bluuebunny/crossref_metadata_2025_split huggingface dataset:
Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance
Authors: Ly Neang S. , Bulitta Jürgen B. , Rao Gauri G. , Landersdorfer Cornelia B. , Holden Patricia N. , Forrest Alan , Bergen Phillip J. , Nation Roger L. , Li Jian , Tsuji Brian T. 
Published: March 2015

Abstract

Objectives
Colistin is an ‘old’ drug, which is being increasingly utilized due to limited therapeutic options. However, resistance emergence during monotherapy is concerning. Here, our objective was to optimize colistin combinations against Pseudomonas aeruginosa by profiling the time course of synergistic killing and prevention of resistance.

Methods
Hollow-fibre infection models over 10 days simulated clinically relevant dosage regimens of colistin and doripenem against two heteroresistant P. aeruginosa strains (MIC 1 mg/L) and one resistant (MIC 128 mg/L) strain (inoculum 109.3 cfu/mL). New mathematical mechanism-based models (MBMs) were developed using S-ADAPT.

Results
Against heteroresistant P. aeruginosa strains, colistin monotherapy resulted in initial killing (up to 2.64 log10 cfu/mL) within 24 h followed by regrowth. High-intensity combinations involving free steady-state colistin concentrations of 5 mg/L achieved complete eradication (&gt;9.3 log10 killing) within 48 h. These combinations achieved synergy with up to 9.38 log10 greater killing compared with the most active monotherapy. Against the colistin-resistant strain, the combination yielded marked initial synergy with up to 6.11 log10 cfu/mL bacterial reductions within 72 h followed by regrowth. The MBMs quantified total and resistant subpopulations and the proposed synergy between colistin and doripenem.

Conclusions
Our findings provide insight into optimal antibiotic treatment and may serve as a framework for new drug combinations and combination modelling.
Wide dissemination of linezolid-resistant Staphylococcus epidermidis in Greece is associated with a linezolid-dependent ST22 clone
Authors: Karavasilis Vasilios , Zarkotou Olympia , Panopoulou Maria , Kachrimanidou Melina , Themeli-Digalaki Katerina , Stylianakis Antonios , Gennimata Vassiliki , Ntokou Eleni , Stathopoulos Constantinos , Tsakris Athanasios , Pournaras Spyros ,   on behalf of the Greek Study Group on Staphylococcal Linezolid Resistance, Kouskouni E. , Vrioni G. , Mamali V. , Kousouli E. , Papagiannakopoulou P. , Kristo I. , Dafopoulou K. , Hadjichristodoulou C. , Carle P. , Kimouli M. , Perivolioti E. , Nepka M. , Foudoulis K. , Stathoulopoulou F. , Papanikolaou P. , Poulou A. , Tsorlini Eleni 
Published: March 2015

Abstract

Objectives
Dependence on linezolid was recently described as significant growth acceleration of linezolid-resistant Staphylococcus epidermidis (LRSE) isolates upon linezolid exposure. We investigated the possible contribution of linezolid dependence to LRSE dissemination in Greece.

Methods
Linezolid resistance rates were estimated in six tertiary hospitals located throughout Greece between 2011 and 2013. Sixty-three randomly selected LRSE recovered in these hospitals during this period were studied. Growth curve analysis was conducted with and without linezolid. Clonality of the isolates was investigated by PFGE and MLST.

Results
During the study period, the LRSE rate in the participating hospitals rose significantly from 6.9% to 9% (P = 0.006); the increase was more prominent in ICUs (from 15.1% to 20.9%; P = 0.005). Forty-seven (74.6%) of the 63 LRSE, derived from all study hospitals, clearly exhibited linezolid dependence, growing significantly faster in the presence of 16 and 32 mg/L linezolid. Of note, 61 (96.8%) LRSE exhibited a single macrorestriction pattern and belonged to ST22, which included all linezolid-dependent LRSE. The remaining two LRSE belonged to unique STs. Five of six linezolid-dependent isolates tested also exhibited linezolid dependence upon exposure to 8 mg/L linezolid. Interestingly, five of six ST22 linezolid-non-dependent isolates tested developed linezolid dependence when linezolid exposure preceded growth analysis.

