bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isavuconazole Concentration in Real-World Practice: Consistency with Results from Clinical Trials
Authors: Andes David , Kovanda Laura , Desai A. , Kitt Therese , Zhao M. , Walsh Thomas J. 
Published: May 2018

ABSTRACT
Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not evident from clinical trials. In order to establish whether this requirement also applies to isavuconazole, we examined the plasma concentrations of 283 samples from patients receiving isavuconazole in clinical practice and compared the values with those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/ml in 90% of patients). These findings suggest that routine TDM may not be necessary for isavuconazole in most instances.
Helicobacter pylori Biofilm Formation Is Differentially Affected by Common Culture Conditions, and Proteins Play a Central Role in the Biofilm Matrix
Authors: Windham Ian H. , Servetas Stephanie L. , Whitmire Jeannette M. , Pletzer Daniel , Hancock Robert E. W. , Merrell D. Scott 
Published: May 2018

ABSTRACT

The concept of
Helicobacter pylori
biofilm formation is relatively new. To help provide a foundation for future biofilm studies, we characterized the biofilm formation ability of a common
H. pylori
lab strain, G27. The goal of this study was to evaluate biofilm formation by G27 in response to common culture conditions and to explore the biofilm matrix. Our results indicate that while various types of growth media did not dramatically affect biofilm formation, surface selection had a significant effect on the final biofilm mass. Furthermore, enzymatic assays and confocal microscopy revealed that proteins appear to be the primary structural component of the
H. pylori
extracellular matrix; extracellular DNA (eDNA) and polysaccharides were also present but appear to play a secondary role. Finally, we found that two well-characterized antibiofilm cationic peptides differentially affected early and late-stage biofilms. Together these results provide interesting avenues for future investigations that will seek to understand
H. pylori
biofilm formation.

IMPORTANCE
The study of
H. pylori
biofilm formation is still in its infancy. As such, there is great variability in how biofilm assays are performed across labs. While several groups have begun to investigate factors that influence
H. pylori
biofilm formation, it is not yet understood how
H. pylori
biofilm formation may vary based on commonly used conditions. These inconsistencies lead to difficulties in interpretation and comparison between studies. Here, we set out to characterize biofilm formation by a commonly available lab strain, G27. Our findings provide novel insight into optimal biofilm conditions, the biofilm matrix, and possible mechanisms to block or disrupt biofilm formation.
Identification of Novel Acinetobacter baumannii Type VI Secretion System Antibacterial Effector and Immunity Pairs
Authors: Fitzsimons Timothy C. , Lewis Jessica M. , Wright Amy , Kleifeld Oded , Schittenhelm Ralf B. , Powell David , Harper Marina , Boyce John D. 
Published: May 2018

ABSTRACT

The type VI secretion system (T6SS) is a macromolecular machine that delivers protein effectors into host cells and/or competing bacteria. The effectors may be delivered as noncovalently bound cargo of T6SS needle proteins (VgrG/Hcp/PAAR) or as C-terminal extensions of these proteins. Many
Acinetobacter baumannii
strains produce a T6SS, but little is known about the specific effectors or how they are delivered. In this study, we show that
A. baumannii
AB307-0294 encodes three
vgrG
loci, each containing a
vgrG
gene, a T6SS toxic effector gene, and an antitoxin/immunity gene. Each of the T6SS toxic effectors could kill
Escherichia coli
when produced in
trans
unless the cognate immunity protein was coproduced. To determine the role of each VgrG in effector delivery, we performed interbacterial competitive killing assays using
A. baumannii
AB307-0294
vgrG
mutants, together with
Acinetobacter baylyi
prey cells expressing pairs of immunity genes that protected against two toxic effectors but not a third. Using this approach, we showed that AB307-0294 produces only three T6SS toxic effectors capable of killing
A. baylyi
and that each VgrG protein is specific for the carriage of one effector. Finally, we analyzed a number of
A. baumannii
genomes and identified significant diversity in the range of encoded T6SS VgrG and effector proteins, with correlations between effector types and
A. baumannii
global clone lineages.
Characterization of Flagellum and Toxin Phase Variation in Clostridioides difficile Ribotype 012 Isolates
Authors: Anjuwon-Foster Brandon R. , Maldonado-Vazquez Natalia , Tamayo Rita 
Published: May 2018

