bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of signature volatiles to discriminate Candida albicans, glabrata, krusei and tropicalis using gas chromatography and mass spectrometry
Authors: Hertel Moritz , Hartwig Stefan , Schütte Eyke , Gillissen Bernhard , Preissner Robert , Schmidt‐Westhausen Andrea Maria , Paris Sebastian , Kastner Isabell , Preissner Saskia 
Published: December 2015

SummaryOral candidiasis is the most frequent fungal infection of the oral cavity. Clinical diagnoses require mycological confirmation, which is time‐consuming in case of culture testing. The aim of the study was to identify signature volatiles to develop a chairside breath test to diagnose oral candidiasis. Headspaces above Candida albicans, glabrata, tropicalis, krusei cultures, and growth media as control were analysed after eight and 24 h using offline gas chromatography and mass spectrometry. The identification of signature volatiles was assisted using various microbial databases. Retrieved volatile patterns enabled Candida species discrimination in vitro. For C. albicans 3‐methyl‐2‐butanone and styrene and for C. krusei a combination of p‐xylene, 2‐octanone, 2‐heptanone and n‐butyl acetate were found to be specific. 1‐hexanol was found in C. tropicalis, but is emitted by a variety of other microorganisms. C. glabrata was characterised through the absence of these volatiles. The development of a breath test is a promising approach in confirming suspicions of oral candidiasis. To confirm the retrieved results in vivo, breath tests in affected and healthy subjects have to be performed.
Xpert MTB/Rif for the diagnosis of extrapulmonary tuberculosis – an experience from a tertiary care centre in South India
Authors: Suzana Shirly , Ninan Marilyn M. , Gowri Mahasampath , Venkatesh Krishnan , Rupali Priscilla , Michael Joy S. 
Published: December 2015

AbstractObjectiveThe Xpert MTB/Rif, with a detection limit of 131 CFU/ml, plays a valuable role in the diagnosis of extrapulmonary tuberculosis, both susceptible and resistant. This study aims at evaluating the Xpert MTB/Rif for the same, at a tertiary care centre in south India, assessing it against both culture and a composite gold standard (CGS).MethodsWe tested consecutive samples from patients suspected of extrapulmonary tuberculosis with Xpert MTB/Rif, evaluated its sensitivity and specificity against solid and/or liquid culture and CGS. An individual analysis of different sample types (tissue biopsies, fluids, pus, lymph node biopsies and CSF) given an adequate sample size, against both culture and CGS, was also performed.ResultsIn total, 494 samples were analysed against culture. Compared to culture, the sensitivity of Xpert MTB/Rif was 89% (95% CI 0.81–0.94) and its specificity was 74% (95% CI 0.70–0.78). When Xpert MTB/Rif was compared to the CGS, pooled sensitivity was 62% (95% CI 0.56–0.67) and specificity was 100% (95% CI 0.91–1.00).ConclusionThis assay performs better than the currently available conventional laboratory methods. The rapidity with which results are obtained is an added advantage, and its integration into a routine diagnostic protocol must be considered.
Class I and II HLA antibodies in pediatric patients with thalassemia major
Authors: Yee Marianne E. McPherson , Shah Ankoor , Anderson Alan R. , Boudreaux Jeanne , Bray Robert A. , Gebel Howard M. , Josephson Cassandra D. 
Published: December 2015

BACKGROUNDHLA alloimmunization is a potential complication of red blood cell (RBC) transfusion with detrimental consequences for future organ or hematopoietic stem cell transplantation.STUDY DESIGN AND METHODSThe study aimed to determine the prevalence and specificity of HLA antibodies among pediatric patients with thalassemia major (TM) and antibody changes over time while on leukoreduced chronic transfusion therapy. HLA antibodies were measured at two or more time points in children and young adults ages 3 to 21 years with TM. HLA Class I and II antibodies were measured by FlowPRA screening. Positive screening assays were confirmed with LabScreen single‐antigen bead assays for antibody specificity.RESULTSHLA antibodies were detected in 10 of 19 (53%) subjects: seven of 19 (37%) with HLA Class I and II antibodies, two of 19 (11%) with only HLA Class I antibodies, and one of 19 (5%) with only HLA Class II antibodies. Subjects with HLA antibodies were older (14.6 years vs. 7.1 years, p = 0.05), predominantly male (80%), and more likely to have a remote history of nonleukoreduced transfusions (p = 0.057). Median time between testing was 3.7 years. De novo HLA antibodies were detected in two of 11 patients who initially had negative panel‐reactive antibody screens, while one subject lost detection of Class II antibody. Two of seven patients with HLA antibodies had antibodies to self‐HLA.CONCLUSIONHLA antibodies have a high prevalence in TM patients and may be associated with nonleukoreduced transfusions and older age. For such patients, antibody identification will be useful if subsequent organ or stem cell transplantation is needed.
On -invariants attached to cyclic cubic number fields
Authors: Delbourgo Daniel , Chao Qin 
Published: December 2015

