bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical Innovation Then and Now: Perspectives of Innovators Responsible for Transformative Drugs
Authors: Xu Shuai , Kesselheim Aaron S.
Published: January 2015

The discovery and development of new therapeutics has always been central to improving health worldwide. However, there is ongoing concern regarding the current state of medical innovation. Output from the pharmaceutical industry has been criticized for not being “transformative,” that is, offering substantial improvements in patient outcomes over existing therapeutics. While the cost of drug development continues to rise, breakthrough therapies remain elusive and one half of Phase 3 studies fail. Venture capital, a traditional source of funding for new breakthrough biomedical innovations, has decreased investment by 30% in the biotechnology and medical device sectors from 2007 to 2013. Stakeholders question whether the new drugs approved each year by the FDA —many criticized as marginal improvements over existing therapies — justify the enormous investment.
Global Emergency Legal Responses to the 2014 Ebola Outbreak: Public Health and the Law
Authors: Hodge James G. , Barraza Leila , Measer Gregory , Agrawal Asha
Published: January 2015

From their relative obscurity over the past three decades, varied strains of Ebola disease have emerged as a substantial global biothreat. The current outbreak of Ebola, beginning in March 2014 in Guinea, is projected to infect tens of thousands of people before being brought under control. Some estimate the outbreak could exceed 100,000 cases and extend another 12-18 months. Ebola’s spread has the potential to extend across the globe, but is concentrated in several African countries (e.g., Democratic Republic of Congo, Sierra Leone, Liberia, Guinea, Nigeria, and Senegal). Collectively, these countries are home to nearly 290 million people. Among Liberia’s population of 4.1 million, over 1,100 people have already died from Ebola in less than 6 months; by comparison, if this same outbreak and death rate occurred in the United States, over 88,000 Americans would perish.
Hypothalamic‐Pituitary‐Adrenal Axis Functioning in Huntington's Disease and its Association with Depressive Symptoms and Suicidality
Authors: Hubers A. A. M. , van der Mast R. C. , Pereira A. M. , Roos R. A. C. , Veen L. J. , Cobbaert C. M. , van Duijn E. , Giltay E. J.
Published: January 2015

Hyperactivity of the hypothalamic‐pituitary‐adrenal (HPA) axis has been reported in Huntington's disease (HD). In non‐HD populations, alterations in HPA axis activity have been associated with depression and suicidality. The present study aims to compare HPA axis activity between HD mutation carriers and controls, and examine its association with depressive symptoms and suicidality. To this end, salivary cortisol concentrations at seven time points, as well as depressive symptoms and suicidality, were assessed in 49 pre‐motor, 102 motor symptomatic mutation carriers and 55 controls, at baseline and follow‐up combined. Differences in parameters of HPA axis activity between these three groups, and their associations with depressive symptoms and suicidality in HD mutation carriers, were analysed using multilevel regression analyses. There were no differences in parameters of HPA axis activity between mutation carriers and controls, whereas pre‐motor symptomatic mutation carriers had a significantly higher area under the curve to the increase (AUCi) compared to motor symptomatic mutation carriers. In the entire HD cohort, HPA axis activity was not associated with depressive symptoms or suicidality. After stratifying mutation carriers into pre‐motor, early and advanced disease stages, β values differed between these groups. Remarkably, a higher AUCi was significantly associated with depressive symptoms in pre‐motor and early disease stage mutation carriers, with a reverse nonsignificant association in advanced disease stage mutation carriers. The lower AUCi in motor symptomatic mutation carriers and the varying associations with depressive symptoms and suicidality in pre‐motor, early and advanced disease stages could possibly be explained by exhaustion of the HPA axis after prolonged stress‐induced HPA axis hyperactivity and deserves further longitudinal study.
Adenoviral vectors as novel vaccines for influenza
Authors: Coughlan Lynda , Mullarkey Caitlin , Gilbert Sarah
Published: January 2015

Objectives

Influenza is a viral respiratory disease causing seasonal epidemics, with significant annual illness and mortality. Emerging viruses can pose a major pandemic threat if they acquire the capacity for sustained human-to-human transmission. Vaccination reduces influenza-associated mortality and is critical in minimising the burden on the healthcare system. However, current vaccines are not always effective in at-risk populations and fail to induce long-lasting protective immunity against a range of viruses.

Key findings

The development of ‘universal’ influenza vaccines, which induce heterosubtypic immunity capable of reducing disease severity, limiting viral shedding or protecting against influenza subtypes with pandemic potential, has gained interest in the research community. To date, approaches have focused on inducing immune responses to conserved epitopes within the stem of haemagglutinin, targeting the ectodomain of influenza M2e or by stimulating cellular immunity to conserved internal antigens, nucleoprotein or matrix protein 1.

