bluuebunny/crossref_metadata_2025 huggingface dataset:
Strategic Capacity Management When Customers Have Boundedly Rational Expectations
Authors: Huang Tingliang , Liu Qian
Published: June 2015

In retailing industries, such as apparel, sporting goods, customer electronics, and appliances, many firms deploy sophisticated modeling and optimization software to conduct dynamic pricing in response to uncertain and fluctuating market conditions. However, the possibility of markdown pricing creates an incentive for customers to strategize over the timing of their purchases. How should a retailing firm optimally account for customer behavior when making its pricing and stocking/capacity decisions? For example, is it optimal for a firm to create rationing risk by deliberately under stocking products? In this study, we develop a stylized modeling framework to answer these questions. In our model, customers strategize over the timing of their purchases. However, customers have boundedly rational expectations in the sense of anecdotal reasoning about the firm's fill rate, i.e., they have to rely on anecdotes, past experiences, or word‐of‐mouth to infer the firm's fill rate. In our modeling framework, we distinguish two settings: (i) capacity commitment, where the firm commits to its capacity level in the long run, or (ii) the firm dynamically changes it in each season. For both settings, within the simplest form of anecdotal reasoning, we prove that strategic capacity rationing is not optimal independent of customer risk preferences. Then, using a general form of anecdotal reasoning, we provide sufficient conditions for capacity rationing to be optimal for both settings, respectively. We show that the result of strategic capacity rationing being suboptimal is fairly robust to different valuation distributions and utility functions, heterogeneous sample size, and price optimization.
Contribution of Congenital Anomalies to Neonatal Mortality Rates in Malta
Authors: Gatt Miriam , England Kathleen , Grech Victor , Calleja Neville
Published: June 2015

Background

Neonatal mortality is a public health concern, and congenital anomalies contribute significantly to this mortality. This paper describes trends in neonatal mortality in Malta separately for congenital anomaly and non‐congenital anomaly causes.

Methods

Data for neonatal deaths of 22‐week gestation onwards registered between 1994–2013 were obtained from the National Mortality Register. Chi‐square tests were used to analyse 5‐year time trends and differences in proportions of causes of neonatal deaths. Neonatal mortality was compared with other European countries.

Results

Between 1994 and 2013, 441 neonatal deaths and 84 821 livebirths were registered, giving a neonatal mortality of 5.2 per 1000 livebirths. Congenital anomalies accounted for 36.7% (n = 162) of the neonatal deaths, while the remaining 63.3% (n = 279) were attributed to non‐congenital causes. During the 20‐year period, neonatal mortality due to non‐congenital causes decreased from 4.6 per 1000 livebirths in 1994–98 to 2.5 per 1000 in 2009–13, while that due to congenital anomalies remained stable (2.0 per 1000 livebirths in 1994–98 and 2.2 per 1000 in 2009–13). This has resulted in comparatively higher proportions of neonatal deaths attributed to congenital anomalies in recent years (45.9% in 2009–13 vs. 29.9% in 1994–98). Comparing neonatal mortality reported from European countries, Malta has a high rate most marked for deaths due to congenital anomalies.

Conclusions

During 1994–2013, neonatal mortality has decreased due to a decline of non‐congenital causes of death, possibly related to improved health care. The proportionate neonatal mortality attributed to congenital anomalies has increased and is the highest reported from Europe. This may be explained by the fact that termination of pregnancy is illegal in Malta.
Two Periods of Skarn Mineralization in theBaizhangyanW–MoDeposit, SouthernAnhui Province, SoutheastChina: Evidence from ZirconU–Pband MolybdeniteRe–Osand Sulfur Isotope Data
Authors: Li Chunhai , Jiang Yaohui , Xing Guangfu , Guo Kunyi , Li Chao , Yu Minggang , Zhao Peng , Wang Zheng
Published: June 2015

