bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis
Authors: Alsaad N. , Dijkstra J. A. , Akkerman O. W. , de Lange W. C. M. , van Soolingen D. , Kosterink J. G. W. , van der Werf T. S. , Alffenaar J. W. C. 
Published: April 2016

ABSTRACT

For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and
in vitro
PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible
Mycobacterium tuberculosis
(drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (ƒAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (f
T
> MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean ± standard deviation [SD]): metabolic clearance (CL

m

), 1.57 ± 3.71 liters/h; volume of distribution (
V
), 0.30 ± 0.05 liters · kg lean body mass
−1
; drug clearance/creatinine clearance ratio (

f
r

), 0.02 ± 0.13; gamma distribution rate constant (ktr_po), 2.18 ± 1.14; gamma distribution shape factor (n_po), 2.15 ± 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒ
T
> MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.)
Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance
Authors: Cheah Soon-Ee , Li Jian , Tsuji Brian T. , Forrest Alan , Bulitta Jürgen B. , Nation Roger L. 
Published: April 2016

ABSTRACT

Infections caused by multidrug-resistant
Acinetobacter baumannii
are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical
A. baumannii
strains in a dynamic one-compartment
in vitro
model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log
10
killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log
10
CFU/ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.
ICE
Spy
009, a Conjugative Genetic Element Carrying
mef
(E) in Streptococcus pyogenes
Authors: Del Grosso Maria , Camilli Romina , Rizzi Ermanno , Pietrelli Alessandro , De Bellis Gianluca , Pantosti Annalisa 
Published: April 2016

ABSTRACT

Efflux-mediated macrolide resistance due to
mef
(E) and
mel
, carried by the mega element, is common in
Streptococcus pneumoniae
, for which it was originally characterized, but it is rare in
Streptococcus pyogenes
. In
S. pyogenes
, mega was previously found to be enclosed in Tn
2009
, a composite genetic element of the Tn
916
family containing
tet
(M) and conferring erythromycin and tetracycline resistance. In this study,
S. pyogenes
isolates containing
mef
(E), apparently not associated with other resistance determinants, were examined to characterize the genetic context of mega. By whole-genome sequencing of one isolate, MB56Spyo009, we identified a novel composite integrative and conjugative element (ICE) carrying mega, designated ICE
Spy
009, belonging to the ICE
Sa
2603 family. ICE
Spy
009 was 55 kb long, contained 61 putative open reading frames (ORFs), and was found to be integrated into
hylA
, a novel integration site for the ICE
Sa
2603 family. The modular organization of the ICE was similar to that of members of the ICE
Sa
2603 family carried by different streptococcal species. In addition, a novel cluster of accessory resistance genes was found inside a region that encloses mega. PCR mapping targeting ICE
Spy
009 revealed the presence of a similar ICE in five other isolates under study. While in three isolates the integration site was the same as that of ICE
Spy
009, in two isolates the ICE was integrated into
rplL
, the typical integration site of the ICE
Sa
2603 family. ICE
Spy
009 was able to transfer macrolide resistance by conjugation to both
S. pyogenes
and
S. pneumoniae
, showing the first evidence of the transferability of mega from
S. pyogenes
.
Elucidation of Mechanisms of Ceftazidime Resistance among Clinical Isolates of Pseudomonas aeruginosa by Using Genomic Data
Authors: Kos Veronica N. , McLaughlin Robert E. , Gardner Humphrey A. 
Published: April 2016

ABSTRACT

Ceftazidime is one of the few cephalosporins with activity against
Pseudomonas aeruginosa
. Using whole-genome comparative analysis, we set out to determine the prevalent mechanism(s) of resistance to ceftazidime (CAZ) using a set of 181 clinical isolates. These isolates represented various multilocus sequence types that consisted of both ceftazidime-susceptible and -resistant populations. A presumptive resistance mechanism against ceftazidime was identified in 88% of the nonsusceptible isolates using this approach.
The Metalloprotease Mpl Supports Listeria monocytogenes Dissemination through Resolution of Membrane Protrusions into Vacuoles
Authors: Alvarez Diego E. , Agaisse Hervé 
Published: April 2016

