bluuebunny/crossref_metadata_2025 huggingface dataset:
Optical treatment of amblyopia in older children and adults is essential prior to enrolment in a clinical trial
Authors: Gao Tina Y. , Anstice Nicola , Babu Raiju J. , Black Joanna M. , Bobier William R. , Dai Shuan , Guo Cindy X. , Hess Robert F. , Jenkins Michelle , Jiang Yannan , Kearns Lisa , Kowal Lionel , Lam Carly S. Y. , Pang Peter C. K. , Parag Varsha , South Jayshree , Staffieri Sandra Elfride , Wadham Angela , Walker Natalie , Thompson Benjamin ,   the Binocular Treatment of Amblyopia Using Videogames (BRAVO) Study Team
Published: January 2018

Purpose

Optical treatment alone can improve visual acuity (VA) in children with amblyopia, thus clinical trials investigating additional amblyopia therapies (such as patching or videogames) for children require a preceding optical treatment phase. Emerging therapies for adult patients are entering clinical trials. It is unknown whether optical treatment is effective for adults with amblyopia and whether an optical correction phase is required for trials involving adults.

Methods

We examined participants who underwent optical treatment in the Binocular Treatment for Amblyopia using Videogames (BRAVO) clinical trial (ANZCTR ID: ACTRN12613001004752). Participants were recruited in three age groups (7 to 12, 13 to 17, or ≥18 years), and had unilateral amblyopia due to anisometropia and/or strabismus, with amblyopic eye VA of 0.30–1.00 logMAR (6/12 to 6/60, 20/40 to 20/200). Corrective lenses were prescribed based on cycloplegic refraction to fully correct any anisometropia. VA was assessed using the electronic visual acuity testing algorithm (e‐ETDRS) test and near stereoacuity was assessed using the Randot Preschool Test. Participants were assessed every four weeks up to 16 weeks, until either VA was stable or until amblyopic eye VA improved to better than 0.30 logMAR, rendering the participant ineligible for the trial.

Results

Eighty participants (mean age 24.6 years, range 7.6–55.5 years) completed four to 16 weeks of optical treatment. A small but statistically significant mean improvement in amblyopic eye VA of 0.05 logMAR was observed (S.D. 0.08 logMAR; paired t‐test p < 0.0001). Twenty‐five participants (31%) improved by ≥1 logMAR line and of these, seven (9%) improved by ≥2 logMAR lines. Stereoacuity improved in 15 participants (19%). Visual improvements were not associated with age, presence of strabismus, or prior occlusion treatment. Two adult participants withdrew due to intolerance to anisometropic correction.

Sixteen out of 80 participants (20%) achieved better than 0.30 logMAR VA in the amblyopic eye after optical treatment. Nine of these participants attended additional follow‐up and four (44%) showed further VA improvements.

Conclusions

Improvements from optical treatment resulted in one‐fifth of participants becoming ineligible for the main clinical trial. Studies investigating additional amblyopia therapies must include an appropriate optical treatment only phase and/or parallel treatment group regardless of patient age. Optical treatment of amblyopia in adult patients warrants further investigation.
Plasma metabolome analysis of patients with major depressive disorder
Authors: Kawamura Noriyuki , Shinoda Kosaku , Sato Hajime , Sasaki Kazunori , Suzuki Makoto , Yamaki Kumi , Fujimori Tamaki , Yamamoto Hiroyuki , Osei‐Hyiaman Douglas , Ohashi Yoshiaki
Published: January 2018

Aim

This study sought to characterize the plasma metabolite profiling of patients with major depressive disorder (MDD).

Methods

Psychiatric assessments were made with the Structured Clinical Interview for DSM‐IV Axis I Disorders. In the exploratory cohort, plasma metabolite profiles of 34 MDD patients and 31 mentally healthy controls were compared using capillary electrophoresis‐mass spectrometry. Among the candidate metabolites, we focused on a metabolite showing the largest difference. The absolute concentrations were measured in two cohorts from a psychiatric primary care clinic to characterize the accuracy of the metabolite biomarker.

Results

Among 23 metabolites significantly lower in the MDD group than in healthy controls, we focused on phosphoethanolamine (PEA) as a candidate. The reduction of PEA levels in MDD was checked in independent clinical sample sets. An ion‐chromatography‐fluorescence detection method was developed to measure plasma PEA levels. In the preliminary cohort, we examined 34 MDD and 43 non‐MDD subjects. The area under the receiver–operator curve (AUC) was 0.92, with sensitivity/specificity greater than 88%, at a cut‐off of 1.46 μM. In the checking cohort, with 10 MDD and 13 non‐MDD subjects, AUC was 0.89, with sensitivity/specificity of 86% and 100%, respectively, at a cut‐off of 1.48 μM. Plasma PEA inversely correlated with MDD severity, depressed mood, loss of interest, and psychomotor retardation.

