bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating range to a vocalizing fin whale using the timing and amplitude of multipath arrivals
Authors: Weirathmueller Michelle J. , Wilcock William S. D. , Hilmo Rose S.
Published: October 2017

A semi-automated method is described to range to vocalizing fin whales using the timing and amplitude of multipath arrivals measured on seafloor receivers. Calls are detected and multipath arrivals identified with a matched filter. Multipath times and relative amplitudes are predicted as a function of range by ray tracing. Because the direct and first water-column multiple arrivals are not always observed, different hypotheses for the observed arrival paths must be considered. For two arrivals, an amplitude threshold is used to determine if the first arrival is the direct path and if not, the call is disregarded as distant. When three or more arrivals are detected, three hypotheses for the paths of arrivals are considered; the solution is the hypothesis and range that minimizes the timing and optionally, amplitude ratio or absolute amplitude residual. The method is tested with data from two ocean bottom seismometers, one on the Juan de Fuca Ridge and the other in the Cascadia Basin. Solutions obtained by minimizing a combined residual from timing and an empirical absolute amplitude model extracted from the data yield reliable ranges up to 5 km at both sites, and are sufficient to estimate call density using point transect distance sampling.
Lumped-parameters equivalent circuit for condenser microphones modeling
Authors: Esteves Josué , Rufer Libor , Ekeom Didace , Basrour Skandar
Published: October 2017

This work presents a lumped parameters equivalent model of condenser microphone based on analogies between acoustic, mechanical, fluidic, and electrical domains. Parameters of the model were determined mainly through analytical relations and/or finite element method (FEM) simulations. Special attention was paid to the air gap modeling and to the use of proper boundary condition. Corresponding lumped-parameters were obtained as results of FEM simulations. Because of its simplicity, the model allows a fast simulation and is readily usable for microphone design. This work shows the validation of the equivalent circuit on three real cases of capacitive microphones, including both traditional and Micro-Electro-Mechanical Systems structures. In all cases, it has been demonstrated that the sensitivity and other related data obtained from the equivalent circuit are in very good agreement with available measurement data.
The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1
Authors: Meijles Daniel N. , Sahoo Sanghamitra , Al Ghouleh Imad , Amaral Jefferson H. , Bienes-Martinez Raquel , Knupp Heather E. , Attaran Shireen , Sembrat John C. , Nouraie Seyed M. , Rojas Mauricio M. , Novelli Enrico M. , Gladwin Mark T. , Isenberg Jeffrey S. , Cifuentes-Pagano Eugenia , Pagano Patrick J.
Published: October 2017

Endothelial cell senescence induced by TSP1 and its receptor CD47 is mediated by Nox1-dependent oxidative stress.
A Retrospective Cohort Analysis Shows that Coadministration of Minocycline with Colistin in Critically Ill Patients Is Associated with Reduced Frequency of Acute Renal Failure
Authors: Lodise Thomas P. , Fan Weihong , Griffith David C. , Dudley Michael N. , Sulham Katherine A.
Published: October 2017

Nonclinical studies have suggested that oxidative damage, caspase-mediated apoptosis, and inducible nitric oxide synthase levels may be involved in the pathogenesis of colistin (CST)-associated acute renal failure. MIN inhibits caspase 1, caspase 3, and inducible nitric oxide synthase, leading to the hypothesis that coadministration of CST with MIN (CST-MIN) may reduce the incidence of acute renal failure as well as produce additive or synergistic antimicrobial effects. A multicenter retrospective cohort study was conducted using the Premier Research database to examine the impact of CST-MIN on acute renal failure. Inclusion criteria were as follows: age of ≥18 years, intensive care unit admission at CST initiation, primary International Classification of Diseases 9 (ICD-9) diagnosis of pneumonia or sepsis, nondialysis at hospital admission, and discharge between January 2010 and December 2015. ICD-9 code 584.XX or ICD-10 code N17 was used to define acute renal failure. Baseline comparisons, 1:8 propensity score matching, and confirmatory logistic regression analyses were conducted. In total, 4,817 patients received CST and met inclusion criteria; 93 received CST-MIN. Unadjusted frequency of acute renal failure was significantly lower in patients receiving CST-MIN than CST (11.8% versus 23.7%,
P
= 0.007). Similar results were seen in propensity score matching (12.0% versus 22.3%,
P
= 0.031) and logistic regression analyses (odds ratio of 0.403,
P
= 0.006). Mortalities and 30-day readmission rates were similar between groups. The acute renal failure rate was not impacted by prevalence of baseline renal disease. CST-MIN in critically ill patients may reduce CST-associated acute renal failure. Further evaluation of this combination in prospective clinical studies is warranted.
Reduced Chlorhexidine and Daptomycin Susceptibility in Vancomycin-Resistant Enterococcus faecium after Serial Chlorhexidine Exposure
Authors: Bhardwaj Pooja , Hans Amrita , Ruikar Kinnari , Guan Ziqiang , Palmer Kelli L.
Published: October 2017

