bluuebunny/crossref_metadata_2025 huggingface dataset:
A conserved Lkb1 signaling axis modulates TORC2 signaling in budding yeast
Authors: Alcaide-Gavilán Maria , Lucena Rafael , Schubert Katherine , Artiles Karen , Zapata Jessica , Kellogg Douglas R.
Published: April 2018

Nutrient availability, growth rate and cell size are closely linked. For example, in budding yeast, the rate of cell growth is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. Thus, cells grow slowly in poor nutrients and are nearly half the size of cells growing in rich nutrients. Moreover, large cells grow faster than small cells. A signaling network that surrounds Tor kinase complex 2 (TORC2) plays an important role in enforcing these proportional relationships. Cells that lack components of the TORC2 network fail to modulate their growth rate or size in response to changes in nutrient availability. Here, we show that budding yeast homologs of the Lkb1 tumor suppressor kinase are required for normal modulation of TORC2 signaling and in response to changes in carbon source. Lkb1 kinases activate Snf1/AMPK to initiate transcription of genes required for utilization of poor carbon sources. However, Lkb1 influences TORC2 signaling via a novel pathway that is independent of Snf1/AMPK. Of the three Lkb1 homologs in budding yeast, Elm1 plays the most important role in modulating TORC2. Elm1 activates a pair of related kinases called Gin4 and Hsl1. Previous work found that loss of Gin4 and Hsl1 causes cells to undergo unrestrained growth during a prolonged mitotic arrest, which suggests that play a role in linking cell cycle progression to cell growth. We found that Gin4 and Hsl1 also control the TORC2 network. In addition, Gin4 and Hsl1 are themselves influenced by signals from the TORC2 network, consistent with previous work showing that the TORC2 network constitutes a feedback loop. Together, the data suggest a model in which the TORC2 network sets growth rate in response to carbon source, while also relaying signals via Gin4 and Hsl1 that set the critical amount of growth required for cell cycle progression. This kind of close linkage between control of cell growth and size would suggest a simple mechanistic explanation for the proportional relationship between cell size and growth rate.
Many rice genes are differentially spliced between roots and shoots but cytokinin has minimal effect on splicing
Authors: Freese Nowlan H. , Estrada April R. , Blakley Ivory C. , Duan Jinjie , Loraine Ann E.
Published: April 2018

Alternatively spliced genes produce multiple spliced isoforms, called transcript variants. In differential alternative splicing, transcript variant abundance differs across sample types. Differential alternative splicing is common in animal systems and influences cellular development in many processes, but its extent and significance is not as well known in plants. To investigate alternative splicing in plants, we examined RNA-Seq data from rice seedlings. The data included three biological replicates per sample type, approximately 30 million sequence alignments per replicate, and four sample types: roots and shoots treated with exogenous cytokinin delivered hydroponically or a mock treatment. Cytokinin treatment triggered expression changes in thousands of genes but had negligible effect on splicing patterns. However, many genes were alternatively spliced between mock-treated roots and shoots, indicating that our methods were sufficiently sensitive to detect differential splicing in a data set. Quantitative fragment analysis of reverse transcriptase-PCR products made from newly prepared rice samples confirmed nine of ten differential splicing events between rice roots and shoots. Differential alternative splicing typically changed the relative abundance of splice variants that co-occurred in a data set. Analysis of a similar (but less deeply sequenced) RNA-Seq data set from Arabidopsis showed the same pattern. In both the Arabidopsis and rice RNA-Seq data sets, most genes annotated as alternatively spliced had small minor variant frequencies. Of splicing choices with abundant support for minor forms, most alternative splicing events were located within the protein-coding sequence and maintained the annotated reading frame. A tool for visualizing protein annotations in the context of genomic sequence (ProtAnnot) together with a genome browser (Integrated Genome Browser) were used to visualize and assess effects of differential splicing on gene function. In general, differentially spliced regions coincided with conserved regions in the encoded proteins, indicating that differential alternative splicing is likely to affect protein function between root and shoot tissue in rice.
Wnt/β-catenin regulates an ancient signaling network during zebrafish scale development
Authors: Aman Andrew J. , Fulbright Alexis N. , Parichy David M.
Published: April 2018

Understanding how patterning influences cell behaviors to generate three dimensional morphologies is a central goal of developmental biology. Additionally, comparing these regulatory mechanisms among morphologically diverse tissues allows for rigorous testing of evolutionary hypotheses. Zebrafish skin is endowed with a coat of precisely patterned bony scales. We use in-toto live imaging during scale development and manipulations of cell signaling activity to elucidate core features of scale patterning and morphogenesis. These analyses show that scale development requires the concerted activity of Wnt/β-catenin, Ectodysplasin (Eda) and Fibroblast growth factor (Fgf) signaling. This regulatory module coordinates Hedgehog (HH) dependent collective cell migration during epidermal invagination, a cell behavior not previously implicated in skin appendage morphogenesis. Our analyses demonstrate the utility of zebrafish scale development as a tractable system in which to elucidate mechanisms of developmental patterning and morphogenesis, and suggest a single, ancient origin of skin appendage patterning mechanisms in vertebrates.
A transgenic pig model expressing a ZsGreen1 reporter across an extensive array of tissues
Authors: Desaulniers Amy T. , Cederberg Rebecca A. , Carreiro Elizabeth P. , Gurumurthy Channabasavaiah B. , White Brett R.
Published: April 2018

