bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pilot Study of a Bayesian Approach To Estimate Vancomycin Exposure in Obese Patients with Limited Pharmacokinetic Sampling
Authors: Carreno Joseph J. , Lomaestro Ben , Tietjan John , Lodise Thomas P. 
Published: March 2017

ABSTRACT

This study evaluated the predictive performance of a Bayesian PK estimation method (ADAPT V) to estimate the 24-h vancomycin area under the curve (AUC) with limited pharmacokinetic (PK) sampling in adult obese patients receiving vancomycin for suspected or confirmed Gram-positive infections. This was an Albany Medical Center Institutional Review Board-approved prospective evaluation of 12 patients. Patients had a median (95% confidence interval) age of 61 years (39 to 71 years), a median creatinine clearance of 86 ml/min (75 to 120 ml/min), and a median body mass index of 45 kg/m
2
(40 to 52 kg/m
2
). For each patient, five PK concentrations were measured, and four different vancomycin population PK models were used as Bayesian priors to estimate the vancomycin AUC (AUC
FULL
). Using each PK model as a prior, data-depleted PK subsets were used to estimate the 24-h AUC (i.e., peak and trough data [AUC
PT
], midpoint and trough data [AUC
MT
], and trough-only data [AUC
T
]). The 24-h AUC derived from the full data set (AUC
FULL
) was compared to the AUC derived from data-depleted subsets (AUC
PT
, AUC
MT
, and AUC
T
) for each model. For the four sets of analyses, AUC
FULL
estimates ranged from 437 to 489 mg·h/liter. The AUC
PT
provided the best approximation of the AUC
FULL
; AUC
MT
and AUC
T
tended to overestimate AUC
FULL
. Further prospective studies are needed to evaluate the impact of AUC monitoring in clinical practice, but the findings from this study suggest that the vancomycin AUC can be estimated with good precision and accuracy with limited PK sampling using Bayesian PK estimation software.
WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent “β-Lactam Enhancer” Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones
Authors: Moya Bartolome , Barcelo Isabel M. , Bhagwat Sachin , Patel Mahesh , Bou German , Papp-Wallace Krisztina M. , Bonomo Robert A. , Oliver Antonio 
Published: March 2017

ABSTRACT

Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against
Pseudomonas aeruginosa
, including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (
mexR
), porin-deficient (
oprD
), and AmpC-hyperproducing (
dacB
) derivatives of PAO1, and MBL-expressing clinical strains ST175 (
bla
VIM-2
) and ST111 (
bla
VIM-1
). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent

K
i

[

K
i

app
] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the
P. aeruginosa
mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam–WCK enhancer combinations represent a promising β-lactam “enhancer-based” approach to treat MDR
P. aeruginosa
infections, bypassing the need for MBL inhibition.
Assessment and Optimizations of Candida albicans
In Vitro
Biofilm Assays
Authors: Lohse Matthew B. , Gulati Megha , Valle Arevalo Ashley , Fishburn Adam , Johnson Alexander D. , Nobile Clarissa J. 
Published: March 2017

ABSTRACT

Candida albicans
biofilms have a significant medical impact due to their rapid growth on implanted medical devices, their resistance to antifungal drugs, and their ability to seed disseminated infections. Biofilm assays performed
in vitro
allow for rapid, high-throughput screening of gene deletion libraries or antifungal compounds and typically serve as precursors to
in vivo
studies. Here, we compile and discuss the protocols for several recently published
C. albicans
in vitro
biofilm assays. We also describe improved versions of these protocols as well as novel
in vitro
assays. Finally, we consider some of the advantages and disadvantages of these different types of assays.
Reoxidation of the Thiol-Disulfide Oxidoreductase MdbA by a Bacterial Vitamin K Epoxide Reductase in the Biofilm-Forming Actinobacterium Actinomyces oris
Authors: Luong Truc Thanh , Reardon-Robinson Melissa E. , Siegel Sara D. , Ton-That Hung 
Published: March 2017

