bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel approach to assess pulmonary function in patients with chronic obstructive pulmonary disease using tissue velocity imaging.
Authors: Zheng Xiao-Zhi , Wu Jing , Tan Xu-Yan
Published: May 2016

Aims: To explore the feasibility of quantitative evaluation of pulmonary function in patients with chronic obstructive pulmonary disease (COPD) using tissue velocity imaging (TVI) and strain rate imaging (SRI) via transthoracic lung ultrasonography. Material and methods: Eighty inpatients with clinically diagnosed COPD underwent pulmonary function test and transthoracic lung ultrasound on the same day. Lung ultrasound variables and pulmonary function parameters were analyzed. Results: All patients with COPD had faster breathing and significant reduced lung function compared with healthy participants (p<0.05). The lung ultrasound parameters, velocity (max-min, cm/s), displacement (max-min, mm), strain (max-min, %) and strain rate (max-min, 1/s) were significantly higher in patients with COPD (p<0.05). A good negative correlation was found between lung ultrasound variables and pulmonary function parameters in patients with COPD. Stepwise multiple regression analysis indicated that the velocity (max-min, cm/s) was the only independent determinant of FEV1/FVC (%). With the use of FEV1/FVC<70% as the criteria of irreversible pulmonary function impairment to distinguish an abnormal pulmonary function, the area under the ROC was 0.99 for the velocity (max-min, cm/s) of the lung tissue in the process of breathing. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the cut off value (1.19 cm/s) was 97.63%, 100%, 100%, 80%,  and 98%, respectively (p<0.001). Conclusions: Tissue velocity imaging via transthoracic lung ultrasound is a useful modality in the assessment of pulmonary function in patients with COPD.
Gas discharge plasma treatment of poly(ethylene glycol-co-1,3/1,4 cyclohexanedimethanol terephthalate) for enhanced paint adhesion
Authors: Salapare Hernando S. , Cosiñero Hannah Shamina O. , Suarez Beverly Anne T. , Bacaoco Miguel Y. , Nuñez Julius Andrew P. , Guittard Frédéric , Ramos Henry J.
Published: May 2016

Low-energy hydrogen-ions and tetrafluoromethane-ions produced from a gas discharge ion source were irradiated to poly(ethylene glycol-co-1,3/1,4 cyclohexanedimethanol terephthalate) (PETG) sheets for enhancing paint adhesion. The ion beams were characterized using a cast steel mass spectrometer, while the untreated and treated samples were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, contact angle measurements, and profilometry. The paint adhesion was determined by using the standard method for evaluating adhesion by knife [ASTM D6677-07, Standard Test Method for Evaluating Adhesion by Knife (ASTM International, West Conshohocken, PA, 2012)] and was correlated with the calculation of the work of adhesion derived from the Young–Dupré equation. After plasma treatment, a significant decrease in the contact angle was observed in all samples, except for the CF4 ion-treated samples with the discharge current of 3 mA and an irradiation time of 30 min. At longer irradiation times, the treated samples showed lesser changes in the contact angle measurement. The increase in the average and root-mean-square surface roughness was observed on the samples after plasma treatment. The samples treated with either H2 or CF4 ions for 15 min showed a direct correlation between the discharge current and surface roughness. The samples treated for 30 min showed no significant correlation between the surface roughness and discharge current, which can be attributed to the possible melting of the samples since PETG has a low melting point. The observation made in this study on the relationship of wettability and surface roughness is consistent with the Wenzel wetting mode. Scanning electron micrographs showed surface etching on the hydrogen ion-treated samples while no significant surface changes were observed for the CF4 ion-treated samples. In general, paint adhesion was stronger for samples that exhibited enhanced wettability and high work of adhesion. The optimal work of adhesion to double the paint adhesion performance was at least 84.79 mN/m. The increase in the surface roughness after the treatment provided an increased friction between the paint and the PETG surface. The increase in the paint adhesion was also due to the covalent, hydrogen, and van der Waals bonding that are typically observed for highly wettable surfaces.
Ballistic electron and photocurrent transport in Au/organic/Si(001) diodes with PDI8-CN2 interlayers
Authors: Buzio Renato , Gerbi Andrea , Marré Daniele , Barra Mario , Cassinese Antonio
Published: May 2016

