bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of Ceftazidime-Avibactam against Extended-Spectrum- and AmpC β-Lactamase-Producing Enterobacteriaceae Collected in the INFORM Global Surveillance Study from 2012 to 2014
Authors: Karlowsky James A. , Biedenbach Douglas J. , Kazmierczak Krystyna M. , Stone Gregory G. , Sahm Daniel F. 
Published: March 2016

ABSTRACT

The
in vitro
activity of ceftazidime-avibactam was evaluated against 34,062 isolates of
Enterobacteriaceae
from patients with intra-abdominal, urinary tract, skin and soft-tissue, lower respiratory tract, and blood infections collected in the INFORM (International Network For Optimal Resistance Monitoring) global surveillance study (176 medical center laboratories in 39 countries) in 2012 to 2014. Overall, 99.5% of
Enterobacteriaceae
isolates were susceptible to ceftazidime-avibactam using FDA approved breakpoints (susceptible MIC of ≤8 μg/ml; resistant MIC of ≥16 μg/ml). For individual species of the
Enterobacteriaceae
, the ceftazidime-avibactam MIC inhibiting ≥90% of isolates (MIC
90
) ranged from 0.06 μg/ml for
Proteus
species to 1 μg/ml for
Enterobacter
spp. and
Klebsiella pneumoniae
. Carbapenem-susceptible isolates of
Escherichia coli
,
K. pneumoniae
,
Klebsiella oxytoca
, and
Proteus mirabilis
with a confirmed extended-spectrum β-lactamase (ESBL) phenotype, or a ceftazidime MIC of ≥16 μg/ml if the ESBL phenotype was not confirmed by clavulanic acid inhibition, were characterized further to identify the presence of specific ESBL- and plasmid-mediated AmpC β-lactamase genes using a microarray-based assay and additional PCR assays. Ceftazidime-avibactam demonstrated potent activity against molecularly confirmed ESBL-producing (
n
= 5,354; MIC
90
, 0.5 μg/ml; 99.9% susceptible), plasmid-mediated AmpC-producing (
n
= 246; MIC
90
, 0.5 μg/ml; 100% susceptible), and ESBL- and AmpC-producing (
n
= 152; MIC
90
, 1 μg/ml; 100% susceptible) isolates of
E. coli
,
K. pneumoniae
,
K. oxytoca
, and
P. mirabilis
. We conclude that ceftazidime-avibactam demonstrates potent
in vitro
activity against globally collected clinical isolates of
Enterobacteriaceae
, including isolates producing ESBLs and AmpC β-lactamases.
PI4 Kinase Is a Prophylactic but Not Radical Curative Target in Plasmodium vivax-Type Malaria Parasites
Authors: Zeeman Anne-Marie , Lakshminarayana Suresh B. , van der Werff Nicole , Klooster Els J. , Voorberg-van der Wel Annemarie , Kondreddi Ravinder R. , Bodenreider Christophe , Simon Oliver , Sauerwein Robert , Yeung Bryan K. S. , Diagana Thierry T. , Kocken Clemens H. M. 
Published: March 2016

ABSTRACT

Two
Plasmodium
PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for
in vivo
testing as causal prophylactic and radical-cure agents for
Plasmodium cynomolgi
sporozoite-infected rhesus macaques, based on their
in vitro
activity against liver stages. Animals were infected with
P. cynomolgi
sporozoites, and compounds were dosed orally. Both the KDU691 and LMV599 compounds were fully protective when administered prophylactically, and the more potent compound LMV599 achieved protection as a single oral dose of 25 mg/kg of body weight. In contrast, when tested for radical cure, five daily doses of 20 mg/kg of KDU691 or 25 mg/kg of LMV599 did not prevent relapse, as all animals experienced a secondary infection due to the reactivation of hypnozoites in the liver. Pharmacokinetic data show that LMV599 achieved plasma exposure that was sufficient to achieve efficacy based on our
in vitro
data. These findings indicate that
Plasmodium
PI4K is a potential drug target for malaria prophylaxis but not radical cure. Longer
in vitro
culture systems will be required to assess these compounds' activity on established hypnozoites and predict radical cure
in vivo
.
Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak
Authors: Kim Yuri , Cheon Shinhye , Min Chan-Ki , Sohn Kyung Mok , Kang Ying Jin , Cha Young-Je , Kang Ju-Il , Han Seong Kyu , Ha Na-Young , Kim Gwanghun , Aigerim Abdimadiyeva , Shin Hyun Mu , Choi Myung-Sik , Kim Sanguk , Cho Hyun-Soo , Kim Yeon-Sook , Cho Nam-Hyuk 
Published: March 2016

ABSTRACT
The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (~35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26.

