bluuebunny/crossref_metadata_2025 huggingface dataset:
Real‐World Assessment of Acute Left Ventricular Lead Implant Success and Complication Rates: Results from the Attain Success Clinical Trial
Authors: HUMMEL JOHN D. , COPPESS MARK A. , OSBORN JEFFREY S. , YEE RAYMOND , FUNG JEFFREY W.H. , AUGOSTINI RALPH , LI SHELBY , HINE DOUGLAS , SINGH JAGMEET P.
Published: August 2016

Background

Left ventricular lead (LVL) implant success rates have historically ranged between 70.5% and 95.5%. To date, there are few large studies that evaluate LVL implant success utilizing a single family of delivery catheters and leads. The Attain Success study was a prospective nonrandomized multicenter global study with the main objectives of assessing single‐system LVL implant success and complication rates.

Methods

Patients undergoing cardiac resynchronization therapy implantation were eligible for enrollment. There was no prespecified level of experience for investigator participation. LVL implant success and complication rates were assessed though 3 months of follow‐up.

Results

A total of 2,014 patients (69.1 ± 12.0 years, 71% male and 38% atrial fibrillation) were enrolled from 114 centers with a follow‐up of 3.5 ± 2.1 months. Coronary sinus cannulation success rate was 96.4% with Attain Family delivery catheters. Implant success rate for Attain Family leads using Attain Family catheters was 94.0%; overall LVL implant success rate was 97.1%. Median procedure time was 4 minutes for cannulation and 9 minutes for LVL placement. Median fluoroscopy time was 17 minutes and median contrast used was 25 cc. There were 55 catheter or LVL‐related complications in 53 subjects; the majority were LVL dislodgements (34, 1.7%) and extracardiac stimulation (11, 0.5%). The Kaplan‐Meier estimate of the 3‐month complication probability was 2.6%.

Conclusion

This study represents the largest prospective evaluation of LVL implantation to date, revealing a high LVL implant success rate and low complication rate using a single family of leads and delivery catheters.
Transcriptional and nontranscriptional events are involved in photic entrainment of the circadian clock in the cricket Gryllus bimaculatus
Authors: Kutaragi Yuki , Miki Taiki , Bando Tetsuya , Tomioka Kenji
Published: August 2016

Most insects show daily activity rhythms that are controlled by endogenous circadian clocks. A basic property of the clock is entrainment to daily environmental cycles to run with an exact 24‐h period. The entrainment is achieved mainly through resetting by light. The present study analyses the light resetting mechanism of the clock in first‐instar nymphal and adult crickets Gryllus bimaculatus (De Geer). A 3‐h light pulse given at early subjective night and late subjective night causes a phase delay and an advance, respectively, of adult locomotor rhythms. The magnitude of the shift caused by the light pulse at circadian time 12 h in constant darkness is significantly smaller than that caused by a 3‐h extension of light phase. Measurement of mRNA levels during the light‐induced phase shifts yielded basically similar results for nymphs and adults. When a 3‐h light pulse is given at early night by light phase extension, an increase of Pdp1 occurs, which is followed by upregulation of the genes Clk and subsequently by per and tim. These changes are eliminated by RNA interference of opsin‐long wavelength, which is expressed in the compound eye and encodes a green‐sensitive opsin, the major photoreceptor for photic entrainment of the clock. No clear changes in mRNA levels are observed for light pulses given at late subjective night or at early subjective night after 24 h of constant darkness. These results suggest that the photic entrainment mechanism of the clock may be shared by nymphal and adult crickets, including transcriptional and nontranscriptional events.
The Role of Perceived Quality Risk in Pricing Remanufactured Products
Authors: Abbey James D. , Kleber Rainer , Souza Gilvan C. , Voigt Guido
Published: August 2016

Recent research indicates that consumers hold significant concerns about the quality of remanufactured products. To better understand this phenomenon, this manuscript combines surveys and experimental studies to identify the antecedents of perceived quality—in the form of perceived risk of functionality and cosmetic defects—and their significant impact on consumers' willingness to pay (wtp) for remanufactured electronics products. The study also controls for alternative explanations for wtp suggested in the literature, such as consumers' wtp for new products, environmental beliefs, disgust aversion toward used products, brand perceptions, risk aversion, and various demographic traits. Importantly, the study empirically estimates the magnitude and distribution of discount factors for remanufactured electronics products—the ratio between wtp for a remanufactured product and wtp for a corresponding new product—among consumers. Finally, the manuscript analytically compares a monopolist's decision to include remanufactured products in its portfolio under both the empirically derived discount factor distributions and the classical linear demand model, which assumes constant discount factors. Interestingly, the classical linear demand model remains reasonably robust for high‐level insights, such as the presence of cannibalization and market expansion effects. However, the analytical model that uses the empirically‐derived distributions of discount factors demonstrates significantly higher profitability than predicted by the classical linear model. This fundamental link between risk perceptions, wtp for remanufactured products, and profitability provides new insights on how to manage demand and product pricing in closed‐loop supply chains.
Genomewide analysis of bull sperm quality and fertility traits
Authors: Puglisi R , Gaspa G , Balduzzi D , Severgnini A , Vanni R , Macciotta NPP , Galli A
Published: August 2016

