bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the Campylobacter jejuni Transcriptional Response to Host Intestinal Extracts Reveals the Involvement of a Widely Conserved Iron Uptake System
Authors: Liu Martha M. , Boinett Christine J. , Chan Anson C. K. , Parkhill Julian , Murphy Michael E. P. , Gaynor Erin C. 
Published: August 2018

ABSTRACTCampylobacter jejuniis a pathogenic bacterium that causes gastroenteritis in humans yet is a widespread commensal in wild and domestic animals, particularly poultry. Using RNA sequencing, we assessedC. jejunitranscriptional responses to medium supplemented with human fecal versus chicken cecal extracts and in extract-supplemented medium versus medium alone.C. jejuniexposed to extracts had altered expression of 40 genes related to iron uptake, metabolism, chemotaxis, energy production, and osmotic stress response. In human fecal versus chicken cecal extracts,C. jejunidisplayed higher expression of genes involved in respiration (fdhTU) and in known or putative iron uptake systems (cfbpA,ceuB,chuC, andCJJ81176_1649–1655[here designated1649–1655]). The1649–1655genes and downstream overlapping gene1656were investigated further. Uncharacterized homologues of this system were identified in 33 diverse bacterial species representing 6 different phyla, 21 of which are associated with human disease. The1649and1650(p19) genes encode an iron transporter and a periplasmic iron binding protein, respectively; however, the role of the downstream1651–1656genes was unknown. A Δ1651–1656deletion strain had an iron-sensitive phenotype, consistent with a previously characterized Δp19mutant, and showed reduced growth in acidic medium, increased sensitivity to streptomycin, and higher resistance to H2O2stress. In iron-restricted medium, the1651–1656andp19genes were required for optimal growth when using human fecal extracts as an iron source. Collectively, this implicates a function for the1649–1656gene cluster inC. jejuniiron scavenging and stress survival in the human intestinal environment.IMPORTANCEDirect comparative studies ofC. jejuniinfection of a zoonotic commensal host and a disease-susceptible host are crucial to understanding the causes of infection outcome in humans. These studies are hampered by the lack of a disease-susceptible animal model reliably displaying a similar pathology to human campylobacteriosis. In this work, we compared the phenotypic and transcriptional responses ofC. jejunito intestinal compositions of humans (disease-susceptible host) and chickens (zoonotic host) by using human fecal and chicken cecal extracts. The mammalian gut is a complex and dynamic system containing thousands of metabolites that contribute to host health and modulate pathogen activity. We identifiedC. jejunigenes more highly expressed during exposure to human fecal extracts in comparison to chicken cecal extracts and differentially expressed in extracts compared with medium alone, and targeted one specific iron uptake system for further molecular, genetic, and phenotypic study.
Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in Neisseria gonorrhoeae
Authors: Wadsworth Crista B. , Arnold Brian J. , Sater Mohamad R. Abdul , Grad Yonatan H. 
Published: August 2018

ABSTRACT

Mosaic interspecifically acquired alleles of the multiple transferable resistance (
mtr
) efflux pump operon correlate with increased resistance to azithromycin in
Neisseria gonorrhoeae
in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we use population genomics, transformations, and transcriptional analyses to dissect the relationship between variant
mtr
alleles and azithromycin resistance. We find that the locus encompassing the
mtrR
transcriptional repressor and the
mtrCDE
pump is a hot spot of interspecific recombination introducing alleles from
Neisseria meningitidis
and
Neisseria lactamica
into
N. gonorrhoeae
, with multiple rare haplotypes in linkage disequilibrium at
mtrD
and the
mtr
promoter region. Transformations demonstrate that resistance to azithromycin, as well as to other antimicrobial compounds such as polymyxin B and crystal violet, is mediated through epistasis between these two loci and that the full-length mosaic
mtrD
allele is required. Gene expression profiling reveals the mechanism of resistance in mosaics couples novel
mtrD
alleles with promoter mutations that increase expression of the pump. Overall, our results demonstrate that epistatic interactions at
mtr
gained from multiple neisserial species has contributed to increased gonococcal resistance to diverse antimicrobial agents.