The recently discoveredBaizhangyan skarn‐porphyry typeW–Modeposit in southernAnhui Province inSE China occurs near theMiddle–LowerYangtzeValley polymetallic metallogenic belt. The deposit is closely temporally‐spatially associated with theMesozoicQingyang granitic complex composed ofgranodiorite, monzoniticgranite, and alkalinegranite. Orebodies of the deposit occur as horizons, veins, and lenses within the limestones ofSinianLantianFormation contacting with buried fine‐grained granite, and diorite dykes. There are two types ofWmineralization: major skarnW–Momineralization and minor granite‐hosted disseminatedMomineralization. Among skarn mineralization, mineral assemblages and cross‐cutting relationships within both skarn ores and intrusions reveal two distinct periods of mineralization, i.e. the firstW–Auperiod related to the intrusion of diorite dykes, and the subsequentW–Moperiod related to the intrusion of the fine‐grained granite. In this paper, we report new zirconU–Pband molybdeniteRe–Osages with the aim of constraining the relationships among the monzonitic granite, fine‐grained granite, diorite dykes, andWmineralization. Zircons of the monzonitic granite, the fine‐grained granite, and diorite dykes yield weighted meanU–Pbages of 129.0 ± 1.2 Ma, 135.34 ± 0.92 Ma and 145.3 ± 1.7 Ma, respectively. Ten molybdeniteRe–Osage determinations yield an isochron age of 136.9 ± 4.5 Ma and a weighted mean age of 135.0 ± 1.2 Ma. The molybdenites have δ34Svalues of 3.6‰–6.6‰ and theirRecontents ranging from 7.23 ppm to 15.23 ppm. A second group of two molybdenite samples yield ages of 143.8 ± 2.1 and 146.3 ± 2.0 Ma, containingReconcentrations of 50.5–50.9 ppm, and with δ34S values of 1.6‰–4.8‰. The molybdenites from these two distinct groups of samples contain moderate concentrations ofRe(7.23–50.48 ppm), suggesting that metals within the deposit have a mixed crust–mantle provenance. Field observation and new age and isotope data obtained in this study indicate that the first diorite dyke‐related skarnW–Aumineralization took place in theEarlyCretaceous peaking at 143.0–146.3 Ma, and was associated with a mixed crust–mantle system. The second fine‐grained granite‐related skarnW–Momineralization took place a little later at 135.0–136.9 Ma, and was crust‐dominated. The fine‐grained granite was not formed by fractionation of theQingyang monzonitic granite. This finding suggests that the first period of skarnW–Aumineralization in theBaizhangyan deposit resulted from interaction between basaltic magmas derived from the upper lithospheric mantle and crustal material at 143.0–146.3 and the subsequent period ofW–Momineralization derived from the crust at 135.0–136.9 Ma.
Fathers' and mothers' attachment representations as predictors of preadolescents' attachment security: A ten‐year follow‐up of Finnish families
Authors: Kouvo Anna M. , Voeten Marinus , Silvén Maarit
Published: June 2015

The question of how mothers' and fathers' representations of attachment correlate ten years later with children's perceptions of attachment relationships was examined in a longitudinal study on Finnish families (N = 42). The parents completed the Adult Attachment Interview (AAI) during the child's first year of life. At 11 years, the children filled out three scales on how secure they perceive the relationship with each parent. Parents' AAI classifications and AAI dimensions based on continuous scales were used as predictors of the preadolescents' attachment security. Regression analyses demonstrated that fathers' but not mothers' State‐of‐Mind and Experience dimensions predicted preadolescents' security of attachment to father. The discussion focuses on the predictive validity of the classical categorical versus the recently proposed continuous approach and the different roles of parents in transmitting security from one generation to another.
Identification of the novel allele, HLA‐C*15:02:01:03, by full‐length genomic sequencing
Authors: Park B. G. , Oh H.‐B. , Jun J.‐H , Yoon C. E. , Kwon O.‐J.
Published: June 2015

The HLA‐C*15:02:01:03 allele differs from the HLA‐C*15:02:01:01 allele by a single‐nucleotide substitution in the 5′ untranslated region (−42 C>A).
Metadata Topic Harmonization and Semantic Search for Linked‐Data‐Driven Geoportals: A Case Study Using ArcGIS Online
Authors: Hu Yingjie , Janowicz Krzysztof , Prasad Sathya , Gao Song
Published: June 2015

Geoportals provide integrated access to geospatial resources, and enable both authorities and the general public to contribute and share data and services. An essential goal of geoportals is to facilitate the discovery of the available resources. Such a process relies heavily on the quality of metadata. While multiple metadata standards have been established, data contributers may adopt different standards when sharing their data via the same geoportal. This is especially the case for user‐generated content where various terms and topics can be introduced to describe similar datasets. While this heterogeneity provides a wealth of perspectives, it also complicates resource discovery. With the fast development of the Semantic Web technologies, there is a rise of Linked‐Data‐driven portals. Although these novel portals open up new ways to organize metadata and retrieve resources, they lack effective semantic search methods. This article addresses the two challenges discussed above, namely the topic heterogeneity brought by multiple metadata standards and the lack of established semantic search in Linked‐Data‐driven geoportals. To harmonize the metadata topics, we employ a natural language processing method, namely Labeled Latent Dirichlet Allocation (LLDA), and train it using standardized metadata from Data.gov. With respect to semantic search, we construct thematic and geographic matching features from the textual metadata descriptions, and train a regression model via a human participants experiment. We evaluate our methods by examining their performances in addressing the two issues. Finally, we implement a semantics‐enabled and Linked‐Data‐driven prototypical geoportal using a sample dataset from Esri's ArcGIS Online.
Complementary effect of oral administration of Lactobacillus paracasei K71 on canine atopic dermatitis
Authors: Ohshima‐Terada Yuri , Higuchi Yuki , Kumagai Takehisa , Hagihara Akihito , Nagata Masahiko
Published: June 2015

Background

Atopic dermatitis is a common skin disease encountered in dogs. Glucocorticoids are commonly recommended for symptomatic therapy and well‐tolerated adjunctive therapies may help to reduce the necessary dose and associated risks of chronic glucocorticoid use.

Hypothesis/Objectives

The purpose of this study was to evaluate the complementary efficacy of oral administration of Lactobacillus paracasei K71 in canine atopic dermatitis (cAD).