Contents

Because the priority of AI industry is to identify subfertile bulls, a predictive model that allowed for the prediction of 91% bulls of low fertility was implemented based on seminological (motility) parameters and DNA status assessed both as DNA fragmentation index (DFI) and by TUNEL assay using sperm of 105 Holstein–Friesian bulls (four batches per bull) selected based on in vivo estimated relative conception rates (ERCR). Thereafter, sperm quality and male fertility traits of bulls were explored by GWAS using a high‐density (777K) Illumina chip. After data editing, 85 bulls and 591,988 SNPs were retained for GWAS. Of 12 SNPs with false discovery rate <0.2, four SNPs located on BTA28 and BTA18 were significantly associated (LD‐adjusted Bonferroni <0.05) with the non‐compensatory sperm parameters DFI and TUNEL. Other SNPs of interest for potential association with TUNEL were found on BTA3, in the same chromosome where associations with non‐compensatory in vivo bull fertility were already reported. Further suggestive SNPs for sperm membrane integrity were located on BTA28, the chromosome where QTL studies previously reported associations with sperm quality traits. Suggestive SNPs for ERCR were found on BTA18 in the vicinity of a site already associated with in vivo bull fertility. Additional SNPs associated with ERCR and sperm kinetic parameters were also identified. In contrast to other, but very few GWAS on fertility traits in bovine spermatozoa, which reported significant SNPs located on BTX, we have not identified SNPs of interest in this sexual chromosome.
Elevating glucose and insulin secretion by carbohydrate formulation diets in late lactation to improve post‐weaning fertility in primiparous sows
Authors: Chen TY , Lines D , Dickson C , Go C , Kirkwood RN , Langendijk P
Published: August 2016

Contents

Primiparous (P1) sows commonly lose excessive body reserves to meet energy requirements for maintenance and milk production during lactation, and consequently, post‐weaning reproductive performance may be compromised. The present studies determined whether ad libitum feeding a glucogenic carbohydrate diet (CHO) during late lactation could stimulate insulin and glucose secretion (experiment 1) and improve subsequent litter size (experiment 2). For experiment 1, 15 P1 sows, and for experiment 2, 99 P1 sows (198.5 ± 2.7 kg) were allocated randomly according to suckled litter size (≥10 piglets), either to a CHO diet (14.3 MJ DE/kg, 19.8% crude protein) or a standard lactation diet (control; 14.2 DE MJ/kg, 19.5% crude protein) at 8 days before weaning. The CHO diet aimed to provide glucogenic content (extruded wheat, dextrose and sugar) as energy sources instead of fat sources without changing total dietary energy. Pre‐prandial plasma glucose and insulin concentrations were not influenced by treatments. However, post‐prandial plasma glucose and insulin concentrations and their peaks were both higher (p < .05) compared to the control treatment. Body weight loss during lactation was relatively low at 3%–4% for both treatments and did not differ between control and CHO treatments (−7.6 ± 1.6 vs −5.4 ± 1.2 kg; p > .05). Second litter size was not influenced by diet (p > .05), but the weaning‐to‐mating interval was shorter in CHO sows (p < .05). This study demonstrates that providing an enriched CHO diet in late lactation did influence post‐weaning follicle growth but did not improve subsequent litter size. This may be due to the primiparous sows in this study not experiencing severe negative energy balance and there was no second litter syndrome in this farm which limited the ability of diet to improve sow fertility.
Small‐scale field experiments provide important insights to restore the rock habitat of Australia's most endangered snake
Authors: Goldingay Ross L. , Newell David A.
Published: August 2016

Habitat disturbance poses a major threat to biodiversity worldwide. The broad‐headed snake (Hoplocephalus bungaroides) has become Australia's most endangered snake due to a dependence on rock habitats that are subject to high rates of human‐induced degradation. The permanence of degradation can only be reversed by outcrop restoration. We constructed experimental outcrops near (<150 m) and far (>500 m) from roads and walking trails (access points). We tested two hypotheses over a 14‐year period: that outcrop restoration can restore habitat quality, and that the frequency of outcrop degradation is influenced by distance from access points. We confirmed that habitat value was restored: lizard prey of the broad‐headed snake was more abundant in constructed compared to natural outcrops; broad‐headed snakes were detected equally in constructed and natural outcrops. Disturbance to constructed outcrops occurred more often and was more severe at near compared to far outcrops. The probability of occupancy by broad‐headed snakes was 0.75 ± 0.13 in 29 far outcrops compared to 0.41 ± 0.11 in 35 near outcrops, suggesting a response to disturbance and more frequent poaching at near outcrops. Habitat restoration for the broad‐headed snake should have its greatest value at locations far from access points. Restricting access should be a principal strategy to manage rock outcrop ecosystems. Outcrop disturbance is not unique to Australia. These findings have relevance to management of rock outcrops worldwide. Habitat restoration is an expensive conservation tool for endangered species, particularly if unsuccessful. Small‐scale restoration experiments that aim to refine procedures should precede large‐scale restoration.
Bronchiectasis in yellow nail syndrome
Authors: Woodfield Georgia , Nisbet Mitzi , Jacob Joe , Mok Wing , Loebinger Michael R. , Hansell David M. , Wells Athol U. , Wilson Robert
Published: August 2016

ABSTRACT

Background and objective

Yellow nail syndrome (YNS) is a rare and poorly described disease process. In this case–control study, clinical features and findings on HRCT were compared with idiopathic bronchiectasis (IBx).