Background

The advent of genetically engineered pig production has revealed a wide array of opportunities to enhance both biomedical and agricultural industries. One powerful method to develop these models is transgenesis; however, selection of a suitable promoter to drive transgene expression is critical. The cytomegalovirus (CMV) promoter is the most commonly used viral promoter as it robustly drives transgene expression in a ubiquitous nature. However, recent reports suggest that the level of CMV promoter activity is tissue-dependent in the pig. Therefore, the objective of this study was to quantify the activity of the CMV promoter in a wide range of porcine tissues. Swine harboring a CMV-ZsGreen1 transgene with a single integration site were utilized for this study. Thirty five tissue samples were collected from neonatal hemizygous (n = 3) and homozygous (n = 3) transgenic piglets and analyzed for ZsGreen1 abundance via immunoblot.

Results

ZsGreen1 was detected in all tissues examined; however, quantification revealed that ZsGreen1 protein levels were tissue-specific. Within organs of the digestive system, for example, ZsGreen1 was most abundant in the salivary gland, moderately produced in the esophagus and levels were lowest in the stomach. Interestingly, abundance of ZsGreen1 also differed within organ. For instance, levels were highest in the right ventricle compared with other chambers of the heart. There was no effect of transgene dose as ZsGreen1 expression patterns were similar between homozygous and hemizygous piglets.

Conclusions

Ultimately, these results elucidate the tissue-specific activity of the CMV promoter in the neonatal pig. Moreover, this model can serve as a useful tool for research applications requiring reporter gene activity in mammalian organs.
On the deformability of an empirical fitness landscape by microbial evolution
Authors: Bajić Djordje , Vila Jean C.C. , Blount Zachary D. , Sánchez Alvaro
Published: April 2018

A fitness landscape is a map between the genotype and its reproductive success in a given environment. The topography of fitness landscapes largely governs adaptive dynamics, constraining evolutionary trajectories and the predictability of evolution. Theory suggests that this topography can be “deformed” by mutations that produce substantial changes to the environment. In spite of its importance, the deformability of fitness landscapes has not been systematically studied beyond abstract models, and little is known about its reach and consequences in empirical systems. Here we have systematically characterized the deformability of the genome-wide metabolic fitness landscape of the bacteriumE. coli. Deformability is quantified by the non-commutativity of epistatic interactions, which we experimentally demonstrate in mutant strains on the path to an evolutionary innovation. Our analysis shows that the deformation of fitness landscapes by metabolic mutations rarely affects evolutionary trajectories in the short-range. However, mutations with large environmental effects leave these as a “legacy”, producing long-range landscape deformations in distant regions of the genotype space that affect the fitness of later descendants. Our methods and results provide the basis for an integration between adaptive and eco-evolutionary dynamics with complex genetics and genomics.
Phylogenetic evidence for independent origins of GDF1 and GDF3 genes in amphibians and mammals
Authors: Opazo Juan C. , Zavala Kattina
Published: April 2018

Growth differentiation factors 1 (GDF1) and 3 (GDF3) are members of the transforming growth factor superfamily (TGF-β) that is involved in fundamental early-developmental processes that are conserved across vertebrates. The evolutionary history of these genes is still under debate due to ambiguous definitions of homologous relationships among vertebrates. Thus, the goal of this study was to unravel the evolution of the GDF1 and GDF3 genes of vertebrates, emphasizing the understanding of homologous relationships and their evolutionary origin. Surprisingly, our results revealed that the GDF1 and GDF3 genes found in amphibians and mammals are the products of independent duplication events of an ancestral gene in the ancestor of each of these lineages. The main implication of this result is that the GDF1 and GDF3 genes of amphibians and mammals are not 1:1 orthologs. In other words, genes that participate in fundamental processes during early development have been reinvented two independent times during the evolutionary history of tetrapods.
CD95 receptor activation by ligand-induced trimerization is independent of its partial pre-ligand assembly
Authors: Liesche C. , Berndt J. , Fricke F. , Aschenbrenner S. , Heilemann M. , Eils R. , Beaudouin J.
Published: April 2018