Adenoviral vectors are potent inducers of T-cell and antibody responses and have demonstrated safety in clinical applications, making them an excellent choice of vector for delivery of vaccine antigens. In order to circumvent pre-existing immunity in humans, serotypes from non-human primates have recently been investigated. We will discuss the pre-clinical development of these novel vectors and their advancement to clinical trials.
Can a mathematical model predict an individual's trait‐like response to both total and partial sleep loss?
Authors: Ramakrishnan Sridhar , Lu Wei , Laxminarayan Srinivas , Wesensten Nancy J. , Rupp Tracy L. , Balkin Thomas J. , Reifman Jaques
Published: January 2015

Humans display a trait‐like response to sleep loss. However, it is not known whether this trait‐like response can be captured by a mathematical model from only one sleep‐loss condition to facilitate neurobehavioural performance prediction of the same individual during a different sleep‐loss condition. In this paper, we investigated the extent to which the recently developed unified mathematical model of performance (UMP) captured such trait‐like features for different sleep‐loss conditions. We used the UMP to develop two sets of individual‐specific models for 15 healthy adults who underwent two different sleep‐loss challenges (order counterbalanced; separated by 2–4 weeks): (i) 64 h of total sleep deprivation (TSD) and (ii) chronic sleep restriction (CSR) of 7 days of 3 h nightly time in bed. We then quantified the extent to which models developed using psychomotor vigilance task data under TSD predicted performance data under CSR, and vice versa. The results showed that the models customized to an individual under one sleep‐loss condition accurately predicted performance of the same individual under the other condition, yielding, on average, up to 50% improvement over non‐individualized, group‐average model predictions. This finding supports the notion that the UMP captures an individual's trait‐like response to different sleep‐loss conditions.
Siderophile and chalcophile element abundances in shergottites: Implications for Martian core formation
Authors: Yang Shuying , Humayun Munir , Righter Kevin , Jefferson Gwendolyn , Fields Dana , Irving Anthony J.
Published: January 2015

Elemental abundances for volatile siderophile and chalcophile elements for Mars inform us about processes of accretion and core formation. Such data are few for Martian meteorites, and are often lacking in the growing number of desert finds. In this study, we employed laser ablation inductively coupled plasma–mass spectrometry (LA‐ICP‐MS) to analyze polished slabs of 15 Martian meteorites for the abundances of about 70 elements. This technique has high sensitivity, excellent precision, and is generally accurate as determined by comparisons of elements for which literature abundances are known. However, in some meteorites, the analyzed surface is not representative of the bulk composition due to the over‐ or underrepresentation of a key host mineral, e.g., phosphate for rare earth elements (REE). For other meteorites, the range of variation in bulk rastered analyses of REE is within the range of variation reported among bulk REE analyses in the literature. An unexpected benefit has been the determination of the abundances of Ir and Os with a precision and accuracy comparable to the isotope dilution technique. Overall, the speed and small sample consumption afforded by this technique makes it an important tool widely applicable to small or rare meteorites for which a polished sample was prepared. The new volatile siderophile and chalcophile element abundances have been employed to determine Ge and Sb abundances, and revise Zn, As, and Bi abundances for the Martian mantle. The new estimates of Martian mantle composition support core formation at intermediate pressures (14 ± 3 GPa) in a magma ocean on Mars.
microRNA evolution and expression analysis in polyploidized cotton genome
Authors: Xie Fuliang , Zhang Baohong
Published: January 2015

Cotton (Gossypium hirsutum L.), the most important fibre plant in the world, is a tetraploid species, originating from the reunion of two ancestral cotton species ~1–2 million years ago. It has been reported that a great number of genes were quickly erased or preferentially remained after whole‐genome duplication, ultimately leading to morphogenesis evolution. However, microRNAs (miRNAs), a new class of gene regulators, have not been well studied in polyploidization. Here, we systematically investigated miRNA evolution amongst cultivated upland cotton G. hirsutum (AADD) and its two ancestors, G. arboreum (AA) and G. raimondii (DD). Our results show that certain highly conserved miRNAs were likely to be lost, whereas certain were remained after genome polyploidization. Cotton‐specific miRNAs might undergo remarkably expansion, resulting in overall miRNA increase in upland cotton. Based on the sequenced genomes of G. arboreum and G. raimondii, we are capable for the first time to categorize the origin of miRNAs and coding genes in upland cotton. Different genome‐derived miRNAs and miRNA*s displayed asymmetric expression pattern, implicating their diverse functions in upland cotton. No miRNA targeting preference was observed between different genome‐derived miRNAs. The origin of miRNAs and coding genes has no impact on becoming miRNAs and their targets, despite some miRNAs and their targets are extremely conserved in the three cotton species. GO‐ and KEGG‐based analysis of conserved miRNAs show that conserved miRNAs and their targets participate in a series of important biological processes and metabolism pathways. Additionally, A‐derived miRNAs might be more responsible for ovule and fibre development.
Inborn errors of ketone body utilization
Authors: Hori Tomohiro , Yamaguchi Seiji , Shinkaku Haruo , Horikawa Reiko , Shigematsu Yosuke , Takayanagi Masaki , Fukao Toshiyuki
Published: January 2015

Succinyl‐CoA:3‐ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl‐CoA thiolase (beta‐ketothiolase or T2) deficiency are classified as autosomal recessive disorders of ketone body utilization characterized by intermittent ketoacidosis. Patients with mutations retaining no residual activity on analysis of expression of mutant cDNA are designated as severe genotype, and patients with at least one mutation retaining significant residual activity, as mild genotype. Permanent ketosis is a pathognomonic characteristic of SCOT‐deficient patients with severe genotype. Patients with mild genotype, however, may not have permanent ketosis, although they may develop severe ketoacidotic episodes similar to patients with severe genotype. Permanent ketosis has not been reported in T2 deficiency. In T2‐deficient patients with severe genotype, biochemical diagnosis is done on urinary organic acid analysis and blood acylcarnitine analysis to observe characteristic findings during both ketoacidosis and non‐episodic conditions. In Japan, however, it was found that T2‐deficient patients with mild genotype are common, and typical profiles were not identified on these analyses. Based on a clinical study of ketone body utilization disorders both in Japan and worldwide, we have developed guidelines for disease diagnosis and treatment. These diseases are treatable by avoiding fasting and by providing early infusion of glucose, which enable the patients to grow without sequelae.
Assertion and Assurance: Some Empirical Evidence
Authors: Turri John
Published: January 2015