Methods

A review of all patients attending an adult bronchiectasis clinic between 2007 and 2013 identified 25 YNS patients. IBx patients were matched in a 2:1 ratio for age, duration of symptoms and gender.

Results

Median age of onset was 53 years. There were 12 male and 23 Caucasian YNS patients. Respiratory manifestations included chronic productive cough (100%), chronic rhinosinusitis (88%), pleural effusions (20%) and lymphoedema (12%). Chest symptoms preceded yellow nails in the majority (68%). Abnormal nails persisted at follow‐up in 23 of 25 patients but improved in 14.

In both disorders, there was symmetrical, predominantly lower lobe bronchiectasis on HRCT. Extent (P = 0.04), severity (P = 0.03) and bronchial wall thickness (P = 0.05) scores were lower in YNS, with less upper and middle lobe disease. Multivariate analysis showed an independent association with increased mucus plugging in YNS. There was a similar prevalence of Pseudomonas aeruginosa infection and mild lung function abnormalities.

Conclusion

Bronchiectasis in YNS is less severe than IBx but is associated with increased mucus plugging, onset is in middle age and there is no female predominance. Treatment targeted at improved secretion clearance may improve both chest and nail symptoms, with consideration of long‐term macrolide antibiotics.
Communities of Place? New Evidence for the Role of Distance and Population Size in Community Attachment
Authors: McKnight Matthew L. , Sanders Scott R. , Gibbs Benjamin G. , Brown Ralph B.
Published: August 2016

Historically, ecological features of a community, such as population size, were considered fundamental aspects of the community experience. Yet methodological advances and the rise of globalization have challenged many classical assumptions rooted in the ecological tradition. Using recent data—the Montana Health Matters Study 2010 (N = 3,508)—we explore whether community attachment links with distance and population size in Montana. Surprisingly, a statistically significant relationship to community attachment appears only when distance from urban centers and community population size are modeled together. Perceived quality of community services partly explains this relationship, but only for the distance measure. Altogether, as globalization is undoubtedly transforming rural life, we argue that “communities of place” may still endure when distance to urban centers and population size are simultaneously accounted for.
Stratigraphic architecture resulting from dune interactions: White Sands Dune Field, New Mexico
Authors: Brothers Sarah C. , Kocurek Gary , Brothers Thomas C. , Buynevich Ilya V.
Published: August 2016

Aeolian dune interactions provide the dynamics for field‐scale pattern emergence and evolution within a set of boundary conditions. Although morphologies for a spectrum of dune interactions are recognized, associated stratigraphic architectures are unknown and have probably been misidentified in the rock record. A unique data set for the White Sands Dune Field in New Mexico (USA) allowed for a detailed analysis in which the morphological evolution of defect and bedform repulsion interactions is chronicled over a decadal time‐series of images and coupled with the resulting stratigraphic architecture, documented from cross‐strata exposed in interdune areas and ground‐penetrating radar imaging of dune interiors. Defect and bedform repulsions represent a class of interactions in which the faster‐migrating dune termination or defect (defect repulsion), or pair of defects (bedform repulsion), collides with the target dune downwind. Results document that during the collision, the defect(s) of the impactor dune recombine(s) with a segment of the target dune, and the redundant target dune segment is ejected as a parabolic‐shaped ejecta dune. The ejecta dune assumes a more barchanoid shape as it migrates downwind. The interaction architecture consists of lateral truncation of the target set by an interaction bounding surface. Defect cross‐strata tangentially approach the surface in plan‐view, and downlap onto the surface in cross‐section. The orientation of the defect cross‐strata is at an acute angle to the trend of the interaction surface. Orientations of the defect cross‐strata, which represent the defect approach angle, and the target dune cross‐strata, which represent the general dune migration direction, diverge at a high angle. Defect cross‐strata typically consist of wind‐ripple laminae, in contrast to the target set that may house grainflow cross‐strata. In the transport direction, the erosional interaction surface curves to become subparallel to subjacent and superjacent cross‐strata where the defect and target unify into a single lee face.
A high resolution map of the Arabidopsis thaliana developmental transcriptome based on RNA‐seq profiling
Authors: Klepikova Anna V. , Kasianov Artem S. , Gerasimov Evgeny S. , Logacheva Maria D. , Penin Aleksey A.
Published: August 2016