The authors use ballistic electron emission microscopy (BEEM) to probe hot-electron and photocurrent transport in Au/organic/n-Si(001) diodes incorporating the n-type perylene diimide semiconductor PDI8-CN2. For the case of an ultrathin organic interlayer, hot-electron injection is weak and can be detected only at randomly distributed nanosized domains, where BEEM provides electronic barrier heights of ∼0.67 and ∼0.94 eV, respectively. No ballistic transport is detected for devices with a 10 nm-thick interlayer. Regardless of the organic layer thickness, BEEM reveals laterally uniform contributions due to scanning tunneling microscopy-induced photocurrent (STM-PC), with a characteristic energy onset at ∼1.2 eV and a broad intensity peak in the 2–4 eV range. The authors give insight on such spectroscopic features by examination of temperature-dependent spectra and of literature data. This study shows that PDI8-CN2 limits the penetration of Au toward Si, likely due to stiff intermolecular interactions and reactivity of the cyano groups. Moreover, ballistic transmittance is remarkably suppressed and photocurrent transport takes place via defects or recombination centers. Our analysis of electronic and STM-PC fingerprints appears useful for the characterization of several organic-on-inorganic interfaces of interest for heterostructures and devices.
A Monte Carlo study on 223Ra imaging for unsealed radionuclide therapy
Authors: Takahashi Akihiko , Miwa Kenta , Sasaki Masayuki , Baba Shingo
Published: May 2016

Purpose:

Radium‐223 (223Ra), an α‐emitting radionuclide, is used in unsealed radionuclide therapy for metastatic bone tumors. The demand for qualitative 223Ra imaging is growing to optimize dosimetry. The authors simulated 223Ra imaging using an in‐house Monte Carlo simulation code and investigated the feasibility and utility of 223Ra imaging.

Methods:

The Monte Carlo code comprises two modules, hexagon and nai. The hexagon code simulates the photon and electron interactions in the tissues and collimator, and the nai code simulates the response of the NaI detector system. A 3D numeric phantom created using computed tomography images of a chest phantom was installed in the hexagon code. 223Ra accumulated in a part of the spine, and three x‐rays and 19 γ rays between 80 and 450 keV were selected as the emitted photons. To evaluate the quality of the 223Ra imaging, the authors also simulated technetium‐99m (99mTc) imaging under the same conditions and compared the results.

Results:

The sensitivities of the three photopeaks were 147 counts per unit of source activity (cps MBq−1; photopeak: 84 keV, full width of energy window: 20%), 166 cps MBq−1 (154 keV, 15%), and 158 cps MBq−1 (270 keV, 10%) for a low‐energy general‐purpose (LEGP) collimator, and those for the medium‐energy general‐purpose (MEGP) collimator were 33, 13, and 8.0 cps MBq−1, respectively. In the case of 99mTc, the sensitivity was 55 cps MBq−1 (141 keV, 20%) for LEGP and 52 cps MBq−1 for MEGP. The fractions of unscattered photons of the total photons reflecting the image quality were 0.09 (84 keV), 0.03 (154 keV), and 0.02 (270 keV) for the LEGP collimator and 0.41, 0.25, and 0.50 for the MEGP collimator, respectively. Conversely, this fraction was approximately 0.65 for the simulated 99mTc imaging. The sensitivity with the LEGP collimator appeared very high. However, almost all of the counts were because of photons that penetrated or were scattered in the collimator; therefore, the proportions of unscattered photons were small.

Conclusions:

Their simulation study revealed that the most promising scheme for 223Ra imaging is an 84‐keV window using an MEGP collimator. The sensitivity of the photopeaks above 100 keV is too low for 223Ra imaging. A comparison of the fractions of unscattered photons reveals that the sensitivity and image quality are approximately two‐thirds of those for 99mTc imaging.
Minimizing treatment planning errors in proton therapy using failure mode and effects analysis
Authors: Zheng Yuanshui , Johnson Randall , Larson Gary
Published: May 2016

Purpose:

Failure mode and effects analysis (FMEA) is a widely used tool to evaluate safety or reliability in conventional photon radiation therapy. However, reports about FMEA application in proton therapy are scarce. The purpose of this study is to apply FMEA in safety improvement of proton treatment planning at their center.

Methods:

The authors performed an FMEA analysis of their proton therapy treatment planning process using uniform scanning proton beams. The authors identified possible failure modes in various planning processes, including image fusion, contouring, beam arrangement, dose calculation, plan export, documents, billing, and so on. For each error, the authors estimated the frequency of occurrence, the likelihood of being undetected, and the severity of the error if it went undetected and calculated the risk priority number (RPN). The FMEA results were used to design their quality management program. In addition, the authors created a database to track the identified dosimetric errors. Periodically, the authors reevaluated the risk of errors by reviewing the internal error database and improved their quality assurance program as needed.

