bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial discovery and the research library
Authors: Lafia Sara , Jablonski Jon , Kuhn Werner , Cooley Savannah , Medrano F. Antonio
Published: June 2016

Academic libraries have always supported research across disciplines by integrating access to diverse contents and resources. They now have the opportunity to reinvent their role in facilitating interdisciplinary work by offering researchers new ways of sharing, curating, discovering, and linking research data. Spatial data and metadata support this process because location often integrates disciplinary perspectives, enabling researchers to make their own research data more discoverable, to discover data of other researchers, and to integrate data from multiple sources. The Center for Spatial Studies at the University of California, Santa Barbara (UCSB) and the UCSB Library are undertaking joint research to better enable the discovery of research data and publications. The research addresses the question of how to spatially enable data discovery in a setting that allows for mapping and analysis in a GIS while connecting the data to publications about them. It suggests a framework for an integrated data discovery mechanism and shows how publications may be linked to associated data sets exposed either directly or through metadata on Esri's Open Data platform. The results demonstrate a simple form of linking data to publications through spatially referenced metadata and persistent identifiers. This linking adds value to research products and increases their discoverability across disciplinary boundaries.
Distinct roles of the histone chaperones NAP1 and NRP and the chromatin‐remodeling factor INO80 in somatic homologous recombination in Arabidopsis thaliana
Authors: Zhou Wangbin , Gao Juan , Ma Jing , Cao Lin , Zhang Chi , Zhu Yan , Dong Aiwu , Shen Wen‐Hui
Published: June 2016

Homologous recombination (HR) of nuclear DNA occurs within the context of a highly complex chromatin structure. Despite extensive studies of HR in diverse organisms, mechanisms regulating HR within the chromatin context remain poorly elucidated. Here we investigate the role and interplay of the histone chaperones NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) and NAP1‐RELATED PROTEIN (NRP) and the ATP‐dependent chromatin‐remodeling factor INOSITOL AUXOTROPHY80 (INO80) in regulating somatic HR in Arabidopsis thaliana. We show that simultaneous knockout of the four AtNAP1 genes and the two NRP genes in the sextuple mutant m123456‐1 barely affects normal plant growth and development. Interestingly, compared with the respective AtNAP1 (m123‐1 and m1234‐1) or NRP (m56‐1) loss‐of‐function mutants, the sextuple mutant m123456‐1 displays an enhanced plant hypersensitivity to UV or bleomycin treatments. Using HR reporter constructs, we show that AtNAP1 and NRP act in parallel to synergistically promote somatic HR. Distinctively, the AtINO80 loss‐of‐function mutation (atino80‐5) is epistatic to m56‐1 in plant phenotype and telomere length but hypostatic to m56‐1 in HR determinacy. Further analyses show that expression of HR machinery genes and phosphorylation of H2A.X (γ‐H2A.X) are not impaired in the mutants. Collectively, our study indicates that NRP and AtNAP1 synergistically promote HR upstream of AtINO80‐mediated chromatin remodeling after the formation of γ‐H2A.X foci during DNA damage repair.
Mucous membrane pemphigoid in dogs: a retrospective study of 16 new cases
Authors: Tham Heng L. , Olivry Thierry , Linder Keith E. , Bizikova Petra
Published: June 2016

Background

Mucous membrane pemphigoid (MMP) is a chronic autoimmune subepidermal blistering disease of dogs, cats and humans.

Objectives

The goal of this study was to describe the clinical, histological and immunological features and treatment outcomes of canine MMP.

Animals

Sixteen dogs were diagnosed with MMP based on the presence of mucosal‐ or mucocutaneous‐predominant vesiculation and/or ulceration, histological confirmation of subepidermal clefting and an age of disease onset greater than 6 months.

Results

Six of 16 dogs (38%) were German shepherd dogs and their crosses. The median age of disease onset was 6 years (range: 1–10 years). At the time of presentation, the dogs exhibited erosions and ulcers in the oral cavity (11 of 16; 69%), nasal (nine of 16; 56%), periocular (eight of 16; 50%) and genital (six of 16; 38%) regions. Haired skin lesions were less frequent (six of 16; 38%) and involved mostly concave pinnae. Information on treatment outcome was available for 11 dogs (69%). A complete remission (CR) of lesions was achieved in 10 of 11 dogs (91%). The median time to CR was 33 weeks (range: 6–64 weeks). Treatment regimens varied widely but six of 10 (60%) dogs received a combination of tetracycline antibiotic and niacinamide alone, or with another drug, at the time of CR. Forty percent of the dogs in which CR had occurred experienced lesion relapse upon drug dose reduction.