IMPORTANCE
Recently, a large outbreak initiated by an MERS-CoV-infected traveler from the Middle East swept South Korea and resulted in 186 confirmed cases with 38 deaths. This is the largest outbreak outside the Middle East, and it raised strong concerns about the possible emergence of MERS-CoV mutations. Here, we isolated 13 new viral genomes and found that 12 of them possess a point mutation in the receptor-binding domain of viral spike protein, resulting in reduced affinity to the human cognate receptor, CD26, compared to the wild-type virus. These unexpected findings suggest that MERS-CoV adaptation in humans may be driven by host immunological pressure.
Valpromide Inhibits Lytic Cycle Reactivation of Epstein-Barr Virus
Authors: Gorres Kelly L. , Daigle Derek , Mohanram Sudharshan , McInerney Grace E. , Lyons Danielle E. , Miller George 
Published: March 2016

ABSTRACT
Reactivation of Epstein-Barr virus (EBV) from latency into the lytic phase of its life cycle allows the virus to spread among cells and between hosts. Valproic acid (VPA) inhibits initiation of the lytic cycle in EBV-infected B lymphoma cells. While VPA blocks viral lytic gene expression, it induces expression of many cellular genes, because it is a histone deacetylase (HDAC) inhibitor. Here we show, using derivatives of VPA, that blockade of EBV reactivation is separable from HDAC inhibition. Valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented expression of two EBV genes, BZLF1 and BRLF1, that mediate lytic reactivation. VPM also inhibited expression of a viral late gene, but not early genes, when BZLF1 was exogenously expressed. Unlike VPA, VPM did not activate lytic expression of Kaposi’s sarcoma-associated herpesvirus. Expression of cellular immediate-early genes, such as FOS and EGR1, is kinetically upstream of the EBV lytic cycle. VPM did not activate expression of these cellular immediate-early genes but decreased their level of expression when induced by butyrate, an HDAC inhibitor. VPM did not alter expression of several other cellular immediate-early genes, including STAT3, which were induced by the HDAC inhibitors in cells refractory to lytic induction. Therefore, VPM selectively inhibits both viral and cellular gene expression. VPA and VPM represent a new class of antiviral agents. The mechanism by which VPA and VPM block EBV reactivation may be related to their anticonvulsant activity.

IMPORTANCE
Epstein-Barr virus, (EBV), a human tumor virus, establishes a life-long latent infection. Reactivation of EBV into the lytic phase of its life cycle allows the virus to spread. Previously, we showed that EBV reactivation was blocked by valproic acid (VPA), an inhibitor of cellular histone deacetylases (HDACs). VPA alters the expression of thousands of cellular genes. In this study, we demonstrate that valpromide (VPM), an amide derivative of valproic acid that is not an HDAC inhibitor, prevented initiation of the EBV lytic cycle. VPA induced lytic reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV), but VPM did not. Unlike VPA, VPM did not activate cellular immediate-early gene expression. VPM is a new type of antiviral agent. VPM will be useful in probing the mechanism of EBV lytic reactivation and may have therapeutic application.
What a Dinner Party! Mechanisms and Functions of Interkingdom Signaling in Host-Pathogen Associations
Authors: Kendall Melissa M. , Sperandio Vanessa 
Published: March 2016

ABSTRACT
Chemical signaling between cells is an effective way to coordinate behavior within a community. Although cell-to-cell signaling has mostly been studied in single species, it is now appreciated that the sensing of chemical signals across kingdoms can be an important regulator of nutrient acquisition, virulence, and host defense. In this review, we focus on the role of interkingdom signaling in the interactions that occur between bacterial pathogens and their mammalian hosts. We discuss the quorum-sensing (QS) systems and other mechanisms used by these bacteria to sense, respond to, and modulate host signals that include hormones, immune factors, and nutrients. We also describe cross talk between these signaling pathways and strategies used by the host to interfere with bacterial signaling, highlighting the complex bidirectional signaling networks that are established across kingdoms.
Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty
Authors: Blikman T , Rienstra W , van Raaij T M , ten Hagen A J , Dijkstra B , Zijlstra W P , Bulstra S K , van den Akker-Scheek I , Stevens M 
Published: March 2016

