bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Systematic Review and Meta-Analyses Show that Carbapenem Use and Medical Devices Are the Leading Risk Factors for Carbapenem-Resistant Pseudomonas aeruginosa
Authors: Voor in ‘t holt Anne F. , Severin Juliëtte A. , Lesaffre Emmanuel M. E. H. , Vos Margreet C. 
Published: February 2014

ABSTRACT

A systematic review and meta-analyses were performed to identify the risk factors associated with carbapenem-resistant
Pseudomonas aeruginosa
and to identify sources and reservoirs for the pathogen. A systematic search of PubMed and Embase databases from 1 January 1987 until 27 January 2012 identified 1,662 articles, 53 of which were included in a systematic review and 38 in a random-effects meta-analysis study. The use of carbapenem, use of fluoroquinolones, use of vancomycin, use of other antibiotics, having medical devices, intensive care unit (ICU) admission, having underlying diseases, patient characteristics, and length of hospital stay were significant risk factors in multivariate analyses. The meta-analyses showed that carbapenem use (odds ratio [OR] = 7.09; 95% confidence interval [CI] = 5.43 to 9.25) and medical devices (OR = 5.11; 95% CI = 3.55 to 7.37) generated the highest pooled estimates. Cumulative meta-analyses showed that the pooled estimate of carbapenem use was stable and that the pooled estimate of the risk factor “having medical devices” increased with time. We conclude that our results highlight the importance of antibiotic stewardship and the thoughtful use of medical devices in helping prevent outbreaks of carbapenem-resistant
P. aeruginosa
.
Robust and Persistent Replication of the Genotype 6a Hepatitis C Virus Replicon in Cell Culture
Authors: Yu Mei , Peng Betty , Chan Katie , Gong Ruoyu , Yang Huiling , Delaney William , Cheng Guofeng 
Published: February 2014

ABSTRACT
Genotype 6 (GT6) hepatitis C virus (HCV) is prevalent in Southeast Asia and southern China, where it can constitute up to 50% of HCV infections. Despite this, no direct-acting antivirals are approved to treat GT6 HCV infection, and no cell culture systems have been described. In this study, we aimed to develop a GT6 HCV subgenomic replicon to facilitate the identification and development of new HCV therapies with pan-genotype activity. A subgenomic replicon cDNA encoding a GT6a consensus sequence plus an NS5A amino acid substitution (S232I) was synthesized. Electroporation of RNA encoding the GT6a replicon into Huh-7-derived cells consistently yielded 20 to 100 stable replicon colonies. Genotypic analyses of individual replicon colonies revealed new adaptive mutations across multiple viral nonstructural proteins. The E30V and K272R mutations in NS3 and the K34R mutation in NS4A were observed most frequently and were confirmed to enhance GT6a replicon replication in the presence of the NS5A amino acid substitution S232I. These new adaptive mutations allowed establishment of robust luciferase-encoding GT6a replicons for reproducible quantification of HCV replication, and the luciferase-encoding replicons enabled efficient determinations of antiviral activity for HCV inhibitors in a 384-well assay format. While nucleoside/nucleotide NS5B inhibitors and cyclophilin A inhibitors had similar antiviral activities against both GT6a and GT1b replicons, some nonnucleoside NS5B inhibitors, NS3 protease inhibitors, and NS5A inhibitors had less antiviral activity against GT6a replicons. In conjunction with other genotype replicons, this robust GT6a replicon system will aid in the development of pan-genotypic HCV regimens.
Expression of the Essential Kinase PfCDPK1 from Plasmodium falciparum in Toxoplasma gondii Facilitates the Discovery of Novel Antimalarial Drugs
Authors: Gaji Rajshekhar Y. , Checkley Lisa , Reese Michael L. , Ferdig Michael T. , Arrizabalaga Gustavo 
Published: February 2014