Conclusions and clinical importance

Canine MMP is a chronic and relapsing disease requiring long term treatment. Combination therapy is often needed to achieve CR.
Optimizing transfusion therapy in the chronically transfused patient
Authors: Ang A. L.
Published: June 2016

Patients may require regular transfusion due to congenital or acquired conditions resulting in haemolysis, ineffective blood cell production, bone marrow failure or a combination of these. In South‐East Asia, the most common congenital cause is thalassaemia while acquired causes include haematological malignancies such as myelodysplastic syndrome (MDS) and acute leukaemia. The major goal of transfusion in these patients is to minimize complications from their conditions. Due to the frequent transfusions, their cumulative risks from transfusion are higher than other patients. The transfusion‐associated adverse events which may affect these patients include mild adverse reactions such as febrile non‐haemolytic transfusion reactions and urticaria, as well as severe complications such as haemolytic transfusion reactions, anaphylaxis, transfusion‐transmitted infections, transfusion‐associated circulatory overload and transfusion‐related acute lung injury (TRALI). In addition, patients who need regular red cell transfusion are at risk of transfusional haemosiderosis. Therefore, measures should be taken to maximize the efficacy of transfusion and minimize the adverse effects of transfusion in these patients.
Haemovigilance – building one from none
Authors: Marwaha N.
Published: June 2016

Haemovigilance is a surveillance system which aims to detect and analyse adverse events and reactions in the blood transfusion chain to improve blood safety by instituting corrective and preventive actions. Setting up such a system is a complex task, and it involves both organizational and operational aspects, which may vary between countries depending upon the structure and regulation of blood transfusion services. First and foremost, it should be a part of the National Blood Policy. The organizational structure should ideally have governmental oversight to the programme through its Ministry of Health or equivalent authority. Haemovigilance advisory committees are required to give direction to the programme. During the phase of planning, the following issues need to be addressed: i) whether reporting of all adverse events in the transfusion chain is required, ii) whether reporting will be voluntary or mandatory, iii) what would be the flow of information, iv) adoption of definitions of adverse events and reactions as per international consensus, v) uniform reporting formats and vi) requisite resources. At the reporting end, awareness and training of staff who would be involved in haemovigilance activities needs to be conducted. A validated system for collection, collation and analysis of haemovigilance data is required. Mechanisms for regular publications of haemovigilance reports with recommendations for better transfusion practices should be put in place. This would help in directing policy decisions to improve blood safety. It should also be aimed to establish linkage with the international haemovigilance network and database for exchange of information between member countries.
Assessing the risk of transfusion‐transmitted emerging infectious diseases
Authors: Custer B.
Published: June 2016

Background

Emerging infectious diseases (EIDs) remain a source of significant concern in blood safety.

Methods

Emerging infectious diseases of concern will be described and methods used to conduct risk assessment will be reviewed, with a focus on transfusion medicine. The issues that make EIDs more challenging for blood safety compared to other areas of public health will be demonstrated through specific examples.

Results

Current EIDs include mosquito‐borne infections such as dengue, chikungunya and Zika virus. In addition, tick‐borne infections such as Babesia, Borrelia, Anaplasma and Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) are or have the potential to become significant EIDs in transfusion. Other zoonoses, such as HEV, are expected to emerge or re‐emerge. Often in risk assessment, assumptions are made that transfusion‐transmitted (TT) infection will have the same progression as infection transmitted in other ways. Even with explosive mosquito‐borne epidemics of chikungunya virus, no evidence of TT has been documented. Substantial TT of dengue virus can occur, but significant clinical outcome differences between recipients of dengue RNA(+) and RNA(−) transfusions have not been found. In contrast, while TT of Babesia microti in the USA is a clear threat, there is no consensus on appropriate risk mitigation.

Generalizations from one route of transmission to another and from one pathogen to another may be appropriate for precaution, but may lead to ineffective and cost‐ineffective policies. For risk assessment and blood safety policy to be evidence based, studies of the consequences to blood recipients need to be conducted.
An update on indications for platelet transfusion
Authors: Wood E. M. , Crighton G. L. , Estcourt L. J. , McQuilten Z. K. , Stanworth S. J.
Published: June 2016

Platelets are very commonly prescribed blood components, and in many settings, their use is increasing. They may be used either prophylactically (to attempt to prevent bleeding) or therapeutically (to treat bleeding when it occurs). This review provides a summary of the major clinical settings in which platelet transfusions are currently used. Most platelet transfusions are provided prophylactically to thrombocytopenic haematology/oncology patients, although bleeding risks and rates appear to vary substantially between individual patients. Other contexts include major haemorrhage, surgery and invasive procedures, and patients in critical care and neonatal intensive care. Since platelet transfusions carry risks and costs, and evidence of benefit for platelet transfusion in many clinical settings is not yet available, additional clinical studies to establish the utility of platelet transfusions and other interventions to prevent or manage bleeding are needed.
Current status and new developments in the production of plasma derivatives
Authors: Burnouf T.
Published: June 2016