I report three experiments relevant to evaluating Krista Lawlor's theory of assurance, respond to her criticism of the knowledge account of assertion, and propose an alternative theory of assurance.
Quantifying Flood Risks in the Netherlands
Authors: Jongejan R. B. , Maaskant B.
Published: January 2015

The Flood Risk in the Netherlands project (Dutch acronym: VNK2) is a large‐scale probabilistic risk assessment for all major levee systems in the Netherlands. This article provides an overview of the methods and techniques used in the VNK2 project. It also discusses two examples that illustrate the potential of quantitative flood risk assessments such as VNK2 to improve flood risk management processes: (i) informing political debates about the risks of flooding and the effectiveness of risk management actions, and (ii) (re)directing research efforts towards important sources of uncertainty.
Immune System‐Related Differentially Expressed Genes, Transcription Factors and microRNAs in Post‐Menopausal Females with Osteopenia
Authors: Ma M. , Luo S. , Chen X. , Yuan F. , Cai J. , Lu L. , Yin F.
Published: January 2015

This study was to identify differentially expressed genes (DEGs) in post‐menopausal females with osteopenia and further screened the potentially involved transcription factors (TFs) and microRNAs (miRNAs). Data set GSE13850 of circulating B lymphocytes from post‐menopausal females with low or high bone mineral density (BMD) was downloaded from Gene Expression Omnibus. Limma package in R was used to identify DEGs following raw data processing. Enrichment analysis was performed using DAVID (Database for Annotation, Visualization and Integrated Discovery) and visualized using plug‐in EnrichmentMap of Cytoscape software. The TFs of DEGs were screened using UCSC (University of California, Santa Cruz) Genome Browser, and miRNAs targeting DEGs were predicted using TarBase, TargetScan and miRecord databases, followed by constructing regulatory networks using Cytoscape software. Totally 52 DEGs were obtained from post‐menopausal females with low BMD compared with those with high BMD. Those DEGs including IL‐4R, IL‐2RG, TGF‐β1 and CD74 were mostly related to functions associated with immune response, lymphocyte activation, T cell differentiation, leucocyte activation and immune system process. NFAT, NF‐κB and EGR family members might have a regulatory effect on these DEGs. PAX5 could regulate 15 DEGs including ZFP36L2 and KLF13. Abundant miRNAs were also found to target dysregulated ZFP36L2 and KLF13. Dysregulated IL‐4R, IL‐2RG, TGF‐β1 and CD74 may mediate the interplay of immune changes and oestrogen deficiency‐induced osteopenia, and disorder functions of NF‐κB, NFAT and EGR family members. PAX5 and various miRNAs might exert regulatory effect on osteopenia via targeting ZFP36L2 and KLF13.
Do Neighborhood Organizational Resources Impact Recidivism?
Authors: Wallace Danielle
Published: January 2015

There is a growing literature investigating how neighborhood organizations impact crime, although recidivism or reoffending has been excluded from this discussion. Combining data on recidivism and organizational availability in Chicago with the 2000 Census and the 2007–2011 American Community Survey, this study models the effect of three types of organizations important for ex‐prisoners (emergency assistance, employment, and education) and their changes on neighborhood‐level recidivism from 2001 to 2006. Results show that changes in the availability of certain types of organizations impact recidivism. Non‐trivial losses (losing two or more organizations) of educational organizations across years increase neighborhood recidivism. Also, disadvantage moderates the effect of non‐trivial gains in organizations; specifically, in low‐disadvantage neighborhoods, gains in employment organizations decrease recidivism. These results suggest that ex‐prisoners are exposed to variability in local organizational environments, and this variability has an impact on overall recidivism. Neighborhood‐based policy aimed at lowering recidivism should not only work to increase these organizations in neighborhoods, but also work to stabilize their presence.
Phylogeny, divergence times and biogeography of window flies (Scenopinidae) and the therevoid clade (Diptera: Asiloidea)
Authors: WINTERTON SHAUN L. , WARE JESSICA L.
Published: January 2015

The evolution of the ‘therevoid’ clade, with an emphasis on window flies (Scenopinidae), is presented by combining DNA sequence data with morphological characters for living and fossil species. The therevoid clade represents a group of four families (Apsilocephalidae, Evocoidae, Scenopinidae and Therevidae) of lower brachyceran Diptera in the superfamily Asiloidea. A comprehensive phylogenetic analysis using parsimony and likelihood methods was undertaken using extensive taxon sampling from all families and subfamilies, and compared with outgroup taxa sampled from the related families Asilidae, Mydidae, Apioceridae and Empididae. Fifty‐nine morphological characters (adult, larval and pupal) were combined with 6.4 kb of DNA sequences for two ribosomal genes (16S and 18S ribosomal DNA) and three protein‐encoding genes [cytochrome oxidase I (COI), triose phosphate isomerase (TPI) and the CPSase region of carbamoyl‐phosphate synthase‐aspartate transcarbamoylase‐dihydroorotase (CAD)]. Results from combined analyses of morphological and molecular data for 78 taxa representing all families of the therevoid clade are presented. Specific hypotheses of the relationship between respective families and subfamilies were tested statistically using four‐cluster likelihood mapping. The therevoid clade is a well‐supported monophyletic group within Asiloidea, with Evocoidae sister to Apsilocephalidae and Therevidae sister to Scenopinidae. Temporal and zoogeographical aspects of therevoid clade evolution were investigated using Bayesian divergence time estimates and Lagrange ancestral range scenarios. The effect of inclusion of fossils as terminal taxa on phylogenetic and divergence time estimation was investigated, with morphological scoring for fossil representatives included in the analyses rather than used simply as minimum age constraints. In each analysis there was either improvement in estimation, or only marginal and localized loss in tree resolution, and with younger estimates of divergence time across the tree. The historical biogeography of the therevoid clade was examined with multiple trans‐Antarctic vicariance events between Australasia and South America evident during the Late Cretaceous to early Palaeogene. Scenopininae is newly subdivided into two tribes, Metatrichini trib.n. and Scenopinini Fallén stat.r.

