bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection
Authors: Cates Jordan E. , Mitrani-Gold Fanny S. , Li Gang , Mundy Linda M. 
Published: May 2015

ABSTRACT
A systematic literature review and meta-analysis were conducted to estimate the antibacterial treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and skin structure infection (ABSSSI) noninferiority trials. The primary endpoints included an early clinical treatment response (ECTR) defined as cessation of lesion spread at 48 to 72 h postrandomization and the test-of-cure (TOC) response defined as total resolution of the infection at 7 to 14 days posttreatment. The systematic review identified no placebo-controlled trials in ABSSSI, 4 placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy for placebo in ABSSSI, 12 linezolid trials in ABSSSI, 3 ceftaroline trials in ABSSSI, and 2 trials for nonantibacterial treatment. The ECTR rates at 48 to 72 h and corresponding 95% confidence intervals (CI) were 78.7% (95% CI, 61.1 to 96.3%) for linezolid, 74.0% (95% CI, 69.7 to 78.3%) for ceftaroline, and 59.0% (95% CI, 52.8 to 65.3%) for nonantibacterial treatment. The early clinical treatment effect could not be estimated, given no available placebo or proxy for placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled estimates of the TOC treatment response were 31.0% (95% CI, 6.2 to 55.9%) for the proxy for placebo, 88.1% (95% CI, 81.0 to 95.1%) for linezolid, and 86.1% (95% CI, 83.7 to 88.6%) for ceftaroline. The TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The antibacterial treatment effect estimation at TOC will inform on the design and analysis of future noninferiority ABSSSI clinical trials.
The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence
Authors: Johnson Benjamin K. , Colvin Christopher J. , Needle David B. , Mba Medie Felix , Champion Patricia A. DiGiuseppe , Abramovitch Robert B. 
Published: May 2015

ABSTRACT

Mycobacterium tuberculosis
must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for
M. tuberculosis
intracellular replication and growth
in vivo
. Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of
M. tuberculosis
with ethoxzolamide recapitulates
phoPR
mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces
M. tuberculosis
growth in both macrophages and infected mice. Ethoxzolamide inhibits
M. tuberculosis
carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence.
Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections
Authors: Phee Lynette M. , Betts Jonathan W. , Bharathan Binutha , Wareham David W. 
Published: May 2015

ABSTRACT

The spread of multidrug-resistant
Acinetobacter baumannii
(MDRAB) has led to the renaissance of colistin (COL), often the only agent to which MDRAB remains susceptible. Effective therapy with COL is beset with problems due to unpredictable pharmacokinetics, toxicity, and the rapid selection of resistance. Here, we describe a potent synergistic interaction when COL was combined with fusidic acid (FD) against
A. baumannii
. Synergy
in vitro
was assessed against 11 MDRAB isolates using disc diffusion, checkerboard methodology (fractional inhibitory concentration index [FICI] of ≤ 0.5, susceptibility breakpoint index [SBPI] of >2), and time-kill methodology (≥2 log
10
CFU/ml reduction). The ability of FD to limit the emergence of COL resistance was assessed in the presence and absence of each drug alone and in combination. Synergy was demonstrated against all strains, with an average FICI and SBPI of 0.064 and 78.85, respectively. In time-kill assays, COL-FD was synergistic and rapidly bactericidal, including against COL-resistant strains. Fusidic acid prevented the emergence of COL resistance, which was readily selected with COL alone. This is the first description of a novel COL-FD regimen for the treatment of MDRAB. The combination was effective at low concentrations, which should be therapeutically achievable while limiting toxicity. Further studies are warranted to determine the mechanism underlying the interaction and the suitability of COL-FD as an unorthodox therapy for the treatment of multidrug-resistant Gram-negative infections.
Combinations of β-Lactam Antibiotics Currently in Clinical Trials Are Efficacious in a DHP-I-Deficient Mouse Model of Tuberculosis Infection
Authors: Rullas Joaquín , Dhar Neeraj , McKinney John D. , García-Pérez Adolfo , Lelievre Joël , Diacon Andreas H. , Hugonnet Jean-Emmanuel , Arthur Michel , Angulo-Barturen Iñigo , Barros-Aguirre David , Ballell Lluís 
Published: May 2015

ABSTRACT

We report here a dehydropeptidase-deficient murine model of tuberculosis (TB) infection that is able to partially uncover the efficacy of marketed broad-spectrum β-lactam antibiotics alone and in combination. Reductions of up to 2 log CFU in the lungs of TB-infected mice after 8 days of treatment compared to untreated controls were obtained at blood drug concentrations and time above the MIC (
T
>MIC
) below clinically achievable levels in humans. These findings provide evidence supporting the potential of β-lactams as safe and mycobactericidal components of new combination regimens against TB with or without resistance to currently used drugs.
Effect of Variants of Penicillin-Binding Protein 2 on Cephalosporin and Carbapenem Susceptibilities in Neisseria gonorrhoeae
Authors: Bharat Amrita , Demczuk Walter , Martin Irene , Mulvey Michael R. 
Published: May 2015