CD95 (Fas, APO-1, TNFRSF6) is a widely expressed single-pass transmembrane protein that is implicated in cell death, inflammatory response, proliferation and cell migration. CD95 ligand (CD95L, FasL, TNFSF6), is a potent apoptotic inducer in the membrane form but not when cleaved into soluble CD95L (sCD95L). Here, we aimed at understanding the relation between ligand-receptor multimerization and receptor activation by correlating the kinetics of ligand binding, receptor oligomerization, FADD (FAS-Associated via Death Domain) recruitment and caspase-8 activation inside living cells. Using single molecule localization microscopy and Förster resonance energy transfer imaging we show that the majority of CD95 receptors on the plasma membrane are monomeric at rest. This was confirmed functionally as the wild-type receptor is not blocked by a receptor mutant that cannot bind ligand. Moreover, using time-resolved fluorescence imaging approaches we demonstrated that receptor multimerization follows instantaneously ligand binding, whereas FADD recruitment is delayed. This process can explain the typical delay time seen with caspase-8 activity reporters. Finally, the low activity of sCD95L, which was caused by inefficient FADD recruitment, was not explained by the low avidity for the receptor but by a receptor clustering mechanism that was different from the one induced by the strong apoptosis inducer IZ-sCD95L. Our results reveal that receptor activation is modulated by the capacity of its ligand to trimerize it.

Highlights

At a density of less than 10 receptors per µm2CD95 exists as monomer (58%) and dimer (42%)

Pre-formed dimers do not contribute to ligand-induced CD95 apoptotic signaling

The PLAD of CD95 attenuates overexpression-induced, ligand-independent cell death

soluble CD95L can rapidly multimerize CD95 after binding but it is still a poor inducer of apoptosis through inefficient FADD recruitment

FADD recruitment kinetics but not ligand binding kinetics correlates with caspase-8 onset of activity
Gene inversion increases evolvability in bacteria
Authors: Merrikh Christopher , Merrikh Houra
Published: April 2018

In bacteria, most genes are encoded on the leading strand, co-orienting the movement of the replication machinery with RNA polymerases. This co-orientation bias reduces the frequency of highly detrimental head-on collisions between the two machineries. This and other work set up the expectation that over evolutionary time, head-on alleles are selected against, maximizing genome co-orientation. Our findings challenge this model. Using the well-established GC skew method, we reveal the evolutionary inversion record of all chromosomally encoded genes in multiple divergent bacterial pathogens. We find that a surprisingly large number of co-oriented genes have inverted to, and are retained in the head-on orientation. Furthermore, we find that these head-on genes, (including key antibiotic resistance and virulence genes) have higher rates of nonsynonymous mutations and are more frequently under positive selection (dN/dS>1). Based on these results, we propose that bacteria increase their evolvability through gene inversion and promotion of head-on replication-transcription collisions.
The quantification of protein-protein interaction interfaces using solvent-excluded surface-defined properties
Authors: Wang Lincong
Published: April 2018

Protein-protein interaction (PPI) is the cornerstone of nearly every biological process. During last forty years PPI interfaces have been investigated extensively both in vitro and in silico in order to understand both the strength and specificity of PPI. At least three different models, the buried surface model, the O-ring model and the rim- and-core model, have been proposed for PPI interface. However none of them provide much detail about PPI and a single model that reconciles them remains elusive. To identify common physical and geometrical features shared by various PPI interfaces we have analyzed several solvent-excluded surface (SES)-defined properties for a set of well-studied protein-protein complexes with crystal structures. Our analysis shows that the SES-defined properties for the interface atoms of a PPI partner are in general different from those for the surface atoms of a water-soluble protein. Most significantly we find that the partially-buried atoms of a PPI partner have unique SES-defined properties that set them well apart from either the buried atoms or the accessible atoms. Based on distinct SES-defined properties for the accessible, buried and partially-buried atoms shared by various PPI interfaces we propose a new model specified by a list of SES-defined properties shared by various PPI interfaces. Our model is quantitative in nature and should be useful for PPI site identification, protein-protein docking and structure-based design of chemicals targeting PPI.
FGFR1 tyrosine kinase domain duplication in pilocytic astrocytoma with anaplasia
Authors: Ballester Leomar Y. , Penas-Prado Marta , Leeds Norman E. , Huse Jason T. , Fuller Gregory N.
Published: April 2018

We report the case of a 27-yr-old male with visual field loss who had a 4.9-cm complex cystic mass in the right occipital lobe. Histologic examination showed pilocytic astrocytoma (PA) with anaplasia, and molecular characterization revealed FGFR1 duplication with additional variants of unknown significance in several genes (ARID1A, ARID1B, CHEK2, EPHA5, and MLL2). This is one of only a very few reported cases of anaplastic PA with characterization of molecular alterations.
Precision oncogenomics in pediatrics: a personal reflection
Authors: Campbell Cindy , Greenfield Jeffrey P.
Published: April 2018

Cindy Campbell, a bereaved parent who lost her son to a rare pediatric brain tumor, shares her experience and frustration over the lack of treatment options and minimal research funding in pediatric oncology. She invites Dr. Jeffrey P. Greenfield to reflect on the situation and share his professional experiences pertaining to advances in oncogenomics and pediatric brain tumors. They share a passion for making this technology available to all pediatric brain tumor patients in the future and using data to inform treatment protocols and improve outcomes.
Production of High-Titer Retrovirus and Lentivirus Vectors
Authors: Sena-Esteves Miguel , Gao Guangping
Published: April 2018