Conclusion

These results suggest that plasma PEA level could be a candidate biomarker of MDD in the clinical setting. Further studies comparing MDD and mentally healthy controls are needed to confirm the utility of PEA as a biomarker for depression.
Understanding the roles of glutamine synthetase, glutaminase, and glutamate decarboxylase autoantibodies in imbalanced excitatory/inhibitory neurotransmission as etiological mechanisms of autism
Authors: Hamed Najat O. , Al‐Ayadhi Laila , Osman Mohamed A. , Elkhawad Abdalla O. , Qasem Hanan , Al‐Marshoud Majida , Merghani Nada M. , El‐Ansary Afaf
Published: January 2018

Aim

Autism is a heterogeneous neurological disorder that is characterized by impairments in communication and social interactions, repetitive behaviors, and sensory abnormalities. The etiology of autism remains unclear. Animal, genetic, and post‐mortem studies suggest that an imbalance exists in the neuronal excitation and inhibition system in autism. The aim of this study was to determine whether alterations of the measured parameters in children with autism are significantly associated with the risk of a sensory dysfunction.

Methods

The glutamine synthetase (GS), kidney‐type glutaminase (GLS1), and glutamic acid decarboxylase autoantibody levels were analyzed in 38 autistic children and 33 age‐ and sex‐matched controls using enzyme‐linked immunosorbent assays.

Results

The obtained data demonstrated significant alterations in glutamate and glutamine cycle enzymes, as represented by GS and GLS1, respectively. While the glutamic acid decarboxylase autoantibodies levels were remarkably increased, no significant difference was observed compared to the healthy control participants.

Conclusion

The obtained data indicate that GS and GLS1 are promising indicators of a neuronal excitation and inhibition system imbalance and that combined measured parameters are good predictive biomarkers of autism.
Results of early treatment for de novo donor‐specific antibodies in pediatric kidney transplant recipients in a cross‐sectional and longitudinal cohort
Authors: Charnaya Olga , Tuchman Shamir , Moudgil Asha
Published: January 2018

The development of dnDSA anti‐HLA antibodies has been shown to be a significant risk factor for graft failure. In 2008, we instituted a routine protocol of standardized monitoring and treatment of dnDSA in pediatric kidney transplant recipients. Of 67 first‐time pediatric kidney transplant recipients, 26 (38%) developed dnDSA after 1.36 (IQ 1‐2.14) years. Coefficient of variance of tacrolimus, a surrogate marker of non‐adherence, was found to be the single most important risk factor for dnDSA development. Overall, there was a significant reduction in dnDSA with treatment in 19 (76%) children. No difference in graft survival and estimated glomerular filtration rate was noted between dnDSA negative and those treated for dnDSA. There was an increased risk of hospitalization in those treated for dnDSA. This study suggests that early detection and treatment of dnDSA can help to prevent graft failure and preserve graft function in the short term. Future studies and longer follow‐up are needed to fully elucidate the effect of early detection and treatment of dnDSA in pediatric kidney transplant recipients.
Mathematical Demonstration and Experimental Activity: A Wittgensteinian Philosophy of Physics
Authors: Bitbol Michel
Published: January 2018

This article aims at reducing the gap between mathematics and physics from a Wittgensteinian point of view. This gap is usually characterized by two discriminating features. (1) The propositions of physics assert something which might be false; they have a hypothetical character. On the contrary, since mathematical propositions are rules that condition the form of assertions, they remain immune from falsification. (2) The propositions of physics refer to facts that may confirm or refute them. On the contrary, since mathematical propositions have no meaning independently of the demonstration procedures, it cannot be said that they refer to “facts” that pre‐exist demonstrations. If we take a closer look, however, these two differences fade away. On the one hand, the propositions of physics are more resistant to experimental tests than has been said in the wake of logical positivism. On the other hand, the “factual” empirical material is defined and co‐constituted by instruments whose arrangement is determined by the theory to be tested (just as mathematical propositions are defined and co‐constituted by demonstration procedures). I conclude by discussing the possibility of a Wittgensteinian philosophy of contemporary physics.
The full‐length sequence of the HLA‐C allele, HLA‐C*03:40:01
Authors: Li L. , Li Z. , Zou H.‐Y.
Published: January 2018

Confirmed the full‐length sequence of HLA‐C*03:40:01 by cloning and sequencing in a Chinese donor.
MUN (MERISTEM UNSTRUCTURED), encoding a SPC24 homolog of NDC80 kinetochore complex, affects development through cell division in Arabidopsis thaliana
Authors: Shin Jinwoo , Jeong Goowon , Park Jong‐Yoon , Kim Hoyeun , Lee Ilha
Published: January 2018