ABSTRACT

We have previously shown that genetic disruption of
Toxoplasma gondii
calcium-dependent protein kinase 3 (TgCDPK3) affects calcium ionophore-induced egress. We examined whether
Plasmodium falciparum
CDPK1 (PfCDPK1), the closest homolog of TgCDPK3 in the malaria parasite
P. falciparum
, could complement a TgCDPK3 mutant strain. PfCDPK1 is essential and plays critical roles in merozoite development, motility, and secretion. We show that expression of PfCDPK1 in the TgCDPK3 mutant strain rescues the egress defect. This phenotypic complementation requires the localization of PfCDPK1 to the plasma membrane and kinase activity. Interestingly, PfCDPK1-expressing
Toxoplasma
becomes more sensitive to egress inhibition by purfalcamine, a potent inhibitor of PfCDPK1 with low activity against TgCDPK3. Based on this result, we tested eight small molecules previously determined to inhibit the kinase activity of recombinant PfCDPK1 for their abilities to inhibit ionophore-induced egress in the PfCDPK1-expressing strain. While two of these chemicals did not inhibit egress, we found that six drugs affected this process selectively in PfCDPK1-expressing
Toxoplasma
. Using mutant versions of PfCDPK1 and TgCDPK3, we show that the selectivities of dasatinib and PLX-4720 are regulated by the gatekeeper residue in the ATP binding site. Importantly, we have confirmed that the three most potent inhibitors of egress in the PfCDPK1-expressing strain effectively kill
P. falciparum
. Thus, we have established and validated a recombinant strain of
Toxoplasma
that can be used as a surrogate for the discovery and analysis of PfCDPK1-specific inhibitors that can be developed as antimalarials.
Comparative Microbiological Studies of Transcription Inhibitors Fidaxomicin and the Rifamycins in Clostridium difficile
Authors: Babakhani Farah , Seddon Jaime , Sears Pamela 
Published: February 2014

ABSTRACT

Fidaxomicin (FDX) is a narrow-spectrum antibiotic for the treatment of
Clostridium difficile
-associated diarrhea. While FDX and rifamycins share the same target (RNA polymerase), FDX exhibits a unique mode of action distinct from that of rifamycins. In comparative microbiological studies with
C. difficile
, FDX interacted synergistically with rifamycins, demonstrated a lower propensity for the development of resistance to rifamycins, and exhibited no cross-resistance with rifamycins. These results highlight differences in the mechanisms of action of FDX and rifamycins.
In Vitro
Activity of Plazomicin against 5,015 Gram-Negative and Gram-Positive Clinical Isolates Obtained from Patients in Canadian Hospitals as Part of the CANWARD Study, 2011-2012
Authors: Walkty A. , Adam H. , Baxter M. , Denisuik A. , Lagacé-Wiens P. , Karlowsky J. A. , Hoban D. J. , Zhanel G. G. 
Published: February 2014

ABSTRACT

Plazomicin is a next-generation aminoglycoside that is not affected by most clinically relevant aminoglycoside-modifying enzymes. The
in vitro
activities of plazomicin and comparator antimicrobials were evaluated against a collection of 5,015 bacterial isolates obtained from patients in Canadian hospitals between January 2011 and October 2012. Susceptibility testing was performed using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method, with MICs interpreted according to CLSI breakpoints, when available. Plazomicin demonstrated potent
in vitro
activity against members of the family
Enterobacteriaceae
, with all species except
Proteus mirabilis
having an MIC
90
of ≤1 μg/ml. Plazomicin was active against aminoglycoside-nonsusceptible
Escherichia coli
, with MIC
50
and MIC
90
values identical to those for aminoglycoside-susceptible isolates. Furthermore, plazomicin demonstrated equivalent activities versus extended-spectrum β-lactamase (ESBL)-producing and non-ESBL-producing
E. coli
and
Klebsiella pneumoniae
, with 90% of the isolates inhibited by an MIC of ≤1 μg/ml. The MIC
50
and MIC
90
values for plazomicin against
Pseudomonas aeruginosa
were 4 μg/ml and 16 μg/ml, respectively, compared with 4 μg/ml and 8 μg/ml, respectively, for amikacin. Plazomicin had an MIC
50
of 8 μg/ml and an MIC
90
of 32 μg/ml versus 64 multidrug-resistant
P. aeruginosa
isolates. Plazomicin was active against methicillin-susceptible and methicillin-resistant
Staphylococcus aureus
, with both having MIC
50
and MIC
90
values of 0.5 μg/ml and 1 μg/ml, respectively. In summary, plazomicin demonstrated potent
in vitro
activity against a diverse collection of Gram-negative bacilli and Gram-positive cocci obtained over a large geographic area. These data support further evaluation of plazomicin in the clinical setting.
Pharmacokinetics of Ofloxacin and Levofloxacin for Prevention and Treatment of Multidrug-Resistant Tuberculosis in Children
Authors: Thee S. , Garcia-Prats A. J. , McIlleron H. M. , Wiesner L. , Castel S. , Norman J. , Draper H. R. , van der Merwe P. L. , Hesseling A. C. , Schaaf H. S. 
Published: February 2014

