bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic performance and costs of contingent screening models for trisomy 21 incorporating non‐invasive prenatal testing
Authors: Maxwell Susannah , O'Leary Peter , Dickinson Jan E. , Suthers Graeme K.
Published: March 2017

Background

Contingent screening for trisomy 21 using non‐invasive prenatal testing has the potential to reduce invasive diagnostic testing and increase the detection of trisomy 21.

Aim

To describe the diagnostic and economic performance of prenatal screening models for trisomy 21 that use non‐invasive prenatal testing as a contingent screen across a range of combined first trimester screening risk cut‐offs from a public health system perspective.

Methods

Using a hypothetical cohort of 300 000 pregnancies, we modelled the outcomes of 25 contingent non‐invasive prenatal testing screening models and compared these to conventional screening, offering women with a high‐risk (1 > 300) combined first trimester screening result an invasive test. The 25 models used a range of risk cut‐offs. High‐risk women were offered invasive testing. Intermediate‐risk women were offered non‐invasive prenatal testing. We report the cost of each model, detection rate, costs per diagnosis, invasive tests per diagnosis and the number of fetal losses per diagnosis.

Results

The cost per prenatal diagnosis of trisomy 21 using the conventional model was $51 876 compared to the contingent models which varied from $49 309–66 686. The number of diagnoses and cost per diagnosis increased as the intermediate‐risk threshold was lowered. Results were sensitive to trisomy 21 incidence, uptake of testing and cost of non‐invasive prenatal testing.

Conclusion

Contingent non‐invasive prenatal testing models using more sensitive combined first trimester screening risk cut‐offs than conventional screening improved the detection rate of trisomy 21, reduced procedure‐related fetal loss and could potentially be provided at a lower cost per diagnosis than conventional screening.
Who is and isn't having babies with Down syndrome in western Sydney: a ten year hospital cohort study
Authors: Moses Rebecca M. , Brown James H.W. , Wright Dale C. , Diplock Hayley , Melov Sarah J. , McGee Therese Mary
Published: March 2017

Background

Screening for Down syndrome (DS) is a key component of antenatal care, recommended to be universally offered to women irrespective of age or background. Despite this, the diagnosis of DS is often not made until the neonatal period.

Aims

To retrospectively describe and compare the differences in populations with an antenatal diagnosis (AD) and neonatal diagnosis (ND) of DS and to explore why an antenatal diagnosis was not made.

Materials and methods

The cohorts were women cared for at Westmead Hospital whose pregnancy received a diagnosis of DS between 2006 and 2015. The demographic variables of the AD and ND cohorts were examined and reasons why an antenatal diagnosis was not made in the ND cohort were analysed.

Results

There were 127 diagnoses of DS in the 10‐year period, of which 41% were in the ND cohort (n = 52) and 59% in the AD (n = 75). Declaring a religious affiliation rather than Nil Religion was significantly more common in the ND cohort (88.5%) and especially the ND sub‐cohort who declined DS screening/testing (95.8%) than the AD cohort (72%, P < 0.05). Women who were not offered screening were significantly younger (P < 0.001) than those who were, with 69% and 20% being ≤30 years, respectively.

Conclusions

The proportion of DS pregnancies diagnosed in the antenatal period in western Sydney could be increased by ensuring younger women are not falsely reassured that DS screening is unnecessary for them. While religious affiliation may be a factor when women decline screening, ensuring appropriate counselling remains important.
Autoinhibitory properties of the parent but not of the N‐oxide metabolite contribute to infusion rate‐dependent voriconazole pharmacokinetics
Authors: Hohmann Nicolas , Kreuter Rebecca , Blank Antje , Weiss Johanna , Burhenne Jürgen , Haefeli Walter E. , Mikus Gerd
Published: March 2017

Aims

The pharmacokinetics of voriconazole show a nonlinear dose–exposure relationship caused by inhibition of its own CYP3A‐dependent metabolism. Because the magnitude of autoinhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated.

Methods

Twelve healthy participants received 100 mg voriconazole intravenous over 4 h, 400 mg over 6 h, 4 h, and 2 h in a crossover design. Oral midazolam (3 μg) was given at the end of infusion. Blood and urine samples were collected up to 48 h. Voriconazole and its N‐oxide metabolite were quantified using high‐performance liquid chromatography coupled to tandem mass spectrometry. Midazolam estimated metabolic clearance (eCLmet) was calculated using a limited sampling strategy. Voriconazole‐N‐oxide inhibition of cytochrome P450 (CYP) isoforms 2C19 and 3A4 were assessed with the P450‐Glo luminescence assay.

Results

Area under the concentration–time curve for 400 mg intravenous voriconazole was 16% (90% confidence interval: 12–20%) lower when administered over 6 h compared to 2 h infusion. Dose‐corrected area under the concentration–time curve for 100 mg over 4 h was 34% lower compared to 400 mg over 4 h. Midazolam eCLmet was 516 ml min–1 (420–640) following 100 mg 4 h–1 voriconazole, 152 ml min–1 (139–166) for 400 mg 6 h–1, 192 ml min–1 (167–220) for 400 mg 4 h−1, and 202 ml min–1 (189–217) for 400 mg 2 h–1. Concentration giving 50% CYP inhibition of voriconazole N‐oxide was 146 ± 23 μmol l–1 for CYP3A4, and 40.2 ± 4.2 μmol l–1 for CYP2C19.