Conclusions
The rapid LRSE dissemination in Greek hospitals threatens linezolid activity. The observation that most LRSE belonged to ST22 and expressed dependence on linezolid clearly implies that the spread of linezolid resistance should have been driven by this trait, which provided the LRSE with a selective advantage under linezolid pressure.
HIV-1 integrase genotyping is reliable and reproducible for routine clinical detection of integrase resistance mutations even in patients with low-level viraemia
Authors: Armenia D. , Fabeni L. , Alteri C. , Di Pinto D. , Di Carlo D. , Bertoli A. , Gori C. , Carta S. , Fedele V. , Forbici F. , D'Arrigo R. , Svicher V. , Berno G. , Pizzi D. , Nicastri E. , Sarmati L. , Pinnetti C. , Ammassari A. , D'Offizi G. , Latini A. , Andreoni M. , Antinori A. , Ceccherini-Silberstein F. , Perno C. F. , Santoro M. M. 
Published: March 2015

Abstract

Objectives
Integrase drug resistance monitoring deserves attention because of the increasing number of patients being treated with integrase strand-transfer inhibitors. Therefore, we evaluated the integrase genotyping success rate at low-level viraemia (LLV, 51–1000 copies/mL) and resistance in raltegravir-failing patients.

Methods
An integrase genotypic resistance test (GRT) was performed on 1734 HIV-1 samples collected during 2006–13. Genotyping success rate was determined according to the following viraemia levels: 51–500, 501–1000, 1001–10 000, 10 001–100 000 and &gt;100 000 copies/mL. The reproducibility of integrase GRT was evaluated in 41 plasma samples processed in duplicate in two reference centres. The relationship between LLV and resistance prevalence was evaluated in a subset of 120 raltegravir-failing patients.

Results
Overall, the integrase genotyping success rate was 95.7%. For viraemia levels 51–500 and 501–1000 copies/mL, the rate of success was 82.1% and 94.0%, respectively. GRT was reproducible, producing sequences with a high similarity and an equal resistance profile regardless of the sequencing centre or viraemia level. Resistance was detected both at LLV and at viraemia &gt;1000 copies/mL (51–500 copies/mL = 18.2%; 501–1000 = 37.5%; 1001–10 000 = 53.7%; 10 001–100 000 = 30.0%; and &gt;100 000 = 30.8%). At viraemia ≤500 copies/mL, Q148H/K/R and N155H had the same prevalence (9.1%), while the Y143C/H/R was completely absent. At early genotyping (within 3 months of raltegravir treatment), Q148H/K/R and N155H mutations were detected regardless of the viraemia level, while Y143C/H/R was observed only in samples with viraemia &gt;1000 copies/mL.

Conclusions
Our findings prove the reliability of HIV-1 integrase genotyping and reinforce the concept that this assay may be useful in the management of failures even at LLV.
Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe
Authors: Swartz J. E. , Vandekerckhove L. , Ammerlaan H. , de Vries A. C. , Begovac J. , Bierman W. F. W. , Boucher C. A. B. , van der Ende M. E. , Grossman Z. , Kaiser R. , Levy I. , Mudrikova T. , Paredes R. , Perez-Bercoff D. , Pronk M. , Richter C. , Schmit J. C. , Vercauteren J. , Zazzi M. , Židovec Lepej S. , De Luca A. , Wensing A. M. J. 
Published: March 2015

Abstract

Background
The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice.

Methods
A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm.

Results
Efficacy analysis of 1608 patients showed virological suppression to &lt;50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count &lt;200 cells/mm³ (P &lt; 0.001), GSS &lt;3 (P = 0.002) and use of lamivudine (P &lt; 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS &lt;3. After 1 year of second-line therapy, viral load was suppressed to &lt;50 copies/mL in 73.5% (OT).

Conclusions
In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS &lt;3.
Small molecule inhibitors of the annexin A2 heterotetramer prevent human papillomavirus type 16 infection
Authors: Woodham Andrew W. , Taylor Julia R. , Jimenez Andrew I. , Skeate Joseph G. , Schmidt Thomas , Brand Heike E. , Da Silva Diane M. , Kast W. Martin 
Published: March 2015

Abstract

Objectives
High-risk human papillomavirus (HPV) infection leads to the development of several human cancers that cause significant morbidity and mortality worldwide. HPV type 16 (HPV16) is the most common of the cancer-causing genotypes and gains entry to the basal cells of the epithelium through a non-canonical endocytic pathway that involves the annexin A2/S100A10 heterotetramer (A2t). A2t is composed of two annexin A2 monomers bound to an S100A10 dimer and this interaction is a potential target to block HPV16 infection. Here, recently identified small molecule inhibitors of A2t (A2ti) were investigated for their ability to prevent HPV16 infection in vitro.