The most commonly used method for production of retrovirus and lentivirus vectors in research laboratories is of transient transfection of 293T cells with a lentivirus vector plasmid, packaging genome plasmid(s), and an envelope expression plasmid. High-titer stocks are obtained by concentration of vector supernatants by ultracentrifugation.
Monitoring Lentivirus Vector Stocks for Replication-Competent Viruses
Authors: Sena-Esteves Miguel , Gao Guangping
Published: April 2018

The potential emergence of replication-competent lentiviruses (RCLs) during vector production and the significant biosafety risk that this represents has led to the development of lentivirus vector production systems to minimize the risk of generating RCLs. Second- and third-generation lentivirus vector production systems appear to be safe, because there are no reports of RCL generation in either system. Screening of lentivirus vector stocks for RCLs involves serial passaging of transduced cells for 30 d with weekly monitoring of p24 levels in supernatants using an ELISA Kit.
Isolation and Analysis of Xenopus Germinal Vesicles
Authors: Morgan Garry T.
Published: April 2018

The giant nucleus or germinal vesicle (GV) of Xenopus oocytes provides an unusual opportunity to analyze nuclear structure and function in exquisite detail by light microscopy. Detailed here are two rapid procedures for using manually isolated GVs in combination with fluorescent reporter proteins to investigate the lampbrush chromosomes and nuclear bodies of oocytes. One procedure provides spreads of nuclear components in an unfixed and life-like, although not living, form. The other describes the isolation of intact, functional GVs directly into mineral oil offering possibilities for direct observation of nuclear dynamics.
Chemiluminescence
Authors: Kricka Larry J.
Published: April 2018

Radioactive reagents have been gradually replaced by nonisotopic reagents for some tasks in molecular biology. Concern over laboratory safety and the economic and environmental aspects of radioactive waste disposal have been key factors in this change. Generally, the new nonisotopic systems have improved in terms of analytical sensitivity and the time required to obtain a result. The most prominent nonisotopic analytical methods exploit chemiluminescence, described here. This technique has been particularly effective when used in combination with an enzyme label, so that the amplifying properties of an enzyme label and the high sensitivity of a chemiluminescent detection reaction are combined to produce an ultrasensitive assay (e.g., chemiluminescent detection of peroxidase- and alkaline phosphatase-labeled proteins and nucleic acid probes). In all of the commonly used applications in molecular biology, the analytical performance of the chemiluminescent systems approaches that of 125I- or 32P-based systems. Chemiluminescent systems also avoid the lengthy signal detection times required with 32P-based methods, yielding results in minutes rather than days. In addition, chemiluminescent probes can be easily stripped from membranes, allowing the membranes to be reprobed many times without significant loss of resolution. Experimental protocols for directly attaching nonisotopic labels to nucleic acids and indirect labeling methods based on biotin, fluorescein, and digoxigenin labels are now well established. The ancillary reagents (e.g., avidin, streptavidin, antidigoxigenin, and antifluorescein enzyme conjugates) required for the indirect methods are widely available.
Supply chain performance: how lean practices efficiently drive improvements
Authors: Tortorella Guilherme Luz , Giglio Ricardo , Limon-Romero Jorge
Published: April 2018

Purpose

The purpose of this paper aims at investigating which lean supply chain management (LSCM) practices efficiently improve the supply chain performance.

Design/methodology/approach

To achieve that, a cross-sectional survey was carried out with 113 manufacturing companies undergoing a lean implementation. The proposed method combines complementary methods of multivariate data analysis in order to determine which bundles of LSCM practices more efficiently entail improvements on supply chain performance.

Findings

The findings justify why some LSCM initiatives may find larger barriers than others, compromising their success due to misguided implementation efforts according to the desired performance improvement.

Originality/value

The empirical examination on the efficiency of LSCM practices with regards to a certain set of performance indicators provides guidelines with respect to LSCM implementation depending on which performance indicators are envisioned for improvement.
Determinants of collaborative interfaces in public-private IT outsourcing relationships
Authors: Duhamel Francois Bernard , Gutiérrez-Martínez Isis , Picazo-Vela Sergio , Luna-Reyes Luis
Published: April 2018

Purpose

Collaborations between public administrations and private sector represent a specific challenge to manage contractual and organizational relationships among partners with different goals, working cultures, norms, rules and processes. Therefore, the main research question of this paper is: What are the antecedents of effective collaboration in public-private IT outsourcing relations? Thus, the purpose of this paper is to identify the determinants of collaborative interface characteristics as scaffolding structures to manage public-private IT outsourcing relations effectively.

Design/methodology/approach

Two cases of public-private IT outsourcing relationships in Mexico were used to compare and contrast the main antecedents of collaborative interface characteristics. Case selection was based on the success in each case, as perceived by the collaborating members involved. A successful case and a less successful case of application development for the provision of public services from two state administrations in Mexico were chosen. Data gathering took place via face-to-face interviews.

Findings

The quality of the organizational interface depends on the interactions between exchange of knowledge and mutual trust, along with the commitment between partners. Trust, commitment and knowledge sharing interacted to enhance interface characteristics that have an impact on public and political values.