Results:

In total, the authors identified over 36 possible treatment planning related failure modes and estimated the associated occurrence, detectability, and severity to calculate the overall risk priority number. Based on the FMEA, the authors implemented various safety improvement procedures into their practice, such as education, peer review, and automatic check tools. The ongoing error tracking database provided realistic data on the frequency of occurrence with which to reevaluate the RPNs for various failure modes.

Conclusions:

The FMEA technique provides a systematic method for identifying and evaluating potential errors in proton treatment planning before they result in an error in patient dose delivery. The application of FMEA framework and the implementation of an ongoing error tracking system at their clinic have proven to be useful in error reduction in proton treatment planning, thus improving the effectiveness and safety of proton therapy.
Supersonic intensity and non-negative intensity for prediction of radiated sound
Authors: Liu Daipei , Peters Herwig , Marburg Steffen , Kessissoglou Nicole
Published: May 2016

Two numerical methods to identify the surface areas of a vibrating structure that radiate sound are presented. The supersonic intensity identifies only the supersonic wave components of the sound field contributing to far-field radiated sound. The supersonic intensity is calculated using a two-dimensional convolution between a spatial radiation filter and the sound field. To compute the spatial radiation filter, the shortest surface distance between two points on the structure is calculated using the geodesic distance method. The non-negative intensity is based on acoustic radiation modes and identifies the radiated sound power from a vibrating structure. Numerical models of a baffled plate, a cylinder and an engine crankcase are presented. The supersonic intensity is shown to be difficult to implement at low frequencies due to the size of the spatial radiation filter and accuracy of the surface distances. A cut-off coefficient associated with the acoustic wavenumber of the spatial radiation filter is used to reduce the aperture error. A comparison of the two intensity-based techniques both in terms of a sound power ratio and the modal assurance criterion is introduced to identify the optimal values of the cut-off coefficients that result in better convergence between the intensity techniques.
Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability
Authors: Zvezdova Ekaterina , Mikolajczak Judith , Garreau Anne , Marcellin Marlène , Rigal Lise , Lee Jan , Choi Seeyoung , Blaize Gaëtan , Argenty Jérémy , Familiades Julien , Li Liqi , Gonzalez de Peredo Anne , Burlet-Schiltz Odile , Love Paul E. , Lesourne Renaud
Published: May 2016

The protein Themis1 enables thymocyte selection by promoting T cell receptor signaling.
BTG1 ameliorates liver steatosis by decreasing stearoyl-CoA desaturase 1 (SCD1) abundance and altering hepatic lipid metabolism
Authors: Xiao Fei , Deng Jiali , Guo Yajie , Niu Yuguo , Yuan Feixiang , Yu Junjie , Chen Shanghai , Guo Feifan
Published: May 2016

A transcription cofactor alters the expression of genes involved in lipid metabolism in the liver to suppress hepatic steatosis.
Paper of note in
Science Translational Medicine
Authors: Ferrarelli Leslie K.
Published: May 2016

This week’s article describes a potential new target to boost or prevent ovulation.
Alternative splicing in development
Authors: Gough Nancy R.
Published: May 2016

Alternative splicing is critical for skeletal muscle health and glutamatergic synaptic function.
Cancerous splice variants
Authors: Gough Nancy R.
Published: May 2016

Alternative splicing drives metabolic changes in cancer and enables metastasis.
Glia dictate neuronal morphology
Authors: Wong Wei
Published: May 2016

Increased extracellular chloride concentration mediated by a glial cell prevents a neuronal ending from forming microvilli.
In Vivo
Rectal Mucosal Barrier Function Imaging in a Large-Animal Model by Using Confocal Endomicroscopy: Implications for Injury Assessment and Use in HIV Prevention Studies
Authors: Vargas Gracie , Vincent Kathleen Listiak , Zhu Yong , Szafron David , Brown Tyra Caitlin , Villarreal Paula Patricia , Bourne Nigel , Milligan Gregg N. , Motamedi Massoud
Published: May 2016

