bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endobronchial ultrasound‐guided transbronchial needle aspiration: Safe as it sounds
Authors: Vaidya Preyas J. , Munavvar Mohammed , Leuppi Joerg D. , Mehta Atul C. , Chhajed Prashant N. 
Published: June 2017

ABSTRACTReal‐time endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) has earned its place as a standard of care in the evaluation of mediastinal and hilar lymphadenopathy. It is a minimally invasive and a safe procedure with high diagnostic accuracy and efficacy. The increased usage of EBUS‐TBNA worldwide has thrown light on its possible complications including death. The complications range from minor to life threatening in few and may occur either early or later in the course after the procedure. The present review summarizes the reported complications from EBUS‐TBNA, their outcome and the modalities used for their management.
Product and process innovation and total factor productivity: Evidence for manufacturing in four Latin American countries
Authors: Demmel M. Constanza , Máñez Juan A. , Rochina‐Barrachina María E. , Sanchis‐Llopis Juan A. 
Published: June 2017

AbstractThe literature on firm productivity recognizes the important role played by firm innovation activities on firm productivity in developed countries. However, the literature for developing and emerging economies is scarce and far from conclusive. The aim of this paper is to study the innovation–productivity link (distinguishing between process and product innovations) for manufacturing at the firm level for four Latin American countries (two classified as upper‐middle income countries by the World Bank—Argentina and Mexico—and two as lower‐middle income—Colombia and Peru). We aim testing whether the level of development is a mediating factor in the innovation–productivity link. The data used have been drawn from the World Bank panel enterprise surveys, for 2006 and 2010. First, we estimate total factor productivity (TFP) and, second, we use the estimated TFP as a regressor or as dependent variable, in two models for testing self‐selection of the most productive firms into innovation or the existence of returns to innovation in terms of productivity. Our results confirm the mediating role of the level of development in the innovation–productivity link: both the self‐selection and the returns‐to‐innovation hypotheses work only for the upper‐middle income countries.
Skewed Invariant Natural Killer T (iNKT) Cells, Impaired iNKT:B Cell Help and Decreased SAP Expression in Blood Lymphocytes from Patients with Common Variable Immunodeficiency
Authors: Erazo‐Borrás L. V. , Álvarez‐Álvarez J. A. , Perez‐Romero C. A. , Orrego‐Arango J. C. , Franco‐Restrepo J. L. , Trujillo‐Vargas C. M. 
Published: June 2017

AbstractCommon variable immunodeficiency (CVID) is a syndrome with predominantly defective B cell function. However, abnormalities in the number and function of other lymphocyte subpopulations in peripheral blood (PB) have been described in most patients. We have analysed the distribution of iNKT cell subpopulations in the PB of CVID patients and the ability of these cells to provide in vitro cognate B cell help. The total of iNKT cells was reduced in the PB of CVID patients, especially CD4+, CD4‐/CD8‐ and CCR5+/CXCR3+. These findings were associated with an enrichment of memory‐like and a tendency towards a reduction in TNF‐α‐expressing effector iNKT cells in the peripheral blood mononuclear cells (PBMC) of CVID patients. Moreover, an accumulation of follicular helper iNKT cells in the PB of CVID patients was demonstrated. CVID αGalCer‐pulsed iNKT cells are not able to induce autologous B cell proliferation although they do induce proliferation to healthy donor B cells. Interestingly, autologous and heterologous co‐cultures did not differ in the amount of immunoglobulin secreted by B cells in vitro. Finally, reduced intracellular SAP expression in iNKT cells and other lymphocytes in the blood from CVID patients was observed. These results provide further insights into the immunological mechanisms underlying the iNKT cell defects and the potential targets to improve B cell help in CVID.
Maximum Likelihood Estimators in Regression Models for Error‐prone Group Testing Data
Authors: Huang Xianzheng , Sarker Warasi Md Shamim 
Published: June 2017

AbstractSince Dorfman's seminal work on the subject, group testing has been widely adopted in epidemiological studies. In Dorfman's context of detecting syphilis, group testing entails pooling blood samples and testing the pools, as opposed to testing individual samples. A negative pool indicates all individuals in the pool free of syphilis antigen, whereas a positive pool suggests one or more individuals carry the antigen. With covariate information collected, researchers have considered regression models that allow one to estimate covariate‐adjusted disease probability. We study maximum likelihood estimators of covariate effects in these regression models when the group testing response is prone to error. We show that, when compared with inference drawn from individual testing data, inference based on group testing data can be more resilient to response misclassification in terms of bias and efficiency. We provide valuable guidance on designing the group composition to alleviate adverse effects of misclassification on statistical inference.
Towards a cultural geopolitics: on the making of a documentary-poetry film about a post-conflict place
Authors: Riding James , Wake-Walker Jack 
Published: June 2017