Research limitations/implications

This paper used and extended an outsourcing technology enactment model to emphasize the quality of organizational interfaces as a main antecedent for the success of public-private IT outsourcing relations.

Practical implications

Effectively designing work practices and contracts implies the development of flexible contracts, objects and routines to adjust project requirements to fulfill better public-private goals. Such flexible contracts and practices are only possible in a trusting environment where participants shape their mutual understanding of the project.

Originality/value

The paper contributes to the literature on public-private IT outsourcing relationships by offering a theoretical framework on key antecedents and processes of success of these relationships.
Nature, extent and ecological implications of night‐time light from road vehicles
Authors: Gaston Kevin J. , Holt Lauren A.
Published: April 2018

The erosion of night‐time by the introduction of artificial lighting constitutes a profound pressure on the natural environment. It has altered what had for millennia been reliable signals from natural light cycles used for regulating a host of biological processes, with impacts ranging from changes in gene expression to ecosystem processes.

Studies of these impacts have focused almost exclusively on those resulting from stationary sources of light emissions, and particularly streetlights. However, mobile sources, especially road vehicle headlights, contribute substantial additional emissions.

The ecological impacts of light emissions from vehicle headlights are likely to be especially high because these are (1) focused so as to light roadsides at higher intensities than commonly experienced from other sources, and well above activation thresholds for many biological processes; (2) projected largely in a horizontal plane and thus can carry over long distances; (3) introduced into much larger areas of the landscape than experience street lighting; (4) typically broad “white” spectrum, which substantially overlaps the action spectra of many biological processes and (5) often experienced at roadsides as series of pulses of light (produced by passage of vehicles), a dynamic known to have major biological impacts.

The ecological impacts of road vehicle headlights will markedly increase with projected global growth in numbers of vehicles and the road network, increasing the local severity of emissions (because vehicle numbers are increasing faster than growth in the road network) and introducing emissions into areas from which they were previously absent. The effects will be further exacerbated by technological developments that are increasing the intensity of headlight emissions and the amounts of blue light in emission spectra.

Synthesis and applications. Emissions from vehicle headlights need to be considered as a major, and growing, source of ecological impacts of artificial night‐time lighting. It will be a significant challenge to minimise these impacts whilst balancing drivers' needs at night and avoiding risk and discomfort for other road users. Nonetheless, there is potential to identify solutions to these conflicts, both through the design of headlights and that of roads.
Power, Process, Plumbing: Big G and Small g Gender in Victoria's Family Violence Policy Subsystem
Authors: Yates Sophie
Published: April 2018

In this article, I introduce the framework of ‘big G’ (categorical) and ‘small g’ (process) gender to explore the varied ways in which actors in Victoria's family violence policy subsystem talk about and understand gender. I explain why such varied definitions of gender pose a problem for domestic and family violence (DFV) advocates, and how big G definitions might be associated with reluctance to accept gendered explanations for DFV. Conversely, I show how small g definitions (coupled with an analysis of power in relationships) can help us appreciate the way gender influences a variety of forms of DFV, and thus understand how to address the problem. Lastly, I use examples from interviews with policy actors to connect participants’ understanding of gender with their attitudes to the role of gender in DFV, and discuss the practical and theoretical implications of my research for feminist DFV advocates and policymakers.
Accuracy of medication information sources compared to the best possible medication history for patients presenting to the emergency department
Authors: Chen Hayley H , Taylor Simone E , Harding Andrew M , Taylor David McD
Published: April 2018

Objective

To assess the accuracy of medication information sources available for adult patients presenting to the ED, compared to a best possible medication history (BPMH).

Methods

This prospective observational study was undertaken in the ED of a major tertiary‐referral teaching hospital. A convenience sample of consecutive adult patients taking one or more regular medications was included. A BPMH was ascertained using patient/carer interviews, where available, and confirmed with one or more other sources. For residential care facility (RCF) patients, the RCF medication chart and at least one other source were used. Information sources compared with the BPMH were community pharmacy dispensing history, patient's own medications, patient's medication list, general practitioner letter, medications stored in and labelled on dose administration aids (DAAs) and the RCF chart. Number of discrepancies per patient for each source was determined by comparing medications and dose regimens to those documented in the BPMH.

Results

A total of 455 patients (median age 71 years) took a median of six ‘regular’ and two ‘as required’ medications. The median number (range) of discrepancies per patient for regular medication names and dosages were RCF chart 0 (0–3), DAA contents 2.0 (0–9), patient's medication list 2.5 (0–16), DAA medications label 3.0 (0–7), community pharmacy history 3.0 (0–19), general practitioner letter 3.0 (0–18) and patient's own medications 4.0 (0–16). Overall, 40.4% of discrepancies were deemed ‘moderate’ or ‘high’ clinical significance. Omission errors accounted for 55.6% of discrepancies.

