bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fluconazole-Resistant Candida auris Is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses
Authors: Pathirana Ruvini U. , Friedman Justin , Norris Hannah L. , Salvatori Ornella , McCall Andrew D. , Kay Jason , Edgerton Mira 
Published: November 2017

ABSTRACT

Candida auris
is a newly identified species causing invasive candidemia and candidiasis. It has broad multidrug resistance (MDR) not observed for other pathogenic
Candida
species. Histatin 5 (Hst 5) is a well-studied salivary cationic peptide with significant antifungal activity against
Candida albicans
and is an attractive candidate for treating MDR fungi, since antimicrobial peptides induce minimal drug resistance. We investigated the susceptibility of
C. auris
to Hst 5 and neutrophils, two first-line innate defenses in the human host. The majority of
C. auris
clinical isolates, including fluconazole-resistant strains, were highly sensitive to Hst 5: 55 to 90% of cells were killed by use of 7.5 μM Hst 5. Hst 5 was translocated to the cytosol and vacuole in
C. auris
cells; such translocation is required for the killing of
C. albicans
by Hst 5. The inverse relationship between fluconazole resistance and Hst 5 killing suggests different cellular targets for Hst 5 than for fluconazole.
C. auris
showed higher tolerance to oxidative stress than
C. albicans
, and higher survival within neutrophils, which correlated with resistance to oxidative stress
in vitro
. Thus, resistance to reactive oxygen species (ROS) is likely one, though not the only, important factor in the killing of
C. auris
by neutrophils. Hst 5 has broad and potent candidacidal activity, enabling it to combat MDR
C. auris
strains effectively.
In Vitro
Activity of the Siderophore Cephalosporin, Cefiderocol, against Carbapenem-Nonsusceptible and Multidrug-Resistant Isolates of Gram-Negative Bacilli Collected Worldwide in 2014 to 2016
Authors: Hackel Meredith A. , Tsuji Masakatsu , Yamano Yoshinori , Echols Roger , Karlowsky James A. , Sahm Daniel F. 
Published: November 2017

ABSTRACT

The
in vitro
activity of the investigational siderophore cephalosporin, cefiderocol (formerly S-649266), was determined against a 2014–2016, 52-country, worldwide collection of clinical isolates of carbapenem-nonsusceptible
Enterobacteriaceae
(
n
= 1,022), multidrug-resistant (MDR)
Acinetobacter baumannii
(
n
= 368), MDR
Pseudomonas aeruginosa
(
n
= 262),
Stenotrophomonas maltophilia
(
n
= 217), and
Burkholderia cepacia
(
n
= 4) using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB), prepared according to a recently approved (2017), but not yet published, CLSI protocol, was used to test cefiderocol; all other antimicrobial agents were tested using CAMHB. The concentration of cefiderocol inhibiting 90% (MIC
90
) of isolates of carbapenem-nonsusceptible
Enterobacteriaceae
was 4 μg/ml; cefiderocol MICs ranged from 0.004 to 32 μg/ml, and 97.0% (991/1,022) of isolates demonstrated cefiderocol MICs of ≤4 μg/ml. The MIC
90
s for cefiderocol for MDR
A. baumannii
, MDR
P. aeruginosa
, and
S. maltophilia
were 8, 1, and 0.25 μg/ml, respectively, with 89.7% (330/368), 99.2% (260/262), and 100% (217/217) of isolates demonstrating cefiderocol MICs of ≤4 μg/ml. Cefiderocol MICs for
B. cepacia
ranged from 0.004 to 8 μg/ml. We conclude that cefiderocol demonstrated potent
in vitro
activity against a 2014–2016, worldwide collection of clinical isolates of carbapenem-nonsusceptible
Enterobacteriaceae
, MDR
A. baumannii
, MDR
P. aeruginosa
,
S. maltophilia
, and
B. cepacia
isolates as 96.2% of all (1,801/1,873) isolates tested had cefiderocol MICs of ≤4 μg/ml.
Comparative
In Vitro
Activities of Relebactam, Imipenem, the Combination of the Two, and Six Comparator Antimicrobial Agents against 432 Strains of Anaerobic Organisms, Including Imipenem-Resistant Strains
Authors: Goldstein Ellie J. C. , Citron Diane M. , Tyrrell Kerin L. , Leoncio Eliza , Merriam C. Vreni 
Published: November 2017

ABSTRACT
Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.
Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis
Authors: Abbadi Bruno L. , Villela Anne D. , Rodrigues-Junior Valnês S. , Subtil Fernanda T. , Dalberto Pedro F. , Pinheiro Ana P. S. , Santos Diógenes S. , Machado Pablo , Basso Luiz A. , Bizarro Cristiano V. 
Published: November 2017