We describe an algorithm for finding the coefficients of $F(X)$ modulo powers of $p$, where $p\neq 2$ is a prime number and $F(X)$ is the power series associated to the zeta function of Kubota and Leopoldt. We next calculate the 5-adic and 7-adic ${\it\lambda}$-invariants attached to those cubic extensions $K/\mathbb{Q}$ with cyclic Galois group ${\mathcal{A}}_{3}$ (up to field discriminant ${<}10^{7}$), and also tabulate the class number of $K(e^{2{\it\pi}i/p})$ for $p=5$ and $p=7$. If the ${\it\lambda}$-invariant is greater than zero, we then determine all the zeros for the corresponding branches of the $p$-adic $L$-function and deduce ${\rm\Lambda}$-monogeneity for the class group tower over the cyclotomic $\mathbb{Z}_{p}$-extension of $K$.Supplementary materials are available with this article.
β-Lactamase Characterization of Gram-Negative Pathogens Recovered from Patients Enrolled in the Phase 2 Trials for Ceftazidime-Avibactam: Clinical Efficacies Analyzed against Subsets of Molecularly Characterized Isolates
Authors: Mendes Rodrigo E. , Castanheira Mariana , Gasink Leanne , Stone Gregory G. , Nichols Wright W. , Flamm Robert K. , Jones Ronald N. 
Published: December 2015

ABSTRACT

The correlation of the clinical efficacies of ceftazidime-avibactam and comparators (carbapenems) was evaluated against baseline Gram-negative isolates having characterized β-lactam resistance mechanisms from complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) phase 2 trials.
Enterobacteriaceae
displaying ceftriaxone and/or ceftazidime MICs of ≥2 μg/ml (69 isolates) and nonfermentative Gram-negative bacilli (NF-GNB [three isolates]) with ceftazidime MICs of ≥16 μg/ml were characterized for their narrow- and extended-spectrum β-lactamase (ESBL) content.
Enterobacteriaceae
(one isolate) and NF-GNB (three isolates) with imipenem/meropenem MICs of ≥2 and ≥16 μg/ml, respectively, were tested for carbapenemases. All cUTI
E. coli
had the lineage background investigated (ST131-like versus non-ST131-like). The primary efficacy endpoint was microbiological response (eradication) at test of cure (TOC) for cUTI and clinical response (inferred microbiological eradication) at TOC for cIAI. A total of 34.1% of baseline cUTI (36.4%) and cIAI (33.1%) pathogens met the MIC-based screening criteria (screen positive). All screen-positive cUTI pathogens were CTX-M-producing
E. coli
, except for one
E. cloacae
isolate with AmpC overexpression. The majority (66.7%) of screen-positive cIAI isolates produced CTX-M-type coupled with a diverse array of other β-lactamases. Similar favorable responses were observed with ceftazidime-avibactam (93.3%) and carbapenems (90.9%), when a non-ESBL
Enterobacteriaceae
isolate was recovered at the baseline visit. When an ESBL
Enterobacteriaceae
isolate was present, the favorable responses were 85.7% and 80.0% with ceftazidime-avibactam and carbapenems, respectively. Higher favorable responses were observed with ceftazidime-avibactam (75.0%) than with carbapenems (66.7%) when an ST131-like
E. coli
isolate was recovered at baseline, as when a non-ST131-like isolate was present (93.8% versus 86.7%, respectively). The efficacy of ceftazidime-avibactam was similar to that of carbapenems for treatment of cUTI and cIAI caused by ESBL organisms.
Role of the Outer Membrane and Porins in Susceptibility of β-Lactamase-Producing Enterobacteriaceae to Ceftazidime-Avibactam
Authors: Pagès Jean-Marie , Peslier Sabine , Keating Thomas A. , Lavigne Jean-Philippe , Nichols Wright W. 
Published: December 2015

