bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Streptococcus pneumoniae Penicillin-Binding Protein 2x and Actinomadura R39 DD-Peptidase Activities by Ceftaroline
Authors: Zervosen Astrid , Zapun André , Frère Jean-Marie 
Published: November 2012

ABSTRACT

Although the rate of acylation of a penicillin-resistant form of
Streptococcus pneumoniae
penicillin-binding protein 2x (PBP2x) by ceftaroline is 80-fold lower than that of its penicillin-sensitive counterpart, it remains sufficiently high (

k
2
/K

= 12,600 M
−1
s
−1
) to explain the sensitivity of the penicillin-resistant strain to this new cephalosporin. Surprisingly, the
Actinomadura
R39 DD-peptidase is not very sensitive to ceftaroline.
Both Fidaxomicin and Vancomycin Inhibit Outgrowth of Clostridium difficile Spores
Authors: Allen Charlotte A. , Babakhani Farah , Sears Pam , Nguyen Ly , Sorg Joseph A. 
Published: November 2012

ABSTRACT

Fidaxomicin (FDX) is approved to treat
Clostridium difficile
-associated diarrhea and is superior to vancomycin in providing a sustained clinical response (cure without recurrence in the subsequent 25 days). The mechanism(s) behind the low recurrence rate of FDX-treated patients could be multifactorial. Here, we tested effects of FDX, its metabolite OP-1118, and vancomycin on spore germination and determined that none affected the initiation of spore germination but all inhibited outgrowth of vegetative cells from germinated spores.
Chlorhexidine and Mupirocin Susceptibilities of Methicillin-Resistant Staphylococcus aureus from Colonized Nursing Home Residents
Authors: McDanel Jennifer S. , Murphy Courtney R. , Diekema Daniel J. , Quan Victor , Kim Diane S. , Peterson Ellena M. , Evans Kaye D. , Tan Grace L. , Hayden Mary K. , Huang Susan S. 
Published: November 2012

ABSTRACT

Chlorhexidine and mupirocin are used in health care facilities to eradicate methicillin-resistant
Staphylococcus aureus
(MRSA) carriage. The objective of this study was to assess the frequency of chlorhexidine and mupirocin resistance in isolates from nares carriers in multiple nursing homes and to examine characteristics associated with resistance. Nasal swab samples were collected from approximately 100 new admissions and 100 current residents in 26 nursing homes in Orange County, CA, from October 2008 to May 2011. MRSA isolates were tested for susceptibility by using broth microdilution, disk diffusion, and Etest; for genetic relatedness using pulsed-field gel electrophoresis; and for
qac
gene carriage by PCR. Characteristics of the nursing homes and their residents were collected from the Medicare Minimum Data Set and Long-Term Care Focus. A total of 829 MRSA isolates were obtained from swabbing 3,806 residents in 26 nursing homes. All isolates had a chlorhexidine MIC of ≤4 μg/ml. Five (0.6%) isolates harbored the
qacA
and/or
qacB
gene loci. Mupirocin resistance was identified in 101 (12%) isolates, with 78 (9%) isolates exhibiting high-level mupirocin resistance (HLMR). HLMR rates per facility ranged from 0 to 31%. None of the isolates with HLMR displayed
qacA
or
qacB
, while two isolates carried
qacA
and exhibited low-level mupirocin resistance. Detection of HLMR was associated with having a multidrug-resistant MRSA isolate (odds ratio [OR], 2.69;
P
= 0.004), a history of MRSA (OR, 2.34;
P
< 0.001), and dependency in activities of daily living (OR, 1.25;
P
= 0.004). In some facilities, HLMR was found in nearly one-third of MRSA isolates. These findings may have implications for the increasingly widespread practice of MRSA decolonization using intranasal mupirocin.
Mupirocin and Chlorhexidine Resistance in Staphylococcus aureus in Patients with Community-Onset Skin and Soft Tissue Infections
Authors: Fritz Stephanie A. , Hogan Patrick G. , Camins Bernard C. , Ainsworth Ali J. , Patrick Carol , Martin Madeline S. , Krauss Melissa J. , Rodriguez Marcela , Carey-Ann Burnham D. 
Published: November 2012