Conclusions

Voriconazole pharmacokinetics is modulated by infusion rate, an autoinhibitory contribution voriconazole metabolism by CYP3A and 2C19 and to a lesser extent its main N‐oxide metabolite for CYP2C19. To avoid reduced exposure, the infusion rate should be 2 h.
Cost‐effectiveness of a new urinary biomarker‐based risk score compared to standard of care in prostate cancer diagnostics – a decision analytical model
Authors: Dijkstra Siebren , Govers Tim M. , Hendriks Rianne J. , Schalken Jack A. , Van Criekinge Wim , Van Neste Leander , Grutters Janneke P.C. , Sedelaar John P. Michiel , van Oort Inge M.
Published: March 2017

Objective

To assess the cost‐effectiveness of a new urinary biomarker‐based risk score (SelectMDx; MDxHealth, Inc., Irvine, CA, USA) to identify patients for transrectal ultrasonography (TRUS)‐guided biopsy and to compare this with the current standard of care (SOC), using only prostate‐specific antigen (PSA) to select for TRUS‐guided biopsy.

Materials and Methods

A decision tree and Markov model were developed to evaluate the cost‐effectiveness of SelectMDx as a reflex test vs SOC in men with a PSA level of >3 ng/mL. Transition probabilities, utilities and costs were derived from the literature and expert opinion. Cost‐effectiveness was expressed in quality‐adjusted life years (QALYs) and healthcare costs of both diagnostic strategies, simulating the course of patients over a time horizon representing 18 years. Deterministic sensitivity analyses were performed to address uncertainty in assumptions.

Results

A diagnostic strategy including SelectMDx with a cut‐off chosen at a sensitivity of 95.7% for high‐grade prostate cancer resulted in savings of €128 and a gain of 0.025 QALY per patient compared to the SOC strategy. The sensitivity analyses showed that the disutility assigned to active surveillance had a high impact on the QALYs gained and the disutility attributed to TRUS‐guided biopsy only slightly influenced the outcome of the model.

Conclusion

Based on the currently available evidence, the reduction of over diagnosis and overtreatment due to the use of the SelectMDx test in men with PSA levels of >3 ng/mL may lead to a reduction in total costs per patient and a gain in QALYs.
Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication
Authors: Kishimoto Keiko , Nomura Jun , Ellegood Jacob , Fukumoto Keita , Lerch Jason P. , Moreno‐De‐Luca Daniel , Bourgeron Thomas , Tamada Kota , Takumi Toru
Published: March 2017

Duplications of human chromosome 2q13 have been reported in patients with neurodevelopmental disorder including autism spectrum disorder. Nephronophthisis‐1 (NPHP1) was identified as a causative gene in the minimal deletion on chromosome 2q13 for familial juvenile type 1 nephronophthisis and Joubert syndrome, an autosomal recessive neurodevelopmental disorder characterized by a cerebellar and brain stem malformation, hypotonia, developmental delay, ataxia, and sometimes associated with cognitive impairment. NPHP1 encodes a ciliary protein, nephrocystin‐1, which is expressed in the brain, yet its function in the brain remains largely unknown. In this study, we generated bacterial artificial chromosome‐based transgenic mice, called 2q13 dup, that recapitulate human chromosome 2q13 duplication and contain one extra copy of the Nphp1 transgene. To analyze any behavioral alterations in 2q13 dup mice, we conducted a battery of behavioral tests. Although 2q13 dup mice show no significant differences in social behavior, they show deficits in spontaneous alternation behavior and fear memory. We also carried out magnetic resonance imaging to confirm whether copy number gain in this locus affects the neuroanatomy. There was a trend toward a decrease in the cerebellar paraflocculus of 2q13 dup mice. This is the first report of a genetic mouse model for human 2q13 duplication.
The available intravenous iron formulations: History, efficacy, and toxicology
Authors: Auerbach Michael , Macdougall Iain
Published: March 2017

A number of intravenous iron formulations have been developed over the past 65 years which rely on dextran or other compounds to prevent uncontrolled release of free iron to the circulation. High molecular weight dextran was associated with a number of serious adverse reactions and was removed from markets worldwide in 2009. The preponderance of published evidence suggests that the formulations of parenteral iron currently available in the United States, including low molecular weight iron dextran, are all safe and effective and there are no major, clinically important differences among them in terms of either efficacy or safety. For patients with chemotherapy induced anemia or with anemia of end stage renal disease who are being treated with hemodialysis, it is reasonable to use any of the iron formulations, including iron sucrose and ferric gluconate, as frequent patient encounters with health caregivers are a routine part of care and the need to administer multiple low doses of IV iron is not a major disadvantage. However, a single infusion of a total iron dose is as effective and safe when giving iron preparations containing low molecular weight iron dextran, ferumoxytol, iron isomaltoside, or ferric carboxymaltose. Use of a single total dose infusion results in a decreased number of intravenous infusions with a lower cumulative risk for infusion reactions or extravasations, a reduced need for multiple office visits and repeated utilization of medical staff, and increased convenience for physicians and patients.
Competing Accounts of Progress: The Redemptive Purpose of Memory in J.B. Metz and Theodor Adorno
Authors: LaCouter Travis
Published: March 2017