Arabidopsis thaliana is a long established model species for plant molecular biology, genetics and genomics, and studies of A. thaliana gene function provide the basis for formulating hypotheses and designing experiments involving other plants, including economically important species. A comprehensive understanding of the A. thaliana genome and a detailed and accurate understanding of the expression of its associated genes is therefore of great importance for both fundamental research and practical applications. Such goal is reliant on the development of new genetic and genomic resources, involving new methods of data acquisition and analysis. We present here the genome‐wide analysis of A. thaliana gene expression profiles across different organs and developmental stages using high‐throughput transcriptome sequencing. The expression of 25 706 protein‐coding genes, as well as their stability and their spatiotemporal specificity, was assessed in 79 organs and developmental stages. A search for alternative splicing events identified 37 873 previously unreported splice junctions, approximately 30% of them occurred in intergenic regions. These potentially represent novel spliced genes that are not included in the TAIR10 database. These data are housed in an open‐access web‐based database, TraVA (Transcriptome Variation Analysis, http://travadb.org/), which allows visualization and analysis of gene expression profiles and differential gene expression between organs and developmental stages.
Gastric carcinoma in canines and humans, a review
Authors: Hugen S. , Thomas R. E. , German A. J. , Burgener I. A. , Mandigers P. J. J.
Published: August 2016

Gastric carcinoma (GC) is the most common neoplasm in the stomach of dogs. Although incidence in the general population is reported to be low, breed‐specific GC has a high incidence. Median age at presentation ranges from 8 to approximately 10 years. The disease is mostly located in the lesser curvature and antropyloric region of the stomach. Unfortunately, diagnosis is usually made when the disease is at an advanced stage and, therefore, prognosis is poor. Due to similarities in clinical presentation, diagnosis, histology and prognosis, canine GC may serve as a valuable model for human GC. Extensive pedigrees of canine gastric carcinoma cases could reveal insights for human gastric carcinoma. Putative species differences include the role of Helicobacter in pathogenesis, the wide array of genetic data and screening available for humans, and treatment protocols that are available for human GC.
Evaluation ofPax5expression and comparison with BLA.36 and CD79αcy in feline non‐Hodgkin lymphoma
Authors: Felisberto R. , Matos J. , Alves M. , Cabeçadas J. , Henriques J.
Published: August 2016

Paired box gene 5 (Pax5) is a widely used B‐cell marker for human and canine non‐Hodgkin's lymphoma (nHL); however, in the literature there is only one case report using Pax5 in a cat B‐cell lymphoma. The purposes of this study were to investigate the expression and detection of B‐cell specific activator protein (BSAP) using a monoclonal anti‐Pax5 antibody in felinenHL(FnHL) tissue samples to evaluate its diagnostic relevance as a B‐cell marker. A total of 45FnHLsamples in 45 cats were evaluated. B‐cell lymphoma was the most common immunophenotype (51.1%) for all the samples and T‐cell the most common immunophenotype (64.3%) for the gastrointestinal (GI) form. Pax5 stained 82.6% of all B‐cell lymphomas and no expression was found in any of the T‐cell lymphomas. Anti‐Pax5 antibody staining inFnHLis similar to that reported in human and canine counterparts and may offer an excellent B‐cell marker in cats.
Diagnostic performance of molecular and conventional methods for identification of dermatophyte species from clinically infected Arabian horses in Egypt
Authors: Tartor Yasmine H. , El Damaty Hend M. , Mahmmod Yasser S.
Published: August 2016

Background

Rapid and accurate identification of dermatophytes is crucial for the effective control of disease outbreaks. Current methods based on culture and microscopic characteristics may require weeks before positive identification is made.

Objectives

To (i) identify the most common pathogenic dermatophytes affecting Arabian horses; (ii) compare the performance of direct microscopy (DM), culture, PCR using hair samples (PCRhair) and PCR based on culture isolates (PCRculture) for the diagnosis of dermatophytosis.

Methods

Samples of hair and crusts of skin lesions from Arabian horses were collected on a monthly basis by scraping skin of affected horses. Samples were divided into three portions: the first portion was used for microscopic examination, the second for culture and the third portion for PCR amplification of intergenic spacer (ITS) regions.

Results

Out of 200 horses examined, 70 (35%) showed cutaneous lesions characteristic of dermatophytosis. DM revealed that 70.4% were positive for fungal elements and 85.7% were culture positive. The identified species were Microsporum canis, Trichophyton verrucosum, T. mentagrophytes var. mentagrophytes and M. equinum. Among 25 selected samples, 64, 92, 91.3 and 52% were positive for dermatophytes, as determined by DM, culture, PCRculture and PCRhair, respectively.

Conclusions

The dermatophytes M. canis, T. verrucosum, T. mentagrophytes var. mentagrophytes and M. equinum were the most common cause of dermatophytosis in Arabian horses. Although the number of samples was small, the ITS‐based PCR may be a useful diagnostic tool when combined with culture.
In Vitro Biomechanical Testing of the Tube Knot
Authors: Chang Stephany , Dong Fanglong , Lagman Minette , Schmidt Peggy L. , Irizarry Kristopher L. , Schulz David , Fahie Maria A.
Published: August 2016

Objective

To compare in vitro biomechanical properties of the tube knot (TB) to a crimp clamp (CC) system, and square knot (SQ) using 3 monofilament materials.