ABSTRACT

Decolonization measures, including mupirocin and chlorhexidine, are often prescribed to prevent
Staphylococcus aureus
skin and soft tissue infections (SSTI). The objective of this study was to determine the prevalence of high-level mupirocin and chlorhexidine resistance in
S. aureus
strains recovered from patients with SSTI before and after mupirocin and chlorhexidine administration and to determine whether carriage of a mupirocin- or chlorhexidine-resistant strain at baseline precluded
S. aureus
eradication. We recruited 1,089 patients with community-onset SSTI with or without
S. aureus
colonization. In addition to routine care, 483 patients were enrolled in a decolonization trial: 408 received intranasal mupirocin (with or without antimicrobial baths), and 258 performed chlorhexidine body washes. Patients were followed for up to 12 months with repeat colonization cultures. All
S. aureus
isolates were tested for high-level mupirocin and chlorhexidine resistance. At baseline, 23/1,089 (2.1%) patients carried a mupirocin-resistant
S. aureus
strain and 10/1,089 (0.9%) patients carried chlorhexidine-resistant
S. aureus
. Of 4 patients prescribed mupirocin, who carried a mupirocin-resistant
S. aureus
strain at baseline, 100% remained colonized at 1 month compared to 44% of the 324 patients without mupirocin resistance at baseline (
P
= 0.041). Of 2 patients prescribed chlorhexidine, who carried a chlorhexidine-resistant
S. aureus
strain at baseline, 50% remained colonized at 1 month compared to 48% of the 209 patients without chlorhexidine resistance at baseline (
P
= 1.0). The overall prevalence of mupirocin and chlorhexidine resistance is low in
S. aureus
isolates recovered from outpatients, but eradication efforts were less successful in patients carrying a mupirocin-resistant
S. aureus
strain at baseline.
Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients
Authors: Goutelle Sylvain , Baudry Thomas , Gagnieu Marie-Claude , Boibieux André , Livrozet Jean-Michel , Peyramond Dominique , Chidiac Christian , Tod Michel , Ferry Tristan ,   on behalf of the Lyon HIV Cohort Study Group
Published: November 2012

ABSTRACTLimited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h−1;P= 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter−1;P= 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.
Streptococcus pneumoniae Capsular Serotype Invasiveness Correlates with the Degree of Factor H Binding and Opsonization with C3b/iC3b
Authors: Hyams Catherine , Trzcinski Krzysztof , Camberlein Emilie , Weinberger Daniel M. , Chimalapati Suneeta , Noursadeghi Mahdad , Lipsitch Marc , Brown Jeremy S. 
Published: November 2012

ABSTRACT

Different capsular serotypes of
Streptococcus pneumoniae
vary markedly in their ability to cause invasive infection, but the reasons why are not known. As immunity to
S. pneumoniae
infection is highly complement dependent, variations in sensitivity to complement between
S. pneumoniae
capsular serotypes could affect invasiveness. We have used 20 capsule-switched variants of strain TIGR4 to investigate whether differences in the binding of the alternative pathway inhibitor factor H (FH) could be one mechanism causing variations in complement resistance and invasive potential between capsular serotypes. Flow cytometry assays were used to assess complement factor binding and complement-dependent neutrophil association for the TIGR4 capsule-switched strains. FH binding varied with the serotype and inversely correlated with the results of factor B binding, C3b/iC3b deposition, and neutrophil association. Differences between strains in FH binding were lost when assays were repeated with
pspC
mutant strains, and loss of PspC also reduced differences in C3b/iC3b deposition between strains. Median FH binding was high in capsule-switched mutant strains expressing more invasive serotypes, and a principal component analysis demonstrated a strong correlation between serotype invasiveness, high FH binding, and resistance to complement and neutrophil association. Further data obtained with 33 clinical strains also demonstrated that FH binding negatively correlated with C3b/iC3b deposition and that median FH binding was high in strains expressing more invasive serotypes. These data suggest that variations in complement resistance between
S. pneumoniae
strains and the association of a serotype with invasiveness could be related to capsular serotype effects on FH binding.
A randomised efficacy and discontinuation study of etanercept versus adalimumab (RED SEA) for rheumatoid arthritis: a pragmatic, unblinded, non-inferiority study of first TNF inhibitor use: outcomes over 2 years
Authors: Jobanputra Paresh , Maggs Fiona , Deeming Alison , Carruthers David , Rankin Elizabeth , Jordan Alison C , Faizal Abdul , Goddard Carolyn , Pugh Mark , Bowman Simon J , Brailsford Sue , Nightingale Peter 
Published: November 2012