Kinetochore, a protein super‐complex on the centromere of chromosomes, mediates chromosome segregation during cell division by providing attachment sites for spindle microtubules. The NDC80 complex, composed of four proteins, NDC80, NUF2, SPC24 and SPC25, is localized at the outer kinetochore and connects spindle fibers to the kinetochore. Although it is conserved across species, functional studies of this complex are rare in Arabidopsis. Here, we characterize a recessive mutant, meristem unstructured‐1 (mun‐1), exhibiting an abnormal phenotype with unstructured shoot apical meristem caused by ectopic expression of the WUSCHEL gene in unexpected tissues. mun‐1 is a weak allele because of the insertion of T‐DNA in the promoter region of the SPC24 homolog. The mutant exhibits stunted growth, embryo arrest, DNA aneuploidy, and defects in chromosome segregation with a low cell division rate. Null mutants of MUN from TALEN and CRISPR/Cas9‐mediated mutagenesis showed zygotic embryonic lethality similar to nuf2‐1; however, the null mutations were fully transmissible via pollen and ovules. Interactions among the components of the NDC80 complex were confirmed in a yeast two‐hybrid assay and in planta co‐immunoprecipitation. MUN is co‐localized at the centromere with HTR12/CENH3, which is a centromere‐specific histone variant, but MUN is not required to recruit HTR12/CENH3 to the kinetochore. Our results support that MUN is a functional homolog of SPC24 in Arabidopsis, which is required for proper cell division. In addition, we report the ectopic generations of stem cell niches by the malfunction of kinetochore components.
A multi‐parent advanced generation inter‐cross (MAGIC) population for genetic analysis and improvement of cowpea (Vigna unguiculata L. Walp.)
Authors: Huynh Bao‐Lam , Ehlers Jeffrey D. , Huang Bevan Emma , Muñoz‐Amatriaín María , Lonardi Stefano , Santos Jansen R. P. , Ndeve Arsenio , Batieno Benoit J. , Boukar Ousmane , Cisse Ndiaga , Drabo Issa , Fatokun Christian , Kusi Francis , Agyare Richard Y. , Guo Yi‐Ning , Herniter Ira , Lo Sassoum , Wanamaker Steve I. , Xu Shizhong , Close Timothy J. , Roberts Philip A.
Published: January 2018

Multi‐parent advanced generation inter‐cross (MAGIC) populations are an emerging type of resource for dissecting the genetic structure of traits and improving breeding populations. We developed a MAGIC population for cowpea (Vigna unguiculata L. Walp.) from eight founder parents. These founders were genetically diverse and carried many abiotic and biotic stress resistance, seed quality and agronomic traits relevant to cowpea improvement in the United States and sub‐Saharan Africa, where cowpea is vitally important in the human diet and local economies. The eight parents were inter‐crossed using structured matings to ensure that the population would have balanced representation from each parent, followed by single‐seed descent, resulting in 305 F8 recombinant inbred lines each carrying a mosaic of genome blocks contributed by all founders. This was confirmed by single nucleotide polymorphism genotyping with the Illumina Cowpea Consortium Array. These lines were on average 99.74% homozygous but also diverse in agronomic traits across environments. Quantitative trait loci (QTLs) were identified for several parental traits. Loci with major effects on photoperiod sensitivity and seed size were also verified by biparental genetic mapping. The recombination events were concentrated in telomeric regions. Due to its broad genetic base, this cowpea MAGIC population promises breakthroughs in genetic gain, QTL and gene discovery, enhancement of breeding populations and, for some lines, direct releases as new varieties.
Introduction
Authors: Obstfeld David
Published: January 2018

The Introduction provides an overview of the book’s action model. Actors engage in specific social processes to mobilize networks and knowledge to drive both organizational innovation and growth, and many other efforts to get new things done. Innovation takes both more-routine and nonroutine forms, and a particular form of nonroutine action, the creative project, is emphasized as an undertheorized source of innovation in the modern world. Innovation, at the individual level, has four key explanatory variables: (1) brokerage network structure; (2) brokerage process—the action by which a strategic actor leverages his or her network; (3) the strategic actor’s stock of knowledge, whether rooted in experience or education; and (4) the strategic actor’s knowledge articulation skill with which he or she communicates that knowledge for the purposes of engaging or enlisting others. The BKAP model (Brokerage, Knowledge Articulation, Projects) is introduced.
Pioneer Entrepreneurs
Authors: Khaire Mukti
Published: January 2018

This chapter describes pioneer entrepreneurs and their cultural impact. Because market creation is influenced by commentary as well as commerce, pioneer entrepreneurs may be new or established producers or intermediaries in the value chain of their industries. This is a unique conception of the entrepreneur. Consumption of cultural goods (more than other kinds of goods) is influenced by cultural norms that define individuals’ core beliefs about appropriateness and value, as well as their sense of identity. Therefore, pioneer entrepreneurs in creative industries face a formidable challenge when introducing new cultural goods; often, such new goods may not align with prevailing cultural norms, making it difficult to create a market for them. The same challenge also gives pioneers a significant opportunity to influence and change culture by creating a market for new goods through generating discourse that changes cultural norms, optimal framing, and generating consensus about the value of the good.
New World, Old Rules
Authors: Khaire Mukti
Published: January 2018

Globalization and digitalization—the opening of economies across the globe and the advent and spread of the digital medium, respectively—have made the world smaller today. Although this new world has had positive implications for entrepreneurs and pioneer entrepreneurs, it has had negative impacts for incumbents in the creative industries. This chapter addresses the question of whether rules governing the structure and functioning of creative industries are relevant in the current context. Although globalization has typically generated market creation opportunities for pioneer producers and pioneer intermediaries, digitalization has not significantly affected the creation of new categories but has instead provided a new medium for commentary as well as commerce. Understanding how these developments affect creators, producers, and intermediaries suggests that the “old” rules, being foundational, are still applicable and should be followed by firms, creators, and consumers desirous of living in a civil society capable of rejuvenation and change.
Lyric and the Service Sector
Authors: Bernes Jasper
Published: January 2018