ABSTRACT

Clostridioides difficile
causes diarrheal diseases mediated in part by the secreted toxins TcdA and TcdB.
C. difficile
produces flagella that also contribute to motility and bacterial adherence to intestinal cells during infection. Flagellum expression and toxin gene expression are linked via the flagellar alternative sigma factor, SigD. Recently, we identified a flagellar switch upstream of the early flagellar biosynthesis operon that mediates phase variation of both flagellum and toxin production in
C. difficile
strain R20291. However, we were unable to detect flagellar switch inversion in
C. difficile
strain 630, a ribotype 012 strain commonly used in research labs, suggesting that the strain is phase locked. To determine whether a phase-locked flagellar switch is limited to 630 or present more broadly in ribotype 012 strains, we assessed the frequency and phenotypic outcomes of flagellar switch inversion in multiple
C. difficile
ribotype 012 isolates. The laboratory-adapted strain JIR8094, a derivative of strain 630, and six clinical and environmental isolates were all found to be phase-off, nonmotile, and attenuated for toxin production. We isolated low-frequency motile derivatives of JIR8094 with partial recovery of motility and toxin production and found that additional changes in JIR8094 impact these processes. The clinical and environmental isolates varied considerably in the frequency by which flagellar phase-on derivatives arose, and these derivatives showed fully restored motility and toxin production. Taken together, these results demonstrate heterogeneity in flagellar and toxin phase variation among
C. difficile
ribotype 012 strains and perhaps other ribotypes, which could impact disease progression and diagnosis.

IMPORTANCE
C. difficile
produces flagella that enhance bacterial motility and secretes toxins that promote diarrheal disease symptoms. Previously, we found that production of flagella and toxins is coregulated via a flippable DNA element termed the flagellar switch, which mediates the phase-variable production of these factors. Here, we evaluate multiple isolates of
C. difficile
ribotype 012 strains and find them to be primarily flagellar phase off (
flg
-off state). Some, but not all, of these isolates showed the ability to switch between
flg
-on and -off states. These findings suggest heterogeneity in the ability of
C. difficile
ribotype 012 strains to phase-vary flagellum and toxin production, which may broadly apply to pathogenic
C. difficile
.
Reduction in Percentage of Clusters of Candida albicans and Candida parapsilosis Causing Candidemia in a General Hospital in Madrid, Spain
Authors: Escribano Pilar , Sánchez-Carrillo Carlos , Muñoz Patricia , Bouza Emilio , Guinea Jesús 
Published: May 2018

ABSTRACT

The presence of clusters in units with a high incidence of candidemia suggests the need for the prevention of candidemia. We analyzed the percentage of patients involved in clusters and its evolution over a large period of time in a tertiary hospital. We studied 432 patients admitted to Gregorio Marañón Hospital with candidemia caused by
Candida albicans
(
n
= 276) or
Candida parapsilosis
(
n
= 156) between January 2007 and December 2014. Incident isolates were genotyped. A cluster was defined as a group of ≥2 patients infected by an identical genotype; we considered clusters to be “tracking clusters” when the patients involved in the cluster were admitted to the same ward within a period of 24 months. The study period was split into two periods, 2007 to 2010 (period 1) and 2011 to 2014 (period 2). The number of episodes of
C. albicans
and
C. parapsilosis
candidemia (
n
= 262 versus
n
= 170, respectively), the mean incidence (1.62 versus 1.36 episodes per 1,000 admissions, respectively), and the percentage of episodes caused by clusters (overall clusters [40% versus 12%] and tracking clusters [18% versus 3%], respectively) were significantly lower in period 2 than in period 1. Linear regression analysis showed a positive correlation between the overall number of episodes of candidemia and episodes caused by clusters (
r
2
= 0.89). We found a reduction in the number of episodes of candidemia caused by
C. albicans
and
C. parapsilosis
and a decrease in the percentage of episodes caused by clusters over time. Interestingly, the reduction was accompanied by the implementation of a campaign to reduce the number of catheter-related infections.
Adenovirus 5 E1A-Mediated Suppression of p53 via FUBP1
Authors: Frost Jasmine Rae , Mendez Megan , Soriano Andrea Michelle , Crisostomo Leandro , Olanubi Oladunni , Radko Sandi , Pelka Peter 
Published: May 2018