Study Design

In vitro biomechanical study.

Sample Population

Suture loops (n=20 per material/knot construct).

Methods

Monotonic tensile loading (300 mm/min single pull to failure) was performed on knots tied using 3 knots (TB, 5‐throw SQ, and CC system) with each of 3 materials (40# Securos® nylon, #2 polypropylene, and #2 nylon). Ultimate tensile strength, elongation, and stiffness were measured and compared by sequential 1‐ and 2‐way ANOVA.

Results

Ultimate tensile strength was greatest with 40# nylon CC (mean ± SD, 293.6 ± 26.2 N), followed by TB (289.8 ± 9.2 N) and SQ (252.2 ± 8.5 N) with no significant difference between CC and TB. TB with #2 polypropylene (158.1 ± 7.4 N) and #2 nylon (126.3 ± 5.5 N) had significantly greater tensile strength than SQ with #2 polypropylene (143.6 ± 5.3 N) and #2 nylon (110.7 ± 6.2 N). Elongation at failure was significantly greater in 40# nylon TB (25.3 ± 3.2 mm) and SQ (10.8 ± 1.6 mm) compared to CC (5.3 ± 1.0 mm). Both material and knotting method had an effect on ultimate tensile strength, elongation at failure, and stiffness, based on 2‐way ANOVA.

Conclusion

Ultimate tensile strength of TB was equivalent to that of CC; however, elongation at failure was greatest for TB, which may be of concern for clinical applications.
Assessment of water quality in the vicinity of peat extraction sites: The case of Pien‐Saimaa, Finland
Authors: Sääksjärvi Eija , Reinikainen Satu‐Pia , Louhi‐Kultanen Marjatta
Published: August 2016

Peatlands have an important global role as carbon sinks. Locally, however, peat bog extraction can cause pollution in nearby watercourses. The aim of this study is to investigate the application of multivariate methods in the renovation and protection of eutrophic lakes surrounded by agricultural and peat extraction areas. The analytical data used in the study originated from a national water quality database and the period studied was 2000–2013. Multivariate methods: Principal Component Analysis (PCA) and Parallel Factor Analysis (PARAFAC) were applied to solve interactions of variables and pollution sources in a complex water ecosystem. Leaching from the peat bog area was found to be the main source of iron, which has an important role as a precipitator of phosphorus in loose sediment and in water. Nutrient ratios had no direct correlation to algae blooms, but high ratios indicated an increased likelihood of an upcoming bloom.
Relationships between environmental metrics and water temperature: a case study of Polish lowland rivers
Authors: Łaszewski Maksym
Published: August 2016

The article presents relations between environmental metrics and water temperature in small Polish lowland rivers and describes their spatial temperature patterns. Water temperature data was obtained from measurements conducted on nine sites during summer of 2015 with the use of digital data loggers. Selected environmental metrics in the catchments areas were calculated and correlated with water temperature parameters. The results showed that water temperature patterns were generally similar across catchments, except for sites with strong human influence, which caused a decrease in the number and power of statistically significant relationships between environmental metrics and water temperature parameters. The best‐explained water temperature parameter was the minimum and mean daily range, while the best environmental predictors were the Strahler order, catchment area, mean catchment elevation and forested area. Most of the relations proved to be theoretically justified and could be used to further improve temperature monitoring studies and the management of water resources.
Importance Rearrangement within Education, Economy and Natural Protection Ministries for Armenian Composite Supportive Progress (ACASP)
Authors: Petrosyan Azniv F.
Published: August 2016

Sustainable Development is an innovative concept characterized as Composite Appraising Supportive Progress of Armenia (ACASP). Biodiversity concept is another topic having a vast power on public management and employment. Social, economic and environmental impacts optimize sequences within Education (S3), Economy (E5), Air (N3) & Land (N1) Ministries. Seven (7) phases of Operation Research (OR) studies correspond to nine (9) procedures of composite progressive indicators. Two (2) techniques are applied as decision making of utility function and transportation tasks. North-West Corner Rule (NWCR) and Low Cost Cell Rule (LCCR) are applied to manage public employment as per Education (S3), Economy (E5), Land (N1) and Air (N3) magnitudes of ACASP. A motivating approach is pertained not only to pick the order of significance as per biodiversity concept, but also to characterize the process of decision making through operation research techniques, particularly transportation assignments as per origins and destinations with supply and demand applications. The resulting sequence is revealed by sustenance of biodiversity concept with public employment of Armenian CASP.
Nonlinear Observer for Tightly Integrated Inertial Navigation Aided by Pseudo-Range Measurements
Authors: Johansen Tor A. , Hansen Jakob M. , Fossen Thor I.
Published: August 2016