What unifies the accounts of history and progress presented by Adorno's Critical Theory and Metz's political theology? I show: (i) that both resist the ‘magic spell’ of an Enlightenment totality on whose strength the violent excesses of modernity have been built; (ii) that both accomplish this resistance by memory of victims or the ‘losers of history’; and (iii) that both hold out hope for the possibility of progress in time. However, the two accounts differ in important ways. These differences stem from: (i) the transference of historical subjectivity from homo emancipator to the God of Jesus’ passion; (ii) the role of the ‘eschatological proviso’ in guaranteeing theological futuricity; and (iii) the fullness of Metz's eschatological justice as compared to Adorno's conception of progress as the mere ‘avoidance of catastrophe’. This project brings the work of one of the most influential social critics of the twentieth century into dialogue with that of a politically engaged theologian of the same historical‐cultural context. In doing so, I hope to suggest the theological richness of Metz's approach but also the significant contributions of dialectical criticism to the practice of theology in the modern era.
In Defense of Transracialism
Authors: Tuvel Rebecca
Published: March 2017

Former NAACP chapter head Rachel Dolezal's attempted transition from the white to the black race occasioned heated controversy. Her story gained notoriety at the same time that Caitlyn Jenner* graced the cover of Vanity Fair, signaling a growing acceptance of transgender identity. Yet criticisms of Dolezal for misrepresenting her birth race indicate a widespread social perception that it is neither possible nor acceptable to change one's race in the way it might be to change one's sex. Considerations that support transgenderism seem to apply equally to transracialism. Although Dolezal herself may or may not represent a genuine case of a transracial person, her story and the public reaction to it serve helpful illustrative purposes.
Understanding Others in an Alienating World: Comments on Lori Gruen's Entangled Empathy
Authors: Debes Remy
Published: March 2017

Is moral theory alienating? This question, and the worries that lie behind it, motivate much of Lori Gruen's distinctive approach to animal ethics in Entangled Empathy. According to Gruen, the “traditional” methods of moral theory rely on abstractions that strip away the details that give our lives meaning. Although I am deeply sympathetic to these worries, as well as to the alternative ethics Gruen proposes in response to them, in this article I express a few reservations about the argument Gruen uses to motivate her worries and to establish her solution. First, I raise some questions about her conception of “traditional” moral theory and the possible historical figures she means to indict. I then suggest that the principal gear of her argument—her conception of “entangled empathy”—suffers from some inconsistency in application, which risks leading her to posit a thicker notion of empathy than she should want. In particular, her argument risks setting a standard of correctness for “successful” empathy that is implausible on its own terms, but that is also a standard of correctness with morally and politically questionable implications in the human context.
High cover of forest increases the abundance of most grassland butterflies in boreal farmland
Authors: Toivonen Marjaana , Peltonen Aino , Herzon Irina , Heliölä Janne , Leikola Niko , Kuussaari Mikko
Published: March 2017

High cover of forest in the landscape matrix has been shown to weaken the negative effects of habitat fragmentation on grassland butterflies. No studies have however focused on examining species‐specific responses of grassland butterflies to forest.

The data from 3 years of butterfly monitoring in Southern Finland were used to test whether the amount of forest cover in the surrounding landscape affected the abundance of grassland butterfly species in semi‐natural grasslands, field margins, and forest edges.

More than half of the studied species benefitted from high cover of forest. Species with the strongest preference for forested landscapes were Lycaena virgaureae, Argynnis adippe, Argynnis aglaja, and Boloria selene, which probably find suitable resources in herbaceous habitats at forest edges and clearings.

Several small‐sized species were positively affected by surrounding forest cover in field margins but not in the other habitat types. Although field margins are suboptimal habitats for grassland butterflies, they provide important corridors for dispersal. High cover of forest in the landscape matrix may enhance butterfly dispersal along field margins by reducing windiness, which is likely to be most important for small‐sized species with poor dispersal capacity.

The most abundant grassland species showed little or no preference for forested landscapes.

Our results suggest that high cover of forest enhances the persistence of most grassland butterflies, including declining species, in boreal agricultural landscapes. The responses to forest are however strongly dependent on species‐specific properties and habitat types.
Have Japanese People Become Asexual? Love in Japan
Authors: Kobayashi Jun
Published: March 2017

This article examines changing romantic relationships in contemporary Japanese society. It specifically investigates whether Japanese people in their twenties and thirties have become asexual; that is, whether they tend to have few sexual experiences or interests. Data were collected through an internet survey; this article uses a subsample of 9,940 respondents. The dependent variables were the number of lovers respondents had during and after junior high school; the independent variable was the respondents’ age. Regression analyses found a clear trend toward asexual behavior among young men (in their twenties and thirties). However, young women are not as asexual as the previous generation. This asexualization of men may have contributed to Japan’s sharply declining marriage and birth rates. If so, other Asian societies may learn lessons from Japan’s experiences in the future.
Being as Iconic: Aquinas on ‘He Who Is’ as the Name for God
Authors: Rooney James Dominic
Published: March 2017