Animals

Forty one dogs with mild to moderate cAD were recruited by19 animal hospitals.

Methods

Dogs were assigned to receive either the investigational agent (K71 group; n = 20) or cetirizine hydrochloride (control group; n = 21). Previously prescribed medications were allowed to be continued during the 12 week trial. Dogs were assessed by the investigators using the cAD Extent and Severity Index (CADESI) and a medication scoring system. Pet owners assessed their dogs using a visual analog scale (VAS) and pruritus scores.

Results

The CADESI scores, VAS and pruritus scores in both groups at 12 weeks were improved compared with their baselines. The CADESI and pruritus scores in the K71 group were slightly lower than those in the control group and the reduction of medication scores in the K71 group was significantly lower compared with the control group (P < 0.05; Student's t‐test).

Conclusions and clinical importance

Oral administration of K71 can be useful in dogs with cAD as a complementary therapy, by providing a steroid‐sparing effect.
Household Cooking Range Tipover Accident Reconstruction Case Study
Authors: Brickman Dennis B. , Sanders Steven A.
Published: June 2015

A safety engineering accident investigation was conducted to analyze the circumstances surrounding an unwitnessed household child fatality allegedly associated with a cooking-range tipover. An accident reconstruction utilizing child dummies was performed to address various cooking-range tipover scenarios. Unlike previous research, the present test program uses a novel approach with an actual cooking range to evaluate child interaction during a tipover scenario. Results of the accident reconstruction case study indicate that the child’s death is inconsistent with a cooking-range tipover event. The results presented in this paper make a significant contribution to the technical literature concerning the safety analysis of cooking-range tipover events involving children through the utilization of child dummies. Caution should be used to generalize the results presented in this case study to the entire population, because any similar future situation must be analyzed on a case-by-case basis.
Simple synthetic protein scaffolds can create adjustable artificial MAPK circuits in yeast and mammalian cells
Authors: Ryu Jihoon , Park Sang-Hyun
Published: June 2015

Designer scaffolds reveal the minimal requirements of engineered MAPK scaffolds.
Bacterial-induced transformation
Authors: VanHook Annalisa M.
Published: June 2015

Salmonella
infection triggers signaling events that increase the probability of developing cancer in hosts that are genetically predisposed to transformation.
Treating cancer pain
Authors: Ferrarelli Leslie K.
Published: June 2015

Inhibiting vascular endothelial growth factor signaling may decrease pain sensitivity in cancer patients.
Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis
Authors: Garvey E. P. , Hoekstra W. J. , Schotzinger R. J. , Sobel J. D. , Lilly E. A. , Fidel P. L.
Published: June 2015

Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive
Candida albicans
, retained its
in vitro
potency (MIC
50
of ≤0.015 and MIC
90
of 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC
50
of 8 and MIC
90
of 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (
P
< 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 μg/ml) but fully sensitive
in vitro
to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 μg/ml) and moderately resistant to fluconazole (MIC of 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the
in vitro
MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.
Nephrotoxicity Comparison of Two Commercially Available Generic Vancomycin Products
Authors: Sutton Jesse D. , Mynatt Ryan P. , Kaye Keith S. , Murray Kyle P. , Rybak Michael J. , Pogue Jason M.
Published: June 2015

To date, no comparative clinical studies have investigated the effects of different vancomycin products on nephrotoxicity. The objective of this single-center, retrospective, matched-cohort study was to investigate the impact of two different vancomycin products on the development of nephrotoxicity. The study population included adults receiving a single vancomycin product, from either Pfizer or Hospira, for their entire course of therapy. Patients were matched based on underlying nephrotoxicity risk factors. Secondary outcomes included the need for renal replacement therapy, length of hospital stay, and in-hospital mortality. One-hundred forty-six matched pairs (
n
= 292) were included, and they had no significant differences in demographics, comorbid conditions, severity of illness, or vancomycin-associated nephrotoxicity risk factors. The frequency of nephrotoxicity was 8.9% in the Pfizer group and 11.0% in the Hospira group as defined by the 2009 consensus vancomycin guidelines (
P
= 0.56), 17.1% in the Pfizer group and 13.0% in the Hospira group as defined by the Acute Kidney Injury Network (AKIN) (
P
= 0.33), and 10.3% in the Pfizer group and 11.6% in the Hospira group as defined by RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria (
P
= 0.71). There were no differences between groups in regard to nephrotoxicity by any definition or in secondary outcomes. In multivariate analysis of overall nephrotoxicity risk factors, the type of vancomycin product was not independently associated with increased odds of developing nephrotoxicity according to the RIFLE criteria. Based on our results, there are no discernible differences between Pfizer and Hospira vancomycin products in the frequency of nephrotoxicity. Confirmation of these results with other types of vancomycin and different patient populations is warranted.
Development of a Novel Real-Time PCR Assay with High-Resolution Melt Analysis To Detect and Differentiate OXA-48-Like β-Lactamases in Carbapenem-Resistant Enterobacteriaceae
Authors: Hemarajata Peera , Yang Shangxin , Hindler Janet A. , Humphries Romney M.
Published: June 2015