ABSTRACT

Posttranslocational protein folding in the Gram-positive biofilm-forming actinobacterium
Actinomyces oris
is mediated by a membrane-bound thiol-disulfide oxidoreductase named MdbA, which catalyzes oxidative folding of nascent polypeptides transported by the Sec translocon. Reoxidation of MdbA involves a bacterial
v
itamin
K
ep
o
xide
r
eductase (VKOR)-like protein that contains four cysteine residues, C93/C101 and C175/C178, with the latter forming a canonical CXXC thioredoxin-like motif; however, the mechanism of VKOR-mediated reoxidation of MdbA is not known. We present here a topological view of the
A. oris
membrane-spanning protein VKOR with these four exoplasmic cysteine residues that participate in MdbA reoxidation. Like deletion of the VKOR gene, alanine replacement of individual cysteine residues abrogated polymicrobial interactions and biofilm formation, concomitant with the failure to form adhesive pili on the bacterial surface. Intriguingly, the mutation of the cysteine at position 101 to alanine (C101A mutation) resulted in a high-molecular-weight complex that was positive for MdbA and VKOR by immunoblotting and was absent in other alanine substitution mutants and the C93A C101A double mutation and after treatment with the reducing agent β-mercaptoethanol. Consistent with this observation, affinity purification followed by immunoblotting confirmed this MdbA-VKOR complex in the C101A mutant. Furthermore, ectopic expression of the
Mycobacterium tuberculosis
VKOR analog in the
A. oris
VKOR deletion (ΔVKOR) mutant rescued its defects, in contrast to the expression of
M. tuberculosis
VKOR variants known to be nonfunctional in the disulfide relay that mediates reoxidation of the disulfide bond-forming catalyst DsbA in
Escherichia coli
. Altogether, the results support a model of a disulfide relay, from its start with the pair C93/C101 to the C175-X-X-C178 motif, that is required for MdbA reoxidation and appears to be conserved in members of the class
Actinobacteria
.

IMPORTANCE
It has recently been shown in the high-GC Gram-positive bacteria (or
Actinobacteria
)
Actinomyces oris
and
Corynebacterium diphtheriae
that oxidative folding of nascent polypeptides transported by the Sec machinery is catalyzed by a membrane-anchored oxidoreductase named MdbA. In
A. oris
, reoxidation of MdbA requires a bacterial VKOR-like protein, and yet, how VKOR mediates MdbA reoxidation is unknown. We show here that the
A. oris
membrane-spanning protein VKOR employs two pairs of exoplasmic cysteine residues, including the canonical CXXC thioredoxinlike motif, to oxidize MdbA via a disulfide relay mechanism. This mechanism of disulfide relay is essential for pilus assembly, polymicrobial interactions, and biofilm formation and appears to be conserved in members of the class
Actinobacteria
, including
Mycobacterium tuberculosis
.
Growth Trade-Offs Accompany the Emergence of Glycolytic Metabolism in Shewanella oneidensis MR-1
Authors: Chubiz Lon M. , Marx Christopher J. 
Published: March 2017