Plasma fractionation is a unique biotechnology and bioengineering industry characterized by its capacity to extract a diverse range of protein therapeutics that are often the only options for treating life‐threatening pathological conditions of patients suffering from bleeding, immunological disorders, infections or trauma. Current plasma products include several coagulation factors, polyvalent and hyperimmune immunoglobulins (Igs), albumin, protease inhibitors and anticoagulants. In many pathological situations, these products are used for long‐term replacement therapy to compensate for a congenital or acquired protein deficiency. Most products are obtained by plasma fractionation technologies that derive from the cold ethanol fractionation process developed in the mid‐/late 1940s by Cohn and collaborators. Still, in the last 20 years, this core technology has undergone substantial evolutions illustrated by the integration of several viral reduction steps for all products and by the introduction of chromatographic purification steps to extract labile proteins from cryoprecipitate‐poor plasma. The most recent technological changes, intended mostly to improve recoveries and remove trace protein contaminants, concern the production process of intravenous Igs through implementing chromatographic steps and caprylic acid treatment in early stages of the ethanol fractionation process. A number of new fractionation technologies are currently under development and have not been licensed at least for the time being by major regulatory authorities. One target of these technologies is to improve the recovery of the most important plasma protein products, under conditions facilitating large‐scale implementation in emerging countries.
Red blood cell genotyping in China
Authors: Ji Y. L. , van der Schoot C. E.
Published: June 2016

The common antigens of ABO, Rh, MNS, Duffy, Kidd, Diego, Yt and Dombrock blood group systems have a polymorphic distribution in the Chinese population. The Mur antigen and anti‐Mur are more common in the Chinese Han and some minority groups in the southern region of China. Except for the common ABO alleles (A101, A102, B101, O01 and O02), more than 100 new alleles have been reported in the Chinese population, in which the effect of many critical mutations on the variant expression of A and B antigens still needs to be investigated. For RHD genotyping, only 6% of Chinese D+ people were heterozygous for the RHD gene with Dd genotype. Compared with the complete deletion of the RHD gene accounting for D‐ phenotype in the Caucasian population, 20–40% of the Chinese individuals with D‐ phenotype carry RHD variant alleles. Among them, ‘Asian type’ DEL allele (RHD*DEL1 defined by 1227G>A, Lys409Lys) is the most common variant and is classified as D‐, and it can only be identified by absorption/elution testing, which is not routinely conducted. Several studies indicated that the Chinese pregnant women with ‘Asian type’ DEL allele were not immunized by the incompatible pregnancy, which suggested that the ‘Asian type’ DEL recipient could receive D+ blood safely. Weak D type 15 and DVI type 3 are the most common RHD variant alleles, accounting for more than 70% of RhD variants in the Chinese population. In addition, the genotyping analysis for the rare null phenotypes, including the para‐Bombay, Jk(a‐b‐), Lu(a‐b‐), p, Rhnull and KELnull phenotypes, are also summarized.
Choosing the right criteria for donor health and safety
Authors: Ishak N.
Published: June 2016

Blood transfusion services (BTS) have the responsibility to collect and provide safe blood, and also to deliver sufficient quantity to their health systems. Among the key elements to ensure the safety and adequacy of the blood supply is the collection of blood from voluntary, non‐remunerated blood donors, with an established national system for blood donor selection criteria for all types of donations and a rigorous process to assess the suitability of prospective donors. Blood donors are healthy volunteers who give either whole blood or blood components by apheresis with altruistic motives. However, choosing the right criteria for blood donors’ health and safety is an extremely important issue that could have an impact on donors and blood donation. Therefore, regular assessment of donor suitability should be undertaken in accordance with the national criteria for blood donor selection. These criteria should be consistently applied in every blood donation establishment, on each occasion of donation, to all blood donors. If a truly evidence‐based approach were to be adopted, blood centres would continue to monitor donor reactions to validate the safety of the current approaches or modify them as appropriate. Careful evaluation and selection of blood donors involves proactive and protective measures in assuring donor health and safety and indirectly results in an effective outcome in BTS. This article focuses on donor selection criteria that exist for the purpose of protecting the donor. It consists a review of current international standards and practices.
Impact of climate change on the invasive traits of weeds
Authors: Kathiresan Ramanathan , Gualbert Gbehounou
Published: June 2016

Invasive weeds degrade ecosystems and are a threat to plant and animal biodiversity. The literature on biological invasions suggests that only 10% of introduced species become invasive in a new host range. Most introduced plants do not become invasive in a new environment. The invasive behavior of a weed depends on the weed's genetic variability, biotic factors, and climatic factors with which it interacts. The climatic factors that affect the invasive traits of weeds include the atmospheric temperature, soil temperature, precipitation, evaporation, and CO2 concentration. The biological traits that are influenced by a change in any one or more of these climatic factors include the pattern of assimilate partitioning, induction of dormancy or seed germination, herbivore tolerance, propagule production and distribution, variability of plant architecture, photosynthetic rate, and seedbank longevity. The impact of climate change on the invasive traits of certain weed species is reviewed.
Modular modelling with Physiome standards
Authors: Cooling Michael T. , Nickerson David P. , Nielsen Poul M. F. , Hunter Peter J.
Published: June 2016

Key points

The complexity of computational models is increasing, supported by research in modelling tools and frameworks. But relatively little thought has gone into design principles for complex models.

We propose a set of design principles for complex model construction with the Physiome standard modelling protocol CellML.

By following the principles, models are generated that are extensible and are themselves suitable for reuse in larger models of increasing complexity.