Made in collaboration with an independent filmmaker and two poets, the documentary-poetry film Bridges <Bosnia 20> presents life in post-conflict Bosnia-Herzegovina, and delivers a clear message: the war in Bosnia is not yet firmly located in the past. Shot through a computer screen, Bridges <Bosnia 20> forces the viewer to witness the war in Bosnia and its aftermath via-the-gaze of an unknown spectator, sitting on an Apple Mac laptop. Through this modern technological distancing, we re-present here images of war in a digital age, question how war is usually packaged and represented on television, and in turn interrogate, through poetry, how war is traditionally remembered and memorialised. In so doing, Bridges <Bosnia 20> leads us to a conclusion, in Srebrenica, in 2015: in order to invest in the possibility of a just future after conflict, it is necessary to acknowledge the unthinkable realities to which traumatic experience bears witness.
Watch the film Bridges <Bosnia 20> here and visit the Bridges <Bosnia 20> website for more information
In Vivo
Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice
Authors: Kimura Genki , Nakaoki Takahiro , Colley Thomas , Rapeport Garth , Strong Pete , Ito Kazuhiro , Kizawa Yasuo 
Published: June 2017

ABSTRACT

PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on
Aspergillus fumigatus
infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with
A. fumigatus
, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days −7 to +3 or days −7 to 0) were also compared with those of the shorter treatment regimens (days −1 to +3 or days −1 and 0). Early and late interventions with PC945 (2.8 to 350 μg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-γ], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-α] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 μg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of
A. fumigatus
infection in humans.
Antibiotic Resistance as a Stress Response: Recovery of High-Level Oxacillin Resistance in Methicillin-Resistant Staphylococcus aureus “Auxiliary” (
fem
) Mutants by Induction of the Stringent Stress Response
Authors: Kim Choon Keun , Milheiriço Catarina , de Lencastre Hermínia , Tomasz Alexander 
Published: June 2017

ABSTRACT

Studies with methicillin-resistant
Staphylococcus aureus
(MRSA) strain COL have shown that the optimal resistance phenotype requires not only
mecA
but also a large number of “auxiliary genes” identified by Tn
551
mutagenesis. The majority of auxiliary mutants showed greatly increased levels of oxacillin resistance when grown in the presence of sub-MICs of mupirocin, suggesting that the mechanism of reduced resistance in the auxiliary mutants involved the interruption of a stringent stress response, causing reduced production of penicillin-binding protein 2A (PBP 2A).
Pharmacodynamics and Biodistribution of Single-Dose Liposomal Amphotericin B at Different Stages of Experimental Visceral Leishmaniasis
Authors: Voak Andrew A. , Harris Andy , Qaiser Zeeshan , Croft Simon L. , Seifert Karin 
Published: June 2017

ABSTRACT

Visceral leishmaniasis is a neglected tropical disease that causes significant morbidity and mortality worldwide. Characterization of the pharmacokinetics and pharmacodynamics of antileishmanial drugs in preclinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of liposomal amphotericin B (AmBisome) in
Leishmania donovani
-infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver, and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome, >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 h and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome was administered at the advanced stage of infection and compared to those in uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to
L. donovani
-infected livers and spleens. Taken together, our data suggest that organ enlargement and other pathophysiological factors cause infection- and organ-specific drug distribution and elimination after administration of single-dose AmBisome to
L. donovani
-infected mice. Plasma drug levels were not reflective of changes in drug levels in tissues.
Genomewide Analysis of the Antimicrobial Peptides in Python bivittatus and Characterization of Cathelicidins with Potent Antimicrobial Activity and Low Cytotoxicity
Authors: Kim Dayeong , Soundrarajan Nagasundarapandian , Lee Juyeon , Cho Hye-sun , Choi Minkyeung , Cha Se-Yeoun , Ahn Byeongyong , Jeon Hyoim , Le Minh Thong , Song Hyuk , Kim Jin-Hoi , Park Chankyu 
Published: June 2017

ABSTRACT

In this study, we sought to identify novel antimicrobial peptides (AMPs) in
Python bivittatus
through bioinformatic analyses of publicly available genome information and experimental validation. In our analysis of the python genome, we identified 29 AMP-related candidate sequences. Of these, we selected five cathelicidin-like sequences and subjected them to further
in silico
analyses. The results showed that these sequences likely have antimicrobial activity. The sequences were named Pb-CATH1 to Pb-CATH5 according to their sequence similarity to previously reported snake cathelicidins. We predicted their molecular structure and then chemically synthesized the mature peptide for three putative cathelicidins and subjected them to biological activity tests. Interestingly, all three peptides showed potent antimicrobial effects against Gram-negative bacteria but very weak activity against Gram-positive bacteria. Remarkably, ΔPb-CATH4 showed potent activity against antibiotic-resistant clinical isolates and also was observed to possess very low hemolytic activity and cytotoxicity. ΔPb-CATH4 also showed considerable serum stability. Electron microscopic analysis indicated that ΔPb-CATH4 exerts its effects via toroidal pore preformation. Structural comparison of the cathelicidins identified in this study to previously reported ones revealed that these Pb-CATHs are representatives of a new group of reptilian cathelicidins lacking the acidic connecting domain. Furthermore, Pb-CATH4 possesses a completely different mature peptide sequence from those of previously described reptilian cathelicidins. These new AMPs may be candidates for the development of alternatives to or complements of antibiotics to control multidrug-resistant pathogens.
Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Immunocompetent-Rat Respiratory Tract Infection Models Recreating Human Plasma Pharmacokinetics
Authors: Matsumoto Shuhei , Singley Christine M. , Hoover Jennifer , Nakamura Rio , Echols Roger , Rittenhouse Stephen , Tsuji Masakatsu , Yamano Yoshinori 
Published: June 2017