Vancomycin-resistant
Enterococcus faecium
strains (VREfm) are critical public health concerns because they are among the leading causes of hospital-acquired bloodstream infections. Chlorhexidine (CHX) is a bisbiguanide cationic antiseptic that is routinely used for patient bathing and other infection control practices. VREfm are likely frequently exposed to CHX; however, the long-term effects of CHX exposure have not been studied in enterococci. In this study, we serially exposed VREfm to increasing concentrations of CHX for a period of 21 days in two independent experimental evolution trials. Reduced CHX susceptibility emerged (4-fold shift in CHX MIC). Subpopulations with reduced daptomycin (DAP) susceptibility were detected, which were further analyzed by genome sequencing and lipidomic analysis. Across the trials, we identified adaptive changes in genes with predicted or experimentally confirmed roles in chlorhexidine susceptibility (
efrE
), global nutritional stress response (
relA
), nucleotide metabolism (
cmk
), phosphate acquisition (
phoU
), and glycolipid biosynthesis (
bgsB
), among others. Moreover, significant alterations in membrane phospholipids were identified for some populations with reduced DAP susceptibility. Our results are clinically significant because they identify a link between serial subinhibitory CHX exposure and reduced DAP susceptibility. In addition, the CHX-induced genetic and lipidomic changes described in this study offer new insights into the mechanisms underlying the emergence of antibiotic resistance in VREfm.
Evaluation of the Microbiological Efficacy of a Single 2-Gram Dose of Extended-Release Azithromycin by Population Pharmacokinetics and Simulation in Japanese Patients with Gonococcal Urethritis
Authors: Soda Midori , Ito Shin , Matsumaru Naoki , Nakamura Sakiko , Nagase Izumi , Takahashi Hikari , Ohno Yuta , Yasuda Mitsuru , Yamamoto Miho , Tsukamoto Katsura , Itoh Yoshinori , Deguchi Takashi , Kitaichi Kiyoyuki
Published: October 2017

The objective of this study was to analyze the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) parameters of a single 2-g dose of extended-release formulation of azithromycin (AZM-SR) and its microbiological efficacy against gonococcal urethritis. Fifty male patients with gonococcal urethritis were enrolled in this study. In 36 patients, the plasma AZM concentrations were measured using liquid chromatography-tandem mass spectrometry, the AZM MIC values for the
Neisseria gonorrhoeae
isolates were determined, and the microbiological outcomes were assessed. AZM-SR monotherapy eradicated
N. gonorrhoeae
in 30 (83%) of the 36 patients. AZM MICs ranged from 0.03 to 2 mg/liter. The mean value of the area under the concentration-time curve (AUC), estimated by population PK analysis using a two-compartment model, was 20.8 mg · h/liter. Logistic regression analysis showed that the PK/PD target value required to predict an
N. gonorrhoeae
eradication rate of ≥95% was a calculated AUC/MIC of ≥59.5. The AUC/MIC value was significantly higher in patients who achieved microbiological cure than in patients who achieved microbiological failure. Monte Carlo simulation using this MIC distribution revealed that the probability that AZM-SR monotherapy would produce an AUC/MIC exceeding the AUC/MIC target of 59.5 was 47%. Furthermore, the MIC distribution for strains isolated in this study was mostly consistent with that for strains currently circulating in Japan. In conclusion, in Japan, AZM-SR monotherapy may not be effective against gonococcal urethritis. Therefore, use of a single 2-g dose of AZM-SR either with or without other antibiotics could be an option to treat gonococcal urethritis if patients are allergic to ceftriaxone and spectinomycin or are diagnosed to be infected with an AZM-sensitive strain.
Evaluation of Antifungal Efficacy of Three New Cyclic Lipopeptides of the Class Bacillomycin from Bacillus subtilis RLID 12.1
Authors: Ramachandran Ramya , Shrivastava Manjari , Narayanan Namitha N. , Thakur Ram Lal , Chakrabarti Arunaloke , Roy Utpal
Published: October 2017

New lipopeptide homologues (AF
3
, AF
4
, and AF
5
) with antifungal activities against
Candida
and
Cryptococcus
spp. were purified from a cell-free supernatant of
Bacillus subtilis
RLID 12.1. The lipopeptides AF
3
, AF
4
, and AF
5
were identified with the same peptide sequence Asn-Pro-Tyr-Asn-Gln-Thr-Ser with variations in the fatty acid branching type and chain length (
anteiso
-C
17
,
iso
-C
17
, and
iso
-C
18
, respectively). Upon comparing the three homologues for MICs against 81
Candida
(
n
= 64) and
Cryptococcus
(
n
= 17) clinical isolates and their cytotoxicities, we found that AF
4
was the most promising antifungal lipopeptide, since it demonstrated 100% inhibition at geometric mean MICs of 3.31, 3.41, 3.48, and 2.83 μg/ml against
Candida albicans
,
Candida tropicalis
,
Candida auris
, and
Cryptococcus neoformans
, respectively, with low hemolysis values (<6%) and 50% inhibitory concentrations (13.31 μg/ml). The additive effects among the homologues AF
3
, AF
4
, and AF
5
were evaluated against three
Candida
species, along with the cytotoxicity studies. Five combinations exhibited good additive interaction effects: AF
3
/AF
4
(at corresponding concentrations of 4 and 4 μg/ml [4/4 μg/ml]), AF
3
/AF
5
(4/4 μg/ml), AF
3
/AF
5
(2/4 μg/ml), AF
4
/AF
5
(4/4 μg/ml), and AF
4
/AF
5
(2/4 μg/ml) in planktonic cell inhibition and AF
3
/AF
4
(4/4 μg/ml), AF
3
/AF
5
(4/4 μg/ml), and AF
3
/AF
5
(2/4 μg/ml) in the inhibition of biofilm formation. However, combinations AF
3
/AF
4
and AF
3
/AF
5
, which showed >70% cell survival with low hemolysis (<5%), were found to be comparatively effective. We describe here the additive effects of lipopeptide homologues showing reduced cytotoxicity against mammalian cells; these combinations might serve as a potent antibiofilm-forming substitute.
Severe Infusion-Related Adverse Events and Renal Failure in Patients Receiving High-Dose Intravenous Polymyxin B
Authors: John Josiane F. , Falci Diego R. , Rigatto Maria Helena , Oliveira Renata D. , Kremer Thaysa G. , Zavascki Alexandre P.
Published: October 2017