We illustrate these principles with examples including an architectural prototype linking, for the first time, electrophysiology, thermodynamically compliant metabolism, signal transduction, gene regulation and synthetic biology.

The design principles complement other Physiome research projects, facilitating the application of virtual experiment protocols and model analysis techniques to assist the modelling community in creating libraries of composable, characterised and simulatable quantitative descriptions of physiology.

The ability to produce and customise complex computational models has great potential to have a positive impact on human health. As the field develops towards whole‐cell models and linking such models in multi‐scale frameworks to encompass tissue, organ, or organism levels, reuse of previous modelling efforts will become increasingly necessary. Any modelling group wishing to reuse existing computational models as modules for their own work faces many challenges in the context of construction, storage, retrieval, documentation and analysis of such modules. Physiome standards, frameworks and tools seek to address several of these challenges, especially for models expressed in the modular protocol CellML. Aside from providing a general ability to produce modules, there has been relatively little research work on architectural principles of CellML models that will enable reuse at larger scales. To complement and support the existing tools and frameworks, we develop a set of principles to address this consideration. The principles are illustrated with examples that couple electrophysiology, signalling, metabolism, gene regulation and synthetic biology, together forming an architectural prototype for whole‐cell modelling (including human intervention) in CellML. Such models illustrate how testable units of quantitative biophysical simulation can be constructed. Finally, future relationships between modular models so constructed and Physiome frameworks and tools are discussed, with particular reference to how such frameworks and tools can in turn be extended to complement and gain more benefit from the results of applying the principles.
Sub-30 keV patterning of HafSOx resist: Effects of voltage on resolution, contrast, and sensitivity
Authors: Fairley Kurtis C. , Sharps Meredith C. , Mitchson Gavin , Ditto Jeffrey , Johnson Darren W. , Johnson David C.
Published: June 2016

Reducing the accelerating voltage used to pattern a high-resolution inorganic thin film electron beam resist, HafSOx dramatically decreases the dose required to pattern sub-10 nm lines. Ellipsometry measurements of dose curves created for HafSOx show a dramatic increase in sensitivity without any loss in contrast. High resolution patterning at 10 keV show no decrease in obtainable feature size, producing 9 nm wide lines with half the dose required previously and no increase in line edge roughness. Monte Carlo simulations of the incident electron beam into a 22 nm thick HafSOx film predict that even lower primary beam energies, down to 5 keV, could enable patterning of sub-20 nm features with significantly enhanced throughput. This improved film sensitivity at lower beam energies enables increased throughput without loss of patterning resolution and should be extendable to other inorganic photoresists.
Active microrheology of colloidal suspensions: Simulation and microstructural theory
Authors: Nazockdast Ehssan , Morris Jeffrey F.
Published: June 2016

Discrete particle simulations by accelerated Stokesian dynamics (ASD) and a microstructural theory are applied to study the structure and viscosity of hard-sphere Brownian suspensions in active microrheology (MR). The work considers moderate to dense suspensions, from near to far from equilibrium conditions. The microscopic theory explicitly considers many-body hydrodynamic interactions in active MR and is compared with the results of ASD simulations, which include detailed near- and far-field hydrodynamic interactions. We consider probe and bath particles which are spherical and of the same radius a. Two conditions of moving the probe sphere are considered: These apply constant force (CF) and constant velocity (CV), which approximately model magnetic bead and optical tweezer experiments, respectively. The structure is quantified using the probability distribution of colloidal particles around the probe, Pb|p(r)=ng(r), giving the probability of finding a bath particle centered at a vector position r relative to a moving probe particle instantaneously centered at the origin; n is the bath particles number density, and is related to the suspension solid volume fraction, ϕ, by n=3ϕ/4πa3. The pair distribution function for the bath particles relative to the probe, g(r), is computed as a solution to the pair Smoluchowski equation (SE) for 0.2≤ϕ≤0.50, and a range of Péclet numbers, describing the ratio of external force on the probe to thermal forces and defined as Pef=Fexta/(kbT) and PeU=6πηUexta2/(kbT) for CF and CV conditions, respectively. Results of simulation and theory demonstrate that a wake zone depleted of bath particles behind the moving probe forms at large Péclet numbers, while a boundary-layer accumulation develops upstream and near the probe. The wake length saturates at Pef≫1 for CF, while it continuously grows with PeU in CV. This contrast in behavior is related to the dispersion in the motion of the probe under CF conditions, while CV motion has no dispersion; the dispersion is a direct result of many-body nonthermal interactions. This effect is incorporated in the theory as a force-induced diffusion flux in pair SE. We also demonstrate that, despite this difference of structure in the two methods of moving the probe, the probability distribution of particles near the probe is primarily set by the Péclet number, for both CF and CV conditions, in agreement with dilute theories; as a consequence, similar values for apparent viscosity are found for the CF and CV conditions. Using the microscopic theory, the structural anisotropy and Brownian viscosity near equilibrium are shown to be quantitatively similar in both CF and CV motions, which is in contrast with the dilute theory which predicts larger distortions and Brownian viscosities in CV, by a factor of two relative to CF MR. This difference relative to dilute theory arises due to the determining role of many-body interactions associated with the underlying equilibrium structure in the semidilute to concentrated regime.
Competitive Swimming and Handball Participation Have a Positive Influence on Bone Parameters as Assessed by Phalangeal Quantitative Ultrasound in Female Adolescents
Authors: Krahenbuhl Tathyane , Gonçalves Ezequiel Moreira , Guimarães Roseane de Fatima , Guerra-Júnior Gil , Barros-Filho Antonio de Azevedo
Published: June 2016

Purpose:

To examine the influence of participation in competitive sports on bone parameters, as assessed by quantitative ultrasound (QUS) of the phalanges in female adolescents.