Conclusions

A combination of sources is essential to determine the BPMH. RCF charts provided the most accurate information. Other sources had two to four regular medication‐related discrepancies per patient.
Perhaps quality of life should not be used as a trigger for discussing resuscitation and advance care plans
Authors: Rose Michael , Welz Martina
Published: April 2018

As a subjective measure, quality of life should not be used as a trigger for discussing resuscitation, goals of care or advanced care plans. Limitations and challenges in measurement and assessment of quality of life have been recognised. It is a fluid construct and subject to changes and response shifts. Surrogate quality of life estimations may misrepresent individual worth and self‐perceived quality of life. Disagreement over quality of life statements may cause harm.
Wait times are not the problem! Detailed analysis of unsolicited patient complaints from a metropolitan Australian emergency department
Authors: Lawrence Petra , Jarugula Rajeev , Hazelwood Sarah , Fincher Gavin , Hay Karen
Published: April 2018

Objective

To describe characteristics of ED admissions that resulted in unsolicited complaints and compare with overall ED admissions. The site utilised is an inner city tertiary hospital, with 630 beds, with approximately 82 600 annual presentations, where 32.5% were children.

Methods

Complaints between the dates of 27 November 2012 and 10 March 2016 were reviewed. Performance indicators and the distribution of presentations by diagnostic code were reviewed.

Results

A total of 572 different complaint reasons were found and grouped into 12 categories. The most common reasons for complaints were treatment (33.2%) and communication (28.3%), and most complaints concerned medical staff. Other variables including wait times have no effect on patient complaints. Utilising aggregate numbers, the overall paediatric complaint ratio was 0.98:1000 presentations, and the total adult department complaints were 1.78:1000 presentations.

Conclusion

As seen in this study the vast majority of patient complaints were associated with treatment and communication issues and skewed towards doctors. It may be feasible for medical staff to undertake communication training as clinician‐patient communication in the ED is an important aspect in the improvement of patient satisfaction and in decreasing patient complaints as waiting times and triage categories had no major influence on patient complaints.
Serum Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein evaluates liver function and predicts prognosis in liver cirrhosis
Authors: Xu Wen Ping , Wang Ze Rui , Zou Xia , Zhao Chen , Wang Rui , Shi Pei Mei , Yuan Zong Li , Yang Fang , Zeng Xin , Wang Pei Qin , Sultan Sakhawat , Zhang Yan , Xie Wei Fen
Published: April 2018

OBJECTIVE

Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein (WFA+‐M2BP) is a novel glycobiomarker for evaluating liver fibrosis, but less is known about its role in liver cirrhosis (LC). This study aimed to investigate the utility of WFA+‐M2BP in evaluating liver function and predicting prognosis of cirrhotic patients.

METHODS

We retrospectively included 197 patients with LC between 2013 and 2016. Serum WFA+‐M2BP and various biochemical parameters were measured in all patients. With a median follow‐up of 23 months, liver‐related complications and deaths of 160 patients were recorded. The accuracy of WFA+‐M2BP in evaluating liver function, predicting decompensation and mortality were measured by the receiver operating characteristic (ROC) curve, logistic and Cox's regression analyses, respectively.

RESULTS

WFA+‐M2BP levels increased with elevated Child–Pugh classification, especially in patients with hepatitis B virus (HBV) infection. ROC analysis confirmed the high reliability of WFA+‐M2BP for the assessment of liver function using Child–Pugh classification. WFA+‐M2BP was also significantly positively correlated with the model for end‐stage liver disease (MELD) score. Multivariate logistic regression analysis indicated WFA+‐M2BP as an independent predictor of clinical decompensation for compensated patients (odds ratio 11.958, 95% confidence interval [CI] 1.876–76.226, P = 0.009), and multivariate Cox's regression analysis verified WFA+‐M2BP as an independent risk factor for liver‐related death in patients with HBV infection (hazards ratio 10.596, 95% CI 1.356–82.820, P = 0.024).

CONCLUSION

Serum WFA+‐M2BP is a reliable predictor of liver function and prognosis in LC and could be incorporated into clinical surveillance strategies for LC patients, especially those with HBV infection.
Impact of “high” implantation on functionality of self‐expandable bioprosthesis during the short‐ and long‐term outcome of patients who undergo transcatheter aortic valve implantation: Is high implantation beneficial?
Authors: Vavuranakis Manolis , Kariori Maria , Scott Lilly , Kalogeras Konstantinos , Siasos Gerasimos , Vrachatis Dimitrios , Lavda Maria , Kalantzis Charalampos , Vavuranakis Michael , Bei Evangelia , Moldovan Carmen‐Maria , Oikonomou Evangelos , Stefanadis Christodoulos , Tousoulis Dimitrios
Published: April 2018

Aim

High position of the self‐expandable bioprosthesis CoreValve/Evolut R has been proved to affect immediate hemodynamics of the valve. Whether this may have any impact on long‐term procedural outcome has not been defined yet. The purpose of this study was to assess whether the final position of aortic bioprosthesis affects its long‐term functionality.