O’Hara’s “I do this, I do that” poems detail the poet’s movements through the city during periods of leisure. In this chapter, Bernes argues that such leisure periods are usually, implicitly or explicitly, circumscribed by periods of work. This is especially true in Lunch Poems, where the conceit of the book is that many of the poems were written during his “lunch hour.” O’Hara’s lunch-hour pastorals are not so much opposed to the workday and its unfree time of getting things done as they are a space for an alternative kind of work. This chapter proposes that we see O’Hara as poet of service work as much as poet of consumption, reorienting ourselves to the presence of labor (his own and others’) within the poems. In particular, Bernes argues, O’Hara adapts the resources of the lyric poem to the transactional space of service work.
Overflow
Authors: Bernes Jasper
Published: January 2018

The Epilogue considers the possible fate of the artistic critique of labor in the decades to come. As demand for labor weakens because of ongoing structural transformations, the link between art and labor will likewise weaken, Bernes argues. Thus, artists would do well to revive older traditions linking the poet to wagelessness. The Epilogue examines these traditions, beginning with the Renaissance ballad and continuing through the Romantic poetry of vagrancy and the African American fugitive lyric, linking this poetic history to a theoretical investigation of what Karl Marx calls “surplus populations.” The long history of the poetics of wagelessness gives some indication of the aesthetic outlines of the coming era. In closing, Bernes looks at two contemporary poets, Fred Moten and Wendy Trevino, who engage this long tradition and mobilize it to meet the specific conditions of twenty-first-century capitalism.
Re-intermediating Investment Management
Authors: Monk Ashby , Sharma Rajiv , Sinclair Duncan L.
Published: January 2018

Chapter 3 focuses on the re-intermediating aspect of the collaborative model, explaining the idea that institutional investors need to re-engage with their asset managers in order to obtain greater alignment of interests. The chapter recognizes that asset managers can provide value to their investor clients under the right terms and conditions and seeks to understand what such a governance arrangement looks like. It draws inspiration from the sociology–informed relational contracting method, which emphasizes trust, mutual dependency, and cooperation over the long term as key norms of the contractual engagement. Relational contracting is thus proposed as an ideological form of governance between investors and investment managers, which is practically translated into more discrete mandates, greater responsibility for investors, greater transparency, and robust incentive structures. The chapter provides theoretical evidence for the importance of relational contacts and practical guidance for achieving them.
Improvement in detection limit for time-of-flight SIMS analysis of dopants in GaN structures
Authors: Klump Andrew , Zhou Chuanzhen , Stevie Frederick A. , Collazo Ramón , Sitar Zlatko
Published: January 2018

Secondary ion mass spectrometry (SIMS) has been used extensively to monitor dopant levels in semiconductor materials. The preponderance of these measurements has been made with magnetic sector or quadrupole analyzers. Use of time-of-flight (ToF) analyzers has been limited because of an inability to match the detection limit of the other analyzers. Optimization of the ToF-SIMS analysis beam pulse width and analysis frames per cycle is shown to provide as much as an order of magnitude improvement in detection limit. The magnesium dopant in GaN structures was used for the study and analysis was made with Cs+ sputtering source and Bi3+. The count rate for CsMg+ increased by a factor of 11.3 with both improvements applied. This was evidenced by a detection limit improvement for magnesium from 7.5 × 1017 atoms/cm3 to low 1017 atoms/cm3. Increasing the number of analysis frames from one to ten causes cycle time to increase by a factor of five. Hence, there is a tradeoff between improved detection limit and analysis time.
Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin against Staphylococcus aureus Isolates with Different Resistance Phenotypes in Models of Cultured Phagocytic Cells
Authors: Peyrusson Frédéric , Tulkens Paul M. , Van Bambeke Françoise
Published: January 2018

Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examinedin vitroits activity against intracellularStaphylococcus aureus(involved in the persistent character of skin and skin structure infections) by use of a pharmacodynamic model and in relation to cellular pharmacokinetics in phagocytic cells. Compared to oxacillin, vancomycin, linezolid, daptomycin, azithromycin, and moxifloxacin, gepotidacin was (i) more potent intracellularly (the apparent bacteriostatic concentration [Cs] was reached at an extracellular concentration about 0.7× its MIC and was not affected by mechanisms of resistance to the comparators) and (ii) caused a maximal reduction of the intracellular burden (maximum effect) of about −1.6 log10CFU (which was better than that caused by linezolid, macrolides, and daptomycin and similar to that caused by moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100× their MIC, the intracellular persisting fraction was <0.1% with moxifloxacin, 0.5% with gepotidacin, and >1% with the other drugs. The accumulation and efflux of gepotidacin in phagocytes were very fast (kinandkout, ∼0.3 min−1; the plateau was reached within 15 min) but modest (intracellular concentration-to-extracellular concentration ratio, ∼1.6). In cell fractionation studies, about 40 to 60% of the drug was recovered in the soluble fraction and ∼40% was associated with lysosomes in uninfected cells. In infected cells, about 20% of cell-associated gepotidacin was recovered in a sedimentable fraction that also contained bacteria. This study highlights the potential for further study of gepotidacin to fight infections where intracellular niches may play a determining role in bacterial persistence and relapses.
Partially Reciprocal Replacement of FlrA and FlrC in Regulation of Shewanella oneidensis Flagellar Biosynthesis
Authors: Gao Tong , Shi Miaomiao , Gao Haichun
Published: January 2018

In some bacteria with a polar flagellum, an established regulatory hierarchy controlling stepwise assembly of the organelle consists of four regulators: FlrA, σ54, FlrBC, and σ28. Because all of these regulators mediate the expression of multiple targets, they are essential to the assembly of a functional flagellum and therefore to motility. However, this is not the case for the gammaproteobacteriumShewanella oneidensis: cells lacking FlrB, FlrC, or both remain flagellated and motile. In this study, we unravel the underlying mechanism, showing that FlrA and FlrC are partially substitutable for each other in regulating flagellar assembly. While both regulators are bacterial enhancer binding proteins (bEBPs) for σ54, FlrA differs from FlrC in its independence of σ54for its own transcription and its inability to activate the flagellin geneflaA. These differences largely account for the distinct phenotypes resulting from the loss or overproduction of FlrA and FlrC.