Methods:

Female adolescents (n = 329, 13.0–16.7 years old) were classified into handball (n = 55), swimming (n = 49) and control (n = 225) groups. QUS was used to evaluate the amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT), and their z-scores (zAD-SoS and zBTT) were calculated. Anthropometric measurements and Tanner’s stages were also obtained.

Results:

Swimmers had higher AD-SoS (2089 ± 43.8 m/s) and zAD-SoS (0.47 ± 0.8) than controls (2060 ± 54.0 m/s; 0.09 ± 1.0; both p ≤ .05) and both groups of athletes had higher BTT (handball: 1.44 ± 0.2 μs; swimming: 1.45 ± 0.2) and zBTT (handball: 0.71 ± 0.8; swimming: 0.72 ± 1.1) than the control group (1.37 ± 0.2 μs; 0.32 ± 0.9; all p ≤ .05). Swimmers had a higher total training time (TTT: 52.5 ± 27.6 months) and frequency of training per week (FT: 5.38 ± 0.1) compared with the handball group (35.9 ± 18.1; 3.32 ±0.8; p ≤ .05). zAD-SoS, BTT and zBTT were positively correlated with FT, while BTT and zBTT showed a positive correlation with TTT.

Conclusions:

Sports practice influences bone parameters and higher bone parameter values are related to the amount of time and frequency of weekly training. The differences in phalangeal QUS parameters are independent of the impact of weight-bearing exercise.
Papers of note in
Science
Authors: VanHook Annalisa M.
Published: June 2016

This week’s articles highlight immune cell niches and microbe-induced mucus secretion in the intestine and the structural basis of kinase activation by chaperones.
Antibacterial Efficacy of Eravacycline
In Vivo
against Gram-Positive and Gram-Negative Organisms
Authors: Monogue Marguerite L. , Thabit Abrar K. , Hamada Yukihiro , Nicolau David P.
Published: June 2016

Members of the tetracycline class are frequently classified as bacteriostatic. However, recent findings have demonstrated an improved antibacterial killing profile, often achieving ≥3 log
10
bacterial count reduction, when such antibiotics have been given for periods longer than 24 h. We aimed to study this effect with eravacycline, a novel fluorocycline, given in an immunocompetent murine thigh infection model over 72 h against two methicillin-resistant
Staphylococcus aureus
(MRSA) isolates (eravacycline MICs = 0.03 and 0.25 μg/ml) and three
Enterobacteriaceae
isolates (eravacycline MICs = 0.125 to 0.25 μg/ml). A humanized eravacycline regimen, 2.5 mg/kg of body weight given intravenously (i.v.) every 12 h (q12h), demonstrated progressively enhanced activity over the 72-h study period. A cumulative dose response in which bacterial density was reduced by more than 3 log
10
CFU at 72 h was noted over the study period in the two Gram-positive isolates, and eravacycline performed similarly to comparator antibiotics (tigecycline, linezolid, and vancomycin). A cumulative dose response with eravacycline and comparators (tigecycline and meropenem) over the study period was also observed in the Gram-negative isolates, although more variability in bacterial killing was observed for all antibacterial agents. Overall, a bacterial count reduction of ≥3 log was achieved in one of the three isolates with both eravacycline and tigecycline, while meropenem achieved a similar endpoint against two of the three isolates. Bactericidal activity is typically defined
in vitro
over 24 h; however, extended regimen studies
in vivo
may demonstrate an improved correlation with clinical outcomes by better identification of antimicrobial effects.
Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine
Authors: Chen Xinhui , Castillo-Mancilla Jose R. , Seifert Sharon M. , McAllister Kevin B. , Zheng Jia-Hua , Bushman Lane R. , MaWhinney Samantha , Anderson Peter L.
Published: June 2016

Tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC), two nucleos(t)ide analogs (NA), are coformulated as an anti-HIV combination tablet for treatment and preexposure prophylaxis (PrEP). TDF/FTC may have effects on the deoxynucleoside triphosphate (dNTP) pool due to their similar structures and similar metabolic pathways. We carried out a comprehensive clinical study to characterize the effects of TDF/FTC on the endogenous dNTP pool, from baseline to 30 days of TDF/FTC therapy, in both treatment-naive HIV-positive and HIV-negative individuals. dATP, dCTP, dGTP, and TTP were quantified in peripheral blood mononuclear cells (PBMC) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. Forty individuals (19 HIV-positive) were enrolled and underwent a baseline visit and then received TDF/FTC for at least 30 days. Longitudinal measurements were analyzed using mixed-model segmented linear regression analysis. The dNTPs were reduced by 14% to 37% relative to the baseline level within 3 days in both HIV-negative and HIV-positive individuals (P≤ 0.003). These reductions persisted to various degrees at day 30. These findings indicate that dNTP pools are influenced by TDF/FTC therapy. This may alter cellular homeostasis and could increase the antiviral effect through a more favorable analog/dNTP ratio. Further work is needed to elucidate mechanisms, to evaluate the clinical significance of these findings, and to further probe differences between HIV-negative and HIV-positive individuals. (This study has been registered at ClinicalTrials.gov under identifier NCT01040091.)
In Vitro
Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71
Authors: Wang Yizhuo , Li Guiming , Yuan Shilin , Gao Qianqian , Lan Ke , Altmeyer Ralf , Zou Gang
Published: June 2016

Enterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections.
Long-Term Immunity to Trypanosoma cruzi in the Absence of Immunodominanttrans-Sialidase-Specific CD8+T Cells
Authors: Rosenberg Charles S. , Zhang Weibo , Bustamante Juan M. , Tarleton Rick L.
Published: June 2016

Trypanosoma cruziinfection drives the expansion of remarkably focused CD8+T cell responses targeting epitopes encoded by varianttrans-sialidase (TS) genes. Infection of C57BL/6 mice withT. cruziresults in up to 40% of all CD8+T cells committed to recognition of the dominant TSKB20 and subdominant TSKB18 TS epitopes. However, despite this enormous response, these mice fail to clearT. cruziinfection and subsequently develop chronic disease. One possible reason for the failure to cureT. cruziinfection is that immunodomination by these TS-specific T cells may interfere with alternative CD8+T cell responses more capable of complete parasite elimination. To address this possibility, we created transgenic mice that are centrally tolerant to these immunodominant epitopes. Mice expressing TSKB20, TSKB18, or both epitopes controlledT. cruziinfection and developed effector CD8+T cells that maintained an activated phenotype. Memory CD8+T cells from drug-cured TSKB-transgenic mice rapidly responded to secondaryT. cruziinfection. In the absence of the response to TSKB20 and TSKB18, immunodominance did not shift to other known subdominant epitopes despite the capacity of these mice to expand epitope-specific T cells specific for the model antigen ovalbumin expressed by engineered parasites. Thus, CD8+T cell responses tightly and robustly focused on a few epitopes within variant TS antigens appear to neither contribute to, nor detract from, the ability to controlT. cruziinfection. These data also indicate that the relative position of an epitope within a CD8+immunodominance hierarchy does not predict its importance in pathogen control.
Free Sialic Acid Acts as a Signal That Promotes Streptococcus pneumoniae Invasion of Nasal Tissue and Nonhematogenous Invasion of the Central Nervous System
Authors: Hatcher Brandon L. , Hale Joanetha Y. , Briles David E.
Published: June 2016

Streptococcus pneumoniae
(pneumococcus) is a leading cause of bacterial meningitis and neurological sequelae in children worldwide. Acute bacterial meningitis is widely considered to result from bacteremia that leads to blood-brain barrier breakdown and bacterial dissemination throughout the central nervous system (CNS). Previously, we showed that pneumococci can gain access to the CNS through a nonhematogenous route without peripheral blood infection. This access is thought to occur when the pneumococci in the upper sinus follow the olfactory nerves and enter the CNS through the olfactory bulbs. In this study, we determined whether the addition of exogenous sialic acid postcolonization promotes nonhematogenous invasion of the CNS. Previously, others showed that treatment with exogenous sialic acid post-pneumococcal infection increased the numbers of CFU recovered from an intranasal mouse model of infection. Using a pneumococcal colonization model, an
in vivo
imaging system, and a multiplex assay for cytokine expression, we demonstrated that sialic acid can increase the number of pneumococci recovered from the olfactory bulbs and brains of infected animals. We also show that pneumococci primarily localize to the olfactory bulb, leading to increased expression levels of proinflammatory cytokines and chemokines. These findings provide evidence that sialic acid can enhance the ability of pneumococci to disseminate into the CNS and provide details about the environment needed to establish nonhematogenous pneumococcal meningitis.
Genomic Analysis and Comparison of Two Gonorrhea Outbreaks
Authors: Didelot Xavier , Dordel Janina , Whittles Lilith K. , Collins Caitlin , Bilek Nicole , Bishop Cynthia J. , White Peter J. , Aanensen David M. , Parkhill Julian , Bentley Stephen D. , Spratt Brian G. , Harris Simon R.
Published: June 2016