IMPORTANCE
Neisseria gonorrhoeae
is the sexually transmitted bacterial pathogen responsible for more than 100 million cases of gonorrhea worldwide each year. The incidence of resistance to the macrolide azithromycin has increased in the past decade; however, a large proportion of the genetic basis of resistance remains unexplained. This study is the first to conclusively demonstrate the acquisition of macrolide resistance through
mtr
alleles from other
Neisseria
species, demonstrating that commensal
Neisseria
bacteria are a reservoir for antibiotic resistance to macrolides, extending the role of interspecies mosaicism in resistance beyond what has been previously described for cephalosporins. Ultimately, our results emphasize that future fine-mapping of genome-wide interspecies mosaicism may be valuable in understanding the pathways to antimicrobial resistance. Our results also have implications for diagnostics and public health surveillance and control, as they can be used to inform the development of sequence-based tools to monitor and control the spread of antibiotic-resistant gonorrhea.
Identification of Two Regulators of Virulence That Are Conserved in
Klebsiella pneumoniae
Classical and Hypervirulent Strains
Authors: Palacios Michelle , Miner Taryn A. , Frederick Daniel R. , Sepulveda Victoria E. , Quinn Joshua D. , Walker Kimberly A. , Miller Virginia L. 
Published: August 2018

ABSTRACT

Klebsiella pneumoniae
is widely recognized as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of hospital-acquired infections (urinary tract infections [UTI], pneumonia, sepsis) and community-acquired invasive infections. The genetic heterogeneity of
K. pneumoniae
isolates complicates our ability to understand the virulence of
K. pneumoniae
. Characterization of virulence factors conserved between strains as well as strain-specific factors will improve our understanding of this important pathogen. The MarR family of regulatory proteins is widely distributed in bacteria and regulates cellular processes such as antibiotic resistance and the expression of virulence factors.
Klebsiella
encodes numerous MarR-like proteins, and they likely contribute to the ability of
K. pneumoniae
to respond to and survive under a wide variety of environmental conditions, including those present in the human body. We tested loss-of-function mutations in all the
marR
homologues in a murine pneumonia model and found that two (
kvrA
and
kvrB
) significantly impacted the virulence of K1 and K2 capsule type hypervirulent (
hv
) strains and that
kvrA
affected the virulence of a sequence type 258 (ST258) classical strain. In the
hv
strains,
kvrA
and
kvrB
mutants displayed phenotypes associated with reduced capsule production, mucoviscosity, and transcription from
galF
and
manC
promoters that drive expression of capsule synthesis genes. In contrast,
kvrA
and
kvrB
mutants in the ST258 strain had no effect on capsule gene expression or capsule-related phenotypes. Thus, KvrA and KvrB affect virulence in classical and
hv
strains but the effect on virulence may not be exclusively due to effects on capsule production.

IMPORTANCE
In addition to having a reputation as the causative agent for hospital-acquired infections as well as community-acquired invasive infections,
Klebsiella pneumoniae
has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. Due to the rapid emergence of carbapenem resistance among
K. pneumoniae
strains, a better understanding of virulence mechanisms and identification of new potential drug targets are needed. This study identified two novel regulators (KvrA and KvrB) of virulence in
K. pneumoniae
and demonstrated that their effect on virulence in invasive strains is likely due in part to effects on capsule production (a major virulence determinant) and hypermucoviscosity. KvrA also impacts the virulence of classical strains but does not appear to affect capsule gene expression in this strain. KvrA and KvrB are conserved among
K. pneumoniae
strains and thus could regulate capsule expression and virulence in diverse strains regardless of capsule type.
Improvement in psychiatric symptoms after strabismus surgery in adolescent patients in long-term follow-up
Authors: Ozates Serdar , Ezerbolat Ozates Melike , Can Cigdem Ulku , Polat Sibel , Yasar Hakan Halit , Taskale Busra , Gogus Ali Kemal 
Published: August 2018