The rapid global spread of carbapenem-resistant
Enterobacteriaceae
(CRE) poses an urgent threat to public health. More than 250 class D β-lactamases (OXAs) have been described in recent years, with variations in hydrolytic activity for β-lactams. The plasmid-borne OXA-48 β-lactamase and its variants are identified only sporadically in the United States but are common in Europe. Recognition of these OXA-48-like carbapenemases is vital in order to control their dissemination. We developed a real-time PCR assay based on high-resolution melt analysis, using
bla
OXA-48-like
-specific primers coupled with an unlabeled 3′-phosphorylated oligonucleotide probe (LunaProbe) homologous to OXA-48-like carbapenemase genes. The assay was validated using genomic DNA from 48 clinical isolates carrying a variety of carbapenemase genes, including
bla
KPC
,
bla
SME
,
bla
IMP
,
bla
NDM-1
,
bla
VIM
,
bla
OXA-48
,
bla
OXA-162
,
bla
OXA-181
,
bla
OXA-204
,
bla
OXA-244
,
bla
OXA-245
, and
bla
OXA-232
. Our assay identified the presence of
bla
OXA-48-like
β-lactamase genes and clearly distinguished between
bla
OXA-48
and its variants in control strains, including between
bla
OXA-181
and
bla
OXA-232
, which differ by only a single base pair in the assay target region. This approach has potential for use in epidemiological investigations and continuous surveillance to help control the spread of CRE strains producing OXA-48-like enzymes.
Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone
Authors: Garimella T. , Wang R. , Luo W.-L. , Wastall P. , Kandoussi H. , DeMicco M. , Bruce R. D. , Hwang C. , Bertz R. , Bifano M.
Published: June 2015

Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg;
n
= 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg;
n
= 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (
C
max
) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (
R
- and
S
-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for
R
-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24),
S
-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized
C
max
for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.
Prevalence of Plasmodium falciparum Resistance Markers to Sulfadoxine-Pyrimethamine among Pregnant Women Receiving Intermittent Preventive Treatment for Malaria in Uganda
Authors: Mbonye Anthony K. , Birungi Josephine , Yanow Stephanie K. , Shokoples Sandra , Malamba Samuel , Alifrangis Michael , Magnussen Pascal
Published: June 2015

The aim of this study was to assess the prevalence of mutations in
Plasmodium falciparum
dihydrofolate reductase (
Pfdhfr
) and dihydropteroate synthase (
Pfdhps
) genes among pregnant women using sulfadoxine-pyrimethamine (SP) as an intermittent preventive treatment (IPTp). A molecular epidemiological study of
P. falciparum
parasite resistance markers to SP was conducted from August 2010 to February 2012 in Mukono district in central Uganda. DNA was extracted from 413
P. falciparum
-positive samples. Real-time PCR, followed by melting curve analysis, was used to characterize point mutations in the
Pfdhfr
and
Pfdhps
genes that are associated with SP resistance. The prevalence of the single-nucleotide mutations in
Pfdhfr
at codons 51I, 59R, and 108N and in
Pfdhps
at codons 437G and 540E was high (>98%), reaching 100% fixation after one dose of SP, while the prevalence of 581G was 3.3% at baseline, reaching 12.5% after one dose of SP. At baseline, the prevalence of
Pfdhfr
and
Pfdhps
quintuple mutations was 89%, whereas the sextuple mutations (including 581G) were not prevalent (3.9%), reaching 16.7% after one dose of SP. However, the numbers of infections at follow-up visits were small, and hence there was insufficient statistical power to test whether there was a true rise in the prevalence of this allele. The overall high frequency of
Pfdhfr
and
Pfdhps
quintuple mutations throughout pregnancy excluded further analyses of possible associations between certain haplotypes and the risk of lower birth weight and anemia. However, women infected with
P. falciparum
had 1.3-g/dl-lower hemoglobin levels (
P
= 0.001) and delivered babies with a 400-g-lower birth weight (
P
= 0.001) compared to nonparasitemic women. Despite this, 44 women who were
P. falciparum
positive at baseline became negative after one or two doses of SP (i.e., 50.5%), implying that SP-IPTp still has some efficacy.
P. falciparum
resistance markers to SP are high in this population, whereas
P. falciparum
infection was associated with poor birth outcomes.
Discrimination between Native and Tn
6010
-Associated
oqxAB
in Klebsiella spp., Raoultella spp., and other Enterobacteriaceae by Using a Two-Step Strategy
Authors: Guillard Thomas , Lebreil Anne-Laure , Hansen Lars Hestbjerg , Kisserli Aymric , Berger Sibel , Lozniewski Alain , Alauzet Corentine , de Champs Christophe
Published: June 2015