ABSTRACT

This study examined the activity of the novel antimicrobial combination ceftazidime-avibactam against
Enterobacteriaceae
exhibiting different outer membrane permeability profiles, specifically with or without porins and with or without expression of the main efflux pump (AcrAB-TolC). The addition of the outer membrane permeabilizer polymyxin B nonapeptide increased the antibacterial activities of avibactam alone, ceftazidime alone, and ceftazidime-avibactam against the characterized clinical isolates of
Escherichia coli
,
Enterobacter aerogenes
, and
Klebsiella pneumoniae
. This enhancement of activities was mainly due to increased passive penetration of compounds since inhibition of efflux by the addition of phenylalanine-arginine β-naphthylamide affected the MICs minimally. OmpF (OmpK35) or OmpC (OmpK36) pores were not the major route by which avibactam crossed the outer membranes of
E. coli
and
K. pneumoniae
. In contrast, Omp35 and Omp36 allowed diffusion of avibactam across the outer membrane of
E. aerogenes
, although other diffusion channels for avibactam were also present in that species. It was clear that outer membrane permeability and outer membrane pore-forming proteins play a key role in the activity of ceftazidime-avibactam. Nevertheless, the MICs of ceftazidime-avibactam (with 4 mg/liter avibactam) against the ceftazidime-resistant clinical isolates of the three species of
Enterobacteriaceae
studied were ≤8 mg/liter, regardless of outer membrane permeability changes resulting from an absence of defined porin proteins or upregulation of efflux.
Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae
Authors: Turner Kelli L. , Cahill Bethaney K. , Dilello Sarah K. , Gutel Dedra , Brunson Debra N. , Albertí Sebastián , Ellis Terri N. 
Published: December 2015

ABSTRACTAntibiotic-resistant strains ofKlebsiella pneumoniaeoften exhibit porin loss. In this study, we investigated how porin loss impacted the composition of secreted outer membrane vesicles as well as their ability to trigger proinflammatory cytokine secretion by macrophages. We hypothesize that porin loss associated with antibiotic resistance will directly impact both the composition of outer membrane vesicles and their interactions with phagocytic cells. Using clonally related clinical isolates of extended-spectrum beta-lactamase (ESBL)-positiveKlebsiella pneumoniaewith different patterns of porin expression, we demonstrated that altered expression of OmpK35 and OmpK36 results in broad alterations to the protein profile of secreted vesicles. Additionally, the level of OmpA incorporation was elevated in strains lacking a single porin. Porin loss significantly impacted macrophage inflammatory responses to purified vesicles. Outer membrane vesicles lacking both OmpK35 and OmpK36 elicited significantly lower levels of proinflammatory cytokine secretion than vesicles from strains expressing one or both porins. These data demonstrate that antibiotic resistance-associated porin loss has a broad and significant effect on both the composition of outer membrane vesicles and their interactions with phagocytic cells, which may impact bacterial survival and inflammatory reactions in the host.
Stearylamine Liposomal Delivery of Monensin in Combination with Free Artemisinin Eliminates Blood Stages of Plasmodium falciparum in Culture and P. berghei Infection in Murine Malaria
Authors: Rajendran Vinoth , Rohra Shilpa , Raza Mohsin , Hasan Gulam Mustafa , Dutt Suparna , Ghosh Prahlad C. 
Published: December 2015