Methods
A2ti were added to HeLa cells in increasing concentrations prior to the addition of HPV16. Cytotoxicity was evaluated via trypan blue exclusion. HPV16 pseudovirion infection and fluorescently labelled HPV16 capsid internalization was measured with flow cytometry.

Results
A2ti blocked HPV16 infection by 100% without substantial cellular toxicity or reduction in cell growth. Furthermore, A2ti blocked HPV16 entry into epithelial cells by 65%, indicating that the observed inhibition of HPV16 infection is in part due to a block in entry and that non-infectious entry may occur in the absence of A2t binding.

Conclusions
These results demonstrate that targeting A2t may be an effective strategy to prevent HPV16 infection.
A blind CO detection of a distant red galaxy in the HS1700+64
protocluster
Authors: Chapman S. C. , Bertoldi F. , Smail Ian , Blain A. W. , Geach J. E. , Gurwell M. , Ivison R. J. , Petitpas G. R. , Reddy N. , Steidel C. C. 
Published: March 2015

Abstract
We report the blind detection of 12CO emission from a distant red galaxy, HS1700.DRG55. We have used the IRAM Plateau de Bure Interferometer WideX, with its 3.6 GHz of instantaneous dual-polarization bandwidth, to target 12CO(3–2) from galaxies lying in the protocluster at z = 2.300 in the field HS1700+64. If indeed this line in DRG55 is 12CO(3–2), its detection at 104.9 GHz indicates zCO = 2.296. None of the other eight known z ∼ 2.30 protocluster galaxies lying within the primary beam (PB) are detected in 12CO, although the limits are ∼2 × worse towards the edge of the PB where several lie. The optical/near-IR magnitudes of DRG55 (RAB &gt; 27, KAB = 22.3) mean that optical spectroscopic redshifts are difficult with 10-m-class telescopes, but near-IR redshifts would be feasible. The 24-μm-implied star formation rate (210 M⊙ yr−1), stellar mass (∼1011 M⊙) and 12CO line luminosity (3.6 × 1010 K km s−1 pc2) are comparable to other normal12CO-detected star-forming galaxies in the literature, although the galaxy is some ∼2 mag (∼6 ×) fainter in the rest-frame UV than 12CO-detected galaxies at z &gt; 2. The detection of DRG55 in 12CO complements three other 12CO detected UV-bright galaxies in this protocluster from previous studies, and suggests that many optically faint galaxies in the protocluster may host substantial molecular gas reservoirs, and a full blind census of 12CO in this overdense environment is warranted.
Predictors of subjective versus objective cognitive functioning in patients with stable grades II and III glioma
Authors: Gehring Karin , Taphoorn Martin J.B. , Sitskoorn Margriet M. , Aaronson Neil K. 
Published: March 2015

Abstract

Background
Studies in cancer and noncancer populations demonstrate lower than expected correlations between subjective cognitive symptoms and cognitive functioning as determined by standardized neuropsychological tests. This paper systematically examines the association between subjective and objective cognitive functioning in patients with low-grade glioma and the associations of these indicators of cognitive function with clusters of sociodemographic, clinical, and self-reported physical and mental health factors.

Methods
Multiple regression analyses with the subjective and 2 objective indicators of cognitive functioning as dependent variables and 4 clusters of predictor variables were conducted in 169 patients with predominantly low-grade glioma.

Results
Correlations between the subjective and the 2 objective cognitive indicators were negligible (0.04) to low (0.24). Objective cognitive deficits were predominantly associated with sociodemographic (older age, lower education, male sex) and clinical (left hemisphere tumor) variables, while lower ratings of subjective cognitive function were more closely related to self-reported mental health symptoms (fatigue, lower mental well-being), physical (motor) dysfunction and female sex. Self-reported communication deficits were associated significantly with both subjective and objective dysfunction.