We developed a two-step PCR-based strategy to detect genes encoding OqxAB, allowing a specific assignment of Tn
6010
-associated
oqxAB
in
Enterobacteriaceae
. Chromosomal location in this setup was confirmed by hybridization with I-
Ceu
I-restricted genomes. This approach led us to find that
Klebsiella
sp. and
Raoultella
sp. reference strains chromosomally carried
oqxAB
.
Pharmacodynamics of Fosfomycin: Insights into Clinical Use for Antimicrobial Resistance
Authors: Docobo-Pérez F. , Drusano G. L. , Johnson A. , Goodwin J. , Whalley S. , Ramos-Martín V. , Ballestero-Tellez M. , Rodriguez-Martinez J. M. , Conejo M. C. , van Guilder M. , Rodríguez-Baño J. , Pascual A. , Hope W. W.
Published: June 2015

The aim of this study was to improve the understanding of the pharmacokinetic-pharmacodynamic relationships of fosfomycin against extended-spectrum beta-lactamase (ESBL)-producing
Escherichia coli
strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing
E. coli
strains. Human fosfomycin pharmacokinetic profiles were simulated over 4 days. Preliminary studies conducted to determine the dose ranges, including the dose ranges that suppressed the development of drug-resistant mutants, were conducted with regimens from 12 g/day to 36 g/day. The combination of fosfomycin at 4 g every 8 h (q8h) and meropenem at 1 g/q8h was selected for further assessment. The total bacterial population and the resistant subpopulations were determined. No efficacy was observed against the Ec42444 strain (fosfomycin MIC, 64 mg/liter) at doses of 12, 24, or 36 g/day. All dosages induced at least initial bacterial killing against Ec46 (fosfomycin MIC, 1 mg/liter). High-level drug-resistant mutants appeared in this strain in response to 12, 15, and 18 g/day. In the study arms that included 24 g/day, once or in a divided dose, a complete extinction of the bacterial inoculum was observed. The combination of meropenem with fosfomycin was synergistic for bacterial killing and also suppressed all fosfomycin-resistant clones of Ec2974 (fosfomycin MIC, 1 mg/liter). We conclude that fosfomycin susceptibility breakpoints (≤64 mg/liter according to CLSI [for
E. coli
urinary tract infections only]) should be revised for the treatment of serious systemic infections. Fosfomycin can be used to treat infections caused by organisms that demonstrate lower MICs and lower bacterial densities, although relatively high daily dosages (i.e., 24 g/day) are required to prevent the emergence of bacterial resistance. The ratio of the area under the concentration-time curve for the free, unbound fraction of fosfomycin versus the MIC (
f
AUC/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against
E. coli
strains in preventing the emergence of fosfomycin resistance.
In Vivo
Biocompatibility and
In Vitro
Efficacy of Antimicrobial Gendine-Coated Central Catheters
Authors: Jamal Mohamed A. , Hachem Ray Y. , Rosenblatt Joel , McArthur Mark J. , Felix Edd , Jiang Ying , Tailor Ramesh C. , Raad Issam
Published: June 2015

Antimicrobial peripherally inserted central catheters (PICCs) might reduce the incidence of central line-associated bloodstream infections (CLABSI). We tested the biocompatibility of a novel gendine-coated (combination of chlorhexidine [CHX] and gentian violet [GV]) PICC in a rabbit intravascular model and tested antimicrobial efficacy in comparison with commercially available minocycline/rifampin (M/R)- and CHX-treated PICCs in an
in vitro
biofilm colonization model. Gendine-coated and uncoated control PICCs were inserted in the jugular veins of rabbits for 4 days. Histopathological analysis was performed at the end of the 4-day period, and circulating levels of CHX and GV in the blood were measured at different time points using liquid chromatography-mass spectrometry. The antimicrobial efficacy of the PICCs was tested following simulated intravascular indwells of 24 h and 1 week against clinical isolates of methicillin-resistant
Staphylococcus aureus
, vancomycin-resistant enterococci,
Pseudomonas aeruginosa
,
Escherichia coli
,
Acinetobacter baumannii
,
Enterobacter cloacae
,
Candida albicans
, and
Candida glabrata
. Rabbits implanted with gendine-coated PICCs exhibited reduced levels of thrombosis and inflammation compared to those of the rabbits with uncoated controls. No GV was detected in blood samples over the entire study period, and trace concentrations of CHX were detected. The gendine-coated PICCs completely prevented the adherence of all pathogens from 24 h to 1 week (
P
≤ 0.001), while M/R-treated, CHX-treated, and control PICCs did not. Gendine-coated PICCs were highly effective in preventing biofilm formation of multidrug-resistant pathogenic bacteria and fungi. Gendine-coated PICCs were biocompatible in an intravascular setting. Further, the pharmacokinetic testing established that acute systemic exposures of CHX and GV from the gendine-coated catheters were well within safe levels.
Bacterial Internalization, Localization, and Effectors Shape the Epithelial Immune Response during Shigella flexneri Infection
Authors: Lippmann Juliane , Gwinner Frederik , Rey Camille , Tamir Uyanga , Law Helen K. W. , Schwikowski Benno , Enninga Jost
Published: June 2015

