bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology and Clinical Outcomes of Patients with Carbapenem-Resistant Klebsiella pneumoniae Bacteriuria
Authors: Qureshi Zubair A. , Syed Alveena , Clarke Lloyd G. , Doi Yohei , Shields Ryan K. 
Published: March 2014

ABSTRACT

Carbapenem-resistant
Klebsiella pneumoniae
(CRKP) bacteriuria is a frequently encountered clinical condition, but its clinical impact is unknown. We conducted a retrospective cohort study to define the epidemiology and outcomes for patients with CRKP bacteriuria. Patients with positive urine cultures for CRKP were classified as having asymptomatic bacteriuria (ASB) or symptomatic urinary tract infection (UTI). Among 105 patients with CRKP bacteriuria, 80% (84/105 patients) and 20% (21/105 patients) had ASB and UTI, respectively. Older age (
P
= 0.002) and higher Charlson's comorbidity index scores (
P
= 0.001) were associated with ASB. The median duration of hospitalization prior to CRKP bacteriuria was significantly longer for patients with ASB versus UTI (8.5 versus 2 days;
P
= 0.05). In multivariate analysis, male sex (odds ratio [OR], 4.69 [95% confidence interval (CI), 1.44 to 15.26];
P
= 0.01), solid-organ transplantation (OR, 4.50 [95% CI, 1.39 to 14.52];
P
= 0.01), and neurogenic bladder (OR, 18.62 [95% CI, 1.75 to 197.52];
P
= 0.01) were independently associated with UTI. Ten percent (8/84) of the patients with ASB received antimicrobial therapy. The treatment success rate for patients with UTIs was 90% (19/21 patients), including all patients who received doxycycline (
n
= 9). The overall 30-day mortality rate was 6% (6/105 patients); the deaths were unrelated to CRKP infections. Secondary CRKP infections, including UTIs, were notably absent among patients with ASB who were followed for 90 days. In conclusion, identification of CRKP in the urine was most commonly associated with ASB and did not lead to subsequent infections or death among asymptomatic patients. Factors associated with UTIs included male sex, solid-organ transplantation, and neurogenic bladder. Doxycycline may be an effective therapy for CRKP UTIs.
Pseudomonas aeruginosa Ceftolozane-Tazobactam Resistance Development Requires Multiple Mutations Leading to Overexpression and Structural Modification of AmpC
Authors: Cabot Gabriel , Bruchmann Sebastian , Mulet Xavier , Zamorano Laura , Moyà Bartolomé , Juan Carlos , Haussler Susanne , Oliver Antonio 
Published: March 2014

ABSTRACT

We compared the dynamics and mechanisms of resistance development to ceftazidime, meropenem, ciprofloxacin, and ceftolozane-tazobactam in wild-type (PAO1) and mutator (PAOMS, Δ
mutS
)
P. aeruginosa
. The strains were incubated for 24 h with 0.5 to 64× MICs of each antibiotic in triplicate experiments. The tubes from the highest antibiotic concentration showing growth were reinoculated in fresh medium containing concentrations up to 64× MIC for 7 consecutive days. The susceptibility profiles and resistance mechanisms were assessed in two isolated colonies from each step, antibiotic, and strain. Ceftolozane-tazobactam-resistant mutants were further characterized by whole-genome analysis through RNA sequencing (RNA-seq). The development of high-level resistance was fastest for ceftazidime, followed by meropenem and ciprofloxacin. None of the mutants selected with these antibiotics showed cross-resistance to ceftolozane-tazobactam. On the other hand, ceftolozane-tazobactam resistance development was much slower, and high-level resistance was observed for the mutator strain only. PAO1 derivatives that were moderately resistant (MICs, 4 to 8 μg/ml) to ceftolozane-tazobactam showed only 2 to 4 mutations, which determined global pleiotropic effects associated with a severe fitness cost. High-level-resistant (MICs, 32 to 128 μg/ml) PAOMS derivatives showed 45 to 53 mutations. Major changes in the global gene expression profiles were detected in all mutants, but only PAOMS mutants showed
ampC
overexpression, which was caused by
dacB
or
ampR
mutations. Moreover, all PAOMS mutants contained 1 to 4 mutations in the conserved residues of AmpC (F147L, Q157R, G183D, E247K, or V356I). Complementation studies revealed that these mutations greatly increased ceftolozane-tazobactam and ceftazidime MICs but reduced those of piperacillin-tazobactam and imipenem, compared to those in wild-type
ampC
. Therefore, the development of high-level resistance to ceftolozane-tazobactam appears to occur efficiently only in a
P. aeruginosa
mutator background, in which multiple mutations lead to overexpression and structural modifications of AmpC.
Tolerability of Cefazolin after Immune-Mediated Hypersensitivity Reactions to Nafcillin in the Outpatient Setting
Authors: Blumenthal Kimberly G. , Youngster Ilan , Shenoy Erica S. , Banerji Aleena , Nelson Sandra B. 
Published: March 2014