ABSTRACTBacteria increase their metabolic capacity via the acquisition of genetic material or by the mutation of genes already present in the genome. Here, we explore the mechanisms and trade-offs involved whenShewanella oneidensis, a bacterium that typically consumes small organic and amino acids, rapidly evolves to expand its metabolic capacity to catabolize glucose after a short period of adaptation to a glucose-rich environment. Using whole-genome sequencing and genetic approaches, we discovered that deletions in a region including the transcriptional repressor (nagR) that regulates the expression of genes associated with catabolism ofN-acetylglucosamine are the common basis for evolved glucose metabolism across populations. The loss ofnagRresults in the constitutive expression of genes for anN-acetylglucosamine permease (nagP) and kinase (nagK). We demonstrate that promiscuous activities of both NagP and NagK toward glucose allow for the transport and phosphorylation of glucose to glucose-6-phosphate, the initial events of glycolysis otherwise thought to be absent inS. oneidensis.13C-based metabolic flux analysis uncovered that subsequent utilization was mediated by the Entner-Doudoroff pathway. This is an example whereby gene loss and preexisting enzymatic promiscuity, and not gain-of-function mutations, were the drivers of increased metabolic capacity. However, we observed a significant decrease in the growth rate on lactate after adaptation to glucose catabolism, suggesting that trade-offs may explain why glycolytic function may not be readily observed inS. oneidensisin natural environments despite it being readily accessible through just a single mutational event.IMPORTANCEGains in metabolic capacity are frequently associated with the acquisition of novel genetic material via natural or engineered horizontal gene transfer events. Here, we explored how a bacterium that typically consumes small organic acids and amino acids expands its metabolic capacity to include glucose via a loss of genetic material, a process frequently associated with a deterioration of metabolic function. Our findings highlight how the natural promiscuity of transporters and enzymes can be a key driver in expanding metabolic diversity and that many bacteria may possess a latent metabolic capacity accessible through one or a few mutations that remove regulatory functions. Our discovery of trade-offs between growth on lactate and on glucose suggests why this easily gained trait is not observed in nature.
Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial
Authors: Marzin Tobias , Lorkowski Gerhard , Reule Claudia , Rau Stefanie , Pabst Elisabeth , Vester Johannes C , Pabst Helmut 
Published: March 2017

BackgroundSystemic enzyme therapy may improve symptoms of exhaustive eccentric exercise due to anti-inflammatory properties.MethodsIn a randomised, placebo-controlled, two-stage clinical trial, systemic enzyme therapy (Wobenzym) was administered for 72 hours before and 72 hours following a day on which subjects performed an exhaustive eccentric exercise (isokinetic loading of the quadriceps). Efficacy criteria (maximal strength and pain) and time points were selected to account for the multidimensional nature of exercise-induced muscle damage symptoms. Subjects were randomised in a crossover (stage I, n=28) and parallel group design (stage II, n=44).ResultsAnalysis of stage I data demonstrated a significant superiority (Mann-Whitney=0.6153; p=0.0332; one sided) for systemic enzyme therapy compared with placebo. Stage II was designed as a randomised controlled parallel group comparison. Heterogeneity (I2>0.5) between stages led to separate analyses of stage I (endurance-trained subjects) and stage II (strength-trained subjects). Combined analysis resulted in no evidence for corresponding treatment effects. Analysis of pooled biomarker data, however, demonstrated significant favourable effects for systemic enzyme therapy in both stages.ConclusionSystemic enzyme therapy before and after exhaustive eccentric exercise resulted in higher maximal concentric strength in the less strength-trained subjects (stage I) and in significant favourable effects on biomarkers (inflammatory, metabolic and immune) in all subjects. The application of these findings needs further evaluation.
Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus
Authors: Demirci F Yesim , Wang Xingbin , Morris David L , Feingold Eleanor , Bernatsky Sasha , Pineau Christian , Clarke Ann , Ramsey-Goldman Rosalind , Manzi Susan , Vyse Timothy J , Ilyas Kamboh M 
Published: March 2017

BackgroundA major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 – 4.5  Mb) located at 8p23. Initially implicated genes includedFAM167A-BLKandXKR6, of whichBLKreceived major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported.Objective and methodsIn this case –control study, we further investigated the ‘extended’ 8p23 locus (~ 4  Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~1200  subjects) and a replication data set (> 10 000  subjects) comprising European-descent individuals.ResultsMeta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10−8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLKsubregion), our results also revealed two ‘new’ SLE signals, includingSGK223-CLDN23-MFHAS1(6.06 × 10−9≤ meta p ≤ 4.88 × 10−8) andCTSB(meta p = 4.87 × 10−8) subregions that are located > 2 Mb upstream and ~ 0.3  Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putativecis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background.ConclusionsOur results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.
Experimental validation of the tuneable diaphragm effect in modern acoustic stethoscopes
Authors: Nowak Karolina M , Nowak Lukasz J 
Published: March 2017