ABSTRACT

To characterize the relationship between penicillin-binding protein 2 (PBP2/
penA
) and susceptibility to extended-spectrum cephalosporins (ESCs) and carbapenem antibiotics, we compared 17 PBP2 variants in
Neisseria gonorrhoeae
. Nonmosaic and mosaic variants of PBP2 caused decreased susceptibility to ESCs and, to a lesser extent, to carbapenems. An A501P substitution in mosaic XXXIV_A501P conferred decreased susceptibility to ESCs but restored carbapenem susceptibility to wild-type levels. These results could aid the molecular surveillance of antimicrobial resistance to these agents.
Streptococcus pyogenes Triggers Activation of the Human Contact System by Streptokinase
Authors: Nitzsche Ramona , Rosenheinrich Maik , Kreikemeyer Bernd , Oehmcke-Hecht Sonja 
Published: May 2015

ABSTRACT

Severe invasive infectious diseases remain a major and life-threatening health problem. In serious cases, a systemic activation of the coagulation cascade is a critical complication that is associated with high mortality rates. We report here that streptokinase, a group A streptococcal plasminogen activator, triggers the activation of the human contact system. Activation of contact system factors at the surface of the
Streptococcus pyogenes
serotype M49 is dependent on streptokinase and plasminogen. Our results also show that secreted streptokinase is an efficient contact system activator, independent from a contact surface. This results in the processing of high-molecular-weight kininogen and the release of bradykinin, a potent vascular mediator. We further investigated whether the ability of 50 different clinical
S. pyogenes
isolates to activate the contact system is associated with an invasive phenotype. The data reveal that isolates from invasive infections trigger an activation of the contact system more potently than strains isolated from noninvasive infections. The present study gives new insights into the mechanisms by which
S. pyogenes
triggers the human contact system and stresses the function of soluble and surface located plasmin exploited as a group A streptococcal virulence factor through the action of streptokinase.
Regulation of the Min Cell Division Inhibition Complex by the Rcs Phosphorelay in Proteus mirabilis
Authors: Howery Kristen E. , Clemmer Katy M. , Şimşek Emrah , Kim Minsu , Rather Philip N. 
Published: May 2015

ABSTRACT

A key regulator of swarming in
Proteus mirabilis
is the Rcs phosphorelay, which represses
flhDC
, encoding the master flagellar regulator FlhD
4
C
2
. Mutants in
rcsB
, the response regulator in the Rcs phosphorelay, hyperswarm on solid agar and differentiate into swarmer cells in liquid, demonstrating that this system also influences the expression of genes central to differentiation. To gain a further understanding of RcsB-regulated genes involved in swarmer cell differentiation, transcriptome sequencing (RNA-Seq) was used to examine the RcsB regulon. Among the 133 genes identified,
minC
and
minD
, encoding cell division inhibitors, were identified as RcsB-activated genes. A third gene,
minE
, was shown to be part of an operon with
minCD
. To examine
minCDE
regulation, the
min
promoter was identified by 5′ rapid amplification of cDNA ends (5′-RACE), and both transcriptional
lacZ
fusions and quantitative real-time reverse transcriptase (qRT) PCR were used to confirm that the
minCDE
operon was RcsB activated. Purified RcsB was capable of directly binding the
minC
promoter region. To determine the role of RcsB-mediated activation of
minCDE
in swarmer cell differentiation, a polar
minC
mutation was constructed. This mutant formed minicells during growth in liquid, produced shortened swarmer cells during differentiation, and exhibited decreased swarming motility.

IMPORTANCE
This work describes the regulation and role of the MinCDE cell division system in
P. mirabilis
swarming and swarmer cell elongation. Prior to this study, the mechanisms that inhibit cell division and allow swarmer cell elongation were unknown. In addition, this work outlines for the first time the RcsB regulon in
P. mirabilis
. Taken together, the data presented in this study begin to address how
P. mirabilis
elongates upon contact with a solid surface.
Environmental Sensing in Actinobacteria: a Comprehensive Survey on the Signaling Capacity of This Phylum
Authors: Huang Xiaoluo , Pinto Daniela , Fritz Georg , Mascher Thorsten 
Published: May 2015