ObjectiveTo compare adalimumab versus etanercept in patients with active rheumatoid arthritis (RA) to test the hypothesis that adalimumab was not inferior to etanercept in terms of drug continuation by a margin of 15% after 52 weeks of treatment.DesignPragmatic, randomised, parallel group, multicentre, unblinded and non-inferiority trial. Randomisation stratified by baseline use of methotrexate.Participants125 adults with active RA despite treatment with two disease-modifying drugs (DMARDs), including methotrexate randomised (1 : 1) to adalimumab 40 mg alternate weeks or etanercept 50 mg weekly, added to existing medication.MeasurementsThe primary outcome was proportion of patients continuing treatment after 52 weeks. Secondary outcomes included: disease activity score using 28 joints (DAS28), treatment satisfaction (TSQM V.2), health status (Euroqol-5D), drug toxicity and persistence with therapy after 2 years.ResultsPersistence with therapy was 65% for adalimumab versus 56.7% for etanercept (one-sided 95% CI for proportion still taking adalimumab minus proportion on etanercept ≥−7.9%); demonstrating non-inferiority at the 15% margin. After 2 years these figures were: adalimumab 58.3% and etanecept 43.3% (CI ≥−1.7%). The proportion of good, moderate and non-responders based on DAS28-C reactive protein, after 52 weeks, were 26.3%, 33.3% and 40.4%, respectively, for adalimumab versus 16.7%, 31.7% and 51.7%, respectively, for etanercept (p=0.158). Baseline median EQ-5D scores improved from 0.52 to 0.69 for adalimumab and from 0.52 to 0.64 for etanercept (p=0.046) after 52 weeks. Global satisfaction, effectiveness, side effects and convenience scores based on the TSQM were similar for both drugs. Fourteen serious adverse events occurred including two deaths from myocardial infarction, one patient with ovarian cancer and one with acute myeloid leukaemia.ConclusionsClinicians choosing a first tumour necrosis factor inhibitor for active RA, despite trying two DMARDs including methotrexate, may choose either adalimumab or etanercept in the knowledge that these drugs are similarly effective.Clinical trial registration numberEU Clinical Trials Register 2006-006275-21/GB.
Diagnostic value of patterns of symptoms and signs of heart failure: application of latent class analysis with concomitant variables in a cross-sectional study
Authors: Severo Milton , Gaio Ana Rita , Lourenço Patrícia , Alvelos Margarida , Gonçalves Alexandra , Lunet Nuno , Bettencourt Paulo , Azevedo Ana 
Published: November 2012

ObjectiveThe diagnosis of heart failure (HF) requires a compatible clinical syndrome and demonstration of cardiac dysfunction by imaging or functional tests. Since individual symptoms and signs are generally unreliable and have limited value for diagnosing HF, the authors aimed to identify patterns of symptoms and signs, based on findings routinely collected in current clinical practice, and to evaluate their diagnostic value, taking into account the a priori likelihood of HF.DesignCross-sectional evaluation.Participants1115 community participants aged ≥45 years from Porto, Portugal, in 2006–2008.Main outcomes measuresPatterns were identified by latent class analysis, using concomitant variables to predict class membership. Patterns used 11 symptoms/signs, covering dimensions of congestion and hypoperfusion. Sex, age, education, obesity, diabetes and history of myocardial infarction or HF were included as concomitants.ResultsBayesian information criteria supported a solution with three patterns: 10.1% of participants followed a pattern with symptoms of troubled breathing and signs of congestion (pattern 1), 27.8% a pattern characterised mainly by signs of congestion (pattern 2) and 62.1% were essentially asymptomatic (pattern 3); model fit was best when including concomitant variables. The likelihood ratio of patterns 1, 2 and 3 for left ventricular systolic dysfunction was 3.4, 1.1 and 0.6, and for left ventricular diastolic dysfunction 3.5, 1.4 and 0.5, respectively.ConclusionsThe use of concomitant variables can improve the diagnostic value of the symptoms and signs patterns and, consequently, improve the usefulness of the symptoms and signs for diagnosis and as an outcome measure. The potential for application in other settings of complex diagnoses is very high. These models were shown to be useful to standardise and quantify the probabilistic reasoning in clinical diagnosis, upon which decisions of further investigation and even treatment need to be made.
Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials
Authors: Hansen Morten , Sonne David Peick , Mikkelsen Kristian Hallundbæk , Gluud Lise Lotte , Vilsbøll Tina , Knop Filip Krag 
Published: November 2012

IntroductionIn addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM.Methods and analysisIn accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs.Ethics and disseminationThe study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM.ResultsThe study will be disseminated by peer-review publication and conference presentation.Protocol registrationPROSPERO CRD42012002552.
Geographical concentration of falciparum malaria treated in the UK and delay to treatment with artesunate in severe cases: an observational study
Authors: Broderick Claire , Friend Philip , Smith Valerie , Blaze Marie , Gothard Philip , Chiodini Peter L , Whitty Christopher JM 
Published: November 2012