This published work has been registered in ZooBank, http://zoobank.org/urn:lsid:zoobank.org:pub:4974EBF8‐3117‐4189‐B6DE‐7D5BF9B23E53.
Dose accumulation and 3D imaging with He+ ions
Authors: Giannuzzi Lucille A.
Published: January 2015

Ion implantation accumulation is modeled for the theoretical case of using scanning He+ ion microscopy to image a stack of virtual slices from Si and Cu for 3D tomography. Ion implantation during imaging reaches steady state conditions of maximum concentration at the surface when the virtual thickness of all slices exceeds the total ion range. Imaging at low dose and large voxel sizes offers the greatest likelihood of damage-free targets for the best fidelity 3D data sets. The possibility of damage accumulation increases as the voxel size decreases, which may limit the effectiveness of helium ion microscopy imaging for high resolution 3D data sets. In particular, a surface imaging dose of 2.5 × 1016 ions/cm2 distributed through the volume after each slice can create a situation where almost 2.5 × 1013 ions/cm2 may accumulate at the surface of both Si and Cu at a voxel size of 10 × 10 × 10 nm, possibly causing severe crystalline damage to these targets. This model may be used to predict voxel sizes required for high quality 3D tomography data using helium ion microscopy imaging.
Non-Arrhenius temperature dependence of the island density of one-dimensional Al chains on Si(100): A kinetic Monte Carlo study
Authors: Albia Jason R. , Albao Marvin A.
Published: January 2015

Classical nucleation theory predicts that the evolution of mean island density with temperature during growth in one-dimensional systems obeys the Arrhenius relation. In this study, kinetic Monte Carlo simulations of a suitable atomistic lattice-gas model were performed to investigate the experimentally observed non-Arrhenius scaling behavior of island density in the case of one-dimensional Al islands grown on Si(100). Previously, it was proposed that adatom desorption resulted in a transition temperature signaling the departure from classical predictions. Here, the authors demonstrate that desorption above the transition temperature is not possible. Instead, the authors posit that the existence of a transition temperature is due to a combination of factors such as reversibility of island growth, presence of C-defects, adatom diffusion rates, as well as detachment rates at island ends. In addition, the authors show that the anomalous non-Arrhenius behavior vanishes when adatom binds irreversibly with C-defects as observed in In on Si(100) studies.
Interdiffusion in nanometric Fe/Ni multilayer films
Authors: Liu Jiaxing , Barmak Katayun
Published: January 2015

[Fe (3.1 nm)/Ni (3.3 nm)]20 multilayer films were prepared by DC magnetron sputtering onto oxidized Si(100) substrates. The Fe and Ni layers were shown to both be face-centered cubic by x-ray diffraction. Interdiffusion of the Fe and Ni layers in the temperature range of 300–430 °C was studied by x-ray reflectivity. From the decay of the integral intensity of the superlattice peak, the activation energy and the pre-exponential term for the effective interdiffusion coefficient were determined as to 1.06 ± 0.07 eV and 5 × 10−10 cm2/s, respectively. The relevance of the measured interdiffusion coefficient to the laboratory timescale synthesis of L10 ordered FeNi as a rare-earth free permanent magnet is discussed.
Control of InGaAs and InAs facets using metal modulation epitaxy
Authors: Wistey Mark A. , Baraskar Ashish K. , Singisetti Uttam , Burek Greg J. , Shin Byungha , Kim Eunji , McIntyre Paul C. , Gossard Arthur C. , Rodwell Mark J. W.
Published: January 2015

Control of faceting during epitaxy is critical for nanoscale devices. This work identifies the origins of gaps and different facets during regrowth of InGaAs and InAs adjacent to patterned features. Molecular beam epitaxy near SiO2 or SiNx led to gaps, roughness, or polycrystalline growth, but low-arsenic metal modulated epitaxy produced smooth and gap-free (001) planar growth up to the gate. The resulting self-aligned field effect transistors (FETs) were dominated by FET channel resistance rather than source–drain access resistance. Higher As2 fluxes led first to conformal growth, then pronounced {111} facets sloping up away from the mask.
Detective quantum efficiency of photon‐counting x‐ray detectors
Authors: Tanguay Jesse , Yun Seungman , Kim Ho Kyung , Cunningham Ian A.
Published: January 2015

Purpose:

Single‐photon‐counting (SPC) x‐ray imaging has the potential to improve image quality and enable novel energy‐dependent imaging methods. Similar to conventional detectors, optimizing image SPC quality will require systems that produce the highest possible detective quantum efficiency (DQE). This paper builds on the cascaded‐systems analysis (CSA) framework to develop a comprehensive description of the DQE of SPC detectors that implement adaptive binning.