ABSTRACT

The objective of the present study was to assess the safety and tolerability of cefazolin therapy among patients with methicillin-sensitive Gram-positive bacterial infections who develop non-IgE-mediated hypersensitivity reactions (HSRs) to nafcillin. In this retrospective cohort analysis of the Outpatient Parenteral Antimicrobial Therapy program at the Massachusetts General Hospital from 2007 through 2013, we identified patients switched from nafcillin to cefazolin after an immune-mediated HSR. We reviewed patient demographics, details about the original HSR, and outcomes after the switch to cefazolin therapy. HSRs were classified by reaction type and likely mechanism. There were 467 patients treated with nafcillin, of which 60 (12.8%) were switched to cefazolin during their prescribed course. Of the 60 patients who transitioned to cefazolin, 17 (28.3%) were switched because of non-IgE-mediated HSRs. HSRs included maculopapular rash (
n
= 10), immune-mediated nephritis (
n
= 3), isolated eosinophilia (
n
= 2), immune-mediated hepatitis (
n
= 1), and a serum sickness-like reaction (
n
= 1). All but one patient (94.1%) who switched to cefazolin tolerated the drug with resolution of the HSR and completed their therapy with cefazolin. No patient experienced worsening of their rash or progressive organ dysfunction. With appropriate monitoring, therapy with cefazolin after non-IgE-mediated HSRs to nafcillin appears to be safe.
Liposome Encapsulation of Ciprofloxacin Improves Protection against Highly Virulent Francisella tularensis Strain Schu S4
Authors: Hamblin Karleigh A. , Armstrong Stuart J. , Barnes Kay B. , Davies Carwyn , Wong Jonathan P. , Blanchard James D. , Harding Sarah V. , Simpson Andrew J. H. , Atkins Helen S. 
Published: March 2014

ABSTRACTLiposome-encapsulated ciprofloxacin for inhalation (CFI) was investigated as a putative postexposure therapeutic for two strains ofFrancisella tularensis. The efficacies of oral ciprofloxacin and intranasally instilled CFI could not be distinguished in a mouse model of infection with theF. tularensislive vaccine strain (LVS), where a single dose of either formulation offered full protection against a lethal challenge. However, mouse studies with the more virulent Schu S4 strain ofF. tularensisdemonstrated that a higher level of protection against a lethal aerosol infection is provided by CFI than by oral ciprofloxacin. In addition, using this infection model, it was possible to discriminate the efficacy of intranasally instilled CFI from that of aerosolized CFI, with aerosolized CFI providing full protection after just a single dose. The improved efficacy of CFI compared to oral ciprofloxacin is likely due to the high sustained concentrations of ciprofloxacin in the lung. In summary, CFI may be a promising therapy, perhaps enabling the prophylactic regimen to be shortened, for use in the event of a deliberate release ofF. tularensis. The prophylactic efficacy of CFI against other biological warfare (BW) threat agents also warrants investigation.
Nonnucleoside Inhibitors of Norovirus RNA Polymerase: Scaffolds for Rational Drug Design
Authors: Eltahla Auda A. , Lim Kun Lee , Eden John-Sebastian , Kelly Andrew G. , Mackenzie Jason M. , White Peter A. 
Published: March 2014