ABSTRACTPurposeThe force with which the diaphragm chestpiece of a stethoscope is pressed against the body of a patient during an auscultation examination introduces the initial stress and deformation to the diaphragm and the underlying tissues, thus altering the acoustic parameters of the sound transmission path. If the examination is performed by an experienced physician, he will intuitively adjust the amount of the force in order to achieve the optimal sound quality. However, in case of becoming increasingly popular auto-diagnosis and telemedicine auscultation devices with no such feedback mechanisms, the question arises regarding the influence of the possible force mismatch on the parameters of the recorded signal.DesignThe present study describes the results of the experimental investigations on the relation between pressure applied to the chestpiece of a stethoscope and parameters of the transmitted bioacoustic signals. The experiments were carried out using various stethoscopes connected to a force measurement system, which allowed to maintain fixed pressure during auscultation examinations. The signals were recorded during examinations of different volunteers, at various auscultation sites.ResultsThe obtained results reveal strong individual and auscultation-site variability.ConclusionsIt is concluded that the underlying tissue deformation is the primary factor that alters the parameters of the recorded signals.
Severe bradycardia after hypoxaemia and endotracheal intubation and cardiac arrest following glycopyrrolate in a dog
Authors: Scarabelli Stefania , Rigotti Clara , Alderson Briony 
Published: March 2017

A nine‐year‐old neutered male Yorkshire terrier with history of chronic cough underwent bronchoscopy and bronchoalveolar lavage; general anaesthesia was maintained with a variable rate infusion of propofol, and oxygen was insufflated via a urinary catheter in the trachea. At the end of the procedure, desaturation occurred; endotracheal intubation was performed and was immediately followed by severe bradycardia and respiratory arrest. Glycopyrrolate (5 µg/kg) was administered leading to cardiac arrest. Apnoea and asystole were quickly treated with manual positive pressure ventilation, external chest compressions and intravenous administration of 0.04 mg/kg of atropine. This case describes vagally induced bradycardia after intubation, possible predisposing factors and its treatment/prevention with antimuscarinic drugs.
Carbon cycle implications of terrestrial weathering changes since the last glacial maximum
Authors: Brault M.-O. , Mysak L.A. , Matthews H.D. 
Published: March 2017

We examine the importance of the rock weathering feedback mechanism during the last deglacial period (∼16 000–4000 BCE) using an Earth system model of intermediate complexity (the University of Victoria Earth System Climate Model (UVic ESCM)) with four box-model parameterizations of terrestrial weathering. The deglacial climate change is driven by changes in orbital parameters, ice core reconstructions of atmospheric CO2 variability, and prescribed removal of continental ice sheets. Over the course of the 12 000 year simulation period, increases in weathering provide a mechanism that slowly removes CO2 from the atmosphere, in opposition to the observed atmospheric CO2 increase during this period. These processes transfer both carbon and alkalinity to the ocean, the combination of which results in as much as a 1000 Pg C increase in total ocean carbon, relative to a control simulation with constant weathering. However, the rapid expansion of northern hemisphere vegetation introduces a significant uncertainty among the weathering parameterizations. Further experiments to test the individual impacts of weathering dissolved inorganic carbon and alkalinity fluxes on ocean biogeochemistry suggest that the worldwide distribution of rock types and the ratio of carbonate to silicate weathering may be crucially important in obtaining an accurate estimate of changes in global weathering rates.
τ mass andR-value measurements at BES
Authors: Zheng Zhipeng , Fang Shuangshi , Huang Guangshun 
Published: March 2017

A comprehensive review of the measurements of [Formula: see text] lepton mass and R-values in the energy region between 2–5 GeV, achieved at the BES experiment, is presented. In addition to the evaluation of their impact on the test of Standard Model, we also highlighted the present status and the most recent developments. In particular, we made an extensive discussion on the prospects for future improvements at the BESIII experiment.
Particle Swarm Optimization with Intelligent Mutation for Nonlinear Mixed-Integer Reliability-Redundancy Allocation
Authors: Sheikhpour Saeide , Mahani Ali 
Published: March 2017