Injury occurring on the surface of the rectal mucosal lining that causes defects in barrier function may result in increased risk for transmission of infection by HIV and other pathogens. Such injury could occur from microbicidal or other topical agents, mechanical trauma during consensual or nonconsensual intercourse, or inflammatory conditions. Tools for evaluation of rectal mucosal barrier function for assessing the mucosa under these conditions are lacking, particularly those that can provide
in vivo
structural and functional barrier integrity assessment and are adaptable to longitudinal imaging. We investigated confocal endomicroscopy (CE) as a means for
in vivo
imaging of the rectal epithelial barrier in the ovine model following spatially confined injury to the surface at a controlled site using a topical application of the microbicide test agent benzalkonium chloride. Topical and intravenous (i.v.) fluorescent probes were used with CE to provide subcellular resolution imaging of the mucosal surface and assessment of barrier function loss. A 3-point CE grading system based on cellular structure integrity and leakage of dye through the mucosa showed significant differences in score between untreated (1.19 ± 0.53) and treated (2.55 ± 0.75) tissue (
P
< 0.0001). Histological grading confirmed findings of barrier compromise. The results indicate that CE is an effective means for detecting epithelial injury and barrier loss following localized trauma in a large-animal model. CE is promising for real-time rectal mucosal evaluation after injury or trauma or topical application of emerging biomedical prevention strategies designed to combat HIV.
Prospective Study of Plasmodium vivax Malaria Recurrence after Radical Treatment with a Chloroquine-Primaquine Standard Regimen in Turbo, Colombia
Authors: Zuluaga-Idárraga Lina , Blair Silvia , Akinyi Okoth Sheila , Udhayakumar Venkatachalam , Marcet Paula L. , Escalante Ananias A. , Alexander Neal , Rojas Carlos
Published: May 2016

Plasmodium vivax
recurrences help maintain malaria transmission. They are caused by recrudescence, reinfection, or relapse, which are not easily differentiated. A longitudinal observational study took place in Turbo municipality, Colombia. Participants with uncomplicated
P. vivax
infection received supervised treatment concomitantly with 25 mg/kg chloroquine and 0.25 mg/kg/day primaquine for 14 days. Incidence of recurrence was assessed over 180 days. Samples were genotyped, and origins of recurrences were established. A total of 134 participants were enrolled between February 2012 and July 2013, and 87 were followed for 180 days, during which 29 recurrences were detected. The cumulative incidence of first recurrence was 24.1% (21/87) (95% confidence interval [CI], 14.6 to 33.7%), and 86% (18/21) of these events occurred between days 51 and 110. High genetic diversity of
P. vivax
strains was found, and 12.5% (16/128) of the infections were polyclonal. Among detected recurrences, 93.1% (27/29) of strains were genotyped as genetically identical to the strain from the previous infection episode, and 65.5% (19/29) of infections were classified as relapses. Our results indicate that there is a high incidence of
P. vivax
malaria recurrence after treatment in Turbo municipality, Colombia, and that a large majority of these episodes are likely relapses from the previous infection. We attribute this to the primaquine regimen currently used in Colombia, which may be insufficient to eliminate hypnozoites.
Discovery of a Broad-Spectrum Antiviral Compound That Inhibits Pyrimidine Biosynthesis and Establishes a Type 1 Interferon-Independent Antiviral State
Authors: Chung Dong-Hoon , Golden Jennifer E. , Adcock Robert S. , Schroeder Chad E. , Chu Yong-Kyu , Sotsky Julie B. , Cramer Daniel E. , Chilton Paula M. , Song Chisu , Anantpadma Manu , Davey Robert A. , Prodhan Aminul I. , Yin Xinmin , Zhang Xiang
Published: May 2016

Viral emergence and reemergence underscore the importance of developing efficacious, broad-spectrum antivirals. Here, we report the discovery of tetrahydrobenzothiazole-based compound 1, a novel, broad-spectrum antiviral lead that was optimized from a hit compound derived from a cytopathic effect (CPE)-based antiviral screen using Venezuelan equine encephalitis virus. Compound 1 showed antiviral activity against a broad range of RNA viruses, including alphaviruses, flaviviruses, influenza virus, and ebolavirus. Mechanism-of-action studies with metabolomics and molecular approaches revealed that the compound inhibits host pyrimidine synthesis and establishes an antiviral state by inducing a variety of interferon-stimulated genes (ISGs). Notably, the induction of the ISGs by compound 1 was independent of the production of type 1 interferons. The antiviral activity of compound 1 was cell type dependent with a robust effect observed in human cell lines and no observed antiviral effect in mouse cell lines. Herein, we disclose tetrahydrobenzothiazole compound 1 as a novel lead for the development of a broad-spectrum, antiviral therapeutic and as a molecular probe to study the mechanism of the induction of ISGs that are independent of type 1 interferons.
Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years
Authors: Bourguignon Laurent , Cazaubon Yoann , Debeurme Guillaume , Loue Constance , Ducher Michel , Goutelle Sylvain
Published: May 2016