ABSTRACT

Norovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA and is therefore a prime target for antiviral therapies. Using high-throughput screening, nearly 20,000 “lead-like” compounds were tested for inhibitory activity against the NoV genogroup II, genotype 4 (GII.4) RdRp. The four most potent hits demonstrated half-maximal inhibitory concentrations (IC
50
s) between 5.0 μM and 9.8 μM against the target RdRp. Compounds NIC02 and NIC04 revealed a mixed mode of inhibition, while NIC10 and NIC12 were uncompetitive RdRp inhibitors. When examined using enzymes from related viruses, NIC02 demonstrated broad inhibitory activity while NIC04 was the most specific GII.4 RdRp inhibitor. The antiviral activity was examined using available NoV cell culture models; the GI.1 replicon and the infectious GV.1 murine norovirus (MNV). NIC02 and NIC04 inhibited the replication of the GI.1 replicon, with 50% effective concentrations (EC
50
s) of 30.1 μM and 71.1 μM, respectively, while NIC10 and NIC12 had no observable effect on the NoV GI.1 replicon. In the MNV model, NIC02 reduced plaque numbers, size, and viral RNA levels in a dose-dependent manner (EC
50
s between 2.3 μM and 4.8 μM). The remaining three compounds also reduced MNV replication, although with higher EC
50
s, ranging from 32 μM to 38 μM. In summary, we have identified novel nonnucleoside inhibitor scaffolds that will provide a starting framework for the development and future optimization of targeted antivirals against NoV.
Utility of faecal calprotectin in inflammatory bowel disease (IBD): what cut-offs should we apply?
Authors: Dhaliwal A , Zeino Z , Tomkins C , Cheung M , Nwokolo C , Smith S , Harmston C , Arasaradnam R P 
Published: March 2014

BackgroundFaecal calprotectin (FC), a cytosolic protein released by neutrophils (S100 family) in response to inflammation, is a simple, non-invasive test that can be used to differentiate irritable bowel syndrome (IBS) with inflammatory bowel disease (IBD), where there can be considerable symptom overlap.Aims and methodsThe aims of the study were (1) to be able to predict the ability of FC to exclude IBD and determine cut-offs when in remission, (2) to investigate the effects of time and temperature on stability of FC and (3) compare three ELISA kits to measure FC: Buhlmann, PhiCal v1 and PhiCal v2. A total of 311 patients with altered bowel habit were tested for FC; 144 with IBS, 148 with IBD and 19 with other organic causes.ResultsSensitivity and specificity of FC (with PhiCal v2 kit) to distinguish between functional disorder (IBS) and IBD using cut-off 50 μg/g were 88% and 78%, respectively, with a negative predictive value of 87%. Area under the receiver operating curve was 0.84 (CI 0.78 to 0.90). For those with IBD, FC values below 250 μg/g corresponded with remission of disease with a sensitivity and specificity of 90% and 76%, respectively. Area under the receiver operating curve was 0.93 (CI 0.89 to 0.97). FC was stable once extracted and frozen for up to 2.5 months. Pearson correlation was good between Buhlmann assay and PhiCal v2 (r2 = 0.95).ConclusionsFC has up to 87% negative predictive value to exclude IBD, and cut-offs less than 250 μg/g had 90% sensitivity to determine remission in IBD. Once frozen, FC is stable and the ELISA monoclonal plates were broadly comparable.
Downgrading of biopsy based Gleason score in prostatectomy specimens
Authors: Treurniet Kilian M , Trudel Dominique , Sykes Jenna , Evans Andrew J , Finelli Antonio , Van der Kwast Theodorus H 
Published: March 2014

AimsTo assess the frequency and possible causes of downgrading from a Gleason score (GS) 7 at biopsy to a GS ≤6 at radical prostatectomy (RP) in a Canadian referral centre.MethodsData were extracted from diagnostic reports of inhouse biopsies and matching prostatectomy specimens from 2008 to 2011 with a GS 7 at biopsy. Biopsies and corresponding prostatectomy specimens of downgraded cases were reviewed. Pathological features were assessed and possible predictors for downgrading were identified.ResultsBased on pathology reports, 29 (8.9%, 95% CI 5.8% to 11.9%) of the 327 eligible cases were downgraded from biopsy GS 7 to RP GS 6, 72% of them representing a GS ≤6 with tertiary grade 4 at RP. Agreement at review of downgraded RP specimens for Gleason grading was fair and of borderline significance (κ=0.34, 95% CI −0.01 to 0.68, p=0.055) with 65% agreement for tertiary grade. The predominant Gleason grade 4 pattern found in the downgraded biopsies was ill-formed glands. The number of cores with Gleason grade 4 component was found to be the strongest negative predictor of downgrading (prereview OR=0.56 (95% CI 0.39 to 0.80, p=0.002), postreview OR=0.19 (95% CI 0.07 to 0.52, p=0.001)).ConclusionsThe frequency of GS 7 in biopsies subsequently downgraded in RP is low and is associated with International Society of Urological Pathology modified Gleason grade 4 patterns. Downgrading could be attributed in most cases to the presence of a tertiary Gleason grade 4 pattern in the RP specimen. Inter-observer agreement for the presence of tertiary grade 4 in RP specimens is moderate.
Relief variation and erosion of the Variscan belt: detrital geochronology of the Palaeozoic sediments from the Mauges Unit (Armorican Massif, France)
Authors: Ducassou Céline , Poujol Marc , Ruffet Gilles , Bruguier Olivier , Ballèvre Michel 
Published: March 2014