Methods:

The DQE of SPC systems can be described using the CSA approach by propagating the probability density function (PDF) of the number of image‐forming quanta through simple quantum processes. New relationships are developed to describe PDF transfer through serial and parallel cascades to accommodate scatter reabsorption. Results are applied to hypothetical silicon and selenium‐based flat‐panel SPC detectors including the effects of reabsorption of characteristic/scatter photons from photoelectric and Compton interactions, stochastic conversion of x‐ray energy to secondary quanta, depth‐dependent charge collection, and electronic noise. Results are compared with a Monte Carlo study.

Results:

Depth‐dependent collection efficiency can result in substantial broadening of photopeaks that in turn may result in reduced DQE at lower x‐ray energies (20–45 keV). Double‐counting interaction events caused by reabsorption of characteristic/scatter photons may result in falsely inflated image signal‐to‐noise ratio and potential overestimation of the DQE.

Conclusions:

The CSA approach is extended to describe signal and noise propagation through photoelectric and Compton interactions in SPC detectors, including the effects of escape and reabsorption of emission/scatter photons. High‐performance SPC systems can be achieved but only for certain combinations of secondary conversion gain, depth‐dependent collection efficiency, electronic noise, and reabsorption characteristics.
Multimodal Exercise Benefits Mobility in Older Adults With Visual Impairment: A Preliminary Study
Authors: Hackney Madeleine E. , Hall Courtney D. , Echt Katharina V. , Wolf Steven L.
Published: January 2015

Evidence-based recommendations for interventions to reduce fall risk in older adults with visual impairment are lacking. Adapted tango dance (Tango) and a balance and mobility program (FallProof) have improved mobility, balance, and quality of life (QOL) in individuals with movement impairment. This study compared the efficacy of Tango and FallProof for 32 individuals with visual impairment (age: M = 79.3, SD =11 [51–95 years]). Participants were assigned to Tango or FallProof to complete twenty, 90-min lessons within 12 weeks. Participants underwent assessment of balance, dual-tasking, endurance, gait, and vision-related QOL. The balance reactions of participants in both groups improved (p < .001). Endurance, cognitive dual-tasking, and vision-related QOL may have improved more for Tango than FallProof. Group differences and gains were maintained across time. Both programs could be effective options for motor rehabilitation for older adults with visual impairment because they may improve mobility and QOL while reducing fall risk.
Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae at a Single Institution: Insights into Endemicity from Whole-Genome Sequencing
Authors: Mathers Amy J. , Stoesser Nicole , Sheppard Anna E. , Pankhurst Louise , Giess Adam , Yeh Anthony J. , Didelot Xavier , Turner Stephen D. , Sebra Robert , Kasarskis Andrew , Peto Tim , Crook Derrick , Sifri Costi D.
Published: January 2015

The global emergence of
Klebsiella pneumoniae
carbapenemase-producing
K. pneumoniae
(KPC-
Kp
) multilocus sequence type ST258 is widely recognized. Less is known about the molecular and epidemiological details of non-ST258
K. pneumoniae
in the setting of an outbreak mediated by an endemic plasmid. We describe the interplay of
bla
KPC
plasmids and
K. pneumoniae
strains and their relationship to the location of acquisition in a U.S. health care institution. Whole-genome sequencing (WGS) analysis was applied to KPC-
Kp
clinical isolates collected from a single institution over 5 years following the introduction of
bla
KPC
in August 2007, as well as two plasmid transformants. KPC-
Kp
from 37 patients yielded 16 distinct sequence types (STs). Two novel conjugative
bla
KPC
plasmids (pKPC_UVA01 and pKPC_UVA02), carried by the hospital index case, accounted for the presence of
bla
KPC
in 21/37 (57%) subsequent cases. Thirteen (35%) isolates represented an emergent lineage, ST941, which contained pKPC_UVA01 in 5/13 (38%) and pKPC_UVA02 in 6/13 (46%) cases. Seven (19%) isolates were the epidemic KPC-
Kp
strain, ST258, mostly imported from elsewhere and not carrying pKPC_UVA01 or pKPC_UVA02. Using WGS-based analysis of clinical isolates and plasmid transformants, we demonstrate the unexpected dispersal of
bla
KPC
to many non-ST258 lineages in a hospital through spread of at least two novel
bla
KPC
plasmids. In contrast, ST258 KPC-
Kp
was imported into the institution on numerous occasions, with other
bla
KPC
plasmid vectors and without sustained transmission. Instead, a newly recognized KPC-
Kp
strain, ST941, became associated with both novel
bla
KPC
plasmids and spread locally, making it a future candidate for clinical persistence and dissemination.
In Vitro
Prediction of the Evolution of GES-1 β-Lactamase Hydrolytic Activity
Authors: Bontron Séverine , Poirel Laurent , Nordmann Patrice
Published: January 2015