ABSTRACT

Far-upstream element (FUSE) binding protein 1 (FUBP1) was originally identified as a regulator of the oncogene
c-Myc
via binding to the FUSE within the
c-Myc
promoter and activating the expression of the gene. Recent studies have identified FUBP1 as a regulator of transcription, translation, and splicing via its DNA and RNA binding activities. Here we report the identification of FUBP1 as a novel binding partner of E1A. FUBP1 binds directly to E1A via the N terminus (residues 1 to 82) and conserved region 3 (residues 139 to 204) of adenovirus 5 E1A. The depletion of FUBP1 via short interfering RNAs (siRNA) reduces virus growth and drives the upregulation of the cellular stress response by activating the expression of p53-regulated genes. During infection, FUBP1 is relocalized within the nucleus, and it is recruited to viral promoters together with E1A while at the same time being lost from the FUSE upstream of the
c-Myc
promoter. The depletion of FUBP1 affects viral and cellular gene expression. Importantly, in FUBP1-depleted cells, p53-responsive genes are upregulated, p53 occupancy on target promoters is enhanced, and histone H3 lysine 9 is hyperacetylated. This is likely due to the loss of the FUBP1-mediated suppression of p53 DNA binding. We also observed that E1A stabilizes the FUBP1-p53 complex, preventing p53 promoter binding. Together, our results identify, for the first time, FUBP1 as a novel E1A binding protein that participates in aspects of viral replication and is involved in the E1A-mediated suppression of p53 function.

IMPORTANCE
Viral infection triggers innate cellular defense mechanisms that have evolved to block virus replication. To overcome this, viruses have counterevolved mechanisms that ensure that cellular defenses are either disarmed or not activated to guarantee successful replication. One of the key regulators of cellular stress is the tumor suppressor p53 that responds to a variety of cellular stress stimuli and safeguards the integrity of the genome. During infection, many viruses target the p53 pathway in order to deactivate it. Here we report that human adenovirus 5 coopts the cellular protein FUBP1 to prevent the activation of the p53 stress response pathway that would block viral replication. This finding adds to our understanding of p53 deactivation by adenovirus and highlights its importance in infection and innate immunity.
Multiple risk factor control, mortality and cardiovascular events in type 2 diabetes and chronic kidney disease: a population-based cohort study
Authors: Hamada Shota , Gulliford Martin C 
Published: May 2018

ObjectivesThis study aimed to evaluate the effectiveness of multiple risk factor control (MRFC) at reducing mortality and cardiovascular events in diabetes and chronic kidney disease (CKD) in clinical practice.DesignPopulation-based cohort study.SettingPrimary care database in the UK, linked with inpatient and mortality data.ParticipantsParticipants aged 40–79 years with type 2 diabetes and valid serum creatinine measurements, including 11 431 participants with CKD (estimated glomerular filtration rate: eGFR 15–59 mL/min/1.73 m2) and 36 429 participants with non-CKD (eGFR ≥60 mL/min/1.73 m2).ExposuresMRFC consisted of four components: Haemoglobin A1c (HbA1c) <53 mmol/mol (<7.0%), blood pressure <140/90 mm Hg, total cholesterol <5 mmol/L and no smoking. The main exposure variable was the number of risk factors controlled at baseline.Outcome measuresAll-cause and cardiovascular mortality in the overall participants. Cardiovascular events, including coronary heart disease and stroke, in participants limited to those without a history of cardiovascular diseases at baseline.ResultsIn participants with CKD, 37% or 13% met three or four MRFC criteria, respectively. Increasing numbers of risk factors controlled were associated with lower relative hazards for all outcomes studied compared with those meeting no or one criterion. For participants with CKD meeting four criteria, the adjusted HR for all-cause mortality was 0.60 (95% CI 0.53 to 0.69) and the adjusted subdistribution HR for cardiovascular mortality was 0.60 (95% CI 0.50 to 0.70), considering a competing risk of non-cardiovascular death. Participants meeting four criteria also had lower relative hazards for coronary heart disease (adjusted subdistribution HR 0.73, 95% CI 0.59 to 0.91) and stroke (0.63, 95% CI 0.45 to 0.89), considering death as a competing risk.ConclusionsMRFC may lower the increased risks for mortality and cardiovascular events in people with diabetes and CKD. Further research is needed to evaluate appropriateness of MRFC according to individual participants’ health status for improved management of cardiovascular risks in this population.
Surmounting the Learning Curve of Core Suture Placement with Tendon Repair Simulator
Authors: Sirisena Renita , Lahiri Amitabha , Chong Alphonsus Khin-Sze , Foo Tun-Lin 
Published: May 2018

