recurrence has been reported to be predictive of a poor prognosis for patients with perihilar cholangiocarcinoma (pCCA) after resection. The objective of our study was to construct a useful scoring system to predict early recurrence for Bismuth–Corlette type IV pCCA patients in clinic and to investigate the value of early recurrence in directing post-operative surveillance and adjuvant therapy.

Methods

In total, 244 patients who underwent radical resection for type IV pCCA were included. Data on clinicopathological characteristics, perioperative details and survival outcomes were analyzed. Survival curves were generated using the Kaplan–Meier method. Univariate and multivariate logistic-regression models were used to identify factors associated with early recurrence.

Results

Twenty-one months was defined as the cutoff point to distinguish between early and late recurrence. Univariate and multivariate analysis revealed that CA19-9 level >200 U/mL, R1 resection margin, higher N category and positive lymphovascular invasion were independent predictors of early recurrence. The scoring system was constructed accordingly. The early-recurrence rates of patients with scores of 0, 1, 2, 3, 4, and 5 were 23.9%, 38.7%, 60.0%, 78.6%, 83.4%, and 100%, respectively. Adjuvant therapy was significantly associated with higher overall survival rate for patients with early recurrence, but not for those with late recurrence. Patients in the early-recurrence group with scores ≥2 had better prognoses after adjuvant therapy.

Conclusions

A simple scoring system using CA19-9 level, N category, resection margin and lymphovascular invasion status could predict early recurrence, and thus might direct post-operative surveillance and adjuvant therapy for patients with type IV pCCA.
Outer trench slope flexure and faulting at Pacific basin subduction zones
Authors: Garcia Emmanuel Soliman M , Sandwell David T , Bassett Dan
Published: March 2019

Flexure and fracturing of the seafloor on the outer trench wall of subduction zones reflect bending of the lithosphere beyond its elastic limit. To investigate these inelastic processes, we have developed a full nonlinear inversion approach for estimating the bending moment, curvature and outer trench wall fracturing using shipboard bathymetry and satellite altimetry-derived gravity data as constraints. Bending moments and downward forces are imposed along curved trench axes and an iterative method is used to calculate the nonlinear response for 26 sites in the circum-Pacific region having seafloor age ranging from 15 to 148 Ma. We use standard thermal and yield strength envelope models to develop the nonlinear moment versus curvature relationship. Two coefficients of friction of 0.6 and 0.3 are considered and we find that the lower value provides a better overall fit to the data. The main result is that the lithosphere is nearly moment saturated at the trench axis. The effective elastic thickness of the plate on the outer trench slope is at least three times smaller than the elastic thickness of the plate before bending at the outer rise in agreement with previous studies. The average seafloor depth of the unbent plate in these 26 sites matches the Parsons & Sclater depth versus age model beyond 120 Ma. We also use the model to predict the offsets of normal faults on the outer trench walls and compare this with the horst and graben structures observed by multibeam surveys. The model with the lower coefficient of friction fits the fault offset data close to the trench axis. However, the model predicts significant fracturing of the lithosphere between 75 and 150 km away from the trench axis where no fracturing is observed. To reconcile these observations, we impose a thermoelastic pre-stress in the lithosphere prior to subduction. This pre-stress delays the onset of fracturing in better agreement with the data.
The Inflammatory Bowel Disease Drug Azathioprine Induces Autophagy via mTORC1 and the Unfolded Protein Response Sensor PERK
Authors: Hooper Kirsty M , Casanova Victor , Kemp Sadie , Staines Katherine A , Satsangi Jack , Barlow Peter G , Henderson Paul , Stevens Craig
Published: March 2019

Background

Genetic studies have strongly linked autophagy to Crohn’s disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process.

Methods

Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by polymerase chain reaction (PCR) array with changes in signaling pathways examined by immunoblot and quantitative reverse transcription PCR (RT-qPCR). Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) were evaluated by gentamicin protection assays and RT-qPCR, respectively. The marker LC3 was analyzed in peripheral blood mononuclear cells (PBMCs) from pediatric patients by flow cytometry.

Results

Azathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNFα. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy.

Conclusions

Modulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic efficacy of azathioprine in IBD.
Antibacterial prescription in Italian preschool children: analysis of 7 years of data from the Emilia-Romagna region reimbursement database
Authors: D’Annibali Ottavio , Bonaldo Giulia , Donati Monia , Småbrekke Lars , Motola Domenico , Vaccheri Alberto
Published: March 2019

Objectives

To describe antibacterial prescribing patterns in outpatients aged 0–5 years from 2007 to 2013 in the Emilia-Romagna region, assessing sex- and age-specific consumption over time.

Methods

All children aged 0–5 years resident in the Emilia-Romagna region who received at least one prescription of a systemic antibacterial in the period 2007–13 were enrolled. The prescriptions of systemic antibacterials to children were collected from the regional prescription database. Data were stratified by year, sex and age, and analysed in terms of periodic prevalence and of annual prescription rate per 1000 person-years.