ABSTRACT

IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of
Mycobacterium tuberculosis
. Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the
katG
gene. The
katG
(S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.
Salmonella enterica Serovar Typhimurium Alters the Extracellular Proteome of Macrophages and Leads to the Production of Proinflammatory Exosomes
Authors: Hui Winnie W. , Hercik Kamil , Belsare Sayali , Alugubelly Navatha , Clapp Beata , Rinaldi Carlos , Edelmann Mariola J. 
Published: November 2017

ABSTRACT

Salmonella enterica
serovar Typhimurium is a Gram-negative bacterium, which can invade and survive within macrophages. Pathogenic salmonellae induce the secretion of specific cytokines from these phagocytic cells and interfere with the host secretory pathways. In this study, we describe the extracellular proteome of human macrophages infected with
S
. Typhimurium, followed by analysis of canonical pathways of proteins isolated from the extracellular milieu. We demonstrate that some of the proteins secreted by macrophages upon
S
. Typhimurium infection are released via exosomes. Moreover, we show that infected macrophages produce CD63
+
and CD9
+
subpopulations of exosomes at 2 h postinfection. Exosomes derived from infected macrophages trigger the Toll-like receptor 4-dependent release of tumor necrosis factor alpha (TNF-α) from naive macrophages and dendritic cells, but they also stimulate secretion of such cytokines as RANTES, IL-1ra, MIP-2, CXCL1, MCP-1, sICAM-1, GM-CSF, and G-CSF. Proinflammatory effects of exosomes are partially attributed to lipopolysaccharide, which is encapsulated within exosomes. In summary, we show for the first time that proinflammatory exosomes are formed in the early phase of macrophage infection with
S
. Typhimurium and that they can be used to transfer cargo to naive cells, thereby leading to their stimulation.
Mutations in Sugar-Nucleotide Synthesis Genes Restore Holdfast Polysaccharide Anchoring to Caulobacter crescentus Holdfast Anchor Mutants
Authors: Hardy Gail G. , Toh Evelyn , Berne Cécile , Brun Yves V. 
Published: November 2017

ABSTRACT

Attachment is essential for microorganisms to establish interactions with both biotic and abiotic surfaces. Stable attachment of
Caulobacter crescentus
to surfaces requires an adhesive polysaccharide holdfast, but the exact composition of the holdfast is unknown. The holdfast is anchored to the cell envelope by outer membrane proteins HfaA, HfaB, and HfaD.
H
old
f
ast
a
nchor gene mutations result in holdfast shedding and reduced cell adherence. Translocation of HfaA and HfaD to the cell surface requires HfaB. The Wzx homolog HfsF is predicted to be a bacterial polysaccharide flippase. An
hfsF
deletion significantly reduced the amount of holdfast produced per cell and slightly reduced adherence. A Δ
hfsF
Δ
hfaD
double mutant was completely deficient in adherence. A suppressor screen that restored adhesion in the Δ
hfsF
Δ
hfaD
mutant identified mutations in three genes:
wbqV
,
rfbB
, and
rmlA
. Both WbqV and RfbB belong to a family of nucleoside-diphosphate epimerases, and RmlA has similarity to nucleotidyltransferases. The loss of
wbqV
or
rfbB
in the Δ
hfsF
Δ
hfaD
mutant reduced holdfast shedding but did not restore holdfast synthesis to parental levels. Loss of
wbqV
or
rfbB
did not restore adherence to a Δ
hfsF
mutant but did restore adherence and holdfast anchoring to a Δ
hfaD
mutant, confirming that suppression occurs through restoration of holdfast anchoring. The adherence and holdfast anchoring of a Δ
hfaA ΔhfaD
mutant could be restored by
wbqV
or
rfbB
mutation, but such mutations could not suppress these phenotypes in the Δ
hfaB
mutant. We hypothesize that HfaB plays an additional role in holdfast anchoring or helps to translocate an unknown factor that is important for holdfast anchoring.