The use of very high doses of polymyxin B (PMB) against carbapenem-resistant Gram-negative bacilli has been addressed in
in vitro
experiments as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. We conducted a retrospective cohort study assessing patients receiving PMB at >3 mg/kg of body weight/day or a total dose of ≥250 mg/day. The main outcomes were severe infusion-related adverse events according to the Common Terminology Criteria for Adverse Events and the renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 patients were included for analysis of infusion-related events. The mean PMB dose was 3.61 ± 0.97 mg/kg/day (median total dose/day = 268 mg). Severe infusion-related adverse events occurred in two patients, resulting in an incidence of 0.9% (95% confidence interval, 0.2 to 3.2%); one was classified as a life-threatening adverse event, and one was classified as a severe adverse event. Renal failure was analyzed in 115 patients, and 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as risk [27.8%], injury [25.9%], and failure [46.3%]). Treatment with a vasoactive drug, concomitant treatment with nephrotoxic drugs, and baseline creatinine clearance were independent risk factors for renal failure. Neither the PMB daily dose scaled by body weight nor the total daily dose was associated with renal failure. The in-hospital mortality rate was 60% (134 patients): 26% of deaths (57 patients) occurred during treatment, and none occurred during infusion. Our data suggest that high-dose schemes have an acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patient outcomes and minimize the emergence of PMB resistance.
Verapamil Increases the Bioavailability and Efficacy of Bedaquiline but Not Clofazimine in a Murine Model of Tuberculosis
Authors: Xu Jian , Tasneen Rokeya , Peloquin Charles A. , Almeida Deepak V. , Li Si-Yang , Barnes-Boyle Kala , Lu Yu , Nuermberger Eric
Published: October 2017

Drug efflux pumps play important roles in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, clofazimine, and other drugs against
Mycobacterium tuberculosis
, has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances
in vivo
efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the
in vitro
activity of bedaquiline and clofazimine against
M. tuberculosis
clinical isolates, including those harboring
rv0678
mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on the oral bioavailability or efficacy of clofazimine in mice. The addition of verapamil increased the sterilizing activity of a regimen composed of bedaquiline, clofazimine, and pyrazinamide. These results confirm that verapamil has adjunctive activity
in vivo
, but they also demonstrate that the adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters, rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil versus increasing the doses of companion drugs.
Meropenem-Vaborbactam Resistance Selection, Resistance Prevention, and Molecular Mechanisms in Mutants of KPC-Producing Klebsiella pneumoniae
Authors: Sun Dongxu , Rubio-Aparicio Debora , Nelson Kirk , Dudley Michael N. , Lomovskaya Olga
Published: October 2017

Vaborbactam (formerly RPX7009) is a new β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against

K
lebsiella
p
neumoniae

c
arbapenemases (KPC). It has been developed in combination with meropenem. The objective of these studies was to identify the concentrations of both agents associated with the selection or prevention of single-step mutations leading to reduced sensitivity to the combination and to characterize the selected mutations. Eighteen strains of KPC-producing
Klebsiella pneumoniae
with various degrees of sensitivity to meropenem (MICs, 8 to 512 μg/ml) and meropenem-vaborbactam (MICs, ≤0.06 to 32 μg/ml) and preexisting resistance mechanisms were selected from a worldwide collection of isolates recovered from surveillance studies, emphasizing strains for which MICs were in the upper range of the meropenem-vaborbactam MIC distribution. Meropenem and vaborbactam at 8 μg/ml each suppressed the drug resistance mutation frequency to <1 × 10
−8
in 77.8% (14/18) of strains, and all strains were inhibited when the meropenem concentration was increased to 16 μg/ml. Mutants selected at lower drug concentrations showed phenotypes associated with previously described carbapenem resistance mechanisms, including
ompK36
inactivation in mutants selected from OmpK36-proficient strains and an increased
bla
KPC
gene copy number in strains with partially functional
ompK36
. No mutations in the coding region of
bla
KPC
were identified. These data indicate that the selection of mutants with reduced sensitivity to meropenem-vaborbactam from KPC-producing
Klebsiella pneumoniae
strains is associated with previously described mechanisms involving porin mutations and the increase in the
bla
KPC
gene copy number and not changes in the KPC enzyme and can be prevented by the drug concentrations achieved with optimal dosing of the combination.
The Genital Tract Virulence Factor pGP3 Is Essential for Chlamydia muridarum Colonization in the Gastrointestinal Tract
Authors: Shao Lili , Zhang Tianyuan , Melero Jose , Huang Yumeng , Liu Yuanjun , Liu Quanzhong , He Cheng , Nelson David E. , Zhong Guangming
Published: October 2017