Intracellular pathogens are differentially sensed by the compartmentalized host immune system. Nevertheless, gene expression studies of infected cells commonly average the immune responses, neglecting the precise pathogen localization. To overcome this limitation, we dissected the transcriptional immune response to
Shigella flexneri
across different infection stages in bulk and single cells. This identified six distinct transcriptional profiles characterizing the dynamic, multilayered host response in both bystander and infected cells. These profiles were regulated by external and internal danger signals, as well as whether bacteria were membrane bound or cytosolic. We found that bacterial internalization triggers a complex, effector-independent response in bystander cells, possibly to compensate for the undermined host gene expression in infected cells caused by bacterial effectors, particularly OspF. Single-cell analysis revealed an important bacterial strategy to subvert host responses in infected cells, demonstrating that OspF disrupts concomitant gene expression of proinflammatory, apoptosis, and stress pathways within cells. This study points to novel mechanisms through which bacterial internalization, localization, and injected effectors orchestrate immune response transcriptional signatures.
From (p)ppGpp to (pp)pGpp: Characterization of Regulatory Effects of pGpp Synthesized by the Small Alarmone Synthetase of Enterococcus faecalis
Authors: Gaca Anthony O. , Kudrin Pavel , Colomer-Winter Cristina , Beljantseva Jelena , Liu Kuanqing , Anderson Brent , Wang Jue D. , Rejman Dominik , Potrykus Katarzyna , Cashel Michael , Hauryliuk Vasili , Lemos José A
Published: June 2015

The bacterial stringent response (SR) is a conserved stress tolerance mechanism that orchestrates physiological alterations to enhance cell survival. This response is mediated by the intracellular accumulation of the alarmones pppGpp and ppGpp, collectively called (p)ppGpp. In
Enterococcus faecalis
, (p)ppGpp metabolism is carried out by the bifunctional synthetase/hydrolase
E. faecalis
Rel (Rel
Ef
) and the small alarmone synthetase (SAS) RelQ
Ef
. Although Rel is the main enzyme responsible for SR activation in
Firmicutes
, there is emerging evidence that SASs can make important contributions to bacterial homeostasis. Here, we showed that RelQ
Ef
synthesizes ppGpp more efficiently than pppGpp without the need for ribosomes, tRNA, or mRNA. In addition to (p)ppGpp synthesis from GDP and GTP, RelQ
Ef
also efficiently utilized GMP to form GMP 3′-diphosphate (pGpp). Based on this observation, we sought to determine if pGpp exerts regulatory effects on cellular processes affected by (p)ppGpp. We found that pGpp, like (p)ppGpp, strongly inhibits the activity of
E. faecalis
enzymes involved in GTP biosynthesis and, to a lesser extent, transcription of
rrnB
by
Escherichia coli
RNA polymerase. Activation of
E. coli
RelA synthetase activity was observed in the presence of both pGpp and ppGpp, while RelQ
Ef
was activated only by ppGpp. Furthermore, enzymatic activity of RelQ
Ef
is insensitive to relacin, a (p)ppGpp analog developed as an inhibitor of “long” RelA/SpoT homolog (RSH) enzymes. We conclude that pGpp can likely function as a bacterial alarmone with target-specific regulatory effects that are similar to what has been observed for (p)ppGpp.

IMPORTANCE
Accumulation of the nucleotide second messengers (p)ppGpp in bacteria is an important signal regulating genetic and physiological networks contributing to stress tolerance, antibiotic persistence, and virulence. Understanding the function and regulation of the enzymes involved in (p)ppGpp turnover is therefore critical for designing strategies to eliminate the protective effects of this molecule. While characterizing the (p)ppGpp synthetase RelQ of
Enterococcus faecalis
(RelQ
Ef
), we found that, in addition to (p)ppGpp, RelQ
Ef
is an efficient producer of pGpp (GMP 3′-diphosphate).
In vitro
analysis revealed that pGpp exerts complex, target-specific effects on processes known to be modulated by (p)ppGpp. These findings provide a new regulatory feature of RelQ
Ef
and suggest that pGpp may represent a new member of the (pp)pGpp family of alarmones.
Trial of Intensive Acupuncture for Smoking Cessation: A Pilot Study
Authors: McFadden David D , Chon Tony Y , Croghan Ivana T , Schroeder Darrell R , Mallory Molly J , Ebbert Jon O , Hays J Taylor
Published: June 2015

Background

Despite the significant decline in smoking rates in the USA over the last 50 years, 42 million Americans continue to smoke. Although the combination of behavioural counselling with FDA-approved medications offers the best evidence-based treatment approach, 12-month relapse rates remain at >60%. Both healthcare providers and patients are searching for alternative treatment options. Most acupuncture trials have yielded poor results for smoking cessation; however, most trials have not used an intense treatment protocol and maintained treatment for at least 12 weeks.

Methods

We designed a pilot study to address these methodological problems. Twenty-eight smokers were recruited to attend two 1 h acupuncture sessions weekly for 12 weeks. Primary endpoints included completion rate, acceptability of the protocol and side effects. Secondary endpoints included carbon monoxide (CO)-confirmed, 7-day point prevalence quit rates at 12 weeks and 26 weeks.

Results

Sixteen of the 28 patients enrolled (57%) completed 12 weeks of treatment. Of the 17 patients who completed the end-of-study questionnaire, 94% (16/17) rated the programme as helpful, and 82% noted they would recommend it to friends for smoking cessation. Three of the 28 who initially enrolled in the study were confirmed abstinent at 12 weeks (10.7%); one of the 28 (3.6%) was abstinent at 26 weeks.