A modular nonlinear observer for inertial navigation aided by pseudo-range measurements is designed and analyzed. The attitude observer is based on a recent nonlinear complementary filter that uses magnetometer and accelerometer vector measurements to correct the quaternion attitude estimate driven by gyro measurements, including gyro bias estimation. A tightly integrated translational motion observer is driven by accelerometer measurements, employs the attitude estimates, and makes corrections using the pseudo-range and range-rate measurements. It estimates position, range bias errors, velocity and specific force in an earth-fixed Cartesian coordinate frame, where the specific force estimate is used as a reference vector for the accelerometer measurements in the attitude observer. The exponential stability of the feedback interconnection of the two observers is analyzed and found to have a semiglobal region of attraction with respect to the attitude observer initialization and local region of attraction with respect to translational motion observer initialization. The latter is due to linearization of the range measurement equations that is underlying the selection of injection gains by solving a Riccati equation. In typical applications, the pseudo-range equations admit an explicit algebraic solution that can be easily computed and used to accurately initialize the position and velocity estimates. Hence, the limited region of attraction is not seen as a practical limitation of the approach for many applications. Advantages of the proposed nonlinear observer are low computational complexity and a solid theoretical foundation.
Performance Investigation of Cycle-Integrated Parallel Hybrid Turboshafts
Authors: Vratny Patrick C. , Kaiser Sascha , Seitz Arne , Donnerhack Stefan
Published: August 2016

Motivated by the long-term target settings for research and innovation in Europe and in North America, initial investigations of parallel hybrid electric power plant systems have indicated significant in-flight fuel reduction potentials for short range air transport. Based on this topology, a special variant, namely the cycle-integrated parallel hybrid (CIPH), has been investigated. In this special configuration, electric motors supplied by batteries are powering an array of compressor stages of a power plant that are mechanically decoupled from the turbine section. The potentials with regard to in-flight fuel reduction and efficiency improvement of this concept are derived for a 12-ton-helicopter accommodating 19 passengers on a 450 nm mission. For the presented CIPH concept, the axial compressor section of a baseline turboshaft (TS) delivering a maximum shaft power of 3300 kW is electrified with the help of linear electric motors (LEMs). The highest potential for this arrangement was identified in part load for moderate degrees of power hybridization—the share between installed electric power and total power—of around 20%. The first assessment has revealed that this additional degrees-of-freedom allows to almost double the overall efficiency, compared to a conventional power with same technology time horizon, and a reduction in power-specific fuel consumption (PSFC) of roughly 45%. The range capability of a hybrid-powered helicopter has been decreased by more than 50%, mainly driven by the battery mass. However, a fuel burn, and thus, in-flight CO2 reduction of more than 40% against the reference at decreased mission range have been found.
A Macroscopic Model for Simulating the Mucociliary Clearance in a Bronchial Bifurcation: The Role of Surface Tension
Authors: Manolidis Michail , Isabey Daniel , Louis Bruno , Grotberg James B. , Filoche Marcel
Published: August 2016

The mucociliary clearance in the bronchial tree is the main mechanism by which the lungs clear themselves of deposited particulate matter. In this work, a macroscopic model of the clearance mechanism is proposed. Lubrication theory is applied for thin films with both surface tension effects and a moving wall boundary. The flow field is computed by the use of a finite-volume scheme on an unstructured grid that replicates a bronchial bifurcation. The carina in bronchial bifurcations is of special interest because it is a location of increased deposition of inhaled particles. In this study, the mucus flow is computed for different values of the surface tension. It is found that a minimal surface tension is necessary for efficiently removing the mucus while maintaining the mucus film thickness at physiological levels.
The mechanics of the first heartbeat
Authors: Gough Nancy R.
Published: August 2016

Mechanical, not electrical, signals coordinate the first heartbeats in the developing embryo.
Papers of note in
Science Translational Medicine
Authors: Ferrarelli Leslie K.
Published: August 2016

This week’s articles describe a way to promote liver regeneration and a safer therapeutic option for congenital adrenal hyperplasia.
Prepping the premetastatic niche
Authors: Ferrarelli Leslie K.
Published: August 2016

Targeting TLR3 might suppress metastatic growth in the lung.
Pulmonary Deposition and Elimination of Liposomal Amikacin for Inhalation and Effect on Macrophage Function after Administration in Rats
Authors: Malinin Vladimir , Neville Mary , Eagle Gina , Gupta Renu , Perkins Walter R.
Published: August 2016