Gonorrhea is a sexually transmitted disease causing growing concern, with a substantial increase in reported incidence over the past few years in the United Kingdom and rising levels of resistance to a wide range of antibiotics. Understanding its epidemiology is therefore of major biomedical importance, not only on a population scale but also at the level of direct transmission. However, the molecular typing techniques traditionally used for gonorrhea infections do not provide sufficient resolution to investigate such fine-scale patterns. Here we sequenced the genomes of 237 isolates from two local collections of isolates from Sheffield and London, each of which was resolved into a single type using traditional methods. The two data sets were selected to have different epidemiological properties: the Sheffield data were collected over 6 years from a predominantly heterosexual population, whereas the London data were gathered within half a year and strongly associated with men who have sex with men. Based on contact tracing information between individuals in Sheffield, we found that transmission is associated with a median time to most recent common ancestor of 3.4 months, with an upper bound of 8 months, which we used as a criterion to identify likely transmission links in both data sets. In London, we found that transmission happened predominantly between individuals of similar age, sexual orientation, and location and also with the same HIV serostatus, which may reflect serosorting and associated risk behaviors. Comparison of the two data sets suggests that the London epidemic involved about ten times more cases than the Sheffield outbreak.

IMPORTANCE
The recent increases in gonorrhea incidence and antibiotic resistance are cause for public health concern. Successful intervention requires a better understanding of transmission patterns, which is not uncovered by traditional molecular epidemiology techniques. Here we studied two outbreaks that took place in Sheffield and London, United Kingdom. We show that whole-genome sequencing provides the resolution to investigate direct gonorrhea transmission between infected individuals. Combining genome sequencing with rich epidemiological information about infected individuals reveals the importance of several transmission routes and risk factors, which can be used to design better control measures.
Bacterial Hyaluronidase Promotes Ascending GBS Infection and Preterm Birth
Authors: Vornhagen Jay , Quach Phoenicia , Boldenow Erica , Merillat Sean , Whidbey Christopher , Ngo Lisa Y. , Adams Waldorf K. M. , Rajagopal Lakshmi
Published: June 2016

Preterm birth increases the risk of adverse birth outcomes and is the leading cause of neonatal mortality. A significant cause of preterm birth is
in utero
infection with vaginal microorganisms. These vaginal microorganisms are often recovered from the amniotic fluid of preterm birth cases. A vaginal microorganism frequently associated with preterm birth is group B streptococcus (GBS), or
Streptococcus agalactiae
. However, the molecular mechanisms underlying GBS ascension are poorly understood. Here, we describe the role of the GBS hyaluronidase in ascending infection and preterm birth. We show that clinical GBS strains associated with preterm labor or neonatal infections have increased hyaluronidase activity compared to commensal strains obtained from rectovaginal swabs of healthy women. Using a murine model of ascending infection, we show that hyaluronidase activity was associated with increased ascending GBS infection, preterm birth, and fetal demise. Interestingly, hyaluronidase activity reduced uterine inflammation but did not impact placental or fetal inflammation. Our study shows that hyaluronidase activity enables GBS to subvert uterine immune responses, leading to increased rates of ascending infection and preterm birth. These findings have important implications for the development of therapies to prevent
in utero
infection and preterm birth.

IMPORTANCE
GBS are a family of bacteria that frequently colonize the vagina of pregnant women. In some cases, GBS ascend from the vagina into the uterine space, leading to fetal injury and preterm birth. Unfortunately, little is known about the mechanisms underlying ascending GBS infection. In this study, we show that a GBS virulence factor, HylB, shows higher activity in strains isolated from cases of preterm birth than those isolates from rectovaginal swabs of healthy women. We discovered that GBS rely on HylB to avoid immune detection in uterine tissue, but not placental tissue, which leads to increased rates of fetal injury and preterm birth. These studies provide novel insight into the underlying mechanisms of ascending infection.
Evaluation of the uptake and impact of neonatal vitamin A supplementation delivered through the Lady Health Worker programme on neonatal and infant morbidity and mortality in rural Pakistan: an effectiveness trial
Authors: Soofi Sajid , Ariff Shabina , Sadiq Kamran , Habib Atif , Bhatti Zaid , Ahmad Imran , Hussain Masawar , Ali Nabeela , Cousens Simon , Bhutta Zulfiqar A
Published: June 2016

Background

Despite evidence for the benefits of vitamin A supplementation (VAS) among children 6 to 59 months of age, the feasibility of introduction and potential benefit of VAS in the neonatal period in public health programmes is uncertain.

Objective

The primary objective was to evaluate the feasibility and effectiveness of early neonatal VAS (single dose of 50 000 international units within 48–72 hours after birth) delivered through the public sector Lady Health Worker (LHW) programme in rural Pakistan and to document its association with a reduction in mortality at 6 months of age.

Methods

A community-based, cluster randomised, placebo-controlled trial was undertaken in two districts of rural Pakistan. LHWs dispensed vitamin A/placebo in identical capsules to newborn infants within 48–72 hours of birth. Follow-up visits were undertaken at 1 week of age and every 4 weeks thereafter until 6 months of age.

Results

Of a total of 15 433 consecutive pregnancies among eligible women of reproductive age, 13 225 pregnancies were registered, 12 218 live births identified and 11 028 newborn infants reached by LHWs. Of these, 5380 (49%) received neonatal VAS and 5648 (51%) placebo. The LHWs successfully delivered the capsules to 79% of newborns within 72 hours of birth with no significant adverse effects. Although the proportion of days observed with symptoms of fever, diarrhoea or rapid breathing were lower with neonatal VAS, these differences were not statistically significant. Mortality rates in the two groups were comparable at 6 months of age.