IntroductionResidual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual.Methods and analysisThis multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis.Ethics and disseminationThe study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO).Trial registration number2013-004313-41; Pre-results.
Frailty as a predictor of hospitalisation among community-dwelling older people: a systematic review and meta-analysis
Authors: Kojima Gotaro 
Published: March 2016

BackgroundOwing to detrimental hazards and substantial healthcare burden and costs, hospitalisation of older people has become a major focus. Frailty has increasingly been recognised as an important predictor of hospitalisation. This study aims to identify studies on physical frailty as a predictor of hospitalisation risks and to pool the risk estimates among community-dwelling older people.MethodsA systematic literature search was performed in August 2015 using five databases: EMBASE, MEDLINE, CINAHL, PsycINFO and the Cochrane Library for prospective studies examining physical frailty as a predictor of hospitalisation published in 2000 or later. OR and HR were combined to synthesise pooled effect measures using fixed-effects models. The included studies were assessed for heterogeneity, methodological quality and publication bias. Subgroup analysis and meta-regression analysis were conducted to examine study characteristics in relation to the hospitalisation risks.ResultsOf the 4620 studies identified by the systematic review, 13 studies with average follow-up period of 3.1 years were selected. Frailty and prefrailty were significantly associated with higher hospitalisation risks among 10 studies with OR (pooled OR=1.90, 95% CI 1.74–2.07, p<0.00001; pooled OR=1.26, 95% CI 1.18–1.33, p<0.00001, respectively) and 3 studies with HR (pooled HR=1.30, 95% CI 1.12–1.52, p=0.0007; pooled HR=1.13, 95% CI 1.04–1.24, p=0.005, respectively). Heterogeneity was low to moderate. No publication bias was detected. The studies with older populations and unadjusted outcome measures were associated with higher hospitalisation risks in the subgroup analysis.ConclusionsThis systematic review and meta-analysis demonstrated physical frailty is a significant predictor of hospitalisation among community-dwelling older people. Hospitalisation can potentially be reduced by treating or preventing frailty.
Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial
Authors: Hambardzumyan Karen , Bolce Rebecca J , Saevarsdottir Saedis , Forslind Kristina , Wallman Johan K , Cruickshank Scott E , Sasso Eric H , Chernoff David , van Vollenhoven Ronald F 
Published: March 2016

ObjectivesIn rheumatoid arthritis (RA), predictive biomarkers for subsequent radiographic progression (RP) could improve therapeutic choices for individual patients. We previously showed that the multibiomarker disease activity (MBDA) score in patients with newly diagnosed RA identified patients at risk for RP. We evaluated the MBDA score at multiple time-points as a predictor of RP during 2 years of follow-up.MethodsA subset of patients with RA (N=220) from the Swedish Farmacotherapy (SWEFOT) trial were analysed for MBDA score, disease activity score of 28 joints (DAS28), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at baseline (BL), month 3 and year 1, for predicting RP based on modified Sharp/van der Heijde scores at BL, year 1 and year 2.ResultsPatients with persistently low MBDA (<30) scores or those with a decrease from moderate (30–44) to low MBDA scores, did not develop RP during 2 years of follow-up. The highest risk for RP during 2 years of follow-up (42%) was observed among patients with persistently high (>44) MBDA scores. Among methotrexate non-responders with a high MBDA score at BL or month 3, significantly more of those who received triple therapy had RP at year 2 compared with those who received antitumour necrosis factor therapy.ConclusionsMeasuring the MBDA score both before and during treatment in RA was useful for the assessment of individual patient risk for RP during 2 years of follow-up. In comparison with low CRP, ESR or DAS28, a low MBDA score at any time-point was associated with numerically lower proportions of RP.Trial registration numberNCT00764725.
Today’s Polarized Solid Targets in Borghini’s Footsteps
Authors: Meyer Werner 
Published: March 2016

The development, in the early 1960’s, of the dynamic nuclear polarization process in solid diamagnetic materials, doped with paramagnetic radicals. led to the use of solid polarized targets in numerous nuclear and particle physics experiments. In 1965 Michel Borghini moved from Saclay to CERN, where under his leadership of the polarized target group (until 1978) decisive developments have been made. Target material research and the early frozen spin targets were certainly the basis for the successful story of present day polarized solid targets.
Overtreatment and Cost-Effectiveness of the See-and-Treat Strategy for Managing Cervical Precancer
Authors: Nghiem Van T. , Davies Kalatu R. , Beck J. Robert , Follen Michele , Cantor Scott B. 
Published: March 2016