ABSTRACTListeria monocytogenesis an intracellular pathogen that disseminates within the intestinal epithelium through acquisition of actin-based motility and formation of plasma membrane protrusions that project into adjacent cells. The resolution of membrane protrusions into vacuoles from which the pathogen escapes results in bacterial spread from cell to cell. This dissemination process relies on themlp-actA-plcBoperon, which encodes ActA, a bacterial nucleation-promoting factor that mediates actin-based motility, and PlcB, a phospholipase that mediates vacuole escape. Here we investigated the role of the metalloprotease Mpl in the dissemination process. In agreement with previous findings showing that Mpl is required for PlcB activation, infection of epithelial cells with the ΔplcBor Δmplstrains resulted in the formation of small infection foci. As expected, the ΔplcBstrain displayed a strong defect in vacuole escape. However, the Δmplstrain showed an unexpected defect in the resolution of protrusions into vacuoles, in addition to the expected but mild defect in vacuole escape. The Δmplstrain displayed increased levels of ActA on the bacterial surface in protrusions. We mapped an Mpl-dependent processing site in ActA between amino acid residues 207 to 238. Similar to the Δmplstrain, the ΔactA207–238strain displayed increased levels of ActA on the bacterial surface in protrusions. Although the ΔactA207–238strain displayed wild-type actin-based motility, it formed small infection foci and failed to resolve protrusions into vacuoles. We propose that, in addition to its role in PlcB processing and vacuole escape, the metalloprotease Mpl is required for ActA processing and protrusion resolution.
Macrophage Apoptosis Triggered by IpaD from Shigella flexneri
Authors: Arizmendi Olivia , Picking William D. , Picking Wendy L. 
Published: April 2016

ABSTRACT

Shigellosis, a potentially severe bacillary dysentery, is an infectious gastrointestinal disease caused by
Shigella
spp.
Shigella
invades the human colonic epithelium and avoids clearance by promoting apoptosis of resident immune cells in the gut. This process is dependent on the
Shigella
type III secretion system (T3SS), which injects effector proteins into target cells to alter their normal cellular functions. Invasion plasmid antigen D (IpaD) is a structural component that forms a complex at the tip of the T3SS apparatus needle. Recently, IpaD has also been shown to indirectly induce apoptosis in B lymphocytes. In this study, we explored the cytotoxicity profile during macrophage infection by
Shigella
and discovered that the pathogen induces macrophage cell death independent of caspase-1. Our results demonstrate that IpaD triggers apoptosis in macrophages through activation of host caspases accompanied by mitochondrial disruption. Additionally, we found that the IpaD N-terminal domain is necessary for macrophage killing and SipD, a structural homologue from
Salmonella
, was found to promote similar cytotoxicity. Together, these findings indicate that IpaD is a contributing factor to macrophage cell death during
Shigella
infection.
Population Dynamics of Phage and Bacteria in Spatially Structured Habitats Using Phage λ and Escherichia coli
Authors: Mitarai Namiko , Brown Stanley , Sneppen Kim 
Published: April 2016

ABSTRACT

Bacteria living in physically structured habitats are exposed heterogeneously to both resources and different types of phages. While there have been numerous experimental approaches to examine spatially distributed bacteria exposed to phages, there is little theory to guide the design of these experiments, interpret their results, or expand the inferences drawn to a broader ecological and evolutionary context. Plaque formation provides a window into understanding phage-bacterium interactions in physically structured populations, including surfaces, semisolids, and biofilms. We develop models to address the plaque dynamics for a temperate phage and its virulent mutants. The models are compared with phage λ-
Escherichia coli
system to quantify their applicability. We found that temperate phages gave an increasing number of gradually smaller colonies as the distance increased from the plaque center. For low-lysogen frequency this resulted in plaques with most of the visible colonies at an intermediate distance between the center and periphery. Using spot inoculation, where phages in excess of bacteria were inoculated in a circular area, we measured the frequency and spatial distribution of lysogens. The spot morphology of
c
II-negative (
c
II
−
) and
c
III
−
mutants of phage λ displays concentric rings of high-density lysogenic colonies. The simplest of these ring morphologies was reproduced by including multiplicity of infection (MOI) sensitivity in lysis-lysogeny decisions, but its failure to explain the occasional observation of multiple rings in
c
III
−
mutant phages highlights unknown features of this phage. Our findings demonstrated advantages of temperate phages over virulent phages in exploiting limited resources in spatially distributed microbial populations.