ObjectivesTo quantify geographical concentration of falciparum malaria cases in the UK at a hospital level. To assess potential delay-to-treatment associated with hub-and-spoke distribution of artesunate in severe cases.DesignObservational study using national and hospital data.Setting and participants3520 patients notified to the Malaria Reference Laboratory 2008–2010, 34 patients treated with intravenous artesunate from a tropical diseases centre 2002–2010.Main outcome measuresGeographical location of falciparum cases notified in the UK. Diagnosis-to-treatment times for intravenous artesunate.ResultsEight centres accounted for 43.9% of the UK's total cases; notifications from 107 centres accounted for 10.2% of cases; 51.5% of hospitals seeing malaria notified 5 or fewer cases in 3 years. Centres that saw <10 cases/year treat 26.3% of malaria cases; 6.1% of cases are treated in hospitals seeing <2 cases/year. Concentration of falciparum malaria was highest in Greater London (1925, 54.7%), South East (515, 14.6%), East of England (402, 11.4%) and North West (192, 5.4%). The North East and Northern Ireland each notified 5 or fewer cases per year. Median diagnosis-to-treatment time was 1 h (range 0.5–5) for patients receiving artesunate in the specialist centre; 7.5 h (range 4–26) for patients receiving it in referring hospitals via the hub-and-spoke system (p=0.02); 25 h (range 9–45) for patients receiving it on transfer to the regional centre from a referring hospital (p=0.002).ConclusionsMost UK hospitals see few cases of falciparum malaria and geographical distances are significant. Over 25% of cases are seen in hospitals where malaria is rare, although 60% are seen in hospitals seeing over 50 cases over 3 years. A hub-and-spoke system minimises drug wastage and ensures availability in centres seeing most cases but is associated with treatment delays elsewhere. As with all observational studies, there are limitations, which are discussed.
Dipole showers and automated NLO matching in Herwig++
Authors: Plätzer Simon , Gieseke Stefan 
Published: November 2012

AbstractWe report on the implementation of a coherent dipole shower algorithm along with an automated implementation for dipole subtraction and for performing powheg- and mc@nlo-type matching to next-to-leading order (NLO) calculations. Both programs are implemented as add-on modules to the event generator Herwig++. A preliminary tune of parameters to data acquired at LEP, HERA and Drell-Yan pair production at the Tevatron has been performed, and we find an overall very good description which is slightly improved by the NLO matching.
Vaccination with Irradiated Tumor Cells Pulsed with an Adjuvant That Stimulates NKT Cells Is an Effective Treatment for Glioma
Authors: Hunn Martin K. , Farrand Kathryn J. , Broadley Kate W.R. , Weinkove Robert , Ferguson Peter , Miller Rose J. , Field Cameron S. , Petersen Troels , McConnell Melanie J. , Hermans Ian F. 
Published: November 2012

AbstractPurpose: The prognosis for patients with glioblastoma multiforme (GBM) remains extremely poor despite recent treatment advances. There is an urgent need to develop novel therapies for this disease.Experimental Design: We used the implantable GL261 murine glioma model to investigate the therapeutic potential of a vaccine consisting of intravenous injection of irradiated whole tumor cells pulsed with the immuno-adjuvant α-galactosylceramide (α-GalCer).Results: Vaccine treatment alone was highly effective in a prophylactic setting. In a more stringent therapeutic setting, administration of one dose of vaccine combined with depletion of regulatory T cells (Treg) resulted in 43% long-term survival and the disappearance of mass lesions detected by MRI. Mechanistically, the α-GalCer component was shown to act by stimulating “invariant” natural killer–like T cells (iNKT cells) in a CD1d-restricted manner, which in turn supported the development of a CD4+ T-cell–mediated adaptive immune response. Pulsing α-GalCer onto tumor cells avoided the profound iNKT cell anergy induced by free α-GalCer. To investigate the potential for clinical application of this vaccine, the number and function of iNKT cells was assessed in patients with GBM and shown to be similar to age-matched healthy volunteers. Furthermore, irradiated GBM tumor cells pulsed with α-GalCer were able to stimulate iNKT cells and augment a T-cell response in vitro.Conclusions: Injection of irradiated tumor cells loaded with α-GalCer is a simple procedure that could provide effective immunotherapy for patients with high-grade glioma. Clin Cancer Res; 18(23); 6446–59. ©2012 AACR.