Conclusions

A larger study with a slightly less rigorous and more acceptable treatment protocol is feasible and should be considered.
What matters most for end-of-life care? Perspectives from community-based palliative care providers and administrators
Authors: Mistry Bina , Bainbridge Daryl , Bryant Deanna , Tan Toyofuku Sue , Seow Hsien
Published: June 2015

Objectives

There has been little research conducted to understand the essential meaning of quality, community-based, end-of-life (EOL) care, despite the expansion of these services. The purpose of this study was to define what matters most for EOL care from the perspective of a diverse range of palliative care providers in the community who have daily encounters with death and dying.

Methods

We used interviews to explore the perceptions of providers and administrators from 14 specialised palliative care teams in Ontario, Canada. Participants were prompted with the question ‘What matters most for EOL care?’ Responses were analysed using a phenomenological approach to derive themes depicting the universal essence of EOL care.

Results

Data from 107 respondents were obtained and analysed, from which 40 formulated concepts emerged; these were further grouped into 9 themes. Of the respondents, 39% were nurses, 19% physicians, 27% were supervisors or executives and 15% other. The most predominate concept was thatPatient's Wishes are Fulfilled, cited by almost half the respondents. The most prominent themes wereAddressing the Non-physical Needs,Healthcare Teams’ Nature of Palliative Care Delivery,Patient Wishes are Honoured,Addressing the Physical Needs,Preparing for and Accepting Death,Communication and Relationship Development, andInvolving and Supporting the Family.

Conclusions

9 critical domains of EOL care evolved from the interviews, indicating that quality EOL care extends beyond managing physical pain, but includes a holistic perspective of care, a healthcare team dedicated to the EOL journey and a patient-centred pathway. Tailoring the provision of care to consider these important elements plays a critical role in supporting a positive EOL experience for patients and families.
An approach to acute lower gastrointestinal bleeding
Authors: Frost John , Sheldon Faye , Kurup Arun , Disney Benjamin R , Latif Sherif , Ishaq Sauid
Published: June 2015

Lower gastrointestinal bleeding (LGIB) is a common problem that can be treated via a number of endoscopic, radiological and surgical approaches. Although traditionally managed by the colorectal surgeons, surgery should be considered a last resort given the variety of endoscopic and radiological approaches available. This article provides an overview on the common causes of acute LGIB and the various techniques at our disposal to control it.
Association between New Jersey's Graduated Driver Licensing decal provision and crash rates of young drivers with learners' permits
Authors: Curry Allison E , Pfeiffer Melissa R , Elliott Michael R , Durbin Dennis R
Published: June 2015

New Jersey (NJ) implemented the first-in-the-US Graduated Driver Licensing (GDL) decal provision in May 2010 for young drivers with learner's permits or intermediate licenses. Previous analyses found an association between the provision and crash reduction among intermediate drivers. The aim of this study is to examine the association between NJ’s provision and GDL citation and crash rates among drivers aged <21 years with learner's permits. We estimated monthly per-driver rates from January 2006 through June 2012. Negative binomial modeling compared pre and post decal crash rates adjusted for gender, age, calendar month, and gas price. The monthly GDL citation rate was two per 10 000 drivers in the predecal and postdecal periods. Crashes were rare and rates declined similarly pre and post decal (adjusted rate ratio of postdecal vs predecal slope: 1.04 (0.97 to 1.12)). NJ's GDL decal provision was not associated with a change in citation or crash rates among young NJ drivers with learner's permits.
Portal inflammation during NAFLD is frequent and associated with the early phases of putative hepatic progenitor cell activation
Authors: Carotti Simone , Vespasiani-Gentilucci Umberto , Perrone Giuseppe , Picardi Antonio , Morini Sergio
Published: June 2015

Aims

We investigated whether portal tract inflammation observed in non-alcoholic fatty liver disease (NAFLD) is associated with hepatic progenitor cell compartment activation, as thoroughly evaluated with different markers of the staminal lineage.

Methods

Fifty-two patients with NAFLD were studied. NAFLD activity score, fibrosis and portal inflammation were histologically evaluated. Putative hepatic progenitor cells, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for cytokeratin (CK)-7, CK-19 and epithelial cell adhesion molecule (EpCAM), and a hepatic progenitor cell compartment score was derived. Hepatic stellate cell and myofibroblast activity was determined by immunohistochemistry for α-smooth muscle actin.

Results

Portal inflammation was absent in a minority of patients, mild in 40% of cases and more than mild in about half of patients, showing a strong correlation with fibrosis (r=0.76, p<0.001). Portal inflammation correlated with CK-7-counted putative hepatic progenitor cells (r=0.48, p<0.001), intermediate hepatobiliary cells (r=0.6, p<0.001) and bile ductules/interlobular bile ducts (r=0.6, p<0.001), and with the activity of myofibroblasts (r=0.5, p<0.001). Correlations were confirmed when elements were counted by immunostaining for CK-19 and EpCAM. Lobular inflammation, ballooning, myofibroblast activity and hepatic progenitor cell compartment activation were associated with portal inflammation by univariate analysis. In the multivariate model, the only variable independently associated with portal inflammation was hepatic progenitor cell compartment activation (OR 3.7, 95% CI 1.1 to 12.6).