Pulmonary nontuberculous mycobacterial (PNTM) infections represent a treatment challenge. Liposomal amikacin for inhalation (LAI) is a novel formulation currently in development for the treatment of PNTM infections. The pulmonary deposition and elimination of LAI and its effect on macrophage function were evaluated in a series of preclinical studies in healthy rats. The pulmonary deposition of LAI was evaluated in female rats (
n
= 76) treated with LAI by nebulizer at 10 mg/kg of body weight per day or 90 mg/kg per day for 27 days, followed by dosing of dually labeled LAI (LAI with a lipid label plus an amikacin label) on day 28 with subsequent lung histological and amikacin analyses. In a separate study for assessment of alveolar macrophage function, rats (
n
= 180) received daily treatment with LAI at 90 mg/kg per day or 1.5% saline over three 30-day treatment periods followed by 30-day recovery periods; phagocytic and
Saccharomyces cerevisiae
(yeast) killing capabilities and inflammatory mediator release were assessed at the end of each period. LAI demonstrated equal dose-dependent deposition across all lung lobes and regions. Lipid and amikacin labels showed diffuse extracellular colocalization, followed by macrophage uptake and gradual amikacin elimination. Macrophages demonstrated accumulation of amikacin during treatment periods and nearly complete elimination during recovery periods. No evidence of an inflammatory response was seen. No differences in microsphere uptake or yeast killing were seen between LAI-treated and control macrophages. Neither LAI-treated nor control macrophages demonstrated constitutive inflammatory mediator release; however, both showed normal mediator release on lipopolysaccharide stimulation. LAI is readily taken up by macrophages in healthy rats without compromising macrophage function.
Trivalency of a Nanobody Specific for the Human Respiratory Syncytial Virus Fusion Glycoprotein Drastically Enhances Virus Neutralization and Impacts Escape Mutant Selection
Authors: Palomo Concepción , Mas Vicente , Detalle Laurent , Depla Erik , Cano Olga , Vázquez Mónica , Stortelers Catelijne , Melero José A.
Published: August 2016

ALX-0171 is a trivalent Nanobody derived from monovalent Nb017 that binds to antigenic site II of the human respiratory syncytial virus (hRSV) fusion (F) glycoprotein. ALX-0171 is about 6,000 to 10,000 times more potent than Nb017 in neutralization tests with strains of hRSV antigenic groups A and B. To explore the effect of this enhanced neutralization on escape mutant selection, viruses resistant to either ALX-0171 or Nb017 were isolated after serial passage of the hRSV Long strain in the presence of suboptimal concentrations of the respective Nanobodies. Resistant viruses emerged notably faster with Nb017 than with ALX-0171 and in both cases contained amino acid changes in antigenic site II of hRSV F. Detailed binding and neutralization analyses of these escape mutants as well as previously described mutants resistant to certain monoclonal antibodies (MAbs) offered a comprehensive description of site II mutations which are relevant for neutralization by MAbs and Nanobodies. Notably, ALX-0171 showed a sizeable neutralization potency with most escape mutants, even with some of those selected with the Nanobody, and these findings make ALX-0171 an attractive antiviral for treatment of hRSV infections.
Griffithsin-Modified Electrospun Fibers as a Delivery Scaffold To Prevent HIV Infection
Authors: Grooms Tiffany N. , Vuong Hung R. , Tyo Kevin M. , Malik Danial A. , Sims Lee B. , Whittington Carli P. , Palmer Kenneth E. , Matoba Nobuyuki , Steinbach-Rankins Jill M.
Published: August 2016

Despite current prophylactic strategies, sexually transmitted infections (STIs) remain significant contributors to global health challenges, spurring the development of new multipurpose delivery technologies to protect individuals from and treat virus infections. However, there are few methods currently available to prevent and no method to date that cures human immunodeficiency virus (HIV) infection or combinations of STIs. While current oral and topical preexposure prophylaxes have protected against HIV infection, they have primarily relied on antiretrovirals (ARVs) to inhibit infection. Yet continued challenges with ARVs include user adherence to daily treatment regimens and the potential toxicity and antiviral resistance associated with chronic use. The integration of new biological agents may avert some of these adverse effects while also providing new mechanisms to prevent infection. Of the biologic-based antivirals, griffithsin (GRFT) has demonstrated potent inhibition of HIV-1 (and a multitude of other viruses) by adhering to and inactivating HIV-1 immediately upon contact. In parallel with the development of GRFT, electrospun fibers (EFs) have emerged as a promising platform for the delivery of agents active against HIV infection. In the study described here, our goal was to extend the mechanistic diversity of active agents and electrospun fibers by incorporating the biologic GRFT on the EF surface rather than within the EFs to inactivate HIV prior to cellular entry. We fabricated and characterized GRFT-modified EFs (GRFT-EFs) with different surface modification densities of GRFT and demonstrated their safety and efficacy against HIV-1 infection
in vitro
. We believe that EFs are a unique platform that may be enhanced by incorporation of additional antiviral agents to prevent STIs via multiple mechanisms.
Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay
Authors: Yamamoto Mizuki , Matsuyama Shutoku , Li Xiao , Takeda Makoto , Kawaguchi Yasushi , Inoue Jun-ichiro , Matsuda Zene
Published: August 2016