IMPORTANCEThe assembly of a polar flagellum in bacteria has been characterized as relying on four regulators, FlrA, σ54, FlrBC, and σ28, in a hierarchical manner. They all are essential to the process and therefore to motility, except inS. oneidensis, in which FlrB, FlrC, or both together are not essential. Here we show that FlrA and FlrC, as bEBPs, are partially reciprocal in functionality in this species. As a consequence, the presence of one allows flagellar assembly and motility in the other's absence. Despite this, there are significant differences in the physiological roles played by these two regulators: FlrA is the master regulator of flagellar assembly, whereas FlrC fine-tunes motility. These intriguing observations open up a new avenue to further exploration of the regulation of flagellar assembly.
Epstein-Barr Virus (EBV) Latent Protein EBNA3A Directly Targets and Silences the
STK39
Gene in B Cells Infected by EBV
Authors: Bazot Quentin , Paschos Kostas , Allday Martin J.
Published: January 2018

Epstein-Barr virus (EBV) establishes latent infection in human B cells and is associated with a wide range of cancers. The EBV nuclear antigen 3 (EBNA3) family proteins are critical for B cell transformation and function as transcriptional regulators. It is well established that EBNA3A and EBNA3C cooperate in the regulation of cellular genes. Here, we demonstrate that the gene
STK39
is repressed only by EBNA3A. This is the first example of a gene regulated only by EBNA3A in EBV-transformed lymphoblastoid cell lines (LCLs) without the help of EBNA3C. This was demonstrated using a variety of LCLs carrying either knockout, revertant, or conditional EBNA3 recombinants. Investigating the kinetics of EBNA3A-mediated changes in
STK39
expression showed that
STK39
becomes derepressed quickly after EBNA3A inactivation. This derepression is reversible as EBNA3A reactivation represses
STK39
in the same cells expressing a conditional EBNA3A.
STK39
is silenced shortly after primary B cell infection by EBV, and no
STK39
-encoded protein (SPAK) is detected 3 weeks postinfection. Chromatin immunoprecipitation (ChIP) analysis indicates that EBNA3A directly binds to a regulatory region downstream of the
STK39
transcription start site. For the first time, we demonstrated that the polycomb repressive complex 2 with the deposition of the repressive mark H3K27me3 is not only important for the maintenance of an EBNA3A target gene (
STK39
) but is also essential for the initial establishment of its silencing. Finally, we showed that DNA methyltransferases are involved in the EBNA3A-mediated repression of
STK39
.

IMPORTANCE
EBV is well known for its ability to transform B lymphocytes to continuously proliferating lymphoblastoid cell lines. This is achieved in part by the reprogramming of cellular gene transcription by EBV transcription factors, including the EBNA3 proteins that play a crucial role in this process. In the present study, we found that EBNA3A epigenetically silences
STK39
. This is the first gene where EBNA3A has been found to exert its repressive role by itself, without needing its coregulators EBNA3B and EBNA3C. Furthermore, we demonstrated that the polycomb repressor complex is essential for EBNA3A-mediated repression of
STK39
. Findings in this study provide new insights into the regulation of cellular genes by the transcription factor EBNA3A.
Processing of
Candida albicans
Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence
Authors: Richardson Jonathan P. , Mogavero Selene , Moyes David L. , Blagojevic Mariana , Krüger Thomas , Verma Akash H. , Coleman Bianca M. , De La Cruz Diaz Jacinto , Schulz Daniela , Ponde Nicole O. , Carrano Giulia , Kniemeyer Olaf , Wilson Duncan , Bader Oliver , Enoiu Simona I. , Ho Jemima , Kichik Nessim , Gaffen Sarah L. , Hube Bernhard , Naglik Julian R.
Published: January 2018

Candida albicans
is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans. During mucosal infection,
C. albicans
undergoes a morphological transition from yeast to invasive filamentous hyphae that secrete candidalysin, a 31-amino-acid peptide toxin required for virulence. Candidalysin damages epithelial cell plasma membranes and stimulates the activating protein 1 (AP-1) transcription factor c-Fos (via p38–mitogen-activated protein kinase [MAPK]), and the MAPK phosphatase MKP1 (via extracellular signal-regulated kinases 1 and 2 [ERK1/2]–MAPK), which trigger and regulate proinflammatory cytokine responses, respectively. The candidalysin toxin resides as a discrete cryptic sequence within a larger 271-amino-acid parental preproprotein, Ece1p. Here, we demonstrate that kexin-like proteinases, but not secreted aspartyl proteinases, initiate a two-step posttranslational processing of Ece1p to produce candidalysin. Kex2p-mediated proteolysis of Ece1p after Arg61 and Arg93, but not after other processing sites within Ece1p, is required to generate immature candidalysin from Ece1p, followed by Kex1p-mediated removal of a carboxyl arginine residue to generate mature candidalysin.
C. albicans
strains harboring mutations of Arg61 and/or Arg93 did not secrete candidalysin, were unable to induce epithelial damage and inflammatory responses
in vitro
, and showed attenuated virulence
in vivo
in a murine model of oropharyngeal candidiasis. These observations identify enzymatic processing of
C. albicans
Ece1p by kexin-like proteinases as crucial steps required for candidalysin production and fungal pathogenicity.