The cryptic plasmid is essential forChlamydia muridarumdissemination from the genital tract to the gastrointestinal (GI) tract. Following intravaginal inoculation, aC. muridarumstrain deficient in plasmid-encoded pGP3 or pGP4 but not pGP5, pGP7, or pGP8 failed to spread to the mouse gastrointestinal tract, although mice infected with these strains developed productive genital tract infections. pGP3- or pGP4-deficient strains also failed to colonize the gastrointestinal tract when delivered intragastrically. pGP4 regulates pGP3, while pGP3 does not affect pGP4 expression, indicating that pGP3 is critical forC. muridarumcolonization of the gastrointestinal tract. Mutants deficient in GlgA, a chromosome-encoded protein regulated by pGP4, also consistently colonized the mouse gastrointestinal tract. Interestingly,C. muridarumcolonization of the gastrointestinal tract positively correlated with pathogenicity in the upper genital tract. pGP3-deficientC. muridarumstrains did not induce hydrosalpinx or spread to the GI tract even when delivered to the oviduct by intrabursal inoculation. Thus, the current study not only has revealed that pGP3 is a novel chlamydial colonization factor in the gastrointestinal tract but also has laid a foundation for investigating the significance of gastrointestinalChlamydia.
Studies of Pseudomonas aeruginosa Mutants Indicate Pyoverdine as the Central Factor in Inhibition of Aspergillus fumigatus Biofilm
Authors: Sass Gabriele , Nazik Hasan , Penner John , Shah Hemi , Ansari Shajia Rahman , Clemons Karl V. , Groleau Marie-Christine , Dietl Anna-Maria , Visca Paolo , Haas Hubertus , Déziel Eric , Stevens David A.
Published: October 2017

Pseudomonas aeruginosa
and
Aspergillus fumigatus
are common opportunistic bacterial and fungal pathogens, respectively. They often coexist in airways of immunocompromised patients and individuals with cystic fibrosis, where they form biofilms and cause acute and chronic illnesses. Hence, the interactions between them have long been of interest and it is known that
P. aeruginosa
can inhibit
A. fumigatus
in vitro
. We have approached the definition of the inhibitory
P. aeruginosa
molecules by studying 24
P. aeruginosa
mutants with various virulence genes deleted for the ability to inhibit
A. fumigatus
biofilms. The ability of
P. aeruginosa
cells or their extracellular products produced during planktonic or biofilm growth to affect
A. fumigatus
biofilm metabolism or planktonic
A. fumigatus
growth was studied in agar and liquid assays using conidia or hyphae. Four mutants, the
pvdD pchE
,
pvdD
,
lasR rhlR
, and
lasR
mutants, were shown to be defective in various assays. This suggested the
P. aeruginosa
siderophore pyoverdine as the key inhibitory molecule, although additional quorum sensing-regulated factors likely contribute to the deficiency of the latter two mutants. Studies of pure pyoverdine substantiated these conclusions and included the restoration of inhibition by the pyoverdine deletion mutants. A correlation between the concentration of pyoverdine produced and antifungal activity was also observed in clinical
P. aeruginosa
isolates derived from lungs of cystic fibrosis patients. The key inhibitory mechanism of pyoverdine was chelation of iron and denial of iron to
A. fumigatus
.

IMPORTANCE
Interactions between human pathogens found in the same body locale are of vast interest. These interactions could result in exacerbation or amelioration of diseases. The bacterium
Pseudomonas aeruginosa
affects the growth of the fungus
Aspergillus fumigatus
. Both pathogens form biofilms that are resistant to therapeutic drugs and host immunity.
P. aeruginosa
and
A. fumigatus
biofilms are found
in vivo
, e.g., in the lungs of cystic fibrosis patients. Studying 24
P. aeruginosa
mutants, we identified pyoverdine as the major anti-
A. fumigatus
compound produced by
P. aeruginosa
. Pyoverdine captures iron from the environment, thus depriving
A. fumigatus
of a nutrient essential for its growth and metabolism. We show how microbes of different kingdoms compete for essential resources. Iron deprivation could be a therapeutic approach to the control of pathogen growth.
A Bacteriophage Capsid Protein Is an Inhibitor of a Conserved Transcription Terminator of Various Bacterial Pathogens
Authors: Ghosh Gairika , Reddy Jayavardhana , Sambhare Susmit , Sen Ranjan
Published: October 2017

Rho is a hexameric molecular motor that functions as a conserved transcription terminator in the majority of bacterial species and is a potential drug target. Psu is a bacteriophage P4 capsid protein that inhibits
Escherichia coli
Rho by obstructing its ATPase and translocase activities. In this study, we explored the anti-Rho activity of Psu for Rho proteins from different pathogens. Sequence alignment and homology modeling of Rho proteins from pathogenic bacteria revealed the conserved nature of the Psu-interacting regions in all these proteins. We chose Rho proteins from various pathogens, including
Mycobacterium smegmatis
,
Mycobacterium bovis
,
Mycobacterium tuberculosis
,
Xanthomonas campestris
,
Xanthomonas oryzae
,
Corynebacterium glutamicum
,
Vibrio cholerae
,
Salmonella enterica
, and
Pseudomonas syringae
. The purified recombinant Rho proteins of these organisms showed variable rates of ATP hydrolysis on poly(rC) as the substrate and were capable of releasing RNA from the
E. coli
transcription elongation complexes. Psu was capable of inhibiting these two functions of all these Rho proteins.
In vivo
pulldown assays revealed direct binding of Psu with many of these Rho proteins.
In vivo
expression of
psu
induced killing of
M. smegmatis
,
M. bovis
,
X. campestris
, and
E. coli
expressing
S. enterica
Rho indicating Psu-induced inhibition of Rho proteins of these strains under physiological conditions. We propose that the “universal” inhibitory function of the Psu protein against the Rho proteins from both Gram-negative and Gram-positive bacteria could be useful for designing peptides with antimicrobial functions and that these peptides could contribute to synergistic antibiotic treatment of the pathogens by compromising the Rho functions.