IMPORTANCE
Biofilm formation results in increased resistance to both environmental stresses and antibiotics.
Caulobacter crescentus
requires an adhesive holdfast for permanent attachment and biofilm formation, but the exact mechanism of polysaccharide anchoring to the cell and the holdfast composition are unknown. Here we identify novel polysaccharide genes that affect holdfast anchoring to the cell. We identify a new role for the holdfast anchor protein HfaB. This work increases our specific knowledge of the polysaccharide adhesin involved in
Caulobacter
attachment and the general knowledge regarding production and anchoring of polysaccharide adhesins by bacteria. This work also explores the interactions between different polysaccharide biosynthesis and secretion systems in bacteria.
Comparative Genomics of Myxobacterial Chemosensory Systems
Authors: Sharma Gaurav , Khatri Indu , Subramanian Srikrishna 
Published: November 2017

ABSTRACT

Chemosensory systems (CSS) are among the most complex organizations of proteins functioning cooperatively to regulate bacterial motility and other cellular activities. These systems have been studied extensively in bacteria, and usually, they are present as a single system. Eight CSS, the highest number in bacteria, have been reported in
Myxococcus xanthus
DK1622 and are involved in coordinating diverse functions. Here, we have explored and compared the CSS in all available genomes of order
Myxococcales. Myxococcales
members contain 97 to 476 two-component system (TCS) proteins, which assist the bacteria in surviving and adapting to varying environmental conditions. The number of myxobacterial CSS ranges between 1 and 12, with the largest number in family
Cystobacteraceae
and the smallest in
Nannocystaceae
. CheA protein was used as a phylogenetic marker to infer evolutionary relatedness between different CSS, and six novel CSS (“extra CSS” [ECSS]) were thus identified in the myxobacteria besides the previously reported Che1 to Che8 systems from
M. xanthus
. Che1 to Che8 systems are monophyletic to deltaproteobacteria, whereas the newly identified ECSS form separate clades with different bacterial classes. The comparative modular organization was concordant with the phylogeny. Four clusters lacking CheA proteins were also identified via CheB-based phylogenetic analysis and were categorized as accessory CSS (ACSS). In
Archangium
, an orphan CSS was identified, in which both CheA and CheB were absent. The novel, accessory, and orphan multimodular CSS identified here suggest the emergence of myxobacterial CSS and could assist in further characterizing their roles.

IMPORTANCE
This study is focused on chemosensory systems (CSS), which help the bacterium in directing its movement toward or away from chemical gradients. CSS are present as a single system in most of the bacteria except in some groups, including
Myxococcus xanthus
, which has 8 CSS, the highest number reported to date. This is the first comprehensive study carrying out a comparative analysis of the 22 available myxobacterial genomes, which suggests the evolutionary diversity of these systems. We are interested in understanding the distribution of CSS within all known myxobacteria and their probable evolution.
Patients’ initial steps to cancer diagnosis in Denmark, England and Sweden: what can a qualitative, cross-country comparison of narrative interviews tell us about potentially modifiable factors?
Authors: MacArtney John , Malmström Marlene , Overgaard Nielsen Trine , Evans Julie , Bernhardson Britt-Marie , Hajdarevic Senada , Chapple Alison , Eriksson Lars E , Locock Louise , Rasmussen Birgit , Vedsted Peter , Tishelman Carol , Andersen Rikke Sand , Ziebland Sue 
Published: November 2017

ObjectivesTo illuminate patterns observed in International Cancer Benchmarking Programme studies by extending understanding of the various influences on presentation and referral with cancer symptoms.DesignCross-country comparison of Denmark, England and Sweden with qualitative analysis of in-depth interview accounts of the prediagnostic process in lung or bowel cancer.Participants155 women and men, aged between 35 and 86 years old, diagnosed with lung or bowel cancer in 6 months before interview.SettingParticipants recruited through primary and secondary care, social media and word of mouth. Interviews collected by social scientists or nurse researchers during 2015, mainly in participants’ homes.ResultsParticipants reported difficulties in interpreting diffuse bodily sensations and symptoms and deciding when to consult. There were examples of swift referrals by primary care professionals in all three countries. In all countries, participants described difficulty deciding if and when to consult, highlighting concerns about access to general practitioner appointments and overstretched primary care services, although this appears less prominent in the Swedish data. It was not unusual for there to be more than one consultation before referral and we noted two distinct patterns of repeated consultation: (1) situations where the participant left the primary care consultation with a plan of action about what should happen next; (2) participants were unclear about under which conditions to return to the doctors. This second pattern sometimes extended over many weeks during which patients described uncertainty, and sometimes frustration, about if and when they should return and whether there were any other feasible investigations. The latter pattern appeared more evident in the interviews in England and Denmark than Sweden.ConclusionWe suggest that if clear action plans, as part of safety netting, were routinely used in primary care consultations then uncertainty, false reassurance and the inefficiency and distress of multiple consultations could be reduced.
Women and substance use: a qualitative study on sexual and reproductive health of women who use drugs in Delhi, India
Authors: Sharma Vartika , Sarna Avina , Tun Waimar , Saraswati Lopamudra Ray , Thior Ibou , Madan Ira , Luchters Stanley 
Published: November 2017