IMPORTANCE
Phages are the most abundant organisms on earth, and yet little is known about how phages and bacterial hosts are influencing each other in density and evolution. Phages can be either virulent or temperate, a difference that is highlighted when a spatially structured bacterial population is infected. Phage λ is a temperate phage, with a capacity for dormancy that can be modified by single gene knockouts. The stochastic bias in the lysis-lysogeny decision's probability is reflected in plaque morphologies on bacterial lawns. We present a model for plaque morphology of both virulent and temperate phages, taking into account the underlying survival of bacterial microcolonies. It reproduces known plaque morphologies and speaks to advantages of temperate phages in a spatially structured environment.
Cluster randomised controlled trial of a financial incentive for mothers to improve breast feeding in areas with low breastfeeding rates: the NOSH study protocol
Authors: Relton Clare , Strong Mark , Renfrew Mary J , Thomas Kate , Burrows Julia , Whelan Barbara , Whitford Heather M , Scott Elaine , Fox-Rushby Julia , Anoyke Nana , Sanghera Sabina , Johnson Maxine , Sue Easton , Walters Stephen 
Published: April 2016

IntroductionBreast feeding can promote positive long-term and short-term health outcomes in infant and mother. The UK has one of the lowest breastfeeding rates (duration and exclusivity) in the world, resulting in preventable morbidities and associated healthcare costs. Breastfeeding rates are also socially patterned, thereby potentially contributing to health inequalities. Financial incentives have been shown to have a positive effect on health behaviours in previously published studies.Methods and analysisBased on data from earlier development and feasibility stages, a cluster (electoral ward) randomised trial with mixed-method process and content evaluation was designed. The ‘Nourishing Start for Health’ (NOSH) intervention comprises a financial incentive programme of up to 6 months duration, delivered by front-line healthcare professionals, in addition to existing breastfeeding support. The intervention aims to increase the prevalence and duration of breast feeding in wards with low breastfeeding rates. The comparator is usual care (no offer of NOSH intervention). Routine data on breastfeeding rates at 6–8 weeks will be collected for 92 clusters (electoral wards) on an estimated 10 833 births. This sample is calculated to provide 80% power in determining a 4% point difference in breastfeeding rates between groups. Content and process evaluation will include interviews with mothers, healthcare providers, funders and commissioners of infant feeding services. The economic analyses, using a healthcare provider's perspective, will be twofold, including a within-trial cost-effectiveness analysis and beyond-trial modelling of longer term expectations for cost-effectiveness. Results of economic analyses will be expressed as cost per percentage point change in cluster level in breastfeeding rates between trial arms. In addition, we will present difference in resource use impacts for a range of acute conditions in babies aged 0–6 months.Ethics and disseminationParticipating organisations Research and Governance departments approved the study. Results will be published in peer-reviewed journals and at conference presentations.Trial registration numberISRCTN44898617; Pre-results.
How does audit and feedback influence intentions of health professionals to improve practice? A laboratory experiment and field study in cardiac rehabilitation
Authors: Gude Wouter T , van Engen-Verheul Mariëtte M , van der Veer Sabine N , de Keizer Nicolette F , Peek Niels 
Published: April 2016

ObjectiveTo identify factors that influence the intentions of health professionals to improve their practice when confronted with clinical performance feedback, which is an essential first step in the audit and feedback mechanism.MethodsWe conducted a theory-driven laboratory experiment with 41 individual professionals, and a field study in 18 centres in the context of a cluster-randomised trial of electronic audit and feedback in cardiac rehabilitation. Feedback reports were provided through a web-based application, and included performance scores and benchmark comparisons (high, intermediate or low performance) for a set of process and outcome indicators. From each report participants selected indicators for improvement into their action plan. Our unit of observation was an indicator presented in a feedback report (selected yes/no); we considered selecting an indicator to reflect an intention to improve.ResultsWe analysed 767 observations in the laboratory experiment and 614 in the field study, respectively. Each 10% decrease in performance score increased the probability of an indicator being selected by 54% (OR, 1.54; 95% CI 1.29% to 1.83%) in the laboratory experiment, and 25% (OR, 1.25; 95% CI 1.13% to 1.39%) in the field study. Also, performance being benchmarked as low and intermediate increased this probability in laboratory settings. Still, participants ignored the benchmarks in 34% (laboratory experiment) and 48% (field study) of their selections.ConclusionsWhen confronted with clinical performance feedback, performance scores and benchmark comparisons influenced health professionals' intentions to improve practice. However, there was substantial variation in these intentions, because professionals disagreed with benchmarks, deemed improvement unfeasible or did not consider the indicator an essential aspect of care quality. These phenomena impede intentions to improve practice, and are thus likely to dilute the effects of audit and feedback interventions.Trial registration numberNTR3251, pre-results.
Exploring the acceptability of a clinical decision rule to identify paediatric burns due to child abuse or neglect
Authors: Johnson Emma Louise , Hollén Linda Irene , Kemp Alison Mary , Maguire Sabine 
Published: April 2016