ABSTRACT

Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In this study, we evaluated the efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli (
Pseudomonas aeruginosa
,
Acinetobacter baumannii
, and
Klebsiella pneumoniae
) in immunocompetent-rat respiratory tract infection models recreating plasma pharmacokinetics (PK) profiles in healthy human subjects. A total of 6 clinical isolates (1 cephalosporin-susceptible
P. aeruginosa
isolate, 1 multidrug-resistant
P. aeruginosa
isolate, 2 multidrug-resistant
A. baumannii
isolates, and 2 carbapenem-resistant
K. pneumoniae
isolates) were evaluated. Four-day treatment with a human exposure of 1 g ceftazidime every 8 h as a 0.5-h infusion showed potent efficacy only against a ceftazidime-susceptible isolate, not against five ceftazidime-resistant isolates harboring carbapenemase. With cefiderocol, a human exposure of 2 g every 8 h as a 3-h infusion for 4 days produced a >3 log
10
reduction in the number of viable cells of these carbapenem-resistant isolates in the lungs. When the infusion time was 1 h, bactericidal activity was also observed against all isolates tested, although for 2 of 5 carbapenem-resistant isolates, a 3 log
10
reduction was not achieved. The difference in efficacy achieved by changing the infusion period from 1 h to 3 h was considered to be due to the higher percentage of the dosing interval during which free-drug concentrations were above the MIC (%
fT
MIC
), as observed for β-lactam antibiotics. These results suggest the potential utility of cefiderocol for the treatment of lung infections caused by carbapenem-resistant
P. aeruginosa
,
A. baumannii
, and
K. pneumoniae
strains.
De Novo
Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance
Authors: Jiménez-Ortigosa Cristina , Perez Winder B. , Angulo David , Borroto-Esoda Katyna , Perlin David S. 
Published: June 2017

ABSTRACT

SCY-078 is an orally active antifungal whose target is the β-(1,3)-
d
-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant
Candida glabrata
isolates following drug exposure
in vitro
. Resistant isolates were analyzed using broth microdilution methodology and
FKS
sequencing. The kinetic inhibition parameter IC
50
(50% inhibitory concentration) was also determined from GS complexes. The spectrum of resistance mutations found suggested a partially overlapping but independent binding site for SCY-078 relative to echinocandins on GS.
Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa
Authors: Liebens Veerle , Defraine Valerie , Knapen Wouter , Swings Toon , Beullens Serge , Corbau Romu , Marchand Arnaud , Chaltin Patrick , Fauvart Maarten , Michiels Jan 
Published: June 2017

ABSTRACT

Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on
Pseudomonas aeruginosa
, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (
Enterococcus faecium
,
Staphylococcus aureus
,
Klebsiella pneumoniae
,
Acinetobacter baumannii
,
Pseudomonas aeruginosa
, and
Enterobacter
species) and, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of
P. aeruginosa
infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a small-molecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of
P. aeruginosa
persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 10
6
-fold in both lab strains and clinical isolates of
P. aeruginosa
. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against
P. aeruginosa
with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.
Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers
Authors: Jain Jay Prakash , Leong F. Joel , Chen Lan , Kalluri Sampath , Koradia Vishal , Stein Daniel S. , Wolf Marie-Christine , Sunkara Gangadhar , Kota Jagannath 
Published: June 2017

ABSTRACTThe artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2.
Antimicrobial Susceptibility Trends among Staphylococcus aureus Isolates from U.S. Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program, 2010 to 2016
Authors: Sader Helio S. , Mendes Rodrigo E. , Streit Jennifer M. , Flamm Robert K. 
Published: June 2017

ABSTRACT

We evaluated trends in
Staphylococcus aureus
antimicrobial susceptibility in U.S. hospitals in the 2010–2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. Methicillin-resistant
S. aureus
(MRSA) rates decreased from 50.0% (in 2010) to 42.2% (in 2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim-sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against methicillin-susceptible
S. aureus
(MSSA) and MRSA (97.2% susceptible) with no marked variations.
Biodistribution and
In Vivo
Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl-
sn
-Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B
Authors: Iman Maryam , Huang Zhaohua , Alavizadeh Seyedeh Hoda , Szoka Francis C. , Jaafari Mahmoud R. 
Published: June 2017

ABSTRACT

1,2-Distigmasterylhemisuccinoyl-
sn
-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and
in vitro
antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in
Leishmania major
-infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in
L. major
-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (
P
< 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (
P
< 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The
in vivo
activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.