ABSTRACT
Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed.
IcgA Is a Virulence Factor of Rhodococcus equi That Modulates Intracellular Growth
Authors: Wang Xiaoguang , Coulson Garry B. , Miranda-CasoLuengo Aleksandra A. , Miranda-CasoLuengo Raúl , Hondalus Mary K. , Meijer Wim G. 
Published: February 2014

ABSTRACT

Virulence of the intracellular pathogen
Rhodococcus equi
depends on a 21.3-kb pathogenicity island located on a conjugative plasmid. To date, the only nonregulatory pathogenicity island-encoded virulence factor identified is the cell envelope-associated VapA protein. Although the pathogenicity islands from porcine and equine
R. equi
isolates have undergone major rearrangements, the
virR
operon (
virR-icgA-vapH-orf7-virS
) is highly conserved in both, suggesting these genes play an important role in pathogenicity. VirR and VirS are transcriptional regulators controlling expression of pathogenicity island genes, including
vapA
. Here, we show that while
vapH
and
orf7
are dispensable for intracellular growth of
R. equi
, deletion of
icgA
, formerly known as
orf5
, encoding a major facilitator superfamily transport protein, elicited an enhanced growth phenotype in macrophages and a significant reduction in macrophage viability, while extracellular growth in broth remained unaffected. Transcription of
virS
, located downstream of
icgA
, and
vapA
was not affected by the
icgA
deletion during growth in broth or in macrophages, showing that the enhanced growth phenotype caused by deletion of
icgA
was not mediated through abnormal transcription of these genes. Transcription of
icgA
increased 6-fold within 2 h following infection of macrophages and remained significantly higher 48 h postinfection compared to levels at the start of the infection. The major facilitator superfamily transport protein IcgA is the first factor identified in
R. equi
that negatively affects intracellular replication. Aside from VapA, it is only the second pathogenicity island-encoded structural protein shown to play a direct role in intracellular growth of this pathogenic actinomycete.
Live Attenuated Influenza Vaccine Enhances Colonization of Streptococcus pneumoniae and Staphylococcus aureus in Mice
Authors: Mina Michael J. , McCullers Jonathan A. , Klugman Keith P. 
Published: February 2014

ABSTRACT

Community interactions at mucosal surfaces between viruses, like influenza virus, and respiratory bacterial pathogens are important contributors toward pathogenesis of bacterial disease. What has not been considered is the natural extension of these interactions to live attenuated immunizations, and in particular, live attenuated influenza vaccines (LAIVs). Using a mouse-adapted LAIV against influenza A (H3N2) virus carrying the same mutations as the human FluMist vaccine, we find that LAIV vaccination reverses normal bacterial clearance from the nasopharynx and significantly increases bacterial carriage densities of the clinically important bacterial pathogens
Streptococcus pneumoniae
(serotypes 19F and 7F) and
Staphylococcus aureus
(strains Newman and Wright) within the upper respiratory tract of mice. Vaccination with LAIV also resulted in 2- to 5-fold increases in mean durations of bacterial carriage. Furthermore, we show that the increases in carriage density and duration were nearly identical in all aspects to changes in bacterial colonizing dynamics following infection with wild-type (WT) influenza virus. Importantly, LAIV, unlike WT influenza viruses, had no effect on severe bacterial disease or mortality within the lower respiratory tract. Our findings are, to the best of our knowledge, the first to demonstrate that vaccination with a live attenuated viral vaccine can directly modulate colonizing dynamics of important and unrelated human bacterial pathogens, and does so in a manner highly analogous to that seen following wild-type virus infection.