IMPORTANCE
Candida albicans
is an opportunistic fungal pathogen that causes mucosal infection in millions of individuals worldwide. Successful infection requires the secretion of candidalysin, the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is derived from its parent protein Ece1p. Here, we identify two key amino acids within Ece1p vital for processing and production of candidalysin. Mutations of these residues render
C. albicans
incapable of causing epithelial damage and markedly reduce mucosal infection
in vivo
. Importantly, candidalysin production requires two individual enzymatic events. The first involves processing of Ece1p by Kex2p, yielding immature candidalysin, which is then further processed by Kex1p to produce the mature toxin. These observations identify important steps for
C. albicans
pathogenicity at mucosal surfaces.
Host-Virus Protein Interaction Network Reveals the Involvement of Multiple Host Processes in the Life Cycle of Hepatitis E Virus
Authors: Subramani Chandru , Nair Vidya P. , Anang Saumya , Mandal Sukhen Das , Pareek Madhu , Kaushik Nidhi , Srivastava Akriti , Saha Sudipto , Shalimar  , Nayak Baibaswata , Ranjith-Kumar C. T. , Surjit Milan
Published: January 2018

Hepatitis E virus (HEV) is a pathogen that is transmitted by the fecal-oral route. Owing to the lack of an efficient laboratory model, the life cycle of the virus is poorly understood. During the course of infection, interactions between the viral and host proteins play essential roles, a clear understanding of which is essential to decode the life cycle of the virus. In this study, we identified the direct host interaction partners of all HEV proteins and generated a PPI network. Our functional analysis of the HEV-human PPI network reveals a role of HEV proteins in modulating multiple host biological processes such as stress and immune responses, the ubiquitin-proteasome system, energy and iron metabolism, and protein translation. Further investigations revealed an essential role of several host factors in HEV replication. Collectively, the results from our study provide a vast resource of PPI data from HEV and its human host and identify the molecular components of the viral translation/replication machinery.
Retrospective analysis assessing the spatial and temporal distribution of paediatric acute respiratory tract infections in Ho Chi Minh City, Vietnam
Authors: Ho Nhan Thi , Thompson Corinne , Nhan Le Nguyen Thanh , Van Hoang Minh Tu , Dung Nguyen Thanh , Tran My Phuc , Quang Vo Minh , Minh Ngo Ngoc Quang , Tuan Tran Anh , Hung Nguyen Thanh , Tuan Ha Manh , Vinh Chau Nguyen Van , Wolbers Marcel , Thwaites Guy E , Choisy Marc , Baker Stephen
Published: January 2018

Background

Acute respiratory tract infections (ARIs) are the leading cause of morbidity and mortality in young children in low/middle-income countries. Using routine hospital data, we aimed to examine the spatial distribution, temporal trends and climatic risk factors of paediatric ARIs in Vietnam.

Methods

Data from hospitalised paediatric (<16 years) patients with ARIs residing in Ho Chi Minh City (HCMC) between 2005 and 2010 were retrieved from the two main Children’s Hospitals and the Hospital for Tropical Diseases in HCMC. Spatial mapping and time series analysis were performed after disaggregating data into upper respiratory tract infections (URIs) and lower respiratory tract infections (LRIs).

Results

Over the study period, there were 155 999 paediatric patients admitted with ARIs (33% of all hospital admissions). There were 68 120 URIs (14%) and 87 879 LRIs (19%). The most common diagnoses were acute pharyngitis (28% of all ARI), pneumonia (21%), bronchitis (18%) and bronchiolitis (16%). A significant increasing trend over time was found for both URIs (mean weekly incidence per 1000 population, I=3.12), incidence rate ratio for 1-week increase in time (RR 1.0, 95% CI 1.02 to 1.17) for URI and (I=4.02, RR 1.08 (95% CI 1.006 to 1.16)) for LRI. The weekly URI incidence peaked in May–June and was significantly associated with lags in weekly URI incidence and the average humidity, rainfall and water level. The weekly LRI incidence exhibited significant seasonality (P<0.0001), with an annual peak in September–October and was significantly associated with lags in weekly LRI incidence and lags in weekly average temperature, rainfall and water level.

Conclusions

ARIs are a leading cause of childhood hospitalisation in HCMC, Vietnam. The incidence of ARIs was higher in the wet season and in specific HCMC districts. These results may guide health authorities in where and when to effectively allocate resources for the prevention and control of ARIs.
Small cortical grey matter lesions show no persistent infarction in transient ischaemic attack? A prospective cohort study
Authors: Havsteen Inger , Ovesen Christian , Willer Lasse , Nybing Janus Damm , Ægidius Karen , Marstrand Jacob , Meden Per , Rosenbaum Sverre , Folke Marie Norsker , Christensen Hanne , Christensen Anders
Published: January 2018

Objectives

To find determining factors for persistent infarction signs in patients with transient ischaemic attack (TIA), herein initial diffusion lesion size, visibility on apparent diffusion coefficient (ADC) or fluid-attenuated inversion recovery (FLAIR) and location.