As improving system reliability in a basic system has been always one of the important concerns in reliability engineering; many studies have been developed in this regard. In this paper, a novel intelligent PSO (PSO-IM) is proposed. In suggested approach two different types of mutation operator, which controlled by Fuzzy controller, are applied to standard PSO for finding the best solution of reliability-redundancy allocation problems (RRAP). Also a heuristic inertia weight equation is introduced in our proposed PSO-IM. The main objective of our solution is to achieve maximum reliability in a basic system with acceptable redundancy allocation subject to cost, weight, volume. The proposed method (PSO-IM) significantly improves the search ability of basic PSO and finds the maximum reliability in comparison with previous works.
Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion—A New Role for the AXL Receptor Tyrosine Kinase
Authors: Aguilera Todd A. , Giaccia Amato J. 
Published: March 2017

AbstractWith the clinical impact of CTLA-4 and PD-1/PD-L1 immune checkpoint therapies, widespread interest in cancer immunotherapy has been ignited. However, the rate and extent of clinical responses to approved therapies are limited and often nonexistent in many solid tumors. This is partially because immune checkpoint therapies are most effective against T-cell–inflamed tumors, and non–T-cell–inflamed or T-cell–excluded tumors remain a significant barrier. New strategies are needed to overcome immune resistance mechanisms that arise during tumor development, which result in T-cell exclusion. Approaches may need to be combined with conventional therapies such as chemotherapy, radiotherapy, and molecularly targeted therapy, and many clinical trials are ongoing. This review discusses the challenge of T-cell exclusion and innate oncologic pathways that contribute to this problem, including β-catenin, STAT3, NF-κB, PTEN, and AXL tyrosine kinase. The GAS6/AXL pathway is of interest immunologically, as its targeting can lead to greater antitumor immune responses after radiotherapy. In addition, several targeted therapies that are selective and nonselective for AXL are in preclinical and clinical development in acute myelogenous leukemia and renal cell cancer. There remains much to learn, but the future is bright for anti-AXL therapies, though effective combinations and their impact may not be realized for years to come. Clin Cancer Res; 23(12); 2928–33. ©2017 AACR.
Insufficient Leaflet Remodeling in Patients With Atrial Fibrillation
Authors: Kagiyama Nobuyuki , Hayashida Akihiro , Toki Misako , Fukuda Shota , Ohara Minako , Hirohata Atsushi , Yamamoto Keizo , Isobe Mitsuaki , Yoshida Kiyoshi 
Published: March 2017

Background—
The relationship between annular dilatation caused by atrial fibrillation (AF) and mitral regurgitation (MR) remains controversial. We hypothesized that the small ratio of total leaflet area/annulus area (TLA/AA), reflecting insufficient leaflet remodeling to annular dilatation, is a main component of MR in patients with AF.

Methods and Results—

Three-dimensional transesophageal echocardiographic data of the mitral valve were analyzed in 28 AF patients with moderate or severe MR (MR group), age- and sex-matched 56 AF patients with mild or less MR (non-MR group), and 16 control subjects. AA was significantly greater in both the MR (645±126 mm
2
/m
2
,
P
<0.001) and non-MR groups (568±121 mm
2
/m
2
,
P
=0.001) compared with control subjects (444±108 mm
2
/m
2
). However, TLA/AA was significantly smaller in the MR (1.29±0.10,
P
<0.001), but not in the non-MR group (1.65±0.24,
P
>0.99), compared with control subjects (1.70±0.29). In linear regression analysis, TLA/AA was inversely associated with the effective regurgitant orifice (
r
=−0.73,
P
<0.001). The area under the receiver-operating-characteristics curve of TLA/AA was significantly greater than that of AA (0.95 versus 0.72,
P
<0.001). Multivariable analysis revealed that small TLA/AA (
P
<0.001) was independently associated with significant MR, while AA was not (
P
=0.26).

Conclusions—
In patients with AF, insufficient leaflet remodeling to annular dilatation, rather than crude annular dilatation, was strongly associated with the severity of MR.