Aquinas claims that ‘He Who Is’ is the most proper of the names we have for God. But this attempt to ‘describe’ God with a philosophical concept like ‘being’ can seem dangerously close to creating a false conception based on our limited understanding – an idol. A dominant criticism of Aquinas’ use of this term is that any attempt to use ‘being’ to describe God will inevitably make him merely some object in our ontology alongside other beings, unacceptably mitigating God's radical transcendence and otherness. I will argue that Aquinas has a very creative response to this charge: ‘being’ stands in a unique relationship as the only concept that can ensure we do not draw God under some particular creaturely limit and thus use divine names to create an ‘idol’. In other words, ‘being’ is a special paradigm concept/term which ensures that we preserve humility in our attempts to name God.
Fixed Odds Bookmaking with Stochastic Betting Demands
Authors: Hodges Stewart , Lin Hao , Liu Lan
Published: March 2017

This paper studies fixed odds bookmaking in the market for bets in a British horse race. The bookmaker faces the risk of unbalanced liability exposures. Even random shocks in the noisy betting demands are costly to the bookmaker since his book could become less balanced. In our model, the bookmaker sets appropriate odds to influence the betting flow to mitigate the risk. The stylised fact of the favourite‐longshot bias only arises from the model under specific assumptions. Our model offers insights into the complexity of managing a series of state contingent exposures such as options.
Feeding biomechanics of Late Triassic metoposaurids (Amphibia: Temnospondyli): a 3D finite element analysis approach
Authors: Fortuny Josep , Marcé‐Nogué Jordi , Konietzko‐Meier Dorota
Published: March 2017

The Late Triassic freshwater ecosystems were occupied by different tetrapod groups including large‐sized anamniotes, such as metoposaurids. Most members of this group of temnospondyls acquired gigantic sizes (up to 5 m long) with a nearly worldwide distribution. The paleoecology of metoposaurids is controversial; they have been historically considered passive, bottom‐dwelling animals, waiting for prey on the bottom of rivers and lakes, or they have been suggested to be active mid‐water feeders. The present study aims to expand upon the paleoecological interpretations of these animals using 3D finite element analyses (FEA). Skulls from two taxa, Metoposaurus krasiejowensis, a gigantic taxon from Europe, and Apachesaurus gregorii, a non‐gigantic taxon from North America, were analyzed under different biomechanical scenarios. Both 3D models of the skulls were scaled to allow comparisons between them and reveal that the general stress distribution pattern found in both taxa is clearly similar in all scenarios. In light of our results, both previous hypotheses about the paleoecology of these animals can be partly merged: metoposaurids probably were ambush and active predators, but not the top predators of these aquatic environments. The FEA results demonstrate that they were particularly efficient at bilateral biting, and together with their characteristically anteropositioned orbits, optimal for an ambush strategy. Nonetheless, the results also show that these animals were capable of lateral strikes of the head, suggesting active hunting of prey. Regarding the important skull size differences between the taxa analyzed, our results suggest that the size reduction in the North American taxon could be related to drastic environmental changes or the increase of competitors. The size reduction might have helped them expand into new ecological niches, but they likely remained fully aquatic, as are all other metoposaurids.
Induction of the pho regulon and polyphosphate synthesis against spermine stress in Pseudomonas aeruginosa
Authors: Peng Yu‐Chih , Lu ChienYi , Li Guoqing , Eichenbaum Zehava , Lu Chung‐Dar
Published: March 2017

Growth of Pseudomonas aeruginosa on spermine requires a functional γ‐glutamylpolyamine synthetase PauA2. Not only subjected to growth inhibition by spermine, the pauA2 mutant became more sensitive to β‐lactam antibiotics in human serum. To explore PauA2 as a potential target of drug development, suppressors of the pauA2 mutant, which alleviated toxicity, were isolated from selection plates containing spermine. These suppressors share common phenotypic changes including delayed growth rate, retarded swarming motility, and pyocyanin overproduction. Genome resequencing of a representative suppressor revealed a unique C599T mutation at the phoU gene that results in Ser200Leu substitution and a constitutive expression of the Pho regulon. Identical phenotypes were also observed in a ΔpauA2ΔphoU double knockout mutant and complemented by the wild‐type phoU gene. Accumulation of polyphosphate granules and spermine resistance in the suppressor were reversed concomitantly when expressing exopolyphosphatase PPX from a recombinant plasmid, or by the introduction of deletion alleles in pstS pstC for phosphate uptake, phoB for Pho regulation, and ppk for polyphosphate synthesis. In conclusion, this study identifies polyphosphate accumulation due to an activated Pho regulon and phosphate uptake by the phoU mutation as a potential protection mechanism against spermine toxicity.
The HCPro from thePotyviridaefamily: an enviable multitasking Helper Component that every virus would like to have
Authors: Valli Adrián A. , Gallo Araiz , Rodamilans Bernardo , López‐Moya Juan José , García Juan Antonio
Published: March 2017