Results

The prevalence of children receiving at least one prescription per year varied from 68.0% in 2007 to 59.0% in 2013, while the average prevalence of children receiving five or more prescriptions per year was 6.96%. The annual prescription rate varied from 1621.26 in 2007 to 1372.27 in 2013. Penicillins + β-lactamase inhibitors accounted for 35.3% of total prescriptions, followed by extended-spectrum penicillins (28.6%), macrolides (17.0%) and third-generation cephalosporins (13.9%).

Conclusions

Despite recommendations, a significant overprescription of antibacterials to children still exists, showing no satisfactory improvements over the years. In contrast to Northern European countries, adherence to evidence-based guidelines was poor, with frequent prescribing of broad-spectrum agents for the treatment of mostly viral childhood infectious disease.
Susceptibility of Corn Earworm (Lepidoptera: Noctuidae) to Cry1A.105 and Cry2Ab2 in North and South Carolina
Authors: Bilbo Tom R , Reay-Jones Francis P F , Reisig Dominic D , Greene Jeremy K
Published: March 2019

The corn earworm, Helicoverpa zea (Boddie), is managed in corn and cotton in the United States primarily using transgenic cultivars that produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt). However, increasing reports of resistance to one or more Bt proteins threaten the continued efficacy of Bt traits. To better understand the development of resistance of H. zea to Bt corn and cotton in the southeastern United States, we monitored for resistance to Cry1A.105 and Cry2Ab2 among 22 field populations of H. zea collected in non-Bt and Bt corn expressing Cry1A.105 + Cry2Ab2 during 2017 and 2018. Colonies were established in the laboratory and progeny were screened in diet-overlay bioassays to purified Cry1A.105 and Cry2Ab2 proteins. Compared with two susceptible laboratory colonies, all 14 field colonies tested with Cry1A.105 were highly resistant, with resistance ratios (RRs) ranging from 13.5 to >4,000. For Cry2Ab2, 19 colonies were tested and RRs ranged from 0.26 to 33.7. Field populations were significantly more susceptible to Cry2Ab2 than Cry1A.105. We documented variability in F0 and F1 pupal weight and developmental rates of natural populations of H. zea, but observed no significant correlation with susceptibility to either Cry1A.105 or Cry2Ab2. Our results expand on the recent reports of H. zea resistance to Cry1A and Cry2A proteins and will aid in the design and deployment of future pyramided crops in the United States.
The Speed of Exchange Rate Pass-Through
Authors: Bonadio Barthélémy , Fischer Andreas M , Sauré Philip
Published: March 2019

On January 15, 2015, the Swiss National Bank discontinued its minimum exchange rate policy of 1 euro against 1.2 Swiss francs. This policy change resulted in a sharp, unanticipated, and permanent appreciation of the Swiss franc by more than 11% against the euro. We analyze the pass-through of this unusually clean exchange rate shock into import unit values at the daily frequency using Swiss transaction-level trade data. Our key findings are twofold. First, for goods invoiced in euros, the pass-through is immediate and complete. Second, for goods invoiced in Swiss francs, the pass-through is partial and exceptionally fast: beginning on the second working day after the exchange rate shock, the medium-run pass-through is reached after 12 working days.
Osimertinib for patients with EGFR T790M mutation-positive non–small-cell lung cancer and a poor performance status
Authors: Nakashima Kazuhisa , Kimura Madoka , Akamatsu Hiroaki , Daga Haruko , Imai Hisao , Taira Tetsuhiko , Ko Ryo , Hisamatsu Yasushi , Nishino Kazumi , Sugimoto Takeya , Miyashita Yosuke , Takahashi Toshiaki ,   et al
Published: March 2019

Background

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against EGFR T790M mutation-positive non–small-cell lung cancer (NSCLC) in patients who have good performance status (PS). However, the efficacy and safety of osimertinib for patients with poor PS is unknown.

Methods

We retrospectively evaluated the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2–4 and who were administered 80 mg of osimertinib once daily between March 2016 and February 2017.

Results

Thirty patients (8 men and 22 women) with EGFR T790M mutation-positive NSCLC were evaluated; their median age was 66 years (range: 39–89 years). Twenty-four and six patients had PS scores of 2 and 3, respectively; none had a PS score of 4. All patients had previously been treated with first- or second-generation EGFR-TKIs. T790M was detected in the tumor samples of 23 patients, the blood samples of two patients, and both the tumor and blood samples of five patients. The overall response rate was 53% (95% confidence interval: 36–70%), and the PS score improvement rate was 63%. The median progression-free survival was 8.2 months (95% confidence interval: 4.3–13.2 months), while the median overall survival time was not reached. No patient required treatment cessation owing to adverse events, and no treatment-related deaths occurred.

Conclusions

Osimertinib therapy demonstrates promising efficacy and acceptable safety in patients with EGFR T790M mutation-positive NSCLC who have poor PS.