ABSTRACT

The global emergence of drug resistance in malaria is impeding the therapeutic efficacy of existing antimalarial drugs. Therefore, there is a critical need to develop an efficient drug delivery system to circumvent drug resistance. The anticoccidial drug monensin, a carboxylic ionophore, has been shown to have antimalarial properties. Here, we developed a liposome-based drug delivery of monensin and evaluated its antimalarial activity in lipid formulations of soya phosphatidylcholine (SPC) cholesterol (Chol) containing either stearylamine (SA) or phosphatidic acid (PA) and different densities of distearoyl phosphatidylethanolamine-methoxy-polyethylene glycol 2000 (DSPE-mPEG-2000). These formulations were found to be more effective than a comparable dose of free monensin in
Plasmodium falciparum
(3D7) cultures and established mice models of
Plasmodium berghei
strains NK65 and ANKA. Parasite killing was determined by a radiolabeled [
3
H]hypoxanthine incorporation assay (
in vitro
) and microscopic counting of Giemsa-stained infected erythrocytes (
in vivo
). The enhancement of antimalarial activity was dependent on the liposomal lipid composition and preferential uptake by infected red blood cells (RBCs). The antiplasmodial activity of monensin in SA liposome (50% inhibitory concentration [IC
50
], 0.74 nM) and SPC:Chol-liposome with 5 mol% DSPE-mPEG 2000 (IC
50
, 0.39 nM) was superior to that of free monensin (IC
50
, 3.17 nM), without causing hemolysis of erythrocytes. Liposomes exhibited a spherical shape, with sizes ranging from 90 to 120 nm, as measured by dynamic light scattering and high-resolution electron microscopy. Monensin in long-circulating liposomes of stearylamine with 5 mol% DSPE-mPEG 2000 in combination with free artemisinin resulted in enhanced killing of parasites, prevented parasite recrudescence, and improved survival. This is the first report to demonstrate that monensin in PEGylated stearylamine (SA) liposome has therapeutic potential against malaria infections.
Emergence of
cfr
-Mediated Linezolid Resistance in a Methicillin-Resistant Staphylococcus aureus Epidemic Clone Isolated from Patients with Cystic Fibrosis
Authors: de Dios Caballero Juan , Pastor María Dolores , Vindel Ana , Máiz Luis , Yagüe Genoveva , Salvador Carme , Cobo Marta , Morosini María-Isabel , del Campo Rosa , Cantón Rafael ,   the GEIFQ Study Group
Published: December 2015

ABSTRACT

Resistance to linezolid (LZD) in methicillin-resistant
Staphylococcus aureus
(MRSA) isolates from patients with cystic fibrosis (CF) is due mainly to ribosomal mutations. We report on four CF patients with LZD-resistant MRSA bronchopulmonary infections by strains carrying the
cfr
gene. Strains from one patient also harbored the G2576U mutation (23S rRNA) and the G139R substitution (L3 protein). All strains belonged to the epidemic clone ST125 MRSA IVc. Our results support the monitoring of LZD resistance emergence in CF and non-CF MRSA isolates.
Does Critical Illness Change Levofloxacin Pharmacokinetics?
Authors: Roberts Jason A. , Cotta Menino Osbert , Cojutti Piergiorgio , Lugano Manuela , Rocca Giorgio Della , Pea Federico 
Published: December 2015

ABSTRACT
Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.
Characterization of an Acinetobacter baumannii
lptD
Deletion Strain: Permeability Defects and Response to Inhibition of Lipopolysaccharide and Fatty Acid Biosynthesis
Authors: Bojkovic Jade , Richie Daryl L. , Six David A. , Rath Christopher M. , Sawyer William S. , Hu Qijun , Dean Charles R. 
Published: December 2015

ABSTRACT

Lipid A on the Gram-negative outer membrane (OM) is synthesized in the cytoplasm by the Lpx pathway and translocated to the OM by the Lpt pathway. Some
Acinetobacter baumannii
strains can tolerate the complete loss of lipopolysaccharide (LPS) resulting from the inactivation of early LPS pathway genes such as
lpxC
. Here, we characterized a mutant deleted for
lptD
, which encodes an OM protein that mediates the final translocation of fully synthesized LPS to the OM. Cells lacking
lptD
had a growth defect comparable to that of an
lpxC
deletion mutant under the growth conditions tested but were more sensitive to hydrophobic antibiotics, revealing a more significant impact on cell permeability from impaired LPS translocation than from the loss of LPS synthesis. Consistent with this, ATP leakage and
N
-phenyl-1-naphthylamine (NPN) fluorescence assays indicated a more severe impact of
lptD
deletion than of
lpxC
deletion on inner and outer membrane permeability, respectively. Targeted liquid chromatography-mass spectrometry (LCMS) analysis of LPS intermediates from UDP-3-
O-R
-3-hydroxylauroyl-
N
-acetyl-α-
d
-glucosamine through lipid IV
A
showed that the loss of LptD caused an accumulation of lipid IV
A
. This suggested that pathway intermediate accumulation or mislocalization caused by the blockage of later LPS pathway steps impacts envelope integrity. Supporting this notion, chemical inhibition of lipid A precursor enzymes, including LpxC and FabB/F, in the
lptD
deletion strain partially rescued growth and permeability defects.