AimsTo assess the psychological effects of preoperative primary eye position and surgical correction of strabismus in adolescent patients.MethodsEighty-three adolescent patients with exotropia were included in this observational and prospective study. Patients with preoperative manifest exotropia formed the manifest exotropia group. Patients with intermittent exotropia that had orthophoria with overcorrecting minus lenses and recently increased frequency of manifest phase were indicated for surgery and formed the latent deviation group. All patients were scored with the Turkish version of the Social Appearance Anxiety Scale (SAAS), depression subscale of Hospital Anxiety and Depression Scale (HAD-D) Brief Fear of Negative Evaluation Scale (BFNE), state anxiety subscale of State-Trait Anxiety Inventory (STAI-S) and trait anxiety subscale of State-Trait Anxiety Inventory (STAI-T) before and 1 year after strabismus surgery.ResultsThe mean preoperative scores of the HAD-D, SAAS, BFNE, STAI-S and STAI-T before strabismus surgery were significantly higher in the manifest exotropia group than in the latent deviation group (p≤0.001 for all). Surgical correction significantly improved the outcomes of all scales in the manifest exotropia group (p≤0.001 for all). Outcomes of the STAI-S and STAI-T significantly improved in the latent deviation group after the surgery (p=0.008, p=0.006, respectively), whereas outcomes of the HAD-D, SAAS and BFNE did not improve (p=0.079, p=0.071, p=0.127, respectively). The mean postoperative scores of all scales did not differ between the two groups (p>0.05 for all).ConclusionsStrabismus has psychological consequences in adolescent patients, and the visible eye deviation caused by strabismus is a strong indicator of psychological distress.
Cancer patients’ organisation participation in heath policy decision-making: a snapshot/cluster analysis of the EU-28 countries
Authors: Souliotis Kyriakos , Peppou Lily-Evangelia , Tzavara Chara , Agapidaki Eirini , Varvaras Dimitrios , Buonomo Oreste , Debiais Dominique , Hasurdjiev Stanimir , Sarkozy Francois 
Published: August 2018

ObjectivesEven though patient involvement in health policy decision-making is well documented, studies evaluating the degree and impact of this participation are scarce. This is even more conspicuous in the case of cancer. There is evidence showing that patients with the same type of cancer and at the same stage of the disease will receive different treatments in different countries. Therefore, it is crucial to assess the degree of patient participation in health policy decision-making across Europe, as it may result in health inequalities across countries. In a response to this research call, the present study aimed to provide a snapshot of cancer patients’ organisation (CPO) participation in health policy processes in European Union (EU)-28 countries.SettingCPOs from the EU-28 countries.ParticipantsPrimary and secondary outcome measures: information about participants’ sociodemographic characteristics and their involvement in their CPO was collected as well as data about the CPO. A 17-item index containing questions about the type and impact of participation in various facets of health policy decision-making was used to assess the degree of CPOs participation in health policy decision-making processes and its impact.
Single-arm, open-label, dose-escalation phase I study to evaluate the safety of a herbal medicine SH003 in patients with solid cancer: a study protocol
Authors: Cheon Chunhoo , Kang Sohyeon , Ko Youme , Kim Mia , Jang Bo-Hyoung , Shin Yong-Cheol , Ko Seong-Gyu 
Published: August 2018