Conclusions

While our study demonstrated that neonatal VAS was safe and could be feasibly delivered by LHWs in Pakistan as part of their early postnatal visits, the overall lack of benefit on neonatal and 6-month morbidity and mortality in our population suggests the need for further evaluation of this intervention in populations at risk.

Trial registration number

ClinicalTrials.gov NCT00674089.
Cocooned by complications: fetal survival through placental adherence
Authors: Balachandran Nair Deepa , Beard Marion , Majoko Franz
Published: June 2016

We report a case of a 31-year-old woman with 2 previous caesarean deliveries who presented a diagnostic dilemma. She underwent caesarean section where she was found to have a uterine scar dehiscence with an adherent placenta and required a hysterectomy. While individually representing high risk to the mother and/or fetus, the combination in this case protected the fetus.
Coexistent digital gouty and infective flexor tenosynovitis
Authors: Akram Qasim , Hughes Michael , Muir Lindsay
Published: June 2016

Flexor tenosynovitis of the hand is often caused by trauma or infection. Gouty tenosynovitis is an uncommon presentation of the condition and is usually misdiagnosed as infection with the patient undergoing surgery. The coexistence of infection and gout causing flexor tenosynovitis has never been described before in the literature; we report the first ever case and emphasise the importance of its awareness for optimal treatment. A 54-year-old man was initially diagnosed and treated as having infective flexor tenosynovitis and, later, due to a lack of improvement in his symptoms, was discovered to also have gout. We review the literature and suggest management strategy for use in daily clinical practice, including an algorithm, for this presentation.
Simple vaginal trachelectomy as a fertility-sparing treatment to manage high-grade dyskaryosis following multiple large loop excision of the transformation zone
Authors: Scrivener Claire Grace , Gornall Robert , Rolland Philip
Published: June 2016

A 34-year-old nullipara, wishing to start a family, presented to colposcopy clinic. Her most recent cervical cytology result showed high-grade dyskaryosis. Having undergone four large loop excisions of the transformation zone during the past 6 years, this woman had no remaining vaginal cervix. In order to excise presumed high-grade cervical intraepithelial neoplasia while mitigating obstetric risk, she underwent a simple vaginal trachelectomy and isthmic cerclage. 6 months later, the patient had a negative test of cure. 7 months following surgery she became pregnant naturally. At 29 weeks she had antenatal sepsis of unknown cause, which was treated with intravenous antibiotics. She delivered by caesarean section at 37 weeks and now has a healthy child. This report will discuss the obstetric impact of colposcopic treatment, and simple vaginal trachelectomy as a fertility-sparing treatment option for women who have had multiple loop excision procedures to treat premalignant lesions.
Assessment of PTEN-associated vascular malformations in a patient with Bannayan–Riley–Ruvalcaba syndrome
Authors: Anusic Sandra , Clemens Robert Karl Josef , Meier Thomas Oleg , Amann-Vesti Beatrice Ruth
Published: June 2016

Misdiagnosis of phosphatase and tensin homologue hamartoma syndromes is common. Correct diagnosis has a relevant impact on patients, as the risk of malignancies is high and treatment options are limited. We report the case of a 24-year-old man who presented with symptomatic vascular intramuscular lesions of the left forearm and right calf, macrocephaly, post Hashimoto thyroiditis, a multicystic intracranial paratrigonal lesion, lentiginous hyperpigmented maculae on the foreskin and multiple skin lesions. MRI showed extended fibrofatty changes and malformed vessels in the forearm and calf lesions, also, arteriovenous shunting was present in these lesions. The patient had been treated by embolisation and surgically in the past, with limited results. A multidisciplinary assessment and genetic counselling were undertaken and a surveillance programme was initiated. Treatment options of the symptomatic vascular lesions include excision or possibly cryoablation. Physiotherapy to prevent progression of the contractures should be initiated meanwhile.
Difficult diagnosis: strangulated obturator hernia in an 88-year-old woman
Authors: Leitch Megan Kathleen , Yunaev Michael
Published: June 2016

The obturator hernia is a rare type of hernia that can present a diagnostic challenge for the clinician. We report a case of an 88-year-old woman who presented with a history of right iliac fossa pain, bilious vomiting and diarrhoea. Non-specific findings on examination and blood tests made the diagnosis difficult, however, a CT scan of her abdomen revealed the site of the obstruction and the patient was taken to theatre for emergency surgery. We review the literature with focus on the diagnosis of obturator hernias and the different surgical approaches used. The authors believe that this case is of educational value to healthcare professionals, particularly those working in general practice, emergency departments and on surgical teams. It highlights to doctors that patients with incarcerated obturator hernias can present with or without overt signs of intestinal obstruction and emphasises the fact that an obturator hernia can be an important cause of intestinal obstruction in a thin, elderly woman.