Method

Consecutive patients (pts) who underwent successful TAVI procedure were evaluated and separated into 2 groups according to the implantation depth (ID): Group I: pts with 4 mm <ID ≤13 mm; Group II: pts with ID ≤4 mm. ID was measured utilizing the final aortography after device delivery and was defined as the distance both from the native non‐ and left coronary cusp to the deepest edge of the deployed bioprosthesis in the left ventricle. Clinical outcome and echocardiographic parameters were recorded before the procedure, at discharge, at 1‐month and 1‐year‐follow‐up.

Results

One hundred and ninety‐eight pts (80 ± 5.5 years, 107 males [54%]) treated with the CoreValve/Evolut R bioprostheses were recorded. Group I appeared to have higher peak gradient (17 ± 6.5 vs 14 ± 5.5 mm Hg, P = .02) as well as Vmax (2 ± 0.4 vs 1.84 ± 0.38 m/s, P = .02) at follow‐up after 1 year when compared with Group II (ID <4 mm). Grouping for ID did not affect all‐cause 1‐year mortality. Paravalvular aortic regurgitation, as well as LVEF at discharge, proved to be independent predictors of all‐cause 1‐year mortality when adjusted for cofactors.

Conclusion

Implantation depth under 4 mm seems to have a favorable effect on long‐term hemodynamic valve functionality.
Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice
Authors: Giannopoulos Phillip F. , Chiu Jian , Praticò Domenico
Published: April 2018

The 5‐lipoxygenase (5LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Aβ or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease‐modifying therapeutic approach for tauopathy.
Simulated Transcatheter Aortic Valve Flow: Implications of Elliptical Deployment and Under‐Expansion at the Aortic Annulus
Authors: Sirois Eric , Mao Wenbin , Li Kewei , Calderan Joseph , Sun Wei
Published: April 2018

Clinical use of transcatheter aortic valves (TAVs) has been associated with abnormal deployment, including oval deployment and under‐expansion when placed into calcified aortic annuli. In this study, we performed an integrated computational and experimental investigation to quantify the impact of abnormal deployment at the aortic annulus on TAV hemodynamics. A size 23 mm generic TAV computational model, developed and published previously, was subjected to elliptical deployment at the annulus with eccentricity levels up to 0.68 and to under‐expansion of the TAV at the annulus by up to 25%. The hemodynamic performance was quantified for each TAV deployment configuration. TAV opening geometries were fabricated using stereolithography and then subjected to steady forward flow testing in accordance with ISO‐5840. Centerline pressure profiles were compared to validate the computational model. Our findings show that slight ellipticity of the TAV may not lead to degeneration of hydrodynamic performance. However, under large ellipticity, increases in transvalvular pressure gradients were observed. Under‐expanded deployment has a much greater negative effect on the TAV hemodynamics compared with elliptical deployment. The maximum turbulent viscous shear stress (TVSS) values were found to be significantly larger in under‐expanded TAVs. Although the maximum value of TVSS was not large enough to cause hemolysis in all cases, it may cause platelets activation, especially for under‐expanded deployments.
Autophagy is induced by resistance exercise in young men, but unfolded protein response is induced regardless of age
Authors: Hentilä J. , Ahtiainen J. P. , Paulsen G. , Raastad T. , Häkkinen K. , Mero A. A. , Hulmi J. J.
Published: April 2018

Aim

Autophagy and unfolded protein response (UPR) appear to be important for skeletal muscle homoeostasis and may be altered by exercise. Our aim was to investigate the effects of resistance exercise and training on indicators of UPR and autophagy in healthy untrained young men (n = 12, 27 ± 4 years) and older men (n = 8, 61 ± 6 years) as well as in resistance‐trained individuals (n = 15, 25 ± 5 years).

Methods

Indicators of autophagy and UPR were investigated from the muscle biopsies after a single resistance exercise bout and after 21 weeks of resistance training.

Results

Lipidated LC3II as an indicator of autophagosome content increased at 48 hours post‐resistance exercise (P < .05) and after a resistance training period (P < .01) in untrained young men but not in older men. Several UPRER markers, typically induced by protein misfolding in endoplasmic reticulum, were increased at 48 hours post‐resistance exercise in untrained young and older men (P < .05) but were unaltered after the 21‐week resistance training period regardless of age. UPR was unchanged within the first few hours after the resistance exercise bout regardless of the training status. Changes in autophagy and UPRER indicators did not correlate with a resistance training‐induced increase in muscle strength and size.

Conclusion

Autophagosome content is increased by resistance training in young previously untrained men, but this response may be blunted by ageing. However, unfolded protein response is induced by an unaccustomed resistance exercise bout in a delayed manner regardless of age.
Drug induced liver injury with analysis of alternative causes as confounding variables
Authors: Teschke Rolf , Danan Gaby
Published: April 2018

Aims

Drug‐induced liver injury (DILI) is rare compared to the worldwide frequent acute or chronic liver diseases. Therefore, patients included in series of suspected DILI are at high risk of not having DILI, whereby alternative causes may confound the DILI diagnosis. The aim of this review is to evaluate published case series of DILI for alternative causes.