Conclusions

Portal inflammation is frequent during NAFLD and strongly associated with activation of putative hepatic progenitor cells since the first steps of their differentiation, portal myofibroblast activity and fibrosis.
Republished: Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm
Authors: Khatibi Kasra , Heit Jeremy J , Telischak Nicholas A , Elbers Jorina M , Do Huy M
Published: June 2015

A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral artery (PCA) aneurysm. This aneurysm was successfully treated by endovascular coil sacrifice of the affected segment of the PCA. The patient made an excellent recovery with no significant residual neurologic deficit.
Republished: Covered stents for exclusion of iatrogenic common carotid artery–internal jugular vein fistula and brachiocephalic artery pseudoaneurysm
Authors: Kooraki Soheil , Grohmann Jochen , Elshikh Samer , Urbach Horst , Meckel Stephan
Published: June 2015

Covered stents have rarely been used in neuroendovascular procedures. We report the case of a 74-year-old woman with a complex iatrogenic vascular injury from attempted insertion of a hemodialysis catheter: concurrent brachiocephalic artery pseudoaneurysm and common carotid artery to internal jugular vein fistula. Both lesions were excluded successfully by using two balloon-expandable covered stents with a satisfactory short-term clinical and angiographic outcome.
Routine diversion of patients with STEMI to high-volume PCI centres: modelling the financial impact on referral hospitals
Authors: Pathak Elizabeth Barnett , Comins Meg M , Forsyth Colin J , Strom Joel A
Published: June 2015

Objective

To quantify possible revenue losses from proposed ST-elevation myocardial infarction (STEMI) patient diversion policies for small hospitals that lack high-volume percutaneous coronary intervention (PCI) capability status (ie, ‘STEMI referral hospitals’).

Background

Negative financial impacts on STEMI referral hospitals have been discussed as an important barrier to implementing regional STEMI bypass/transfer protocols. However, there is little empirical data available that directly quantifies this potential financial impact.

Methods

Using detailed financial charges from Florida hospital discharge data, we examined the potential negative financial impact on 112 STEMI referral hospitals from losing all inpatient STEMI revenue. The main outcome was projected revenue loss (PRL), defined as total annual patient with STEMI charges as a proportion of total annual charges for all patients. We hypothesised that for most community hospitals (>90%), STEMI revenue represented only a small fraction of total revenue (<1%). We further examined the financial impact of the ‘worst case’ scenario of loss of all acute coronary syndrome (ACS) (ie, chest pain) patients.

Results

PRLs were $0.33 for every $100 of patient revenue statewide for STEMI and $1.73 for ACS. At the individual hospital level, the 90th centile PRL was $0.74 for STEMI and $2.77 for ACS. PRLs for STEMI were not greater in rural areas compared with major metropolitan areas. Hospital revenue centres that would be most impacted by loss of patients with STEMI were cardiology procedures and intensive care units.

Conclusions

Loss of patient with STEMI revenues would result in only a small financial impact on STEMI referral hospitals in Florida under proposed STEMI diversion/rapid transfer protocols. However, spillover loss of patients with ACS would increase revenue loss for many hospitals.
Obesity and inflammatory arthritis: impact on occurrence, disease characteristics and therapeutic response
Authors: Daïen Claire I , Sellam Jérémie
Published: June 2015

Overweight and obesity are increasing worldwide and now reach about one-third of the world's population. Obesity also involves patients with inflammatory arthritis. Knowing the impact of obesity on rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis) is thus an important issue. This article first reviews the epidemiological and clinical data available on obesity in inflammatory rheumatic diseases, that is, its impact on incident disease, disease characteristics and the therapeutic response. The second part of this review gives an overview of the factors potentially involved in the specifics of inflammatory arthritis in patients with obesity, such as limitations in the clinical assessment, diet, microbiota and adipokines.
Lumbar subarachnoid diverticulum secondary to a sarcoma in the sacral canal of a dog
Authors: Lobacz Monika Anna , Gutierrez Crespo Beatriz Teresa , Philbey Adrian W , Hammond Gawain
Published: June 2015

Subarachnoid extramedullary intraspinal ‘cysts’ containing cerebrospinal fluid (CSF), known as ‘diverticula’, can occur due to chronic inflammation or trauma in human beings and veterinary species. In dogs, these diverticula typically occur in the dorsal subarachnoid space at the level of the first and third cervical vertebrae of young, large breed dogs, or at the level of the caudal thoracic vertebrae of older, medium and small breed dogs. We present a case of a seven‐year‐old female neutered flat‐coated retriever which experienced clinical signs localised to the cauda equina. Myelography and computed radiography (CT) imaging demonstrated a subarachnoid diverticulum in the ventral subarachnoid space at the level of the seventh lumbar vertebra (L7) cranial to a spinal sarcoma.