Background: Attaining competency in placement of core suture with adequate distance from juncture is a key skill for learners of tendon repair. Currently, this is most commonly practiced on animal models in wet laboratory environment. To improve accessibility and availability, we developed a tendon repair trainer that aims to guide learners in obtaining this key competency. Methods: A customized tendon dock was designed and manufactured with additive method that permits insertion of 6mm silicon tendon rods to simulate flexor tendon repair along a digit. Four residents, divided into two groups, were instructed to repair two sets of tendon rods (60 rods per resident) with Kessler suture loop placed at 10 mm from juncture (Group A: rods marked at 10 mm, Group B: unmarked rods). The main criterion for passing was a loop placed within 1 mm of the target distance (10 mm). At a second session, both groups repaired unmarked tendons, and these were marked based on similar criterion. Results: At the first session, 100% of those who repaired marked rods (Group A) passed while 25% of unmarked rods (Group B) attained a pass. At the second session, where both groups repaired unmarked rods, residents from group A achieved a pass rate of 95% while group B achieved 33.3% pass. Conclusions: Learners who had previously repaired marked rods were able to retain their experience when repairing unmarked rods. This suggest that the proposed model may be a helpful adjunct to sharpen learners’ skills prior to practicing tendon repairs in more costly animal or cadaveric models.
The history of hydrocarbon exploration and development in North Yorkshire
Authors: Haarhoff M. Q. , Hughes F. , Heath-Clarke M. , Harrison D. , Taylor C. , Ware D. L. , Emms G. G. , Mortimer A. 
Published: May 2018

Abstract

Hydrocarbon exploration in North Yorkshire began in 1937, targeting Triassic and Permian reservoirs below the surface expression of the Cleveland Anticline. D’Arcy drilled the successful well Eskdale-2, marking the first gas discovery in the Zechstein carbonates in the UK. Since then approximately 100 wells have been drilled in the basin with exploration success relatively high. Out of the 25 pure exploration wells in the region, 13 have found hydrocarbon accumulations (flowed gas) and eight of the discoveries have been developed to date. The primary reservoir is the Permian-aged Zechstein carbonate sequence and, more specifically, the Z2, Kirkham Abbey Formation (KAF), which is a tight carbonate reservoir overprinted by a high permeability fracture system. Despite considerable investment and effort over the years, the historical development story of these fields has been very much one of repeated technical and investment failure, with approximately 39 Bcf (billion cubic feet) of the mapped gas initial in-place (GIIP) of
c
. 326 Bcf produced to date, an estimated recovery factor of 12%.