RNA viruses have very compact genomes and so provide a unique opportunity to study how evolution works to optimize the use of very limited genomic information. A widespread viral strategy to solve this issue concerning the coding space relies on the expression of proteins with multiple functions. Members of the familyPotyviridae, the most abundant group of RNA viruses in plants, offer several attractive examples of viral factors which play roles in diverse infection‐related pathways. The Helper Component Proteinase (HCPro) is an essential and well‐characterized multitasking protein for which at least three independent functions have been described: (i) viral plant‐to‐plant transmission; (ii) polyprotein maturation; and (iii) RNA silencing suppression. Moreover, multitudes of host factors have been found to interact with HCPro. Intriguingly, most of these partners have not been ascribed to any of the HCPro roles during the infectious cycle, supporting the idea that this protein might play even more roles than those already established. In this comprehensive review, we attempt to summarize our current knowledge about HCPro and its already attributed and putative novel roles, and to discuss the similarities and differences regarding this factor in members of this important viral family.
The importance of hydraulic architecture to the distribution patterns of trees in a central Amazonian forest
Authors: Cosme Luiza H. M. , Schietti Juliana , Costa Flávia R. C. , Oliveira Rafael S.
Published: March 2017

Species distributions and assemblage composition may be the result of trait selection through environmental filters. Here, we ask whether filtering of species at the local scale could be attributed to their hydraulic architectural traits, revealing the basis of hydrological microhabitat partitioning in a Central Amazonian forest.

We analyzed the hydraulic characteristics at tissue (anatomical traits, wood specific gravity (WSG)), organ (leaf area, specific leaf area (SLA), leaf area : sapwood area ratio) and whole‐plant (height) levels for 28 pairs of congeneric species from 14 genera restricted to either valleys or plateaus of a terra‐firme forest in Central Amazonia.

On plateaus, species had higher WSG, but lower mean vessel area, mean vessel hydraulic diameter, sapwood area and SLA than in valleys; traits commonly associated with hydraulic safety. Mean vessel hydraulic diameter and mean vessel area increased with height for both habitats, but leaf area and leaf area : sapwood area ratio investments with tree height declined in valley vs plateau species. [Correction added after online publication 29 March 2017: the preceding sentence has been reworded.] Two strategies for either efficiency or safety were detected, based on vessel size or allocation to sapwood.

In conclusion, contrasting hydrological conditions act as environmental filters, generating differences in species composition at the local scale. This has important implications for the prediction of species distributions under future climate change scenarios.
L‐type amino acid transporter 1 expression in esophageal carcinogenesis according to WHO and Japanese classifications of intraepithelial neoplasia
Authors: Hashimoto Hirotsugu , Kurata Atsushi , Kikuchi Hiroyuki , Masuda Yoshio , Fujita Koji , Okuyama Rikiya , Inoue Shigeru , Horiuchi Hajime , Kuroda Masahiko
Published: March 2017

L‐type amino acid transporter 1 (LAT1) has an essential role in cell proliferation especially in neoplasms. Although immunohistochemical expression of LAT1 has been investigated in invasive esophageal carcinoma, its expression in intraepithelial neoplasia (IEN) has not been reported. Further, classification of esophageal IEN is currently different between the World Health Organization (WHO) and Japanese criteria. Therefore, in this study, immunohistochemical expressions of LAT1 along with Ki‐67 were analyzed in 66 esophageal samples of endoscopic submucosal dissection. Extension of cells positive for either marker within the epithelium, along with LAT1 intensity at the base of the epithelium, was evaluated. The results among early IENs, progressed IENs, and invasive carcinoma based on both WHO and Japanese criteria were compared. It was demonstrated that Ki‐67+ cells extended toward the superficial layer in IENs, which was more pronounced in progressed compared with early IENs based on both WHO and Japanese criteria. Although similar results were obtained for LAT1+ cells, LAT1+ cell extended more in invasive carcinoma than in progressed IENs according to the WHO criteria. Further, LAT1 intensity was different between early and progressed IENs based on the Japanese criteria alone. Thus, use of LAT1 immunohistochemistry and Japanese classification may be more meaningful to characterize esophageal carcinogenesis.
Commentary: Leadership Tools That Should Not Be Overlooked
Authors: Franzel Joshua
Published: March 2017

Related Content: Orr and Bennett (PAR July/August 2017)
Alternatives to induced sputum for identifying inflammatory subtypes of asthma
Authors: Simpson Jodie L. , Bafadhel Mona
Published: March 2017

See article, page 671
Objective Bayes Covariate‐Adjusted Sparse Graphical Model Selection
Authors: Consonni Guido , La Rocca Luca , Peluso Stefano
Published: March 2017

We present an objective Bayes method for covariance selection in Gaussian multivariate regression models having a sparse regression and covariance structure, the latter being Markov with respect to a directed acyclic graph (DAG). Our procedure can be easily complemented with a variable selection step, so that variable and graphical model selection can be performed jointly. In this way, we offer a solution to a problem of growing importance especially in the area of genetical genomics (eQTL analysis). The input of our method is a single default prior, essentially involving no subjective elicitation, while its output is a closed form marginal likelihood for every covariate‐adjusted DAG model, which is constant over each class of Markov equivalent DAGs; our procedure thus naturally encompasses covariate‐adjusted decomposable graphical models. In realistic experimental studies, our method is highly competitive, especially when the number of responses is large relative to the sample size.
WRI1‐1, ABI5, NF‐YA3 and NF‐YC2 increase oil biosynthesis in coordination with hormonal signaling during fruit development in oil palm
Authors: Yeap Wan‐Chin , Lee Fong‐Chin , Shabari Shan Dilip Kumar , Musa Hamidah , Appleton David Ross , Kulaveerasingam Harikrishna
Published: March 2017