Since the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus
. Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (± standard deviations) of vancomycin volume of distribution and clearance were 36.3 ± 15.2 liter and 2.0 ± 0.9 liter/h, respectively. In the validation group, the bias and precision were −0.75 mg/liter and 8.76 mg/liter for population predictions and −0.39 mg/liter and 2.68 mg/liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin.
Isolation and Characterization of Escherichia coli Sequence Type 131 and Other Antimicrobial-Resistant Gram-Negative Bacilli from Clinical Stool Samples from Veterans
Authors: Mohamed Muhanad , Clabots Connie , Porter Stephen B. , Thuras Paul , Johnson James R.
Published: May 2016

Emerging multidrug-resistant (MDR) Gram-negative bacilli (GNB), including
Escherichia coli
sequence type 131 (ST131) and its resistance-associated
H
30 subclone, constitute an ever-growing public health threat. Their reservoirs and transmission pathways are incompletely defined. To assess diarrheal stools as a potential reservoir for ST131-
H
30 and other MDR GNB, we cultured 100 clinical stool samples from a Veterans Affairs Medical Center clinical laboratory (October to December 2011) for fluoroquinolone- and extended-spectrum cephalosporin (ESC)-resistant
E. coli
and other GNB, plus total
E. coli
. We then characterized selected resistant and susceptible
E. coli
isolates by clonal group, phylogenetic group, virulence genotype, and pulsotype and screened all isolates for antimicrobial resistance. Overall, 79 of 100 stool samples yielded GNB (52
E. coli
; 48 other GNB). Fifteen samples yielded fluoroquinolone-resistant
E. coli
(10 were ST131, of which 9 were
H
30), 6 yielded ESC-resistant
E. coli
(2 were ST131, both non-
H
30), and 31 yielded susceptible
E. coli
(1 was ST131, non-
H
30), for 13 total ST131-positive samples. Fourteen non-
E. coli
GNB were ESC resistant, and three were fluoroquinolone resistant. Regardless of species, almost half (46%) of the fluoroquinolone-resistant and/or ESC-resistant non-
E. coli
GNB were resistant to at least three drug classes. Fecal ST131 isolates closely resembled reference clinical ST131 isolates according to virulence genotypes and pulsed-field gel electrophoresis (PFGE) profiles. Thus, a substantial minority (30%) of veterans with diarrhea who undergo stool testing excrete antibiotic-resistant GNB, including
E. coli
ST131. Consequently, diarrhea may pose transmission risks for more than just diarrheal pathogens and may help disseminate clinically relevant ST131 strains and other MDR GNB within hospitals and the community.
Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)
Authors: Kovanda Laura L. , Desai Amit V. , Lu Qiaoyang , Townsend Robert W. , Akhtar Shahzad , Bonate Peter , Hope William W.
Published: May 2016

Isavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (
n
= 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 for
Aspergillus
spp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 for
Candida albicans
(up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-
albicans Candida
spp. (up to a MIC of 0.125 mg/liter). The estimations for
Candida
spp. were exploratory considering that no patients with
Candida
infections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.)
Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients
Authors: Alobaid Abdulaziz S. , Wallis Steven C. , Jarrett Paul , Starr Therese , Stuart Janine , Lassig-Smith Melissa , Ordóñez Mejia Jenny Lisette , Roberts Michael S. , Lipman Jeffrey , Roberts Jason A.
Published: May 2016

Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial plasma samples were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m2, respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h; volume of distribution in the central compartment (V1), 11.7 ± 5.8 liters; intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h−1; and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h−1. Higher creatinine clearance (CLCR) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increasedV1, dose adjustment based on CLCRappears to be more important than patient BMI.
Pharmacokinetics of Tedizolid in Morbidly Obese and Covariate-Matched Nonobese Adults
Authors: Pai Manjunath P.
Published: May 2016

Tedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of ≥40 kg/m
2
) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m
2
) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma (
C
max
) and area under the concentration-time curve from 0 h to infinity (AUC
0–∞
) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different (
P
≥ 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution (

V
z

) (
P
= 0.110) and clearance (CL) values (
P
= 0.214) were comparable between groups. Nearly identical (
P
= 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid

V
z

and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC
0–∞
values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.)
Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses
In Vitro
and against Human Metapneumovirus in Hamsters
Authors: Jochmans D. , van Nieuwkoop S. , Smits S. L. , Neyts J. , Fouchier R. A. M. , van den Hoogen B. G.
Published: May 2016

The clinical impact of infections with respiratory viruses belonging to the family
Paramyxoviridae
argues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstrate
in vitro
activity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses tested
in vitro
, with 90% effective concentration (EC
90
) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses.
Mutations in
pepQ
Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis
Authors: Almeida Deepak , Ioerger Thomas , Tyagi Sandeep , Li Si-Yang , Mdluli Khisimuzi , Andries Koen , Grosset Jacques , Sacchettini Jim , Nuermberger Eric
Published: May 2016

The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in
Rv0678
that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance in
Mycobacterium tuberculosis
: loss-of-function mutations in
pepQ
(
Rv2535c
), which corresponds to a putative Xaa-Pro aminopeptidase.
pepQ
mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of
Rv0678
,
mmpS5
, or
mmpL5
between mutant and parent strains. Complementation of a
pepQ
mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both
in vitro
and in mice. Although the mechanism by which mutations in
pepQ
confer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.
Absence of Association between Polymorphisms in the RING E3 Ubiquitin Protein Ligase Gene and
Ex Vivo
Susceptibility to Conventional Antimalarial Drugs in Plasmodium falciparum Isolates from Dakar, Senegal
Authors: Gendrot Mathieu , Fall Bécaye , Madamet Marylin , Fall Mansour , Wade Khalifa Ababacar , Amalvict Rémy , Nakoulima Aminata , Benoit Nicolas , Diawara Silman , Diémé Yaya , Diatta Bakary , Wade Boubacar , Pradines Bruno
Published: May 2016

The RING E3 ubiquitin protein ligase is crucial for facilitating the transfer of ubiquitin. The only polymorphism identified in the E3 ubiquitin protein ligase gene was the D113N mutation (62.5%) but was not significantly associated with the 50% inhibitory concentration (IC
50
) of conventional antimalarial drugs. However, some mutated isolates (D113N) present a trend of reduced susceptibility to piperaquine (
P
= 0.0938). To evaluate the association of D113N polymorphism with susceptibility to antimalarials, more isolates are necessary.
Clustered Intracellular Salmonella enterica Serovar Typhimurium Blocks Host Cell Cytokinesis
Authors: Santos António J. M. , Durkin Charlotte H. , Helaine Sophie , Boucrot Emmanuel , Holden David W.
Published: May 2016

Several bacterial pathogens and viruses interfere with the cell cycle of their host cells to enhance virulence. This is especially apparent in bacteria that colonize the gut epithelium, where inhibition of the cell cycle of infected cells enhances the intestinal colonization. We found that intracellular
Salmonella enterica
serovar Typhimurium induced the binucleation of a large proportion of epithelial cells by 14 h postinvasion and that the effect was dependent on an intact
Salmonella
pathogenicity island 2 (SPI-2) type 3 secretion system. The SPI-2 effectors SseF and SseG were required to induce binucleation. SseF and SseG are known to maintain microcolonies of
Salmonella-
containing vacuoles close to the microtubule organizing center of infected epithelial cells. During host cell division, these clustered microcolonies prevented the correct localization of members of the chromosomal passenger complex and mitotic kinesin-like protein 1 and consequently prevented cytokinesis. Tetraploidy, arising from a cytokinesis defect, is known to have a deleterious effect on subsequent cell divisions, resulting in either chromosomal instabilities or cell cycle arrest. In infected mice, proliferation of small intestinal epithelial cells was compromised in an SseF/SseG-dependent manner, suggesting that cytokinesis failure caused by
S
. Typhimurium delays epithelial cell turnover in the intestine.
Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity
Authors: Hill Danika L. , Wilson Danny W. , Sampaio Natalia G. , Eriksson Emily M. , Ryg-Cornejo Victoria , Harrison G. L. Abby , Uboldi Alessandro D. , Robinson Leanne J. , Beeson James G. , Siba Peter , Cowman Alan F. , Hansen Diana S. , Mueller Ivo , Schofield Louis
Published: May 2016

It is unclear whether naturally acquired immunity to
Plasmodium falciparum
results from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasma-matched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, or
P. falciparum
MSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.
Use of Attenuated but Metabolically Competent Salmonella as a Probiotic To Prevent or Treat Salmonella Infection
Authors: Sabag-Daigle Anice , Blunk Henry M. , Gonzalez Juan F. , Steidley Brandi L. , Boyaka Prosper N. , Ahmer Brian M. M.
Published: May 2016