Methods

Relevant studies were identified using a computerized search of the Medline database for publications from 1993 through 30 October 2017. We used the following terms: drug hepatotoxicity, drug induced liver injury, hepatotoxic drugs combined with diagnosis, causality assessment and alternative causes.

Results

Alternative causes as variables confounding the DILI diagnosis emerged in 22 published DILI case series, ranging from 4 to 47%. Among 13 335 cases of suspected DILI, alternative causes were found to be more likely in 4555 patients (34.2%), suggesting that the suspected DILI was probably not DILI. Biliary diseases such as biliary obstruction, cholangitis, choledocholithiasis, primary biliary cholangitis and primary sclerosing cholangitis were among the most missed diagnoses. Alternative causes included hepatitis B, C and E, cytomegalovirus, Epstein–Barr virus, ischemic hepatitis, cardiac hepatopathy, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and alcoholic liver disease.

Conclusions

In more than one‐third of published global DILI case series, alternative causes as published in these reports confounded the DILI diagnosis. In the future, published DILI case series should include only patients with secured DILI diagnosis, preferentially established by prospective use of scored items provided by robust diagnostic algorithms such as the updated Roussel Uclaf causality assessment method.
Anti‐inflammatory potency testing of topical corticosteroids and calcineurin inhibitors in human volunteers sensitized to diphenylcyclopropenone
Authors: Mose Kristian F. , Andersen Flemming , Røpke Mads A. , Skov Lone , Friedmann Peter S. , Andersen Klaus E.
Published: April 2018

Aims

To quantify the anti‐inflammatory potency of topical corticosteroids and topical calcineurin inhibitors by measuring the contact allergic response to a diphenylcyclopropenone (DPCP) challenge in de novo sensitized human volunteers.

Methods

Two randomized, double‐blind, vehicle‐controlled studies were performed encompassing 76 volunteers: 29 in the first and 47 in the second study. Topical drugs were applied pre‐ and/or post‐treatment in block designs. The compounds were tested simultaneously under occluded patch tests covering DPCP‐induced dermatitis. Inhibitory responses were assessed by visual scoring and measurements of the oedema thickness with ultrasound.

Results

When applied both before and after the DPCP challenge, significant anti‐inflammatory effects were seen in descending order for tacrolimus 0.1% ointment, clobetasol propionate ointment, betamethasone valerate ointment and hydrocortisone butyrate ointment, while pimecrolimus cream, hydrocortisone ointment and vehicles had no significant effect. Only tacrolimus ointment (P < 0.01) demonstrated a consistent significant pre‐treatment inhibitory effect compared with an untreated DPCP control.

Conclusions

This human testing method in which the inflammation of experimentally induced allergic patch test reactions is quantified by objective measurement allows an analysis of the anti‐inflammatory potency of not only topical corticosteroids, but also of drugs that have no effect on vasoconstriction. The method allowed comparison of the potencies of four topical corticosteroids and two calcineurin inhibitors.
Flesh and bone digital sociality: On how humans may go virtual
Authors: Monti Alessandro , Aglioti Salvatore Maria
Published: April 2018

Research on virtual reality (VR) has gained momentum over the last fifteen years or so. In their review, Pan and Hamilton (2018, British Journal of Psychology) show how the different types of VR devices have the potential to probe fundamental psychological constructs, like those underlying social interactions. Expanding on their work, we propose a research agenda to increase the sense of co‐presence and make VR more real than reality through bodily illusions, multisensory stimulation, self‐conscious emotions, and multisubject social cognition.
Participatory and incremental development in an African local government accounting reform
Authors: Lassou Philippe J. C. , Hopper Trevor , Soobaroyen Teerooven , Wynne Andrew
Published: April 2018

Despite significant donor funding, government accounting reforms seeking transparent and effective management of public resources often fail or have limited success, especially in Africa, prompting questions about donors’ implementation approach and calls for studies of successful reforms. This paper investigates a local government accounting reform in Benin supported by a German development agency–perceived as successful due to the participatory, pragmatic, and incremental approach reinforced by conditionalities in the face of neo‐patrimonial leadership.
An improved damage model using the construction technology of virtual load spectrum and its statistical analysis
Authors: Ye N.H. , He Y. , Deng X. , Cheng C.C.
Published: April 2018

In this work, an improved damage model based on construction technology of virtual load spectrum is developed. A predetermined reliability index is used as the termination criterion to calculate the fatigue life, and the results of statistical analysis have shown that the accuracy of fatigue life prediction result has been greatly improved. The model is targeting cyclic loading applications. The main advantage of the model is the use of construction technology of virtual load spectrum for expanding load spectrum and the Monte Carlo method for correcting fatigue damage. Another advantage concerns the link between predetermined reliability criterion and the fatigue life, which puts forward a new method of calculating fatigue life. The convergence proof of the model is presented, and physical experiment data are shown for validation. Several illustrative examples are presented to confirm the accuracy and efficiency of the proposed damage model.