Middle East respiratory syndrome (MERS) is an emerging infectious disease associated with a relatively high mortality rate of approximately 40%. MERS is caused by MERS coronavirus (MERS-CoV) infection, and no specific drugs or vaccines are currently available to prevent MERS-CoV infection. MERS-CoV is an enveloped virus, and its envelope protein (S protein) mediates membrane fusion at the plasma membrane or endosomal membrane. Multiple proteolysis by host proteases, such as furin, transmembrane protease serine 2 (TMPRSS2), and cathepsins, causes the S protein to become fusion competent. TMPRSS2, which is localized to the plasma membrane, is a serine protease responsible for the proteolysis of S in the post-receptor-binding stage. Here, we developed a cell-based fusion assay for S in a TMPRSS2-dependent manner using cell lines expressing
Renilla
luciferase (RL)-based split reporter proteins. S was stably expressed in the effector cells, and the corresponding receptor for S, CD26, was stably coexpressed with TMPRSS2 in the target cells. Membrane fusion between these effector and target cells was quantitatively measured by determining the RL activity. The assay was optimized for a 384-well format, and nafamostat, a serine protease inhibitor, was identified as a potent inhibitor of S-mediated membrane fusion in a screening of about 1,000 drugs approved for use by the U.S. Food and Drug Administration. Nafamostat also blocked MERS-CoV infection
in vitro
. Our assay has the potential to facilitate the discovery of new inhibitors of membrane fusion of MERS-CoV as well as other viruses that rely on the activity of TMPRSS2.
Activity of Tedizolid in Methicillin-Resistant Staphylococcus aureus Experimental Foreign Body-Associated Osteomyelitis
Authors: Park Kyung-Hwa , Greenwood-Quaintance Kerryl E. , Mandrekar Jayawant , Patel Robin
Published: August 2016

We compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant
Staphylococcus aureus
(MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (
n
= 14), tedizolid plus rifampin (
n
= 11), rifampin (
n
= 16), or vancomycin plus rifampin (
n
= 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 μg/ml and 60 μg · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid- plus rifampin-treated animals were not significantly different from those in the vancomycin- plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 μg/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin.
Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease
Authors: Wiens Matthew O. , Kanters Steve , Mills Edward , Peregrina Lucano Alejandro A. , Gold Silvia , Ayers Dieter , Ferrero Luis , Krolewiecki Alejandro
Published: August 2016

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (
C
max
), the time to
C
max
, the elimination rate constant (
k
el
), the absorption rate constant (

K
a

), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and
C
max
were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively.

K
a

and
k
el
were 1.16 h
−1
(95% CrI, 0.59, 1.76 h
−1
) and 0.052 h
−1
(95% CrI, 0.045, 0.059 h
−1
), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.
Rapid Detection of
FKS
-Associated Echinocandin Resistance in Candida glabrata
Authors: Zhao Yanan , Nagasaki Yoji , Kordalewska Milena , Press Ellen G. , Shields Ryan K. , Nguyen M. Hong , Clancy Cornelius J. , Perlin David S.
Published: August 2016

A novel and highly accurate diagnostic assay platform was established for rapid identification of
FKS
mutations associated with echinocandin resistance in
Candida glabrata
. The assay platform uses allele-specific molecular beacon and DNA melt analysis following asymmetric PCR. A dual assay for
FKS1
and
FKS2
was developed to identify within 3 h the most common and clinically relevant resistance-associated mutations, including 8
FKS1
HS1 (wild type [WT], S629P, F625S, D632Y, D632E [T1896G], D632E [T1896A], I634V, and F625F) and 7
FKS2
HS1 (WT, F659del, F659S, F659V, F659L, S663P, and S663F) genotypes. A blinded panel of 188
C. glabrata
clinical isolates was tested by both assays. The molecular diagnostic results from the dual assay were 100% concordant with data obtained from DNA sequencing. This platform has the potential to overcome the deficiencies of existing
in vitro
susceptibility-based assays to identify echinocandin-resistant
C. glabrata
and holds promise as a surrogate diagnostic method to better direct echinocandin therapy.
Gene
bb0318
Is Critical for the Oxidative Stress Response and Infectivity of Borrelia burgdorferi
Authors: Showman Adrienne C. , Aranjuez George , Adams Philip P. , Jewett Mollie W.
Published: August 2016

A greater understanding of the molecular mechanisms that
Borrelia burgdorferi
uses to survive during mammalian infection is critical for the development of novel diagnostic and therapeutic tools to improve the clinical management of Lyme disease. By use of an
in vivo
expression technology (IVET)-based approach to identify
B. burgdorferi
genes expressed
in vivo
, we discovered the
bb0318
gene, which is thought to encode the ATPase component of a putative riboflavin ABC transport system. Riboflavin is a critical metabolite enabling all organisms to maintain redox homeostasis.
B. burgdorferi
appears to lack the metabolic capacity for
de novo
synthesis of riboflavin and so likely relies on scavenging riboflavin from the host environment. In this study, we sought to investigate the role of
bb0318
in
B. burgdorferi
pathogenesis. No
in vitro
growth defect was observed for the Δ
bb0318
clone. However, the mutant spirochetes displayed reduced levels of survival when exposed to exogenous hydrogen peroxide or murine macrophages. Spirochetes lacking
bb0318
were found to have a 100-fold-higher 50% infectious dose than spirochetes containing
bb0318
. In addition, at a high inoculum dose,
bb0318
was found to be important for effective spirochete dissemination to deep tissues for as long as 3 weeks postinoculation and to be critical for
B. burgdorferi
infection of mouse hearts. Together, these data implicate
bb0318
in the oxidative stress response of
B. burgdorferi
and indicate the contribution of
bb0318
to
B. burgdorferi
mammalian infectivity.