ObjectivesTo explore contextual factors that increase vulnerabilities to negative sexual and reproductive health (SRH) outcomes and possible differences in SRH-related behaviours and the needs of women who use drugs (WUD) through non-injecting and injecting routes.DesignQualitative study design using semi-structured in-depth interviews.ParticipantsTwenty women who injected drugs in the past 3 months and 28 women who reported using drugs through non-injecting routes in the past 1 month.SettingInterviews were conducted at community-based, drop-in centres in Delhi, India.ResultsStudy findings illustrate that WUD were sexually active and had multiple sex partners including clients of sex work. Transient relationships were reported and many participants engaged in unsafe sex. Factors which affected safe sex behaviours included: gender power imbalance, limited agency for decision-making, lack of accurate information for correct self-risk assessment, and being under the influence of drugs. Despite high awareness, low and inconsistent contraceptive use was reported. Some participants were coerced to conceive while a few others reported their inability to conceive. Violence was a key determinant for SRH outcomes. Perception of certain adverse health outcomes (such as infertility) to be ‘common and expected among WUD’ influenced access to healthcare. Further, healthcare providers’ stigmatising attitudes and lack of women-centric services deterred women from uptake of healthcare services.ConclusionFindings highlight that SRH-related behaviours and needs of this group are a complex interplay of multiple determinants which need to be addressed at all levels: individual, family, community and institutional. It is imperative to roll out a ‘one-stop-shop’ for a comprehensive package of health services. Expansion of existing drop-in-centres could be considered for setting-up community-based women-centric services with appropriate linkage to drug dependence treatment and reproductive health services.
Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations
Authors: Huang Lei , Jansen Lina , Balavarca Yesilda , Molina-Montes Esther , Babaei Masoud , van der Geest Lydia , Lemmens Valery , Van Eycken Liesbet , De Schutter Harlinde , Johannesen Tom B , Fristrup Claus W , Mortensen Michael B , Primic-Žakelj Maja , Zadnik Vesna , Becker Nikolaus , Hackert Thilo , Mägi Margit , Cassetti Tiziana , Sassatelli Romano , Grützmann Robert , Merkel Susanne , Gonçalves Ana F , Bento Maria J , Hegyi Péter , Lakatos Gábor , Szentesi Andrea , Moreau Michel , van de Velde Tony , Broeks Annegien , Sant Milena , Minicozzi Pamela , Mazzaferro Vincenzo , Real Francisco X , Carrato Alfredo , Molero Xavier , Besselink Marc G , Malats Núria , Büchler Markus W , Schrotz-King Petra , Brenner Hermann 
Published: November 2017

ObjectiveResection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation.DesignData from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003–2016 were analysed. Age-standardised resection rates for overall and stage I–II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models.ResultsA total of 153 698 records were analysed. In population-based registries in 2012–2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I–II tumours, with great international variations. During 2003–2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I–II tumours: 0.05–0.18 and 0.01–0.06 across countries) and increasing age (ORs for patients 70–79 and ≥80 versus those <60 years: 0.37–0.63 and 0.03–0.16 across countries). Patients with advanced-stage tumours (stage III–IV: 63.8%–81.2%) and at older ages (≥70 years: 52.6%–59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application.ConclusionRates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.
Identification Systems and Their Legitimacy in the New Legislation on the Protection of Personal Data
Authors: Benes Vlastimil , Neuwirt Karel , Dostal Otto 
Published: November 2017

In the new digital environment, citizens have the right to use tools to effectively control the usage of personal information related to them. Data protection is one of the fundamental rights in the EU guaranteed by the Charter of Fundamental Rights of the European Union. The article deals with the requirements that electronic identification system operators will have to take into account to ensure that the system in operation meets the requirements for the protection of personal data.
Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage
Authors: Gathier Celine S. , van den Bergh Walter M. , van der Jagt Mathieu , Verweij Bon H. , Dankbaar Jan Willem , Müller Marcella C. , Oldenbeuving Annemarie W. , Rinkel Gabriel J.E. , Slooter Arjen J.C. , Algra Ale , Kesecioglu Jozef , van der Schaaf Irene C. , Dammers Ruben , Dippel Diederik W.J. , Dirven Clemens M.F. , van Kooten Fop , van der Lugt Aad , Coert Bert A. , Horn Janneke , Vandertop W. Peter , Beute Gus N. , van der Pol Bram , Roks Gerwin , van Rooij Willem Jan J. , Sluzewski Menno 
Published: November 2017

Background and Purpose—
Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension.

Methods—
Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis.

Results—
The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6–1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9–5.0).

Conclusions—
Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01613235.