Resistance to β-lactams is constantly increasing due to the emergence of totally new enzymes but also to the evolution of preexisting β-lactamases. GES-1 is a clinically relevant extended-spectrum β-lactamase (ESBL) that hydrolyzes penicillins and broad-spectrum cephalosporins but spares monobactams and carbapenems. However, several GES-1 variants (i.e., GES-2 and GES-5) previously identified among clinical isolates display an extended spectrum of activity toward carbapenems. To study the evolution potential of the GES-1 β-lactamase, this enzyme was submitted to
in vitro
-directed evolution, with selection on increasing concentrations of the cephalosporin cefotaxime, the monobactam aztreonam, or the carbapenem imipenem. The highest resistance levels were conferred by a combination of up to four substitutions. The A6T-E104K-G243A variant selected on cefotaxime and the A6T-E104K-T237A-G243A variant selected on aztreonam conferred high resistance to cefotaxime, ceftazidime, and aztreonam. Conversely, the A6T-G170S variant selected on imipenem conferred high resistance to imipenem and cefoxitin. Of note, the A6T substitution involved in higher MICs for all β-lactams is located in the leader peptide of the GES enzyme and therefore is not present in the mature protein. Acquired cross-resistance was not observed, since selection with cefotaxime or aztreonam did not select for resistance to imipenem, and vice versa. Here, we demonstrate that the β-lactamase GES-1 exhibits peculiar properties, with a significant potential to gain activity against broad-spectrum cephalosporins, monobactams, and carbapenems.
Phenotypic Heterogeneity Enables Uropathogenic Escherichia coli To Evade Killing by Antibiotics and Serum Complement
Authors: Putrinš Marta , Kogermann Karin , Lukk Eliisa , Lippus Markus , Varik Vallo , Tenson Tanel
Published: January 2015

Uropathogenic strains ofEscherichia coli(UPEC) are the major cause of bacteremic urinary tract infections. Survival in the bloodstream is associated with different mechanisms that help to resist serum complement-mediated killing. While the phenotypic heterogeneity of bacteria has been shown to influence antibiotic tolerance, the possibility that it makes cells refractory to killing by the immune system has not been experimentally tested. In the present study we sought to determine whether the heterogeneity of bacterial cultures is relevant to bacterial targeting by the serum complement system. We monitored cell divisions in the UPEC strain CFT073 with fluorescent reporter protein. Stationary-phase cells were incubated in active or heat-inactivated human serum in the presence or absence of different antibiotics (ampicillin, norfloxacin, and amikacin), and cell division and complement protein C3 binding were measured by flow cytometry and immunofluorescence microscopy. Heterogeneity in the doubling times of CFT073 cells in serum enabled three phenotypically different subpopulations to be distinguished, all of them being recognized by the C3 component of the complement system. The population of rapidly growing cells resists serum complement-mediated lysis. The dominant subpopulation of cells with intermediate growth rate is susceptible to serum. The third population, which does not resume growth upon dilution from stationary phase, is simultaneously protected from serum complement and antibiotics.
Fap2 of Fusobacterium nucleatum Is a Galactose-Inhibitable Adhesin Involved in Coaggregation, Cell Adhesion, and Preterm Birth
Authors: Coppenhagen-Glazer S. , Sol A. , Abed J. , Naor R. , Zhang X. , Han Y. W. , Bachrach G.
Published: January 2015

Fusobacterium nucleatumis a common oral anaerobe involved in periodontitis that is known to translocate and cause intrauterine infections. In the oral environment,F. nucleatumadheres to a large diversity of species, facilitating their colonization and creating biological bridges that stabilize the multispecies dental biofilm. Many of these interactions (called coadherences or coaggregations) are galactose sensitive. Galactose-sensitive interactions are also involved in the binding ofF. nucleatumto host cells. Hemagglutination of someF. nucleatumstrains is also galactose sensitive, suggesting that a single galactose-sensitive adhesin might mediate the interaction of fusobacteria with many partners and targets. In order to identify the fusobacterial galactose-sensitive adhesin, a system for transposon mutagenesis in fusobacteria was created. The mutant library was screened for hemagglutination deficiency, and three clones were isolated. All three clones were found to harbor the transposon in the gene coding for the Fap2 outer membrane autotransporter. The threefap2mutants failed to show galactose-inhibitable coaggregation withPorphyromonas gingivalisand were defective in cell binding. Afap2mutant also showed a 2-log reduction in murine placental colonization compared to that of the wild type. Our results suggest that Fap2 is a galactose-sensitive hemagglutinin and adhesin that is likely to play a role in the virulence of fusobacteria.
Vibrio cholerae Represses Polysaccharide Synthesis To Promote Motility in Mucosa
Authors: Liu Zhenyu , Wang Yuning , Liu Shengyan , Sheng Ying , Rueggeberg Karl-Gustav , Wang Hui , Li Jie , Gu Frank X. , Zhong Zengtao , Kan Biao , Zhu Jun
Published: January 2015

The viscoelastic mucus layer of gastrointestinal tracts is a host defense barrier that a successful enteric pathogen, such as
Vibrio cholerae
, must circumvent.
V. cholerae
, the causative agent of cholera, is able to penetrate the mucosa and colonize the epithelial surface of the small intestine. In this study, we found that mucin, the major component of mucus, promoted
V. cholerae
movement on semisolid medium and in liquid medium. A genome-wide screen revealed that
Vibrio
polysaccharide (VPS) production was inversely correlated with mucin-enhanced motility. Mucin adhesion assays indicated that VPS bound to mucin. Moreover, we found that
vps
expression was reduced upon exposure to mucin. In an infant mouse colonization model, mutants that overexpressed VPS colonized less effectively than wild-type strains in more distal intestinal regions. These results suggest that
V. cholerae
is able to sense mucosal signals and modulate
vps
expression accordingly so as to promote fast motion in mucus, thus allowing for rapid spread throughout the intestines.
TfoX-Based Genetic Mapping Identifies Vibrio fischeri Strain-Level Differences and Reveals a Common Lineage of Laboratory Strains
Authors: Brooks John F. , Gyllborg Mattias C. , Kocher Acadia A. , Markey Laura E. H. , Mandel Mark J.
Published: January 2015