IntroductionCancer is a major health problem worldwide and the leading cause of death in many countries. The number of patients with cancer and socioeconomic costs of cancer continues to increase. SH003 is a novel herbal medicine consisting ofAstragalus membranaceus,Angelica gigasandTrichosanthes Kirilowii Maximowicz. Preclinical studies have shown that SH003 has therapeutic anticancer effects. The aim of this study is to determine the maximum tolerated dose of SH003 in patients with solid cancers.Methods and analysisThis study is an open-label, dose-escalation trial evaluating the safety and tolerability of SH003. The traditional 3+3 dose-escalation design will be implemented. Patients with solid cancers will be recruited. According to dose level, the patients will receive one to four tablets of SH003, three times a day for 3 weeks. Toxicity will be evaluated using common terminology criteria for adverse events (CTCAE). Dose-limiting toxicities are defined as grade 3 or higher adverse events based on CTCAE. The maximum tolerated dose will be determined by the highest dose at which no more than one of six patients experiences dose-limiting toxicity.Ethics and disseminationThis study has been approved by the institutional review board of the Ajou University Hospital (reference AJIRB-MED-CT1-16-311). The results of this study will be disseminated through a scientific journal and a conference.Trial registration numberNCT03081819; Pre-results.
Examining ‘institutional entrepreneurship’ in healthcare redesign and improvement through comparative case study research: a study protocol
Authors: Melder Angela , Burns Prue , Mcloughlin Ian , Teede Helena 
Published: August 2018

IntroductionHealthcare service redesign and improvement has become an important activity that health system leaders and clinicians realise must be nurtured and mastered, if the capacity issues that constrain healthcare delivery are to be solved. However, little is known about the critical success factors that are essential for sustaining and scaling up improvement initiatives. This situation limits the impact of these initiatives and undermines the general standing of redesign and improvement activity within healthcare systems. The conduct of the doctoral research detailed in this study protocol will be nested within a broader parent study that seeks to address this problem by drawing on the theory of ‘institutional entrepreneurship’. The doctoral research will apply this idea to understanding the capacities and capabilities required at the organisation level to bring about transformational change in healthcare services.Methods and analysisThe parent study is predominantly qualitative, is multilevel in nature and has been codesigned with five partner healthcare organisations. The focus is a sector-wide attempt in an Australian state jurisdiction to transfer new redesign and improvement knowledge into the public healthcare system. The doctoral research will focus on the implementation of the sector-wide approach in one healthcare service in the jurisdiction. This research involves interviews with project team members and stakeholders involved in two improvement initiatives undertaken by the health service. It will involve interviews with redesign and improvement leaders and senior managers responsible for the overall health service improvement approach. The methods will also include immersive fieldwork, interviews and focus groups. Appropriate methods for coding and thematic extraction will be applied to the qualitative data.Ethics and disseminationEthical approval has been granted by the health service and Monash University Human Research Ethics Committee. Dissemination will be facilitated via academic publication, industry reports and workshops and dissemination events as part of the broader project.
Caesarean sections and the prevalence of preterm and early-term births in Brazil: secondary analyses of national birth registration
Authors: Barros Fernando C , Rabello Neto Dacio de Lyra , Villar Jose , Kennedy Stephen H , Silveira Mariangela F , Diaz-Rossello Jose Luis , Victora Cesar G 
Published: August 2018

ObjectivesTo investigate whether the high rates of caesarean sections (CSs) in Brazil have impacted on the prevalence of preterm and early-term births.DesignIndividual-level, cross-sectional analyses of a national database.SettingAll hospital births occurring in the country in 2015.Participants2 903 716 hospital-delivered singletons in 3157 municipalities, representing >96% of the country’s births.Primary and secondary outcome measuresCS rates and gestational age distribution (<37, 37–38, 39–41 and 42 or more weeks’ gestation). Outcomes were analysed according to maternal education, measured in years of schooling and municipal CS rates. Analyses were also adjusted for maternal age, marital status and parity.ResultsPrevalence of CS was 55.5%, preterm prevalence (<37 weeks’ gestation) was 10.1% and early-term births (37–38 weeks of gestation) represented 29.8% of all births, ranging from 24.9% among women with <4 years of schooling to 39.8% among those with >12 years of education. The adjusted prevalence ratios of preterm and early-term birth were, respectively, 1.215 (1.174–1.257) and 1.643 (1.616–1.671) higher in municipalities with≥80% CS compared with those <30%.ConclusionsBrazil faces three inter-related epidemics: a CS epidemic; an epidemic of early-term births, associated with the high CS rates; and an epidemic of preterm birth, also associated with CS but mostly linked to poverty-related risk factors. The high rates of preterm and early-term births produce an excess of newborns at higher risk of short-term morbidity and mortality, as well as long-term developmental problems. Compared with high-income countries, there is an annual excess of 354 000 preterm and early-term births in Brazil.
Development of a core outcome set for immunomodulation in pregnancy (COSIMPREG): a protocol for a systematic review and Delphi study
Authors: Prins Jelmer R , Holvast Floor , van ’t Hooft Janneke , Bos Arend F , Ganzevoort Jan Willem , Scherjon Sicco A , Robertson Sarah A , Gordijn Sanne J 
Published: August 2018