The oil biosynthesis pathway must be tightly controlled to maximize oil yield. Oil palm accumulates exceptionally high oil content in its mesocarp, suggesting the existence of a unique fruit‐specific fatty acid metabolism transcriptional network. We report the complex fruit‐specific network of transcription factors responsible for modulation of oil biosynthesis genes in oil palm mesocarp. Transcriptional activation of EgWRI1‐1 encoding a key master regulator that activates expression of oil biosynthesis genes, is activated by three ABA‐responsive transcription factors, EgNF‐YA3, EgNF‐YC2 and EgABI5. Overexpression of EgWRI1‐1 and its activators in Arabidopsis accelerated flowering, increased seed size and oil content, and altered expression levels of oil biosynthesis genes. Protein–protein interaction experiments demonstrated that EgNF‐YA3 interacts directly with EgWRI1‐1, forming a transcription complex with EgNF‐YC2 and EgABI5 to modulate transcription of oil biosynthesis pathway genes. Furthermore, EgABI5 acts downstream of EgWRKY40, a repressor that interacts with EgWRKY2 to inhibit the transcription of oil biosynthesis genes. We showed that expression of these activators and repressors in oil biosynthesis can be induced by phytohormones coordinating fruit development in oil palm. We propose a model highlighting a hormone signaling network coordinating fruit development and fatty acid biosynthesis.
Coherence factor and Wiener postfilter in synthetic aperture ultrasound imaging
Authors: Zhao Jinxin , Wang Yuanyuan , Guo Wei , Yu Jinhua
Published: March 2017

The coherence factor (CF) and Wiener postfilter methods have been proposed as effective approaches for reducing the output noise of the delay-and-sum (DAS) beamformer in ultrasound imaging. The theoretical framework between them was also established. However, past researches about the CF and Wiener postfilter methods mainly focused on the summation of an array signal. This paper analyzes the CF and Wiener postfilter in the synthetic aperture (SA) imaging mode, where two-dimensional echo data are recorded. Different CF definitions in the SA imaging are first given and the corresponding Wiener postfilter methods are then proposed, including a Wiener postfilter especially for the SA imaging, named as WienerSA. The performances of different CF and Wiener postfilter methods were evaluated on both simulated and experimental SA data. Results showed that the proposed WienerSA outperformed the other Wiener postfilters in reducing the sidelobe noise level. It obtained the highest contrast ratio among the Wiener postfilter methods, which was even higher than some of the CF methods. Meanwhile it could benefit a much higher contrast-to-noise ratio than those CF methods with further suppression of incoherent noises. Consequently, the WienerSA is believed to be a promising approach in enhancing the SA image quality.
Cardiac regeneration: All work and no repair?
Authors: Kennedy-Lydon Teresa , Rosenthal Nadia
Published: March 2017

Cardiac development may contribute to loss of regenerative capacity in the adult mammalian heart.
Estimation of polio infection prevalence from environmental surveillance data
Authors: Berchenko Yakir , Manor Yossi , Freedman Laurence S. , Kaliner Ehud , Grotto Itamar , Mendelson Ella , Huppert Amit
Published: March 2017

Close monitoring of virus shed into sewage systems allows quantitative surveillance of a polio outbreak.
Macrophages take rheumatoid arthritis up a “Notch”
Authors: Levi Benjamin
Published: March 2017

Notch signaling in bone marrow–derived inflammatory macrophages is central to synovial inflammation seen in rheumatoid arthritis, representing a promising future therapeutic target.
SpxA1 and SpxA2 Act Coordinately To Fine-Tune Stress Responses and Virulence in
Streptococcus pyogenes
Authors: Port Gary C. , Cusumano Zachary T. , Tumminello Paul R. , Caparon Michael G.
Published: March 2017

SpxA is a unique transcriptional regulator highly conserved among members of the phylum
Firmicutes
that binds RNA polymerase and can act as an antiactivator. Why some
Firmicutes
members have two highly similar SpxA paralogs is not understood. Here, we show that the SpxA paralogs of the pathogen
Streptococcus pyogenes
, SpxA1 and SpxA2, act coordinately to regulate virulence by fine-tuning toxin expression and stress resistance. Construction and analysis of mutants revealed that SpxA1
−
mutants were defective for growth under aerobic conditions, while SpxA2
−
mutants had severely attenuated responses to multiple stresses, including thermal and oxidative stresses. SpxA1
−
mutants had enhanced resistance to the cationic antimicrobial molecule polymyxin B, while SpxA2
−
mutants were more sensitive. In a murine model of soft tissue infection, a SpxA1
−
mutant was highly attenuated. In contrast, the highly stress-sensitive SpxA2
−
mutant was hypervirulent, exhibiting more extensive tissue damage and a greater bacterial burden than the wild-type strain. SpxA1
−
attenuation was associated with reduced expression of several toxins, including the SpeB cysteine protease. In contrast, SpxA2
−
hypervirulence correlated with toxin overexpression and could be suppressed to wild-type levels by deletion of
speB
. These data show that SpxA1 and SpxA2 have opposing roles in virulence and stress resistance, suggesting that they act coordinately to fine-tune toxin expression in response to stress. SpxA2
−
hypervirulence also shows that stress resistance is not always essential for
S. pyogenes
pathogenesis in soft tissue.