ABSTRACT

Signal transduction is an essential process that allows bacteria to sense their complex and ever-changing environment and adapt accordingly. Three distinct major types of signal-transducing proteins (STPs) can be distinguished: one-component systems (1CSs), two-component systems (2CSs), and extracytoplasmic-function σ factors (ECFs). Since
Actinobacteria
are particularly rich in STPs, we comprehensively investigated the abundance and diversity of STPs encoded in 119 actinobacterial genomes, based on the data stored in the Microbial Signal Transduction (MiST) database. Overall, we observed an approximately linear correlation between the genome size and the total number of encoded STPs. About half of all membrane-anchored 1CSs are protein kinases. For both 1CSs and 2CSs, a detailed analysis of the domain architectures identified novel proteins that are found only in actinobacterial genomes. Many actinobacterial genomes are particularly enriched for ECFs. As a result of this study, almost 500 previously unclassified ECFs could be classified into 18 new ECF groups. This comprehensive survey demonstrates that actinobacterial genomes encode previously unknown STPs, which may represent new mechanisms of signal transduction and regulation. This information not only expands our knowledge of the diversity of bacterial signal transduction but also provides clear and testable hypotheses about their mechanisms, which can serve as starting points for experimental studies.

IMPORTANCE
In the wake of the genomic era, with its enormous increase in the amount of available sequence information, the challenge has now shifted toward making sense and use of this treasure chest. Such analyses are a prerequisite to provide meaningful information that can help guide subsequent experimental efforts, such as mechanistic studies on novel signaling strategies. This work provides a comprehensive analysis of signal transduction proteins from 119 actinobacterial genomes. We identify, classify, and describe numerous novel and conserved signaling devices. Hence, our work serves as an important resource for any researcher interested in signal transduction of this important bacterial phylum, which contains organisms of ecological, biotechnological, and medical relevance.
Biochemical Characterization of Mycobacterium smegmatis RnhC (MSMEG_4305), a Bifunctional Enzyme Composed of Autonomous N-Terminal Type I RNase H and C-Terminal Acid Phosphatase Domains
Authors: Jacewicz Agata , Shuman Stewart 
Published: May 2015

ABSTRACT

Mycobacterium smegmatis
encodes several DNA repair polymerases that are adept at incorporating ribonucleotides, which raises questions about how ribonucleotides in DNA are sensed and removed. RNase H enzymes, of which
M. smegmatis
encodes four, are strong candidates for a surveillance role. Here, we interrogate the biochemical activity and nucleic acid substrate specificity of
M. smegmatis
RnhC, a bifunctional RNase H and acid phosphatase. We report that (i) the RnhC nuclease is stringently specific for RNA:DNA hybrid duplexes; (ii) RnhC does not selectively recognize and cleave DNA-RNA or RNA-DNA junctions in duplex nucleic acid; (iii) RnhC cannot incise an embedded monoribonucleotide or diribonucleotide in duplex DNA; (iv) RnhC can incise tracts of 4 or more ribonucleotides embedded in duplex DNA, leaving two or more residual ribonucleotides at the cleaved 3′-OH end and at least one or two ribonucleotides on the 5′-PO
4
end; (v) the RNase H activity is inherent in an autonomous 140-amino-acid (aa) N-terminal domain of RnhC; and (vi) the C-terminal 211-aa domain of RnhC is an autonomous acid phosphatase. The cleavage specificity of RnhC is clearly distinct from that of
Escherichia coli
RNase H2, which selectively incises at an RNA-DNA junction. Thus, we classify RnhC as a type I RNase H. The properties of RnhC are consistent with a role in Okazaki fragment RNA primer removal or in surveillance of oligoribonucleotide tracts embedded in DNA but not in excision repair of single misincorporated ribonucleotides.

IMPORTANCE
RNase H enzymes help cleanse the genome of ribonucleotides that are present either as ribotracts (e.g., RNA primers) or as single ribonucleotides embedded in duplex DNA.
Mycobacterium smegmatis
encodes four RNase H proteins, including RnhC, which is characterized in this study. The nucleic acid substrate and cleavage site specificities of RnhC are consistent with a role in initiating the removal of ribotracts but not in single-ribonucleotide surveillance. RnhC has a C-terminal acid phosphatase domain that is functionally autonomous of its N-terminal RNase H catalytic domain. RnhC homologs are prevalent in
Actinobacteria
.
Lower socioeconomic status, adiposity and negative health behaviours in youth: a cross-sectional observational study
Authors: Lord Sarah , Manlhiot Cedric , Tyrrell Pascal N , Dobbin Stafford , Gibson Don , Chahal Nita , Stearne Karen , Fisher Amanda , McCrindle Brian W 
Published: May 2015