IMPORTANCE
Bacteriophage-derived protein factors modulating different bacterial processes could be converted into unique antimicrobial agents. Bacteriophage P4 capsid protein Psu is an inhibitor of the
E. coli
transcription terminator Rho. Here we show that apart from antagonizing
E. coli
Rho, Psu is able to inhibit Rho proteins from various phylogenetically unrelated Gram-negative and Gram-positive pathogens. Upon binding to these Rho proteins, Psu inhibited them by affecting their ATPase and RNA release functions. The expression of Psu
in vivo
kills various pathogens, such as
Mycobacterium
and
Xanthomonas
species. Hence, Psu could be useful for identifying peptide sequences with anti-Rho activities and might constitute part of synergistic antibiotic treatment against pathogens.
Thiol Starvation Induces Redox-Mediated Dysregulation of Escherichia coli Biofilm Components
Authors: Hufnagel David A. , Price Janet E. , Stephenson Rachel E. , Kelley Jesse , Benoit Matthew F. , Chapman Matthew R.
Published: October 2017

A hallmark of bacterial biofilms is the production of an
e
xtra
c
ellular
m
atrix (ECM) that encases and protects the community from environmental stressors. Biofilm formation is an integral portion of the
u
ro
p
athogenic

E
scherichia
c
oli

(UPEC) life cycle. Approximately 2% of UPEC isolates are cysteine auxotrophs. Here, we investigated how cysteine homeostasis impacted UPEC UTI89 strain biofilm formation and, specifically, the production of the ECM components curli and cellulose. Cysteine auxotrophs produced less cellulose and slightly more curli compared to wild-type (WT) strains, and cysteine auxotrophs formed smooth, nonrugose colonies. Cellulose production was restored in cysteine auxotrophs when YfiR was inactivated. YfiR is a redox-sensitive regulator of the diguanylate cyclase, YfiN. The production of curli, a temperature-regulated appendage, was independent of temperature in UTI89 cysteine auxotrophs. In a screen of UPEC isolates, we found that ∼60% of UPEC cysteine auxotrophs produced curli at 37°C, but only ∼2% of cysteine prototrophic UPEC isolates produced curli at 37°C. Interestingly, sublethal concentrations of amdinocillin and trimethoprim-sulfamethoxazole inhibited curli production, whereas strains auxotrophic for cysteine continued to produce curli even in the presence of amdinocillin and trimethoprim-sulfamethoxazole. The dysregulation of ECM components and resistance to amdinocillin in cysteine auxotrophs may be linked to hyperoxidation, since the addition of exogenous cysteine or glutathione restored WT biofilm phenotypes to mutants unable to produce cysteine and glutathione.

IMPORTANCE
Uropathogenic
Escherichia coli
(UPEC) bacteria are the predominant causative agent of urinary tract infections (UTIs). UTIs account for billions of dollars of financial burden annually to the health care industry in the United States. Biofilms are an important aspect of the UPEC pathogenesis cascade and for the establishment of chronic infections. Approximately 2% of UPEC isolates from UTIs are cysteine auxotrophs, yet there is relatively little known about the biofilm formation of UPEC cysteine auxotrophs. Here we show that cysteine auxotrophs have dysregulated biofilm components due to a change in the redox state of the periplasm. Additionally, we show the relationship between cysteine auxotrophs, biofilms, and antibiotics frequently used to treat UTIs.
Stress Introduction Rate Alters the Benefit of AcrAB-TolC Efflux Pumps
Authors: Langevin Ariel M. , Dunlop Mary J.
Published: October 2017

Stress tolerance studies are typically conducted in an all-or-none fashion. However, in realistic settings—such as in clinical or metabolic engineering applications—cells may encounter stresses at different rates. Therefore, how cells tolerate stress may depend on its rate of appearance. To address this, we studied how the rate of stress introduction affects bacterial stress tolerance by focusing on a key stress response mechanism. Efflux pumps, such as AcrAB-TolC ofEscherichia coli, are membrane transporters well known for the ability to export a wide variety of substrates, including antibiotics, signaling molecules, and biofuels. Although efflux pumps improve stress tolerance, pump overexpression can result in a substantial fitness cost to the cells. We hypothesized that the ideal pump expression level would involve a rate-dependent trade-off between the benefit of pumps and the cost of their expression. To test this, we evaluated the benefit of the AcrAB-TolC pump under different rates of stress introduction, including a step, a fast ramp, and a gradual ramp. Using two chemically diverse stresses, the antibiotic chloramphenicol and the jet biofuel precursor pinene, we assessed the benefit provided by the pumps. A mathematical model describing these effects predicted the benefit as a function of the rate of stress introduction. Our findings demonstrate that as the rate of introduction is lowered, stress response mechanisms provide a disproportionate benefit to pump-containing strains, allowing cells to survive beyond the original inhibitory concentrations.