Conclusions
We recommend that both subjective and objective measures of cognitive functioning, together with a measure of psychological distress, be used for comprehensive neuropsychological assessments of patients with glioma to determine which areas are most affected and which specific intervention strategies are most appropriate.
Acute Pancreatitis in the Pediatric Intensive Care Unit
Authors: Goday Praveen S. , Wakeham Martin , Kuhn Evelyn M. , Collins Maureen M. , Werlin Steven L. 
Published: March 2015

ABSTRACTAim:The aim of this study is to describe the demographics and outcomes of children with a discharge diagnosis of acute pancreatitis (AP) from the pediatric intensive care unit (PICU).Methods:Data for this retrospective cohort study were obtained from a multisite, clinical PICU database. PICU discharges with a primary or secondary diagnosis of AP (SAP) between 2009 and 2013 from 113 centers were reviewed. We also obtained the Pediatric Index of Mortality 2 Risk of Mortality (PIM2ROM), an indicator of the severity of illness.Results:Of 360,162 PICU discharges, 2026 with a diagnosis of AP were analyzed further (0.56%)—331 had a primary diagnosis of AP, whereas 1695 had a SAP. Among children with primary AP, median PIM2ROM was 1.0% (interquartile range [IQR] 0.8%–1.4%). Fifty‐five children with primary AP (16.6%) required mechanical ventilation (MV) for a median of 3.8 days (IQR 1.0–9.3). The length of stay (LOS) in PICU was a median of 2.95 days (IQR 1.53–5.90). Only 1 patient died (mortality 0.3%). Among children with secondary AP, median PIM2ROM was 1.1% (IQR 0.8%–4.0%). A total of 711 children (42.0%) with secondary AP required MV for a median of 5.8 days (IQR 1.8–14.0). PICU LOS was a median of 4.43 days (IQR 1.84–11.22). There were 115 deaths in this group (mortality 6.8%). Median PIM2ROM, PICU LOS, mortality (all P < 0.001), and length of MV (P = 0.035) were significantly greater in children with secondary AP than with primary AP.Conclusions:Unlike in adult series, children with AP rarely die. Patients with secondary AP experience more morbidity and mortality than patients with primary AP.
When Doing Wrong Feels So Right: Normalization of Deviance
Authors: Price Mary R. , Williams Teresa C. 
Published: March 2015

Abstract

Normalization of deviance is a term first coined by sociologist Diane Vaughan when reviewing the Challenger disaster. Vaughan noted that the root cause of the Challenger disaster was related to the repeated choice of NASA officials to fly the space shuttle despite a dangerous design flaw with the O-rings. Vaughan describes this phenomenon as occurring when people within an organization become so insensitive to deviant practice that it no longer feels wrong. Insensitivity occurs insidiously and sometimes over years because disaster does not happen until other critical factors line up. In clinical practice, failing to do time outs before procedures, shutting off alarms, and breaches of infection control are deviances from evidence-based practice. As in other industries, health care workers do not make these choices intending to set into motion a cascade toward disaster and harm. Deviation occurs because of barriers to using the correct process or drivers such as time, cost, and peer pressure. As in other industries, operators will often adamantly defend their actions as necessary and justified. Although many other high-risk industries have embraced the normalization of deviance concept, it is relatively new to health care. It is urgent that we explore the impact of this concept on patient harm. We can borrow this concept from other industries and also the steps these other high-risk organizations have found to prevent it.
Medication Review and Patient Outcomes in an Orthopedic Department: A Randomized Controlled Study
Authors: Lisby Marianne , Bonnerup Dorthe Krogsgaard , Brock Birgitte , Gregersen Pernille Axelsen , Jensen Joern , Larsen Maren-Lis , Rungby Joergen , Sonne Jesper , Mainz Jan , Nielsen Lars Peter 
Published: March 2015