IMPORTANCE
For many pathogens, it is generally assumed that stress resistance is essential for pathogenesis. For
Streptococcus pyogenes
, environmental stress is also used as a signal to alter toxin expression. The amount of stress likely informs the bacterium of the strength of the host’s defense response, allowing it to adjust its toxin expression to produce the ideal amount of tissue damage, balancing between too little damage, which will result in its elimination, and too much damage, which will debilitate the host. Here we identify components of a genetic circuit involved in stress resistance and toxin expression that has a fine-tuning function in tissue damage. The circuit consists of two versions of the protein SpxA that regulate transcription and are highly similar but have opposing effects on the severity of soft tissue damage. These results will help us understand how virulence is fine-tuned in other pathogens that have two SpxA proteins.
Intimate partner violence among pregnant women in Rwanda, its associated risk factors and relationship to ANC services attendance: a population-based study
Authors: Rurangirwa Akashi Andrew , Mogren Ingrid , Ntaganira Joseph , Krantz Gunilla
Published: March 2017

Objectives

To investigate the prevalence of four forms of intimate partner violence during pregnancy in Rwandan women, associated sociodemographic and psychosocial factors and relationship to antenatal care service usage.

Design

This was a cross-sectional population-based study conducted in the Northern province of Rwanda and in Kigali city.

Participants and settings

A total of 921 women who gave birth within the past 13 months were included. Villages in the study area were selected using a multistage random sampling technique and community health workers helped in identifying eligible participants. Clinical psychologists, nurses or midwives carried out face-to-face interviews using a structured questionnaire. Bivariable and multivariable logistic regression were used to assess associations.

Results

The prevalence rates of physical, sexual, psychological violence and controlling behaviour during pregnancy were 10.2% (95% CI 8.3 to 12.2), 9.7% (95% CI 7.8 to 11.6), 17.0% (95% CI 14.6 to 19.4) and 20.0% (95% CI 17.4 to 22.6), respectively. Usage of antenatal care services was less common among women who reported controlling behaviour (OR) 1.93 (95% CI 1.34 to 2.79). No statistically significant associations between physical, psychological and sexual violence and antenatal care usage were found. Low socioeconomic status was associated with physical violence exposure (OR) 2.27 (95% CI 1.29 to 3.98). Also, young age, living in urban areas and poor social support were statistically significant in their associations with violence exposure during pregnancy.

Conclusions

Intimate partner violence inquiry should be included in the standard antenatal care services package and professionals should be trained in giving support, advice and care to those exposed. Gender-based violence is criminalised behaviour in Rwanda; existing policies and laws must be followed and awareness raised in society for preventive purposes.
Assessing dose–response effects of national essential medicine policy in China: comparison of two methods for handling data with a stepped wedge-like design and hierarchical structure
Authors: Ren Yan , Yang Min , Li Qian , Pan Jay , Chen Fei , Li Xiaosong , Meng Qun
Published: March 2017

Objectives

To introduce multilevel repeated measures (RM) models and compare them with multilevel difference-in-differences (DID) models in assessing the linear relationship between the length of the policy intervention period and healthcare outcomes (dose–response effect) for data from a stepped-wedge design with a hierarchical structure.

Design

The implementation of national essential medicine policy (NEMP) in China was a stepped-wedge-like design of five time points with a hierarchical structure. Using one key healthcare outcome from the national NEMP surveillance data as an example, we illustrate how a series of multilevel DID models and one multilevel RM model can be fitted to answer some research questions on policy effects.

Setting

Routinely and annually collected national data on China from 2008 to 2012.

Participants

34 506 primary healthcare facilities in 2675 counties of 31 provinces.

Outcome measures

Agreement and differences in estimates of dose–response effect and variation in such effect between the two methods on the logarithm-transformed total number of outpatient visits per facility per year (LG-OPV).

Results

The estimated dose–response effect was approximately 0.015 according to four multilevel DID models and precisely 0.012 from one multilevel RM model. Both types of model estimated an increase in LG-OPV by 2.55 times from 2009 to 2012, but 2–4.3 times larger SEs of those estimates were found by the multilevel DID models. Similar estimates of mean effects of covariates and random effects of the average LG-OPV among all levels in the example dataset were obtained by both types of model. Significant variances in the dose–response among provinces, counties and facilities were estimated, and the ‘lowest’ or ‘highest’ units by their dose–response effects were pinpointed only by the multilevel RM model.

Conclusions

For examining dose–response effect based on data from multiple time points with hierarchical structure and the stepped wedge-like designs, multilevel RM models are more efficient, convenient and informative than the multilevel DID models.
Study protocol for a natural experiment in a lower socioeconomic area to examine the health-related effects of refurbishment to parks including built-shade (ShadePlus)
Authors: Dobbinson S J , Veitch J , Salmon J , Wakefield M , Staiger P K , MacInnis R J , Simmons J
Published: March 2017

Introduction

Parks in disadvantaged suburbs often have low quality and few amenities, which is likely to result in them being underutilised for recreation and physical activity. Refurbishment of parks, including shade, walking paths and other amenities, may have broad health-related benefits.