IMPORTANCE
Following infection with an influenza virus, infected or recently recovered individuals become transiently susceptible to excess bacterial infections, particularly
Streptococcus pneumoniae
and
Staphylococcus aureus
. Indeed, in the absence of preexisting comorbidities, bacterial infections are a leading cause of severe disease during influenza epidemics. While this synergy has been known and is well studied, what has not been explored is the natural extension of these interactions to live attenuated influenza vaccines (LAIVs). Here we show, in mice, that vaccination with LAIV primes the upper respiratory tract for increased bacterial growth and persistence of bacterial carriage, in a manner nearly identical to that seen following wild-type influenza virus infections. Importantly, LAIV, unlike wild-type virus, did not increase severe bacterial disease of the lower respiratory tract. These findings may have consequences for individual bacterial disease processes within the upper respiratory tract, as well as bacterial transmission dynamics within LAIV-vaccinated populations
Systems Biology-Based Identification of Mycobacterium tuberculosis Persistence Genes in Mouse Lungs
Authors: Dutta Noton K. , Bandyopadhyay Nirmalya , Veeramani Balaji , Lamichhane Gyanu , Karakousis Petros C. , Bader Joel S. 
Published: February 2014

ABSTRACT

Identifying
Mycobacterium tuberculosis
persistence genes is important for developing novel drugs to shorten the duration of tuberculosis (TB) treatment. We developed computational algorithms that predict
M. tuberculosis
genes required for long-term survival in mouse lungs. As the input, we used high-throughput
M. tuberculosis
mutant library screen data, mycobacterial global transcriptional profiles in mice and macrophages, and functional interaction networks. We selected 57 unique, genetically defined mutants (18 previously tested and 39 untested) to assess the predictive power of this approach in the murine model of TB infection. We observed a 6-fold enrichment in the predicted set of
M. tuberculosis
genes required for persistence in mouse lungs relative to randomly selected mutant pools. Our results also allowed us to reclassify several genes as required for
M. tuberculosis
persistence
in vivo
. Finally, the new results implicated additional high-priority candidate genes for testing. Experimental validation of computational predictions demonstrates the power of this systems biology approach for elucidating
M. tuberculosis
persistence genes.

IMPORTANCE
Mycobacterium tuberculosis
, the causative agent of tuberculosis (TB), has a genetic repertoire that permits it to persist in the face of host immune responses. Identification of such persistence genes could reveal novel drug targets and elucidate mechanisms by which the organism eludes the immune system and resists drugs. Genetic screens have identified a total of 31 persistence genes, but to date only 15% of the ~4,000
M. tuberculosis
genes have been tested experimentally. In this paper, as an alternative to brute force experimental screens, we describe computational methods that predict new persistence genes by combining known examples with growing databases of biological networks. Experimental testing demonstrated that these predictions are highly accurate, validating the computational approach and providing new information about
M. tuberculosis
persistence in host tissues. Using the new experimental results as additional input highlights additional genes for testing. Our approach can be extended to other data types and target organisms to characterize host-pathogen interactions relevant to this and other infectious diseases.
Dual Role for Inflammasome Sensors NLRP1 and NLRP3 in Murine Resistance to Toxoplasma gondii
Authors: Gorfu Gezahegn , Cirelli Kimberly M. , Melo Mariane B. , Mayer-Barber Katrin , Crown Devorah , Koller Beverly H. , Masters Seth , Sher Alan , Leppla Stephen H. , Moayeri Mahtab , Saeij Jeroen P. J. , Grigg Michael E. 
Published: February 2014