Abstract

The sediments of the Mauges Unit located in the internal zone provide an opportunity of studying the evolution of relief during Palaeozoic time. U–Pb dating on zircon and
39
Ar/
40
Ar on white mica are used to constrain the age and nature of the sources. The first relief identified is marked by an Early Devonian unconformity interpreted as the opening of a northern back-arc basin. Detrital minerals are first reworked from underlying layers indicating a local supply. Magmatic zircons at
c.
400 Ma then record the emergence of a magmatic arc. During the Middle Devonian, the gap in the sedimentary record is attributed to an emersion followed by the disappearance of the relief during the Late Devonian. At the Devonian–Carboniferous boundary, the main collision is followed by the onset of a relief. The continental sedimentation in the Ancenis Basin (late Tournaisian–Viséan) is a coarsening-upwards megasequence indicating an increasing and/or approaching relief. The detrital minerals record the progressive exhumation of Variscan metamorphic (mica at
c.
350 Ma) and magmatic rocks (zircons at
c.
390–340 Ma). The Serpukhovian–Bashkirian sedimentation records the erosion of a proximal metamorphic source (Champtoceaux with micas at
c.
350–340 Ma) showing a much shorter drainage system.

Supplementary material:

Sample coordinates and U–Pb on zircon and
39
Ar/
40
Ar on white mica analyses are available at
http://www.geolsoc.org.uk/SUP18730
.
Palaeozoic evolution of the Variscan Vosges Mountains
Authors: Skrzypek Etienne , Schulmann Karel , Tabaud Anne-Sophie , Edel Jean-Bernard 
Published: March 2014

Abstract
A geological synthesis of the Palaeozoic Vosges Mountains (NE France) is presented using existing observations and new data. The geodynamic evolution involves: (1) Early Palaeozoic sedimentation and magmatism; (2) Late Devonian subduction triggering back-arc spreading; (3) early Lower Carboniferous continental subduction, continent–continent collision and polyphase deformation and metamorphism of the orogenic root; and (4) late Lower Carboniferous orogenic collapse driven by thermal weakening of the middle crust. The evolution is integrated within the framework of the European Variscan Belt. The Northern Vosges comprise sediments of Rhenohercynian affinity separated from Teplá-Barrandian metasediments by a Lower Carboniferous magmatic arc. The latter is correlated with the Mid-German Crystalline Rise, and is ascribed to the south-directed subduction of the Rhenohercynian Basin. The Saxothuringian–Moldanubian suture is thought to be obliterated by the magmatic arc, while the Lalaye–Lubine Fault is interpreted as the Teplá-Barrandian–Moldanubian boundary. The Central Vosges are paralleled with the Moldanubian domain of the Bohemian Massif where identical lithologies record the Devonian–Carboniferous SE-directed subduction of the Saxothuringian passive margin below the Moldanubian upper plate. The Southern Vosges represent the upper Moldanubian crust and are linked to the southern Black Forest. The presence of an oceanic domain to the south of the Vosges–Black Forest remains unclear.

Supplementary material:

List of radiometric ages used for probability plots is available at
http://www.geolsoc.org.uk/SUP18734
.
A plate-kinematic model for the assembly of the Bohemian Massif constrained by structural relationships around granitoid plutons
Authors: Žák Jiří , Verner Kryštof , Janoušek Vojtěch , Holub František V. , Kachlík Václav , Finger Fritz , Hajná Jaroslava , Tomek Filip , Vondrovic Lukáš , Trubač Jakub 
Published: March 2014