Methods and analysis

The study design, methods and planned analyses for a natural experiment examining the effects of refurbishments including built-shade added to parks in disadvantaged outer suburbs of Melbourne are described. Three intervention parks and three comparison parks matched for equivalence of park and neighbourhood characteristics were selected. Using mixed methods, the outcomes will be assessed during three consecutive spring–summer periods (T1: 2013–2014; T2: 2014–2015: T3: 2015–2016). Primary outcomes included: observed park use, physical activity and shade use. Self-reported social connectedness, community engagement and psychological well-being were assessed as secondary outcomes.

Ethics and dissemination

This study was approved by Cancer Council Victoria's Human Research Ethics Committee. Studies such as ShadePlus can improve understanding of the broader effects of park refurbishments (including physical activity levels and sun protection behaviours, as well as social connectedness and psychological well-being). The study findings will be disseminated through established urban planning and parks and recreation networks, peer review publications and conference presentations.
Healthcare professionals’ views of the use and administration of two salvage therapy drugs for acute ulcerative colitis: a nested qualitative study within the CONSTRUCT trial
Authors: Clement Clare , Rapport Frances , Seagrove Anne , Alrubaiy Laith , Williams John
Published: March 2017

Objectives

Insight into healthcare professionals’ views and experiences of the use of ciclosporin and infliximab as salvage therapies for acute ulcerative colitis (UC) and how this may affect participation in a comparison trial is lacking. The study aimed to capture views and opinions of healthcare professionals about the two drugs within the CONSTRUCT trial.

Design

An interview-based qualitative study using Framework Analysis embedded within an open-label, pragmatic randomised trial.

Setting

National Health Service Health Boards and Trusts, including large teaching and district hospitals in England, Scotland and Wales.

Participants

Principal Investigators (PIs) for trial sites (who were all consultant gastroenterologists) and nurses responsible for administering and monitoring the salvage therapy drugs across trial sites. 15 PIs and 8 nurses recruited from a range of sites stratified by site recruitment rates were interviewed.

Results

Interviews revealed that professionals made judgements regarding the salvage therapies largely based on experience of giving the two drugs and perceptions of effectiveness and adverse side effects. A clear preference for infliximab among nurses was revealed, largely based on experiences of administration and drug handling, with some doctors strongly favouring infliximab based on experience of prescribing the drug as well as patient views and the existing evidence base. Most doctors were more equivocal, and all were prepared to suspend preferences and wait for evidence of effectiveness and safety from the CONSTRUCT trial. PIs also questioned guidelines around drug use and restrictions placed on personal autonomy in delivering best patient care.

Conclusions

Findings highlight healthcare professionals’ preference for the salvage treatment, infliximab in treating steroid-resistant UC, largely based on resource intensive nursing requirements of intravenous administration of ciclosporin. Not all doctors expressed this preference, being more equivocal, and all professionals were content to suspend preferences within the CONSTRUCT trial and recognised the importance of establishing relative effectiveness and safety.

Trial registration number

ISRCTN 22663589.
Impact of using indirect left-turns on signalized intersections’ performance
Authors: Taha Mahmoud , Abdelfatah Akmal
Published: March 2017

The majority of traffic delays in urban areas occur at signalized intersections. Due to the limited availability of space and right-of-way, many transportation agencies are considering unconventional traffic control systems for intersections to improve signal efficiency and reduce overall delays. Common unconventional left-turn treatments include the right-turn followed by a U-turn (RTUT) and a U-turn followed by a right-turn (UTRT). The main goal of this study is to determine the traffic operational performance of the three left-turn treatments under different traffic conditions. The results showed that unconventional left-turn control types have less delay and travel time compared to the direct left-turn (DLT), when the U-turn locations are 200 m away from the main intersection. Also, RTUT showed superior performance over the other left-turn control types, when the U-turn locations are 100 m away from the main intersection.
Phylogenomic inferences from reference-mapped and de novo assembled short-read sequence data using RADseq sequencing of California white oaks (Quercus section Quercus)
Authors: Fitz-Gibbon Sorel , Hipp Andrew L. , Pham Kasey K. , Manos Paul S. , Sork Victoria L.
Published: March 2017

The emergence of next generation sequencing has increased by several orders of magnitude the amount of data available for phylogenetics. Reduced representation approaches, such as restriction-sited associated DNA sequencing (RADseq), have proven useful for phylogenetic studies of non-model species at a wide range of phylogenetic depths. However, analysis of these datasets is not uniform and we know little about the potential benefits and drawbacks of de novo assembly versus assembly by mapping to a reference genome. Using RADseq data for 83 oak samples representing 16 taxa, we identified variants via three pipelines: mapping sequence reads to a recently published draft genome of Quercus lobata, and de novo assembly under two sets of locus filters. For each pipeline, we inferred the maximum likelihood phylogeny. All pipelines produced similar trees, with minor shifts in relationships within well-supported clades, despite the fact that they yielded different numbers of loci (68 000 – 111 000 loci) and different degrees of overlap with the reference genome. We conclude that both the reference-aligned and de novo assembly pipelines yield reliable results, and that advantages and disadvantages of these approaches pertain mainly to downstream uses of RADseq data, not to phylogenetic inference per se.