ObjectiveUnderstanding obesity and its modifiable risk factors in youth is key to addressing the burden of cardiovascular disease later in life. Our aim was to examine the associations among adiposity, negative health behaviours and socioeconomic status in youth from the Niagara Region.Design, setting and participantsCross-sectional observational study of 3467 grade 9 students during their mandatory health and physical education class to investigate the association between socioeconomic status (postal code), self-reported health behaviour and adiposity in the Niagara Region, Ontario, Canada.ResultsMedian household income was $63 696 and overall percentage below the after-tax low-income cut-off was 4.2%. Negative health behaviours (especially skipped meals, lower fruit and vegetable consumption, higher screen time) were associated with lower income neighbourhoods, however, the absolute effect was small. Those participants in the lowest income quintile had a significantly greater body mass index z-score than those in the highest (0.72±1.19 vs 0.53±1.12), but the overall trend across quintiles was not statistically significant. A similar trend was noted for waist-to-height ratio. The lowest income neighbourhoods according to after-tax low-income cut-off had small but statistically significant associations with higher adiposity compared with the middle or highest income neighbourhoods.ConclusionsObesity prevention efforts should target modifiable behaviours, with particular attention to adolescents from lower income families and neighbourhoods.
Improving feedback from outpatient medical appointments attended by escorted psychiatric patients in the North London Forensic Service
Authors: McCurdy Kathleen , Croxford Anna 
Published: May 2015

AbstractIt is well established that patients with mental illness are known to have a high level of morbidity and mortality compared to the general population. This is particularly prominent in long-stay psychiatric patients, such as those in secure settings. The Royal College of Psychiatrists recommends that psychiatrists should promote the physical health of their patients and liaise with other specialties. However, there is evidence that communication between psychiatry and other specialties is poor.A survey was carried out at the North London Forensic Service in June 2014. This looked at the views of clinical staff about the frequency and quality of feedback obtained when inpatients attend outpatient hospital appointments at local general hospitals. This survey highlighted the general perception among staff that feedback is poor, with 68.43% of respondents saying that they were “very unsatisfied” or “unsatisfied” with the level and quality of feedback. Clinical staff felt that many patients who attended hospital outpatient appointments, even when escorted by staff, returned with little or no feedback. This was confirmed by a baseline audit across 3 wards showing that details of the appointment (date, time, hospital, and specialty) were only documented in 54.5% of cases and the content of the appointment documented in even fewer cases.A form was designed by junior doctors that provided a simple framework of 6 questions to be answered at the outpatient clinic about the problem, diagnosis, and further actions needed. This was introduced and its impact assessed with a 3-month and 6-month audit of electronic notes, as well as a follow-up survey after 6 months. The audit showed significant improvement in the quality of feedback about the appointment at both the 3-month and 6-month point. The follow-up survey showed that 70% of respondents were aware of the form and 100% of those who were aware of the form had used it at least once and found it helpful. The general satisfaction level improved, but remained low, with 40% of respondents saying that they were “very unsatisfied” or “unsatisfied” with the level and quality of feedback.This QIP shows that the outpatient appointment form is a useful and effective tool when staff know about it and use it. We plan to look at the barriers to using the form and consider future solutions to the need for increased engagement with nursing staff stakeholders in future PDSA cycles.
UNDERSTANDING WHY AMBULANCES ARE CALLED FOR ‘PRIMARY CARE’ PROBLEMS: A SYSTEMATIC MAPPING REVIEW
Authors: Booker Matthew , Shaw Ali RG , Purdy Sarah 
Published: May 2015

BackgroundMembers of the public are increasingly turning to ambulance services for help with urgent problems that could successfully be managed in primary care. The reasons for this are complex, and it is unclear whether variation exists across different global settings and between ambulance systems.MethodsA systematic mapping review is a type of systematic literature review used to summarise diverse and heterogeneous evidence, with the aim of focusing a more in-depth study. We conducted a comprehensive search of published and grey literature, in accordance with a prospectively published protocol. Inclusion criteria were any study from 1980 onwards that explored ambulance use for conditions amenable to primary care management. Perspectives of patients, families, carers, bystanders, health professionals (pre-hospital, in-hospital and primary care) and health service management were included. The ‘Phenomena of Interest’ (P-C) model underpinned the approach, therefore qualitative, quantitative, mixed-methods and interpretative reviews were all included as relevant. A total of 31 studies met inclusion criteria.ResultsWe developed a literature map summarising the evidence under five broad categories. Ambulance use for ‘primary care problems’ appears associated with individual patient-factors, including personal anxieties and risk management strategies, level of health education, and several socio-demographic factors. The link with specific clinical conditions is weaker. Bystanders, carers and family members consistently exhibit strong influence on decision making across the variety of global pre-hospital systems. Health professionals determine ‘inappropriate’ ambulance use in inconsistent ways.ConclusionThere is evidence to suggest socioeconomic and demographic characteristics traditionally associated with minority status and deprivation are associated with ambulance use for primary care problems. The role of formal and informal care-givers in influencing risk management warrants deeper exploration. There is a lack of consensus in the literature on what defines ‘inappropriate’ ambulance use, and from who's perspective this should be determined. Further work needs to explore these conflicts.