Design

Prospective cohort study of patients with clinical TIA receiving 3T-MRI within 72 hours of symptom onset and at 8-week follow-up.

Setting

Clinical workflow in a single tertiary stroke centre between February 2012 and June 2014.

Participants

199 candidate patients were recruited, 64 patients were excluded due to non-TIA discharge diagnosis or no 8-week MRI. 122 patients completed the study.

Primary outcome measures

The primary outcome was visible persistent infarction defined as 8-week FLAIR hyperintensity or atrophy corresponding to the initial diffusion-weighted imaging (DWI) lesion.

Results

50 patients showed 84 initial DWI lesions. 29 (35%) DWI lesions did not result in infarction signs on 8-week FLAIR. 26 (90%, P<0.0001) reversing lesions were located in the cortical grey matter (cGM). cGM location (vs any other location) strongly predicted no 8-week infarction sign development (OR 0.02, 95% CI 0.001 to 0.17) or partial lesion area decrease (>30% of initial DWI-area, OR 14.10, 95% CI 3.61 to 54.72), adjusted for FLAIR-visibility, DWI-area, ADC-confirmation and time to scan (TTS) from symptom onset to baseline MRI. Acute FLAIR-visibility was a strong associated factor for persistent infarction signs (OR 33.06, 95% CI 2.94 to 1432.34). For cGM lesions area size was sole associated factor for persistent infarction signs with a 0.31 cm2(area under the curve (AUC), 0.97) threshold. In eight (16%) DWI-positive patients, all lesions reversed fully.

Conclusions

16% of DWI-positive patients and one-third of acute DWI lesions caused no persistent infarction signs, especially small cGM lesions were not followed by development of persistent infarction signs. Late MRI after TIA is likely to be less useful in the clinical setting, and it is dubious if the absence of old vascular lesions can be taken as evidence of no prior ischaemic attacks.

Trial registration number

NCT01531946; Results.
Associations between physical behaviour patterns and levels of depressive symptoms, anxiety and well-being in middle-aged adults: a cross-sectional study using isotemporal substitution models
Authors: Dillon Christina B , McMahon Elaine , O’Regan Grace , Perry Ivan J
Published: January 2018

Objective

To examine the compositional effects of physical behaviour on mental health.

Design

Cross-sectional study.

Setting

A population-representative random sample (Mitchelstown cohort) was recruited from a large primary care centre in Mitchelstown, County Cork, Ireland.

Participants

In total 3807 potential participants were selected from the practice list. Following exclusion of duplicates, deaths and ineligibles, 3043 were invited to participate and of these, 2047 (49.2% men) completed the questionnaire and physical examination components of the baseline assessment during the study period (April 2010 and May 2011). Accelerometers were introduced into the study in January 2011. Of the 745 participants seen between January and May of 2011, 475 (44.6% men) subjects (response rate 64%) agreed to participate and of these 397 (46.1% men) had valid accelerometer data.

Primary and secondary outcome measures

Participants wore the wrist GENEActiv accelerometer for 7 consecutive days. Data were summarised into 60 s epochs and activity categorised as sedentary behaviour, light or moderate-to-vigorous physical activity (MVPA). Levels of depressive and anxiety symptoms were assessed using the Centre for Epidemiologic Studies Depression scale and the Hospital Anxiety and Depression Scale. Well-being was assessed using the WHO-5 well-being scale.

Results

In adjusted isotemporal models, a 30 min increase in light activity per day was associated with a significant decrease in levels of anxiety symptoms (B=−0.34; 95% CI −0.64 to −0.04) and a significant increase in levels of well-being (B=0.58; 95% CI 0.05 to 1.11). No statistically significant associations were observed between any physical behaviour and depressive symptoms or when sedentary behaviour was substituted with MVPA (P>0.05).

Conclusion

Although based on a cross-sectional study, the findings suggest that substituting light activity for sedentary behaviour may have positive associations with symptoms of anxiety and reported well-being among middle-aged adults.
Impacts of Bicycle Infrastructure in Mid-Sized Cities (IBIMS): protocol for a natural experiment study in three Canadian cities
Authors: Winters Meghan , Branion-Calles Michael , Therrien Suzanne , Fuller Daniel , Gauvin Lise , Whitehurst David G T , Nelson Trisalyn
Published: January 2018

Introduction

Bicycling is promoted as a transportation and population health strategy globally. Yet bicycling has low uptake in North America (1%–2% of trips) compared with European bicycling cities (15%–40% of trips) and shows marked sex and age trends. Safety concerns due to collisions with motor vehicles are primary barriers.

To attract the broader population to bicycling, many cities are making investments in bicycle infrastructure. These interventions hold promise for improving population health given the potential for increased physical activity and improved safety, but such outcomes have been largely unstudied. In 2016, the City of Victoria, Canada, committed to build a connected network of infrastructure that separates bicycles from motor vehicles, designed to attract people of ‘all ages and abilities’ to bicycling.