IMPORTANCE
New antibiotics to treat Gram-negative bacterial infections are urgently needed. Inhibition of LPS biosynthesis is attractive because this would impact viability and cell permeability. Therefore, a better understanding of this pathway is important, especially in strains such as
A. baumannii
ATCC 19606, where LPS biosynthesis is not essential
in vitro
. We show that ATCC 19606 also survives the loss of the final translocation of LPS into the OM (
lptD
deletion). Intriguingly, this impaired cell envelope integrity more than the loss of LPS biosynthesis (
lpxC
deletion), presumably due to the accumulation of toxic intermediates. Supporting this, chemical inhibition of LPS biosynthesis partially reversed this permeability defect. This extends our understanding of the LPS machinery and provides insights into potential interrelationships of the target steps along this important pathway.
Effectiveness of a 5-year school-based intervention programme to reduce adiposity and improve fitness and lifestyle in Indian children; the SYM-KEM study
Authors: Bhave Sheila , Pandit Anand , Yeravdekar Rajiv , Madkaikar Vaishali , Chinchwade Trushna , Shaikh Nasreen , Shaikh Tasneem , Naik Shraddha , Marley-Zagar Ella , Fall Caroline H D 
Published: December 2015

DesignNon-randomised non-blinded school-based intervention study.SettingTwo schools in the cities of Pune and Nasik, India.ParticipantsThe intervention group comprised children attending a Pune school from 7–10 years until 12–15 years of age. Two control groups comprised children of the same age attending a similar school in Nasik, and children in the Pune intervention school but aged 12–15 years at the start of the study.InterventionA 5-year multi-intervention programme, covering three domains: physical activity, diet and general health, and including increased extracurricular and intracurricular physical activity sessions; daily yoga-based breathing exercises; making physical activity a ‘scoring’ subject; nutrition education; healthier school meals; removal of fast-food hawkers from the school environs; and health and nutrition education for teachers, pupils and families.Main outcome measuresBody mass index (BMI), waist circumference, physical fitness according to simple tests of strength, flexibility and endurance; diet; and lifestyle indicators (time watching TV, studying and actively playing).ResultsAfter 5 years the intervention children were fitter than controls in running, long jump, sit-up and push-up tests (p<0.05 for all). They reported spending less time sedentary (watching TV and studying), more time actively playing and eating fruit more often (p<0.05). The intervention did not reduce BMI or the prevalence of overweight/obesity, but waist circumference was lower than in the Pune controls (p=0.004).ConclusionsIt was possible to achieve multiple health-promoting changes in an academically competitive Indian school. These changes resulted in improved physical fitness, but had no impact on the children's BMI or on the prevalence of overweight/obesity.
ORGAN FAILURE AND C-REACTIVE PROTEIN BOTH AFFECT MIDAZOLAM CLEARANCE IN CRITICALLY ILL CHILDREN: A POPULATION PK MODEL
Authors: Vet Nienke J , Brussee Janneke M , de Hoog Matthijs , Mooij Miriam G , Verlaat Carin WM , Tibboel Dick , AJ Knibbe Catherijne , de Wildt Saskia N 
Published: December 2015

ObjectivesTo study the effect of organ failure and inflammation on midazolam clearance in critically ill children, using population pharmacokinetic modeling.MethodsA total of 83 critically ill children (median age 5 months (range 1 day-17 years), n=523 samples) receiving intravenous midazolam for continuous sedation during mechanical ventilation were included. Disease severity was described using the validated and clinically used scores PELOD, PIM2 and PRISM II. Cytokines (IL-1, IL-2, IL-6, TNF-a) and C-reactive protein (CRP) were used as markers for inflammation. A population pharmacokinetic model for midazolam was developed using NONMEM 7.3. Body weight, age, severity of organ failure and inflammatory markers were considered as potential covariates.ResultsIn a two-compartmental PK model, body weight was found as most significant covariate for clearance and volume of distribution. Moreover, both severity of organ failure (PELOD) and inflammation (IL6 and CRP) were significant determinants of clearance (p<0.01), and either of these factors improved the model significantly. With increasing number of organ failures, midazolam clearance significantly reduced. CRP was linearly correlated with clearance (slope −0.095), with higher CRP levels resulting in lower clearances. Either one of the covariates could explain part of the variability in clearance.ConclusionFor midazolam clearance, apart from body weight, we found organ failure reflected by the PELOD score, and inflammation reflected by IL6 and CRP, as significant covariates. Most likely this effect is due to reduced activity of CYP3A in critically ill mechanically ventilated children. Both CRP concentration and organ failure should be considered when dosing midazolam and potentially other CYP3A substrates in critically ill children.