IMPORTANCEEfflux pumps are ubiquitous in nature and provide stress tolerance in the cells of species ranging from bacteria to mammals. Understanding how pumps provide tolerance has far-reaching implications for diverse fields, from medicine to biotechnology. Here, we investigated how the rate of stressor appearance impacts tolerance. We focused on two distinct substrates of AcrAB-TolC efflux pumps, the antibiotic chloramphenicol and the biofuel precursor pinene. Interestingly, tolerance is highly dependent on the rate of stress introduction. Therefore, it is important to consider not only the total quantity of a stressor but also the rate at which it is applied. The implications of this work are significant because environments are rarely static; antibiotic concentrations change during dosing, and metabolic engineering processes change with time.
Awareness and willingness towards pre-exposure prophylaxis against HIV infection among individuals seeking voluntary counselling and testing for HIV in Taiwan: a cross-sectional questionnaire survey
Authors: Lee Yi-Chieh , Chang Sui-Yuan , Lin Kuan-Yin , Chang Lan-Hsin , Liu Wen-Chun , Wu Cheng-Hsin , Sun Hsin-Yun , Hung Chien-Ching , Chang Shan-Chwen
Published: October 2017

Objectives

We aimed to investigate the awareness and willingness towards pre-exposure prophylaxis (PrEP) among individuals seeking voluntary counselling and testing (VCT) for HIV in Taiwan, where PrEP is currently not reimbursed by the insurance.

Methods

Between April and October 2016, a questionnaire interview was conducted among VCT clients to inquire about the attitudes towards PrEP against HIV infection. Multivariate logistic regression analysis was performed to identify the associated factors with willingness to initiate PrEP.

Results

During the 6-month period, 1173 VCT clients (99.8%) completed the interviews, with 67.4% being homosexual or bisexual male. While 67.2% of the clients knew of postexposure prophylaxis, 40.2% heard of PrEP. Overall, 546 clients (46.5%) were willing to initiate PrEP and 89.5% of them would choose event-driven PrEP. In multivariate analysis, male gender (OR 1.796; 95% CI 1.165 to 2.768), full-time job (OR 1.354; 95% CI 1.052 to 1.742), one-night stand (OR 1.374; 95% CI 1.043 to 1.810), having casual sex partners within 3 months (OR 1.329; 95% CI 1.031 to 1.714), condomless anal sex (OR 1.405; 95% CI 1.122 to 1.878) and ever having chemsex or attending a drug party in the past 1 year (OR 2.571; 95% CI 1.541 to 4.287), regular screening for HIV infection (OR 1.321; 95% CI 1.021 to 1.711) and knowledge of PrEP (OR 1.504; 95% CI, 1.159 to 1.953) were associated with willingness to initiate PrEP.

Conclusions

Understanding the willingness to initiate PrEP against HIV among the VCT clients in Taiwan, which was associated with male gender, risky sexual behaviours and awareness of PrEP, will help inform the implementation of PrEP programme.
‘What does that mean?’: a qualitative exploration of the primary and secondary clinical care experiences of young people with continence problems in the UK
Authors: Whale Katie , Cramer Helen , Wright Anne , Sanders Caroline , Joinson Carol
Published: October 2017

Objectives

To explore the clinical care experiences of young people with continence problems.

Design

In-depth semistructured qualitative interviews were conducted by Skype and telephone, with the addition of art-based participatory research techniques. Transcripts were analysed using inductive thematic analysis.

Setting

Primary and secondary care in the UK.

Participants

We interviewed 20 participants (9 females, 11 males) aged 11–20 years. There were six participants with bedwetting alone, five with daytime wetting alone, five with combined (day and night) wetting and four with soiling.

Results

We identified four themes: appointment experiences, treatment experiences, engagement with treatment and internalisation and externalisation of the continence problem. Patient-focused appointments using age-appropriate language were highly desirable. Continuity of care was highlighted as an important aspect of positive clinical experiences; however, this was found to be rare with many participants seeing a different person on each visit. Participants had tried a wide range of treatments for their continence problems with varying degrees of success. Relapse and treatment failure were common. Experiencing relapse was distressing and diminished participants’ belief in the success of future treatments and undermined adherence. Participants would be seen to adopt two opposing coping strategies for dealing with their continence problem— internalisation and externalisation.

Conclusion

Incontinence in young people is challenging to manage. Young people may need to try a range of treatments before their symptoms improve. Due to challenges in treatment, there is an increased risk of poor adherence. During patient-focused appointments, clinicians should work to build rapport with patients and use age-appropriate language. Involving young people in their own care decisions is important. The way in which young people understand their continence problem can influence their coping strategies and adherence to treatment regimes.
Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort
Authors: Coughtrie Abigail L , Behr Elijah R , Layton Deborah , Marshall Vanessa , Camm A John , Shakir Saad A W
Published: October 2017

Objectives

To establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases.

Setting

Suspected proarrhythmia cases were referred by cardiologists across England between 2003 and 2011. Information on demography, symptoms, prior medical and drug histories and data from hospital notes were collected.