Salmonella enterica
is among the most burdensome of foodborne disease agents. There are over 2,600 serovars that cause a range of disease manifestations ranging from enterocolitis to typhoid fever. While there are two vaccines in use in humans to protect against typhoid fever, there are none that prevent enterocolitis. If vaccines preventing enterocolitis were to be developed, they would likely protect against only one or a few serovars. In this report, we tested the hypothesis that probiotic organisms could compete for the preferred nutrient sources of
Salmonella
and thus prevent or treat infection. To this end, we added the
fra
locus, which encodes a utilization pathway for the
Salmonella
-specific nutrient source fructose-asparagine (F-Asn), to the probiotic bacterium
Escherichia coli
Nissle 1917 (Nissle) to increase its ability to compete with
Salmonella
in mouse models. We also tested a metabolically competent, but avirulent,
Salmonella enterica
serovar Typhimurium mutant for its ability to compete with wild-type
Salmonella
. The modified Nissle strain became more virulent and less able to protect against
Salmonella
in some instances. On the other hand, the modified
Salmonella
strain was safe and effective in preventing infection with wild-type
Salmonella
. While we tested for efficacy only against
Salmonella
Typhimurium, the modified
Salmonella
strain may be able to compete metabolically with most, if not all,
Salmonella
serovars, representing a novel approach to control of this pathogen.
Identification of a Lipoteichoic Acid Glycosyltransferase Enzyme Reveals that GW-Domain-Containing Proteins Can Be Retained in the Cell Wall of Listeria monocytogenes in the Absence of Lipoteichoic Acid or Its Modifications
Authors: Percy Matthew G. , Karinou Eleni , Webb Alexander J. , Gründling Angelika
Published: May 2016

Listeria monocytogenes
is a foodborne Gram-positive bacterial pathogen, and many of its virulence factors are either secreted proteins or proteins covalently or noncovalently attached to the cell wall. Previous work has indicated that noncovalently attached proteins with GW (glycine-tryptophan) domains are retained in the cell wall by binding to the cell wall polymer lipoteichoic acid (LTA). LTA is a glycerol phosphate polymer, which is modified in
L. monocytogenes
with galactose and
d
-alanine residues. We identified Lmo0933 as the cytoplasmic glycosyltransferase required for the LTA glycosylation process and renamed the protein GtlA, for
g
lycosyl
t
ransferase
L
TA
A
. Using
L. monocytogenes
mutants lacking galactose or
d
-alanine modifications or the complete LTA polymer, we show that GW domain proteins are retained within the cell wall, indicating that other cell wall polymers are involved in the retention of GW domain proteins. Further experiments revealed peptidoglycan as the binding receptor as a purified GW domain fusion protein can bind to
L. monocytogenes
cells lacking wall teichoic acid (WTA) as well as purified peptidoglycan derived from a wild-type or WTA-negative strain. With this, we not only identify the first enzyme involved in the LTA glycosylation process, but we also provide new insight into the binding mechanism of noncovalently attached cell wall proteins.

IMPORTANCE
Over the past 20 years, a large number of bacterial genome sequences have become available. Computational approaches are used for the genome annotation and identification of genes and encoded proteins. However, the function of many proteins is still unknown and often cannot be predicted bioinformatically. Here, we show that the previously uncharacterized
Listeria monocytogenes
gene
lmo0933
likely codes for a glycosyltransferase required for the decoration of the cell wall polymer lipoteichoic acid (LTA) with galactose residues. Using
L. monocytogenes
mutants lacking LTA modifications or the complete polymer, we show that specific cell wall proteins, often associated with virulence, are retained within the cell wall, indicating that additional cell wall polymers are involved in their retention.
Pseudomonas aeruginosa AmrZ Binds to Four Sites in the
algD
Promoter, Inducing DNA-AmrZ Complex Formation and Transcriptional Activation
Authors: Xu Binjie , Soukup Randal J. , Jones Christopher J. , Fishel Richard , Wozniak Daniel J.
Published: May 2016