Bacterial strain variation exists in natural populations of bacteria and can be generated experimentally through directed or random mutation. The advent of rapid and cost-efficient whole-genome sequencing has facilitated strain-level genotyping. Even with modern tools, however, it often remains a challenge to map specific traits to individual genetic loci, especially for traits that cannot be selected under culture conditions (e.g., colonization level or pathogenicity). Using a combination of classical and modern approaches, we analyzed strain-level variation in
Vibrio fischeri
and identified the basis by which some strains lack the ability to utilize glycerol as a carbon source. We proceeded to reconstruct the lineage of the commonly used
V. fischeri
laboratory strains. Compared to the wild-type ES114 strain, we identify in ES114-L a 9.9-kb deletion with endpoints in
tadB2
and
glpF
; restoration of the missing portion of
glpF
restores the wild-type phenotype. The widely used strains ESR1, JRM100, and JRM200 contain the same deletion, and ES114-L is likely a previously unrecognized intermediate strain in the construction of many ES114 derivatives. ES114-L does not exhibit a defect in competitive squid colonization but ESR1 does, demonstrating that glycerol utilization is not required for early squid colonization. Our genetic mapping approach capitalizes on the recently discovered chitin-based transformation pathway, which is conserved in the
Vibrionaceae
; therefore, the specific approach used is likely to be useful for mapping genetic traits in other
Vibrio
species.
Atrio-oesophageal fistula after transcatheter radiofrequency ablation
Authors: Moss Caroline E , Fernandez-Caballero Sandra , Walker David
Published: January 2015

A 68-year-old woman presented 3 weeks following unsuccessful transcatheter radiofrequency ablation (TcRFA) for treatment of her chronic atrial fibrillation. Neurological signs manifested on day 2 of admission with generalised tonic-clonic seizures and reduced Glasgow Coma Score. She was treated for presumed central nervous system (CNS) infection, intubated and transferred to the intensive care unit. CT of the head showed bilateral oedema secondary to acute embolic stroke. Blood cultures grewStreptococcus viridans, and lumbar puncture findings were consistent with CNS infection. Echocardiography showed only a septostomy puncture from the atrial fibrillation ablation procedure. Thoracic CT demonstrated air in the left atrium, consistent with the diagnosis of atrio-oesophageal fistula, a rarely reported iatrogenic complication of TcRFA. MRI of the head showed significant neurological injury with innumerable embolic infarcts. After discussion with her family regarding the significant neurological insult, and with no signs of any clinical improvement, the patient died on day 8 of admission.
A long-term follow-up of residual mass neuroblastoma in a patient with cystic fibrosis
Authors: Naselli Aldo , Cresta Federico , Favilli Federica , Casciaro Rosaria
Published: January 2015

Purpose

To report a long-term follow-up of a young woman affected by cystic fibrosis (CF) with a residual retroperitoneal mass of neuroblastoma (NBL) after treatment.

Case report

We reviewed the patient's database and analysed a 20-year follow-up by considering pulmonary exacerbation, nutritional condition, pulmonary function (forced expiratory volume in 1 s), microbiological data and residual retroperitoneal mass volume. We observed stable pulmonary and nutritional conditions. No variation was found in the residual retroperitoneal mass volume.

Discussion

We report this case of a patient with CF with previous NBL because such a long time of follow-up of a NBL with a stable retroperitoneal remaining tumour is uncommon and needs to be reported. Multidisciplinary management has been crucial in this case because of the presence of concomitant diseases and consequently, differential diagnosis challenges.
Low serum free thyroxine level in a girl with McCune-Albright syndrome
Authors: Roosimaa Mart , Pajuväli Anett , Peet Aleksandr , Tillmann Vallo
Published: January 2015

A 17-year-old girl with McCune-Albright syndrome (MAS) was suspected of having central hypothyroidism based on an inappropriately normal thyroid-stimulating hormone (TSH) and low free thyroxine (fT4). She was clinically euthyroid and her pituitary appeared normal on MRI. Treatment of hypothyroidism with levothyroxine resulted in suppression of TSH with a low fT4 and high free triiodothyronine (fT3) concentration and hence iatrogenic hyperthyroidism was diagnosed. After discontinuation of levothyroxine, the TSH and fT3 normalised while fT4 remained low. Increased conversion of thyroxine (T4) to triiodothyronine (T3) can be part of MAS. Therefore, fT3 and fT4 should both be measured when evaluating thyroid function in patients with MAS.
Splenic abscess as a potential initial manifestation of quiescent infective endocarditis in a patient with bronchopneumonia
Authors: McOwat Lindsay , Wong Kah Fai , Varughese George I , Nayak Ananth U
Published: January 2015

A 78-year-old woman presented to the acute medical unit with a productive cough, dyspnoea and decreased appetite of 4 days duration. Initial assessment supported a diagnosis of right-sided community-acquired pneumonia and she was started on antibiotics. In view of the clinical finding of splenomegaly, she had an ultrasound and, subsequently, a CT of the abdomen, which revealed a large splenic abscess. Pending cultures from a sample obtained from percutaneous drainage of the abscess, she was started on intravenous meropenem. The initial echocardiogram did not suggest any evidence of endocarditis. The pus drained from the abscess on cultures was subsequently positive forStaphylococcus aureus. An MRI of the spine excluded discitis as a source of infection. Owing to a high index of clinical suspicion a repeat echocardiogram was undertaken after 1-week, which confirmed acute endocarditis. The patient was treated with intravenous antibiotics for 6 weeks with improvement in clinical, radiological and biochemical parameters.
Rare manifestations in a case of Osler-Weber-Rendu disease
Authors: Singh Abhijai , Suri Vikas , Jain Sanjay , Varma Subhash
Published: January 2015