Participants

Two expert cardiologists reviewed data for 293 referred cases: 130 were included. Inclusion criteria were new onset or exacerbation of pre-existing ventricular arrhythmias, QTc >500 ms, QTc >450 ms (men) or >470 ms (women) with cardiac syncope, all secondary to drug administration. Exclusion criteria were acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study. Descriptive analysis of Caucasian cases (95% of included cases, n=124) and culpable drug exposures was performed.

Results

Of the 124 Caucasian cases, 95 (77%) were QTc interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities included hypertension (53%) and patient-reported ‘heart rhythm problems’ (73%). Family history of sudden death (36%) and hypokalaemia at presentation (27%) were common. 165 culpable drug exposures were reported, including antiarrhythmics (42%), of which amiodarone and flecainide were the most common. Sotalol, a beta-blocking agent with antiarrhythmic activity, was also common (15%). 26% reported multiple drugs, of which 84% reported at least one cytochrome (CYP) P450 inhibitor. Potential pharmacodynamics interactions identified were mainly QT prolongation (59%).

Conclusions

Antiarrhythmics, non-cardiac drugs and drug combinations were found to be culpable in a large cohort of 124 clinically validated proarrhythmia cases. Potential clinical factors that may warn the prescriber of potential proarrhythmia include older women, underlying cardiovascular comorbidity, family history of sudden death and hypokalaemia.
Nature-based care opportunities and barriers in oncology contexts: a modified international e-Delphi survey
Authors: Blaschke Sarah , O’Callaghan Clare C , Schofield Penelope
Published: October 2017

Objective

To develop recommendations regarding opportunities and barriers for nature-based care in oncology contexts using a structured knowledge generation process involving relevant healthcare and design experts.

Design

Four-round modified electronic Delphi study. Oncology patients’ nature-based recommendations, uncovered in preceding qualitative investigation, were included in the first round for the expert participants’ consideration. Key items (opportunities and barriers) were developed using data aggregation and synthesis, followed by item prioritisation and 10-point Likert scale ranking (1=not important, 10=very important). Descriptive statistics were calculated to assess items of highest importance representing expert recommendations.

Context

Online Delphi process constituting an electronic international survey.

Participants

A purposive sample of 200 potential panellists (recruitment target n=40) comprising healthcare practitioners, managers, designers, architects and researchers were invited to participate; experts were identified via research networks, snowballing and systematic literature review.

Results

38 experts across seven countries (Australia, USA, UK, New Zealand, Canada, Denmark and Sweden) returned questionnaire 1, which determined consent and acceptance for participation. Initial response rate was 19%, and subsequent response rates were 84%, 82% and 84% for rounds 2, 3 and 4, respectively. The Delphi panel developed recommendations consisting of 10 opportunities and 10 barriers. The following opportunities were rated to be of highest importance: window views from clinical areas onto nature; outdoor settings, gardens and courtyards with easy and effortless access; and nature-based physical exercise adapted to patient requirements. Highest-rated barriers for nature-based oncology care included lack of knowledge and awareness about benefits of nature engagement and inaccessibility, not considering access requirements for the very sick and frail.

Conclusions

Experts suggested and agreed on a set of recommendations, which represent critical considerations for the safe adoption of nature-based oncology opportunities. These findings fill a gap in understanding about helpful nature-based oncology care and may translate into oncology design and innovation.
Is overseas volunteering beneficial to the NHS? The analysis of volunteers’ responses to a feedback questionnaire following experiences in low-income and middle-income countries
Authors: Yeomans Daniel , Le Grace , Pandit Hemant , Lavy Chris
Published: October 2017

Introduction

Locally requested and planned overseas volunteering in low-income and middle-income countries by National Health Service (NHS) staff can have benefits for the host or receiving nation, but its impact on the professional development of NHS staff is not proven. The Knowledge and Skills Framework (KSF) and Leadership Framework (LF) are two tools used by employers as a measure of individuals' development. We have used dimensions from both tools as a method of evaluating the benefit to NHS doctors who volunteer overseas.

Methods

88 NHS volunteers participating with local colleagues in Primary Trauma Care and orthopaedic surgical training courses in sub-Saharan Africa were asked to complete an online self-assessment questionnaire 6 months following their return to the UK. The survey consisted of questions based on qualities outlined in both the KSF and LF.

Results

85 completed responses to the questionnaire were received. In every KSF domain assessed, the majority of volunteers agreed that their overseas volunteering experience improved their practice within the NHS. Self-assessed pre-course and post-course scores evaluating the LF also saw a universal increase, notably in the ‘working with others’ domain.

Discussion

There is a growing body of literature outlining the positive impact of overseas volunteering on NHS staff. Despite increasing evidence that such experiences can develop volunteers’ essential skills, individuals often find it difficult to gain support of their employers. Our study, in line with the current literature, shows that overseas volunteering by NHS staff can provide an opportunity to enhance professional and personal development. Skills gained from volunteering within international links match many of the qualities outlined in both KSF and LF, directly contributing to volunteers’ continued professional development.
What’s up doc? A national cross-sectional study of psychological wellbeing of hospital doctors in Ireland
Authors: Hayes Blánaid , Prihodova Lucia , Walsh Gillian , Doyle Frank , Doherty Sally
Published: October 2017

Objectives

To measure levels of psychological distress, psychological wellbeing and self-stigma in hospital doctors in Ireland.