IntroductionTo establish pregnancy, the maternal immune system must adapt to tolerate the semiallogenic fetus. Less than optimal adaptation of the maternal immune system during (early) pregnancy is implicated in several complications of pregnancy. The development of effective immune modulation interventions as preventive or therapeutic strategies for pregnancy complications holds promise. Several studies sought to evaluate the safety and effectiveness of various approaches. However, a limitation is the high variability in clinical and immune outcomes that are reported. We, therefore, aim to develop a core outcome set for application to studies of immune modulation in pregnancy (COSIMPREG).Methods and analysisWe will use a stepwise approach to develop a COSIMPREG. First, we will perform a systematic review to identify reported outcomes. For this review, Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. Second, we will use the Delphi method to develop a preliminary COSIMPREG. In three rounds, the outcomes of the systematic review will be scored. A panel comprising experts from relevant disciplines and diverse geographical locations will be assembled until a sufficient quality of the panel is reached. We will use predefined decision rules for outcomes. After each round outcomes, including scores, will be returned to the panel for further refinement. The outcomes not excluded after the third round will be taken to a consensus meeting. In this meeting, experts from all relevant disciplines will discuss and finalise the COSIMPREG.Ethics and disseminationFor this study ethical approval is not required. The systematic review will be published in an appropriate open access reproductive immunology journal. Once the COSIMPREG is finalised, it will be published in an open access reproductive immunology journal, and disseminated at appropriate international meetings, as well as through relevant research and scientific societies. Experts involved in the Delphi study will be asked to give informed consent.
Clinicians’ views on treatment adaptations for men with eating disorders: a qualitative study
Authors: Kinnaird Emma , Norton Caroline , Tchanturia Kate 
Published: August 2018

ObjectivesDespite traditional views of eating disorders as a female illness, there is a growing body of evidence that the incidence rate of eating disorders in men is rising. Research suggests that these men may experience unique symptoms and difficulties, however, it is unclear how these unique needs may impact treatment. The aim of this study was to explore clinicians’ views on whether men have gender-specific treatment needs, and how far these needs require treatment adaptations.DesignQualitative interview study using framework analysis to explore the experiences of clinicians working with men with eating disorders.SettingOutpatient National Health Service eating disorder service in London.ParticipantsTen clinicians from a variety of clinical backgrounds participated in the study.ResultsThe following three themes emerged: male-specific issues identified by clinicians, treatment approaches used for this population and the importance of creating a male-friendly environment. Male-specific issues identified by participants included an increased focus on muscularity and difficulty expressing or discussing emotion. Clinicians also suggested that men may be more likely to adopt a performance-based approach to. This was linked by clinicians to the impact of cultural perceptions of masculinity on their patients. Clinicians in this study felt that these individual needs could be met by adapting existing approaches within a supportive, male-friendly environment. However, there was not consensus over specific adaptations, including identifying risk, the need for male-only groups, or whether male patients needed access to male clinicians.ConclusionsAlthough men do present with specific treatment needs, these can typically be met within the framework of typical treatment approaches by experienced clinicians in an environment sensitive to the presence of men in an otherwise female-dominated space. However, there are a lack of explicit guidelines for this process, and areas such as male-only treatment spaces require further research.