Osler-Weber-Rendu disease (OWRD) is a rare vascular dysplasia that presents most commonly with epistaxis. The most dreaded complication, however, is an intracranial haemorrhage. We present a patient with two rare manifestations of OWRD, subdural haematoma and portal venous hypertension, both seldom reported in the literature. The patient made a full recovery and continues to do well at this time.
Bilateral total hip arthroplasty in a young man with hereditary multiple exostoses
Authors: Vaishya Raju , Swami Sandeep , Vijay Vipul , Vaish Abhishek
Published: January 2015

We report a rare case of a young man with hereditary multiple exostoses (HME) who presented with severe pain in the hips, requiring bilateral total hip arthroplasty (THA), along with excision of the exostoses. The reported incidence of exostoses around the hip has been reported from 30% in some series to 90% in other studies of HME. These patients may remain asymptomatic, but if not, their symptoms are usually related to the presence of the exostoses itself and the possibility of hip osteoarthrosis is frequently overlooked. This may account for a low incidence of THA for this condition. Surgical management often remains challenging as such lesions are not commonly encountered in the clinical practice and are often very difficult to treat.
Macular pseudohaemorrhage secondary to Allen Dot artefact
Authors: Michaels Luke , Alexander Philip , Newsom Richard
Published: January 2015

A 34-year-old highly myopic (−11.00 D) woman presented to eye clinic with a 3 day history of right eye paracentral blurring. Visual acuities were 6/6 bilaterally. Clinical examination was normal. Fundus photography showed the classic appearance of a macular haemorrhage. This is a recognised complication of high myopia and would have accounted for the patient's symptoms. However, further photography showed that the haemorrhage seemed to ‘jump’ around the fundus and was even present in the fellow eye. The apparent haemorrhage was revealed to be an imaging artefact. The ‘Allen Dot’ is a 6 mm black mask incorporated into retinal cameras to reduce reflection. Rarely, in highly myopic eyes, optical artefact can result. To the best of our knowledge, we are the first in the literature to report artefacts from the Allen Dot masquerading as ophthalmic disease. This case re-iterates the importance of clinical examination, especially in high myopes, given the current trend towards virtual clinics.
An overview of clinical associate roles in the neurointerventional specialty
Authors: Chittle Melissa D , Vanderboom Teresa , Borsody-Lotti Judith , Ganguli Suvranu , Hanley Patricia , Martino JoAnne , Mueller Peter , Penzias Alexandra , Saltalamacchia Catherine , Sheridan Robert M , Hirsch Joshua A
Published: January 2015

Neurointerventionalists have long partnered with certain types of clinical associates to provide longitudinal care. This overview summarizes differences in education, background, roles, and scopes of practice of the various clinical associates (physician assistants, nurse practitioners, clinical nurse specialists, radiology practitioner assistants, radiologist assistants, and nursing care coordinators). Key differences and similarities are highlighted to alleviate confusion about the roles clinical associates can assume on a neurointerventional service. This overview is intended to guide practices as they consider broadening their clinical support teams.
Residence times of juvenile salmon and steelhead in off-channel tidal freshwater habitats, Columbia River, USA
Authors: Johnson Gary E. , Ploskey Gene R. , Sather Nichole K. , Teel David J.
Published: January 2015

We documented two life history strategies for juvenile salmonids as expressed in off-channel tidal freshwater habitats of the Columbia River: (i) active migrations by upper river Chinook salmon (Oncorhynchus tshawytscha) and steelhead (Oncorhynchus mykiss) during the primary spring and summer migration periods and (ii) overwinter rearing in tidal freshwater habitats by coho salmon (Oncorhynchus kisutch) and naturally produced Chinook salmon mostly from lower river sources. During spring–summer 2007–2008, acoustic-tagged fish originating above Bonneville Dam (rkm 234) had short residence times in off-channel areas (rkm 192–203): median 2.5 and 2.6 h for yearling (mean lengths 134 and 158 mm) and 3.0 and 3.4 h for subyearling (104 and 116 mm) Chinook salmon and 2.5 h for yearling steelhead (215 mm). The percentage of fish in off-channel areas out of the total in the main- and off-channels areas was highest for yearling Chinook salmon (8.1% and 9.3% for 2007 and 2008, respectively) and lowest for steelhead (4.0% for 2008) and subyearling Chinook salmon (3.6% and 6.1% for 2007 and 2008, respectively). In late January and early February 2010, 2011, and 2012, we captured and tagged yearling Chinook and coho salmon occupying off-channel tidal freshwater habitats. Median residence times in off-channel areas were 11.6–25.5 days for juvenile Chinook (106, 115, and 118 mm, respectively by year) and 11.2 days for coho salmon (116 mm). This study is the first to estimate residence times for juvenile salmonids specifically in off-channel areas of tidal fresh water and, most importantly, residence times for Chinook salmon expressing a life history of overwintering in tidal fresh water. The findings support restoration of shallow off-channel habitats in tidal freshwater portions of the Columbia River.