This natural experiment study examines the impacts of the City of Victoria’s investment in a bicycle network on active travel and safety outcomes. The specific objectives are to (1) estimate changes in active travel, perceived safety and bicycle safety incidents; (2) analyse spatial inequities in access to bicycle infrastructure and safety incidents; and (3) assess health-related economic benefits.

Methods and analysis

The study is in three Canadian cities (intervention: Victoria; comparison: Kelowna, Halifax). We will administer population-based surveys in 2016, 2018 and 2021 (1000 people/city). The primary outcome is the proportion of people reporting bicycling. Secondary outcomes are perceived safety and bicycle safety incidents. Spatial analyses will compare the distribution of bicycle infrastructure and bicycle safety incidents across neighbourhoods and across time. We will also calculate the economic benefits of bicycling using WHO’s Health Economic Assessment Tool.

Ethics and dissemination

This study received approval from the Simon Fraser University Office of Research Ethics (study no. 2016s0401). Findings will be disseminated via a website, presentations to stakeholders, at academic conferences and through peer-reviewed journal articles.
Ketamine procedural sedation in the emergency department of an urban tertiary hospital in Dar es Salaam, Tanzania
Authors: Coralic Zlatan , Sawe Hendry R , Mfinanga Juma A , Cortez Alfredo , Koehl Jennifer , Siroker Hannah , Reynolds Teri A
Published: January 2018

Study objective

We describe ketamine procedural sedations and associated adverse events in low-acuity and high-acuity patients in a resource-limited ED.

Methods

This was a prospective observational study of ketamine procedural sedations at the Emergency Medical Department at the Muhimbili National Hospital in Dar es Salaam, Tanzania. We observed consecutive procedural sedations and recorded patient demographics, medications, vital signs, pulse oximetry, capnography and a priori defined adverse events (using standard definitions in emergency medicine sedation guidelines). All treatment decisions were at the discretion of the treating providers who were blinded to study measurements to simulate usual care. Data collection was unblinded if predefined safety parameters were met. For all significant adverse and unblinding events, ketamine causality was determined via review protocol. Additionally, providers and patients were assessed for sedation satisfaction.

Results

We observed 54 children (median 3 years, range 11 days–15 years) and 45 adults (median 33 years, range 18–79 years). The most common indications for ketamine were burn management in children (55.6%) and orthopaedic procedures in adults (68.9%). Minor adverse events included nausea/vomiting (12%), recovery excitation (11%) and one case of transient hypertension. There were nine (9%) patients who had decreased saturation readings (SpO2≤92%). There were three deaths, all in severely injured patients. After review protocol, none of the desaturations or patient deaths were thought to be caused by ketamine. No patient experienced ketamine-related laryngospasm, apnoea or permanent complications. Overall, ketamine was well tolerated and resulted in high patient and provider satisfaction.

Conclusion

In this series of ketamine sedations in an urban, resource-limited ED, there were no serious adverse events attributable to ketamine.
Identification of rare diseases by screening a population selected on the basis of routine pathology results—the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy
Authors: Reynolds Timothy M , Mewies Clare , Hamilton John , Wierzbicki Anthony S
Published: January 2018

Aims

Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder of cholesterol ester storage associated with hepatic disease, cirrhosis and accelerated atherosclerosis. Its prevalence in the general population, patients with dyslipidaemia and raised transaminases is unclear. This study attempted to identify the prevalence of LALD from patients with abnormal results in laboratory databases.

Methods

Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of low high-density lipoprotein-cholesterol (≤0.85 mmol/L; 33 mg/dL) and with elevated alanine or aspartate transaminases (≥60 IU/L) on one occasion or more over a 3-year time interval. Patients were recalled, and a dried blood spot sample was collected for lysosomal acid lipase determination by a fluorimetric enzyme assay. Histopathology databases of liver biopsies were interrogated for patients with features of ‘microvesicular cirrhosis’ or ‘cryptogenic cirrhosis’ in the report. Histological blocks were sampled, and samples were analysed by next-generation sequencing for the presence of mutations in the LAL gene.

Results

Samples were obtained from 1825 patients with dyslipidaemia and elevated transaminases. No cases of LALD were identified. Liver biopsies were obtained from six patients. DNA extraction was successful from four patients. Two patients were homozygous for the LAL c.46A>C;p.Thr16Pro unclassified variant in exon 2.

Conclusions

Pathology databases hold routine information that can be used to identify patients with specific patterns of results or those who had biopsies to allow targeted testing for possible causes of disease. Biochemical screening suggests that the gene frequency of LAL deficiency in adults is less than 1 in 100.
Catalogue of inherited disorders found among the Irish Traveller population
Authors: Lynch Sally Ann , Crushell Ellen , Lambert Deborah M , Byrne Niall , Gorman Kathleen , King Mary D , Green Andrew , O’Sullivan Siobhan , Browne Fiona , Hughes Joanne , Knerr Ina , Monavari Ahmad A , Cotter Melanie , McConnell Vivienne P M , Kerr Bronwyn , Jones Simon A , Keenan Catriona , Murphy Nuala , Cody Declan , Ennis Sean , Turner Jackie , Irvine Alan D , Casey Jillian
Published: January 2018

Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios.

Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population.

Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers.

Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication.

Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.