Abstract

This paper summarizes the current knowledge on the nature, kinematics and timing of movement along major tectonic boundaries in the Bohemian Massif and demonstrates how the Variscan plutonism and deformation evolved in space and time. Four main episodes are recognized: (1) Late Devonian–early Carboniferous subduction and continental underthrusting of the Saxothuringian Unit beneath the Teplá–Barrandian Unit resulted in the orogen-perpendicular shortening and growth of an inboard magmatic arc during
c.
354–346 Ma; (2) the subduction-driven shortening was replaced by collapse of the Teplá–Barrandian upper crust, exhumation of the high-grade (Moldanubian) core of the orogen at
c.
346–337 Ma and by dextral strike-slip along orogen-perpendicular NW–SE shear zones; (3) following closure of a Rhenohercynian Ocean basin, the Brunia microplate was underthrust beneath the eastern flank of the Saxothuringian/Teplá–Barrandian/Moldanubian ‘assemblage’; this process commenced at
c.
346 Ma in the NE and ceased at
c.
335 Ma in the SW; and (4) late readjustments within the amalgamated Bohemian Massif included crustal exhumation and mainly S-type granite plutonism along the edge of the Brunia indentor at
c.
330–327 Ma, and peripheral tectonothermal activity driven by strike-slip faulting and possibly mantle delamination around the consolidated Bohemian Massif's interior until late Carboniferous–earliest Permian times.
An asymmetric dual-processor architecture for low-power information appliances
Authors: Guimbretiére François , Liu Shenwei , Wang Han , Manohar Rajit 
Published: March 2014

As users become increasingly conscious of their energy footprint—either to improve battery life or to respect the environment—improved energy efficiency of systems has gained in importance. This is especially important in the context of information appliances such as e-book readers that are meant to replace books, since their energy efficiency impacts how long the appliance can be used on a single charge of the battery.
In this article, we present a new software and hardware architecture for information appliances that provides significant advantages in terms of device lifetime. The architecture combines a low-power microcontroller with a high-performance application processor, where the low-power microcontroller is used to handle simple user interactions (e.g., turning pages, inking, entering text) without waking up the main application processor. We demonstrate how this architecture is easily adapted to the traditional way of building user interfaces using a user interface markup language. We report on our initial measurements using an E Ink-based prototype. When comparing our hybrid architecture to a simpler solution we found that we can increase the battery life by a factor of 1.72 for a reading task and by a factor of 3.23 for a writing task. We conclude by presenting design guidelines aimed at optimizing the overall energy signature of information appliances.
Transforming Growth Factor-β as a Therapeutic Target in Hepatocellular Carcinoma
Authors: Giannelli Gianluigi , Villa Erica , Lahn Michael 
Published: March 2014

Abstract
Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-β plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial–mesenchymal transition (EMT). TGF-β signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-β signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-β signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGF-β signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-β inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT. Cancer Res; 74(7); 1890–4. ©2014 AACR.
Time-Dependent Changes in Atherosclerotic Plaque Composition in Patients Undergoing Carotid Surgery
Authors: van Lammeren Guus W. , den Ruijter Hester M. , Vrijenhoek Joyce E. P. , van der Laan Sander W. , Velema Evelyn , de Vries Jean-Paul P. M. , de Kleijn Dominique P. V. , Vink Aryan , de Borst Gert Jan , Moll Frans L. , Bots Michiel L. , Pasterkamp Gerard 
Published: March 2014

Background—
Time-dependent trends in the incidence of cardiovascular disease have been reported in high-income countries. Because atherosclerosis underlies the majority of cardiovascular diseases, we investigated temporal changes in the composition of atherosclerotic plaques removed from patients undergoing carotid endarterectomy.

Methods and Results—
The Athero-Express study is an ongoing, longitudinal, vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy in the province of Utrecht from 2002 to 2011. Histopathologic features of plaques of 1583 patients were analyzed in intervals of 2 years. The analysis included quantification of collagen, calcifications, lipid cores, plaque thrombosis, macrophages, smooth muscle cells, and microvessels. Large atheroma, plaque thrombosis, macrophages, and calcifications were less frequently observed over time, with adjusted odds ratios of 0.72 (95% confidence interval, 0.650-0.789), 0.62 (95% confidence interval, 0.569-0.679), 0.87 (95% confidence interval, 0.800-0.940), and 0.75 (95% confidence interval, 0.692-0.816) per 2-year increase in time, respectively. These changes in plaque characteristics were consistently observed in patient subgroups presenting with stroke, transient ischemic attack, ocular symptoms, and asymptomatic patients. Concomitantly, risk factor management and secondary prevention strategies among vascular patients scheduled for carotid endarterectomy significantly improved over the past decade.

Conclusions—
In conclusion, over the past decade, atherosclerotic plaques harvested during carotid endarterectomy show a time-dependent change in plaque composition characterized by a decrease in features currently believed to be causal for plaque instability. This appears to go hand in hand with improvements in risk factor management.