During late stages of cystic fibrosis pulmonary infections,
Pseudomonas aeruginosa
often overproduces the exopolysaccharide alginate, protecting the bacterial community from host immunity and antimicrobials. The transcription of the alginate biosynthesis operon is under tight control by a number of factors, including AmrZ, the focus of this study. Interestingly, multiple transcription factors interact with the far-upstream region of this promoter (P
algD
), in which one AmrZ binding site has been identified previously. The mechanisms of AmrZ binding and subsequent activation remain unclear and require more-detailed investigation. In this study, in-depth examinations elucidated four AmrZ binding sites, and their disruption eliminated AmrZ binding and promoter activation. Furthermore, our
in vitro
fluorescence resonance energy transfer experiments suggest that AmrZ holds together multiple binding sites in P
algD
and thereafter induces the formation of higher-order DNA-AmrZ complexes. To determine the importance of interactions between those AmrZ oligomers in the cell, a DNA phasing experiment was performed. P
algD
transcription was significantly impaired when the relative phase between AmrZ binding sites was reversed (5 bp), while a full-DNA-turn insertion (10 bp) restored promoter activity. Taken together, the investigations presented here provide a deeper mechanistic understanding of AmrZ-mediated binding to P
algD
.

IMPORTANCE
Overproduction of the exopolysaccharide alginate provides protection to
Pseudomonas aeruginosa
against antimicrobial treatments and is associated with chronic
P. aeruginosa
infections in the lungs of cystic fibrosis patients. In this study, we combined a variety of microbiological, genetic, biochemical, and biophysical approaches to investigate the activation of the alginate biosynthesis operon promoter by a key transcription factor named AmrZ. This study has provided important new information on the mechanism of activation of this extremely complex promoter.
F
420
H
2
Is Required for Phthiocerol Dimycocerosate Synthesis in Mycobacteria
Authors: Purwantini Endang , Daniels Lacy , Mukhopadhyay Biswarup
Published: May 2016

Phthiocerol dimycocerosates (PDIM) are a group of cell surface-associated apolar lipids of
Mycobacterium tuberculosis
and closely related mycobacteria, such as
Mycobacterium bovis
and
Mycobacterium leprae
. A characteristic methoxy group of these lipids is generated from the methylation of a hydroxyl group of the direct precursors, the phthiotriols. The precursors arise from the reduction of phthiodiolones, the keto intermediates, by a ketoreductase. The putative phthiodiolone ketoreductase (PKR) is encoded by Rv2951c in
M. tuberculosis
and BCG_2972c in
M. bovis
BCG, and these open reading frames (ORFs) encode identical amino acid sequences. We investigated the cofactor requirement of the BCG_2972c protein. A comparative analysis based on the crystallographic structures of similar enzymes identified structural elements for binding of coenzyme F
420
and hydrophobic phthiodiolones in PKR. Coenzyme F
420
is a deazaflavin coenzyme that serves several key functions in pathogenic and nonpathogenic mycobacteria. We found that an
M. bovis
BCG mutant lacking F
420
-dependent glucose-6-phosphate dehydrogenase (Fgd), which generates F
420
H
2
(glucose-6-phosphate + F
420
→ 6-phosphogluconate + F
420
H
2
), was devoid of phthiocerols and accumulated phthiodiolones. When the mutant was provided with F
420
H
2
, a broken-cell slurry of the mutant converted accumulated phthiodiolones to phthiocerols; F
420
H
2
was generated
in situ
from F
420
and glucose-6-phosphate by the action of Fgd. Thus, the reaction mixture was competent in reducing phthiodiolones to phthiotriols (phthiodiolones + F
420
H
2
→ phthiotriols + F
420
), which were then methylated to phthiocerols. These results established the mycobacterial
p
hthiodiolone
k
eto
r
eductase as an
F
420
H
2
-dependent enzyme (fPKR). A phylogenetic analysis of close homologs of fPKR revealed potential F
420
-dependent lipid-modifying enzymes in a broad range of mycobacteria.

IMPORTANCE
Mycobacterium tuberculosis
is the causative agent of tuberculosis, and phthiocerol dimycocerosates (PDIM) protect this pathogen from the early innate immune response of an infected host. Thus, the PDIM synthesis system is a potential target for the development of effective treatments for tuberculosis. The current study shows that a PDIM synthesis enzyme is dependent on the coenzyme F
420
. F
420
is universally present in mycobacteria and absent in humans. This finding expands the number of experimentally validated F
420
-dependent enzymes in
M. tuberculosis
to six, each of which helps the pathogen to evade killing by the host immune system, and one of which activates an antituberculosis drug, PA-824. This work also has relevance to leprosy, since similar waxy lipids are found in
Mycobacterium leprae
.