Design

National cross-sectional study of randomised sample of hospital doctors. Participants provided sociodemographic data (age, sex, marital status), work grade (consultant, higher/basic specialist trainee), specialty and work hours and completed well-being questionnaires (the Depression Anxiety Stress Scale, WHO Well-being Index, General Health Questionnaire) and single-item scales on self-rated health and self-stigma.

Setting

Irish publicly funded hospitals and residential institutions.

Participants

1749 doctors (response rate of 55%). All hospital specialties were represented except radiology.

Results

Half of participants were men (50.5%). Mean hours worked per week were 57 hours. Over half (52%) rated their health as very good/excellent, while 50.5% reported positive subjective well-being (WHO-5). Over a third (35%) experienced psychological distress (General Health Questionnaire 12). Severe/extremely severe symptoms of depression, anxiety and stress were evident in 7.2%, 6.1% and 9.5% of participants (Depression, Anxiety, Stress Scale 21). Symptoms of distress, depression, anxiety and stress were significantly higher and levels of well-being were significantly lower in trainees compared with consultants, and this was not accounted for by differences in sociodemographic variables. Self-stigma was present in 68.4%.

Conclusions

The work hours of doctors working in Irish hospitals were in excess of European Working Time Directive’s requirements. Just over half of hospital doctors in Ireland had positive well-being. Compared with international evidence, they had higher levels of psychological distress but slightly lower symptoms of depression and anxiety. Two-thirds of respondents reported self-stigma, which is likely to be a barrier to accessing care. These findings have implications for the design of support services for doctors, for discussions on quality of patient care and for future research.
Effect of point-of-care susceptibility testing in general practice on appropriate prescription of antibiotics for patients with uncomplicated urinary tract infection: a diagnostic randomised controlled trial
Authors: Holm Anne , Cordoba Gloria , Møller Sørensen Tina , Rem Jessen Lisbeth , Frimodt-Møller Niels , Siersma Volkert , Bjerrum Lars
Published: October 2017

Objectives

To investigate the effect of adding point-of-care (POC) susceptibility testing to POC culture on appropriate use of antibiotics as well as clinical and microbiological cure for patients with suspected uncomplicated urinary tract infection (UTI) in general practice.

Design

Open, individually randomised controlled trial.

Setting

General practice.

Participants

Women with suspected uncomplicated UTI, including elderly patients above 65, patients with recurrent UTI and patients with diabetes. The sample size calculation predicted 600 patients were needed.

Interventions

Flexicult SSI-Urinary Kit was used for POC culture and susceptibility testing and ID Flexicult was used for POC culture only.

Main outcome measures

Primary outcome: appropriate antibiotic prescribing on the day after consultation defined as either (1) patient with UTI: to prescribe a first-line antibiotic to which the infecting pathogen was susceptible or a second line if a first line could not be used or (2) patient without UTI: not to prescribe an antibiotic. UTI was defined by typical symptoms and significant growth in a reference urine culture performed at one of two external laboratories.

Secondary outcomes: clinical cure on day five according to a 7-day symptom diary and microbiological cure on day 14. Logistic regression models taking into account clustering within practices were used for analysis.

Results

20 general practices recruited 191 patients for culture and susceptibility testing and 172 for culture only. 63% of the patients had UTI and 12% of these were resistant to the most commonly used antibiotic, pivmecillinam. Patients randomised to culture only received significantly more appropriate treatment (OR: 1.44 (95% CI 1.03 to 1.99), p=0.03). There was no significant difference in clinical or microbiological cure.

Conclusions

Adding POC susceptibility testing to POC culture did not improve antibiotic prescribing for patients with suspected uncomplicated UTI in general practice. Susceptibility testing should be reserved for patients at high risk of resistance and complications.

Trial registration number

NCT02323087; Results.
Effects of e-learning in a continuing education context on nursing care: a review of systematic qualitative, quantitative and mixed studies reviews (protocol)
Authors: Rouleau Geneviève , Gagnon Marie-Pierre , Côté José , Payne-Gagnon Julie , Hudson Emilie , Bouix-Picasso Julien , Dubois Carl-Ardy
Published: October 2017

Introduction

Continuing education (CE) is imperative to the future of professional nursing. The use of e-learning by registered nurses for CE is spreading. A review of systematic reviews will be conducted to develop a broad picture of the effects of e-learning in a CE context on nursing care.

Methods and analysis

Systematic qualitative, quantitative and mixed studies reviews published in English, French or Spanish from 1 January 2006 will be included. The outcomes of interest will be extracted and analysed inductively and deductively from the Nursing Care Performance Framework; some themes include nursing resources, nurses’ practice environment, processes, professional satisfaction, and nursing sensitive outcomes. Three reviewers will independently screen first the title and abstract of the papers, and then the full texts in order to assess eligibility. Two teams of two reviewers will extract the selected reviews’ characteristics and data. The results from various types of reviews will be integrated using a data-based convergent synthesis design. We will conduct a thematic synthesis and transform all quantitative and mixed data into qualitative data.

Ethics and dissemination

Ethics approval is not required for review of systematic reviews. We will summarise evidence concerning the negative, neutral and positive effects of various forms of e-learning on different aspects of nursing care. If we find gaps in the literature, we will highlight them and suggest ideas for further research. We will also focus on positive effects and present, if possible, the components and characteristics of e-learning interventions that were found to be successful. We will present this protocol and results in international conferences in nursing, medical, and health informatics domains. We will also submit the results of our work for peer-review publication in a journal indexed in the international bibliographic database of biomedical information.