ObjectiveAn evidence based clinical decision rule (CDR) was developed from a systematic review and epidemiological study to identify burns due to child maltreatment (abuse or neglect). Prior to an implementation evaluation, we aim to explore clinicians' views of the CDR, the likelihood that it would influence their management and factors regarding its acceptability.MethodsA semistructured questionnaire exploring demographics, views of the CDR and data collection pro forma, ability to recognise maltreatment and likelihood of following CDR recommended child protection (CP) action, was administered to 55 doctors and nurses in eight emergency departments and two burns units. Recognition of maltreatment was assessed via four fictitious case vignettes.AnalysisFisher's exact test and variability measured by coefficient of unalikeability.ResultsThe majority of participants found the CDR and data collection pro forma useful (45/55, 81.8%). Only five clinicians said that they would not take the action recommended by the CDR (5/54, 9.3%). Lower grade doctors were more likely to follow the CDR recommendations (p=0.04) than any other grade, while senior doctors would consider it within their decision making. Factors influencing uptake include: brief training, background to CDR development and details of appropriate actions.ConclusionsIt is apparent that clinicians are willing to use a CDR to assist in identifying burns due to child maltreatment. However, it is clear that an implementation evaluation must encompass the influential variables identified to maximise uptake.
Primary care services located with EDs: a review of effectiveness
Authors: Ramlakhan Shammi , Mason Suzanne , O'Keeffe Colin , Ramtahal Alicia , Ablard Suzanne 
Published: April 2016

BackgroundPrimary care focused unscheduled care centres (UCC) co-located with major EDs have been proposed as a solution to the rise in ED attendances. They aim to reduce the burden of primary care patients attending the ED, hence reducing crowding, waits and cost.This review analysed available literature in the context of the impact of general practitioner (GP) delivered, hospital-based (adjacent or within the ED) unscheduled care services on process outcomes, cost-effectiveness and patient satisfaction.MethodsA narrative literature review of studies published between 1980 and 2015 was undertaken. All study types were reviewed and included if they reported a service model using hospital-based primary care clinicians with a control consisting of standard ED clinician-delivered care.ResultsThe electronic searches yielded 7544 citations, with 20 records used in the review. These were grouped into three main themes: process outcomes, cost-effectiveness and satisfaction. A paradoxical increase in attendances has been described, which is likely to be attributable to provider-induced demand, and the evidence for improved throughput is poor. Marginal savings may be realised per patient, but this is likely to be overshadowed by the overall cost of introducing a new service.ConclusionsThere is little evidence to support the implementation of co-located UCC models. A robust evaluation of proposed models is needed to inform future policy.
Primary acute stroke thrombectomy within 3 h for large artery occlusion (PAST3-LAO): a pilot study
Authors: Lodi Yahia , Reddy Varun , Petro Gorge , Devasenapathy Ashok , Hourani Anas , Chou Chun-An 
Published: April 2016

Background and purposeIn recent trials, acute ischemic stroke (AIS) from large artery occlusion (LAO) was resistant to intravenous thrombolysis and adjunctive stent retriever thrombectomy (SRT) was associated with better perfusion and outcomes. Despite benefit, 39–68% of patients had poor outcomes. Thrombectomy in AIS with LAO within 3 h is performed secondary to intravenous thrombolysis, which may be associated with delay. The purpose of our study is to evaluate the safety, feasibility, recanalization rate, and outcome of primary SRT within 3 h without intravenous thrombolysis in AIS from LAO.MethodsBased on an institutionally approved protocol, stroke patients with LAO within 3 h were offered primary SRT as an alternative to intravenous recombinant tissue plasminogen activator. Consecutive patients who underwent primary SRT for LAO within 3 h from 2012 to 2014 were enrolled. Outcomes were measured using the modified Rankin Scale (mRS).Results18 patients with LAO of mean age 62.83±15.32 years and median NIH Stroke Scale (NIHSS) score 16 (10–23) chose primary SRT after giving informed consent. Near complete (TICI 2b in 1 patient) or complete (TICI 3 in 17 patients) recanalization was observed in all patients. Time to recanalization from symptom onset and groin puncture was 188.5±82.7 and 64.61±40.14 min, respectively. NIHSS scores immediately after thrombectomy, at 24 h and 30 days were 4 (0–12), 1 (0–12), and 0 (0–4), respectively. Asymptomatic perfusion-related hemorrhage developed in four patients (22%). 90-day outcomes were mRS 0 in 50%, mRS 1 in 44.4%, and mRS 2 in 5.6%.ConclusionsOur study demonstrates that primary SRT in AIS from LAO is safe and feasible and is associated with complete recanalization and good outcome. Further study is required.