ObjectiveWe investigated the health-related effect of systematic medication review performed by a clinical pharmacist and a clinical pharmacologist on nonelective elderly orthopedic patients.MethodsThis is a nonblinded randomized controlled study of 108 patients 65 years or older treated with at least 4 drugs. For the intervention, the clinical pharmacist reviewed the participants' medication after completion of the usual medication routine. Information was collected from medical charts, interviews with participants, and database registrations of drug purchase. Results were conferred with the clinical pharmacologist, and recommendations were delivered directly to the ward physicians. The control was usual medication routine, that is, physicians prescribing admitting orders. The primary outcome was time to the first unplanned contact to a physician after discharge (i.e., general practitioner, emergency department visit, or readmission) during 3-month follow-up. Secondary outcomes included other health-related outcomes, for example, length of in-hospital stay, mortality, and quality of life.ResultsTime to the first unplanned contact to a physician was 14.9 days (95% confidence interval, 8.9–21.0) in the intervention group compared with 27.3 days (95% confidence interval, 18.9–35.7) in the controls (P= 0.05). Overall, no statistically significant differences were seen in the secondary outcomes apart from “number of” and “time to first” emergency department visits, which were in favor of the intervention group. A marked hesitation of the ward physicians to comply with recommendations was noted (18%).ConclusionsThe study showed that the patients receiving usual care had a significantly longer time to the first unplanned contact to a physician after discharge; however, the fact that less than 1 of 5 recommendations was adopted by the physicians raises concerns as to whether this finding could be attributable to the intervention.
Reducing Isozyme Competition Increases Target Fatty Acid Accumulation in Seed Triacylglycerols of Transgenic Arabidopsis
Authors: van Erp Harrie , Shockey Jay , Zhang Meng , Adhikari Neil D. , Browse John 
Published: March 2015

Abstract
One goal of green chemistry is the production of industrially useful fatty acids (FAs) in crop plants. We focus on hydroxy fatty acids (HFAs) and conjugated polyenoic FAs (α-eleostearic acids [ESAs]) using Arabidopsis (Arabidopsis thaliana) as a model. These FAs are found naturally in seed oils of castor (Ricinus communis) and tung tree (Vernicia fordii), respectively, and used for the production of lubricants, nylon, and paints. Transgenic oils typically contain less target FA than that produced in the source species. We hypothesized that competition between endogenous and transgenic isozymes for substrates limits accumulation of unique FAs in Arabidopsis seeds. This hypothesis was tested by introducing a mutation in Arabidopsis diacylglycerol acyltransferase1 (AtDGAT1) in a line expressing castor FA hydroxylase and acyl-Coenzyme A:RcDGAT2 in its seeds. This led to a 17% increase in the proportion of HFA in seed oil. Expression of castor phospholipid:diacylglycerol acyltransferase 1A in this line increased the proportion of HFA by an additional 12%. To determine if our observations are more widely applicable, we investigated if isozyme competition influenced production of ESA. Expression of tung tree FA conjugase/desaturase in Arabidopsis produced approximately 7.5% ESA in seed lipids. Coexpression of VfDGAT2 increased ESA levels to approximately 11%. Overexpression of VfDGAT2 combined with suppression of AtDGAT1 increased ESA accumulation to 14% to 15%. Our results indicate that isozyme competition is a limiting factor in the engineering of unusual FAs in heterologous plant systems and that reduction of competition through mutation and RNA suppression may be a useful component of seed metabolic engineering strategies.
Understanding the traveling behavior of Muslims in the United States
Authors: Shakona Maloud , Backman Kenneth , Backman Sheila , Norman William , Luo Ye , Duffy Lauren 
Published: March 2015

Purpose– The purpose of this paper is to explore the influence of Islamic beliefs and practices on leisure and travel behavior of Muslims in Clemson, South Carolina. With the increase of Muslims in the USA, from both conversion and immigration, it is important to examine the effects of their religion on leisure and travel behavior.Design/methodology/approach– Using the grounded theory approach, semi-structured interviews with six Muslim men and six Muslim women of different nationalities were conducted in English in the local Mosque of Clemson, South Carolina, in the fall of 2011.Findings– The results provide some evidence that Islamic beliefs and behavioral practices influence leisure and travel behavior of Muslims in the USA. The study identifies seven major themes that play an important role in determining leisure and travel behavior of Muslims in Clemson. These are the importance of mosques, traveling with a Mohram, Hijab and a dress code for men and women, drinking alcohol and being in places where alcohol is served, eating pork, Holy Month of Ramadan and Dabiha.Practical implications– The study highlights the need for tourism marketers to pay more attention to the influence of religion on leisure and travel behavior of Muslim travelers.Originality/value– The study provides the tourism industry with a better understanding of the importance of religion influences on the special needs of Muslim travelers and shows how the industry can better accommodate these needs.