Historical production data show that all the Zechstein reservoirs have experienced early water breakthrough, leading to impaired gas rates and low recoveries. The water influx is due to a highly mobile, but finite aquifer, which under field production conditions preferentially flows through the high permeability fracture system, bypassing the gas stored in the tighter matrix. Third Energy is aiming to resolve the issue of water influx by using artificial lift to encourage the gas to flow. A trial is currently being undertaken at the Pickering gas field and, if this programme is successful, this will provide sufficient confidence for a phased redevelopment programme of surrounding fields.
Whilst North Yorkshire has experienced only limited exploration and production (E&P) activity in the last decade, solving the issue of premature water influx in the KAF fields, combined with the search for unconventional resources in the Bowland section of the Mid and Lower Carboniferous strata will herald a new and exciting phase of E&P activities for this province.
‘Uniformity in Geological Reports’ (1917) by Josef Theodor Erb, petroleum geologist and manager (1874–1934)
Authors: Wannier Mario M. A. 
Published: May 2018

Abstract
One hundred years ago, standards in geological report writing were formalized within the Royal Dutch Shell Group. Chief Geologist Josef Theodor Erb defined these standards in an internal report aimed at geologists working for Shell subsidiaries. His purpose was to raise the level of scientific reporting and to provide a measure of uniformity in geological reports sent to head office from all parts of the world. Ultimately, ‘Uniformity in Geological Reports’ was to allow the chief geologist to readily identify and follow-up on the better business opportunities. With time, Erb's report developed into the Shell ‘Standard Legend’. Erb's career is symptomatic of a developing company culture, which he embraced as his life's goal. Realizing the shortcomings of this narrow personal philosophy of life may have been at the root of the mental problems that led to his death.
Myron Kinley and the ‘Torch of Moreni’
Authors: Spencer Jeff , Furcuta Marius 
Published: May 2018

Abstract
Myron M. Kinley (1898–1978) has been called the first, the dean, the grandfather and the original pioneer oil-well firefighter. He and his father Karl are often credited with being the first to use explosives to extinguish an oil-well fire in 1913 in a California, USA oil field. Myron formed the M.M. Kinley Company in 1923, specializing in controlling well blowouts and extinguishing well fires. During Kinley's long career, he fought hundreds of oil-well fires throughout the world.
On 28 May 1929, after drilling to a depth of 1453 m, the No. 160 Romano-Americana well in Moreni, Romania had a blowout and caught fire. The derrick was destroyed and the 100 m-high flames could be seen in the city of Ploiesti over 50 km away. Attempts to extinguish the well were unsuccessful and the well burned for over 2 years. More than 100 workers were injured and 14 died in the process of trying to extinguish the fire. By the spring of 1931, the ‘Torch of Moreni’ had created a crater 76 m wide and 20 m deep. Newspapers covered the attempts to extinguish the fire and many of the photographs of the fire were used to create postcards.
Kinley first visited the No. 160 well in 1930, but was unable to convince the operators to allow him to try his firefighting methods. It took a second visit, a year later, before he was hired by the Romano-Americana Company, an affiliate of Standard Oil. A three-man crew consisting of Americans Kinley and Grady Chupp, and Romanian Costeca Luper battled the fire for 3 months. The fire was finally extinguished and Kinley was paid his $50 000 fee and he returned to the USA. American newspapers recounted his exploits and praised his heroism. Eighty-five years later, oil production facilities and producing wells surround the crater, and patches of carbonized ground attest to the intensity of the ‘Torch of Moreni’.
Supercontinents: myths, mysteries, and milestones
Authors: Pastor-Galán Daniel , Nance R. Damian , Murphy J. Brendan , Spencer Christopher J. 
Published: May 2018

Abstract
There is an emerging consensus that Earth's landmasses amalgamate quasi-periodically into supercontinents, interpreted to be rigid super-plates essentially lacking tectonically active inner boundaries and showing little internal lithosphere–mantle interactions. The formation and disruption of supercontinents have been linked to changes in sea-level, biogeochemical cycles, global climate change, continental margin sedimentation, large igneous provinces, deep mantle circulation, outer core dynamics and Earth's magnetic field. If these hypotheses are correct, long-term mantle dynamics and much of the geological record, including the distribution of natural resources, may be largely controlled by these cycles. Despite their potential importance, however, many of these proposed links are, to date, permissive rather than proven. Sufficient data are not yet available to verify or fully understand the implications of the supercontinent cycle. Recent advances in many fields of geoscience provide clear directions for investigating the supercontinent cycle hypothesis and its corollaries but they need to be vigorously pursued if these far-reaching ideas are to be substantiated.