Abstract
Background: See-and-treat using loop electrosurgical excision procedure (LEEP) has been recommended as an alternative in managing high-grade cervical squamous intraepithelial lesions, but existing literature lacks evidence of the strategy's cost-effectiveness. We evaluated the overtreatment and cost-effectiveness of the see-and-treat strategy compared with usual care.
Methods: We modeled a hypothetical cohort of 40-year-old females who had not been screened for cervical cancer and followed them through their lifetimes using a Markov model. From a U.S. health-system perspective, the analysis was conducted in 2012 dollars and measured effectiveness in quality-adjusted life-years (QALY). We estimated incremental cost-effectiveness ratios (ICER) using a willingness-to-pay threshold of $50,000/QALY. The robustness of the see-and-treat strategy's cost-effectiveness and its overtreatment rates were further examined in various sensitivity analyses.
Results: In the base-case, the see-and-treat strategy yielded an ICER of $70,774/QALY compared with usual care. For most scenarios in the deterministic sensitivity analysis, this strategy had ICERs larger than $50,000/QALY, and its cost-effectiveness was sensitive to the disutility of LEEP treatment and biopsy-directed treatment adherence under usual care. Probabilistic sensitivity analysis showed that the see-and-treat strategy had a 50.1% chance to be cost-effective. It had an average overtreatment rate of 7.1% and a 78.8% chance to have its overtreatment rate lower than the 10% threshold.
Conclusion: The see-and-treat strategy induced an acceptable overtreatment rate. Its cost-effectiveness, compared with usual care, was indiscriminating at the chosen willingness-to-pay threshold but much improved when the threshold increased.
Impact: The see-and-treat strategy was reasonable for particular settings, that is, those with low treatment adherence. Cancer Epidemiol Biomarkers Prev; 25(5); 807–14. ©2016 AACR.
Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing
Authors: Schrock Alexa B. , Frampton Garrett M. , Herndon Dana , Greenbowe Joel R. , Wang Kai , Lipson Doron , Yelensky Roman , Chalmers Zachary R. , Chmielecki Juliann , Elvin Julia A. , Wollner Mira , Dvir Addie , -Gutman Lior Soussan , Bordoni Rodolfo , Peled Nir , Braiteh Fadi , Raez Luis , Erlich Rachel , Ou Sai-Hong Ignatius , Mohamed Mohamed , Ross Jeffrey S. , Stephens Philip J. , Ali Siraj M. , Miller Vincent A. 
Published: March 2016

Abstract
Purpose: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non–small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation.
Experimental Design: A large pool of NSCLC cases was assayed with well-validated, hybrid capture–based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (Δex19) were identified, and available clinical history was reviewed.
Results: Pathology reports were available for 250 consecutive cases with classical EGFR Δex19 (amino acids 743–754) and were reviewed to assess previous non-hybrid capture–based EGFR testing. Twelve of 71 (17%) cases with EGFR testing results available were negative by previous testing, including 8 of 46 (17%) cases for which the same biopsy was analyzed. Independently, five of six (83%) cases harboring C-helical EGFR Δex19 were previously negative. In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed.
Conclusions: CGP identifies drug-sensitive EGFR Δex19 in NSCLC cases that have undergone prior EGFR testing and returned negative results. Given the proven benefit in progression-free survival conferred by EGFR tyrosine kinase inhibitors in patients with these alterations, CGP should be considered in the initial presentation of advanced NSCLC and when previous testing for EGFR mutations or other driver alterations is negative. Clin Cancer Res; 22(13); 3281–5. ©2016 AACR.
Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma
Authors: Xu-Monette Zijun Y. , Deng Qipan , Manyam Ganiraju C. , Tzankov Alexander , Li Ling , Xia Yi , Wang Xiao-xiao , Zou Dehui , Visco Carlo , Dybkær Karen , Li Jun , Zhang Li , Liang Han , Montes-Moreno Santiago , Chiu April , Orazi Attilio , Zu Youli , Bhagat Govind , Richards Kristy L. , Hsi Eric D. , Choi William W.L. , van Krieken J. Han , Huh Jooryung , Ponzoni Maurilio , Ferreri Andrés J.M. , Parsons Ben M. , Møller Michael B. , Wang Sa A. , Miranda Roberto N. , Piris Miguel A. , Winter Jane N. , Medeiros L. Jeffrey , Li Yong , Young Ken H. 
Published: March 2016

Abstract
Purpose: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.
Experimental Design: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP–treated patients.
Results: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3′ untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.
Conclusions: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593–605. ©2016 AACR.