ABSTRACTInduction of immunity that limitsToxoplasma gondiiinfection in mice is critically dependent on the activation of the innate immune response. In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice. We show thatin vitro Toxoplasmainfection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1β (IL-1β), with no measurable cleavage of IL-18 and no pyroptosis. Paradoxically,Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1β in their serum. Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death. Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality. Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival. Our findings revealT. gondiias a novel activator of the NLRP1 and NLRP3 inflammasomesin vivoand establish a role for these sensors in host resistance to toxoplasmosis.IMPORTANCEInflammasomes are multiprotein complexes that are a major component of the innate immune system. They contain “sensor” proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18.Toxoplasma gondiiis a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance. We report here thatT. gondiiis a novel activator of the NLRP1 and NLRP3 inflammasomesin vivoand establish a role for these sensors in host resistance to toxoplasmosis. Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival.
A randomised double-blind control study of early intracoronary autologous bone marrow cell infusion in acute myocardial infarction (REGENERATE-AMI)
Authors: Hamshere Stephen , Choudhury Tawfiq , Jones Daniel A , Locca Didier , Mills Peter , Rothman Martin , Knight Charles , Parmar Mahesh , Agrawal Samir , Martin John , Mathur Anthony 
Published: February 2014

IntroductionAcute myocardial infarction (AMI) remains a major cause of mortality and morbidity worldwide despite the latest therapeutic advances designed to decrease myocardial injury. Preclinical and emerging clinical evidence show that the intracoronary injection of autologous bone marrow mononuclear cells (BMCs) following AMI leads to improvement in left ventricular ejection function (LVEF). In this clinical trial we will for the first time assess the effect of early (<24 h) infusion of autologous BMCs following AMI on cardiac function.Methods and analysisREGENERATE-AMI is a double-blind, randomised, multicentre, placebo-controlled trial to determine whether early (<24 h) intracoronary infusion of BMCs improves LVEF after AMI. The study will enrol 100 patients presenting with an anterior AMI demonstrating anterior regional wall motion abnormality. Patients will be randomised to receive intracoronary infusion of BMCs or placebo (0.9% saline). Primary endpoint will be change in LVEF at 1 year compared to baseline, measured by cardiac MRI. Secondary endpoints at 6 months include the change in global LVEF relative to baseline measured by quantitative left ventriculography and echocardiography, as well as major adverse cardiac events which is also measured at 1 year.Ethics and disseminationThe study will be performed in agreement with the Declaration of Helsinki and is approved by local ethics committee (NRES Committee London West London: 07/Q0603/76).Trial registrationhttp://clincialtrials.gov(NCT00765453). The results of the trial will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals.
Protocol for an HTA report: Does therapeutic writing help people with long-term conditions? Systematic review, realist synthesis and economic modelling
Authors: Meads C , Nyssen O P , Wong G , Steed L , Bourke L , Ross C A , Hayman S , Field V , Lord J , Greenhalgh T , Taylor S J C 
Published: February 2014

IntroductionLong-term medical conditions (LTCs) cause reduced health-related quality of life and considerable health service expenditure. Writing therapy has potential to improve physical and mental health in people with LTCs, but its effectiveness is not established. This project aims to establish the clinical and cost-effectiveness of therapeutic writing in LTCs by systematic review and economic evaluation, and to evaluate context and mechanisms by which it might work, through realist synthesis.MethodsIncluded are any comparative study of therapeutic writing compared with no writing, waiting list, attention control or placebo writing in patients with any diagnosed LTCs that report at least one of the following: relevant clinical outcomes; quality of life; health service use; psychological, behavioural or social functioning; adherence or adverse events. Searches will be conducted in the main medical databases including MEDLINE, EMBASE, PsycINFO, The Cochrane Library and Science Citation Index. For the realist review, further purposive and iterative searches through snowballing techniques will be undertaken. Inclusions, data extraction and quality assessment will be in duplicate with disagreements resolved through discussion. Quality assessment will include using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Data synthesis will be narrative and tabular with meta-analysis where appropriate. De novo economic modelling will be attempted in one clinical area if sufficient evidence is available and performed according to the National Institute for Health and Care Excellence (NICE) reference case.