bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Epidemiology and Mechanism of Sulbactam Resistance in Acinetobacter baumannii Isolates with Diverse Genetic Backgrounds in China
Authors: Yang Yunxing , Fu Ying , Lan Peng , Xu Qingye , Jiang Yan , Chen Yan , Ruan Zhi , Ji Shujuan , Hua Xiaoting , Yu Yunsong
Published: January 2018

Sulbactam is a plausible option for treating
Acinetobacter
infections because of its intrinsic antibacterial activity against the members of the
Acinetobacter
genus, but the mechanisms of sulbactam resistance have not been fully studied in
Acinetobacter baumannii
. In this study, a total of 2,197 clinical
A. baumannii
isolates were collected from 27 provinces in China. Eighty-eight isolates with various MICs for sulbactam were selected on the basis of their diverse clonality and underwent multilocus sequence typing (MLST), antimicrobial susceptibility testing, and resistance gene screening. The copy number and relative expression of
bla
TEM-1D
and
ampC
were measured via quantitative PCR and quantitative reverse transcription-PCR, respectively. The genetic structure of multicopy
bla
TEM-1D
was determined using the whole-genome sequencing technology. The cefoperazone-sulbactam resistance rate of the 2,197 isolates was 39.7%. The rate of positivity for
bla
TEM-1D
or IS
Aba1-ampC
in the sulbactam-nonsusceptible group (64.91% and 78.95%, respectively) was significantly higher than that in the sulbactam-susceptible group (0% and 0%, respectively;
P
< 0.001). The MIC of sulbactam (
P
< 0.001) varied considerably between the groups expressing
ampC
with or without upstream IS
Aba1
. Notably, the genetic structure of the multicopy
bla
TEM-1D
gene in strain ZS3 revealed that
bla
TEM-1D
was embedded within four tandem copies of the cassette IS
26-bla
TEM-1D
-Tn
3
-IS
26
. Therefore,
bla
TEM-1D
and IS
Aba1-ampC
represent the prevalent mechanism underlying sulbactam resistance in clinical
A. baumannii
isolates in China. The structure of the four tandem copies of
bla
TEM-1D
first identified may increase sulbactam resistance.
Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis
Authors: Launay Manon , Roux Antoine , Beaumont Laurence , Douvry Benoit , Lecuyer Lucien , Douez Emmanuel , Picard Clément , Grenet Dominique , Jullien Vincent , Boussaud Véronique , Guillemain Romain , Billaud Eliane M.
Published: January 2018

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (
C
0
) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL)
C
0
measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (
P
= 0.001* [asterisk means that statistical test is significant]), and the PSZ
C
0
exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (
P
< 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL
C
0
/dose ratio (
C
0
/
D
) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (
P
= 0.034*). The ERL
C
0
/
D
was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI;
P
= 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.
Novel Pyrimidines as Antitubercular Agents
Authors: Inoyama Daigo , Paget Steven D. , Russo Riccardo , Kandasamy Srinivasan , Kumar Pradeep , Singleton Eric , Occi James , Tuckman Margareta , Zimmerman Matthew D. , Ho Hsin Pin , Perryman Alexander L. , Dartois Véronique , Connell Nancy , Freundlich Joel S.
Published: January 2018

Mycobacterium tuberculosis
infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their
in vitro
activity,
in vitro
cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
The C-Terminal Region of Bacillus subtilis SwrA Is Required for Activity and Adaptor-Dependent LonA Proteolysis
Authors: Hughes Anna C. , Subramanian Sundharraman , Dann Charles E. , Kearns Daniel B.
Published: January 2018

SwrA is the master activator of flagellar biosynthesis in
Bacillus subtilis
, and SwrA activity is restricted by regulatory proteolysis in liquid environments. SwrA is proteolyzed by the LonA protease but requires a proteolytic adaptor protein, SmiA. Here, we show that SwrA and SmiA interact directly. To better understand SwrA activity, SwrA was randomly mutagenized and loss-of-function and gain-of-function mutants were localized primarily to the predicted unstructured C-terminal region. The loss-of-function mutations impaired swarming motility and activation from the

P
fla-che

promoter. The gain-of-function mutations increased protein stability but did not abolish SmiA binding, suggesting that SmiA association was a precursor to, but not sufficient for, LonA-dependent proteolysis. Finally, one allele abolished simultaneously SwrA activity and regulatory proteolysis, suggesting that the two functions may be in steric competition.

IMPORTANCE
SwrA is the master activator of flagellar biosynthesis in
Bacillus subtilis
, and its mechanism of activation is poorly understood. Moreover, SwrA levels are restricted by SmiA, the first adaptor protein reported for the Lon family of proteases. Here, we show that the C-terminal region of SwrA is important for both transcriptional activation and regulatory proteolysis. Competition between the two processes at this region may be critical for responding to cell contact with a solid surface and the initiation of swarming motility.
Genotyping Multidrug-Resistant Mycobacterium tuberculosis from Primary Sputum and Decontaminated Sediment with an Integrated Microfluidic Amplification Microarray Test
Authors: Linger Yvonne , Knickerbocker Christopher , Sipes David , Golova Julia , Franke Molly , Calderon Roger , Lecca Leonid , Thakore Nitu , Holmberg Rebecca , Qu Peter , Kukhtin Alexander , Murray Megan B. , Cooney Christopher G. , Chandler Darrell P.
Published: January 2018

There is a growing awareness that molecular diagnostics for detect-to-treat applications will soon need a highly multiplexed mutation detection and identification capability. In this study, we converted an open-amplicon microarray hybridization test for multidrug-resistant (MDR)
Mycobacterium tuberculosis
into an entirely closed-amplicon consumable (an amplification microarray) and evaluated its performance with matched sputum and sediment extracts. Reproducible genotyping (the limit of detection) was achieved with ∼25
M. tuberculosis
genomes (100 fg of
M. tuberculosis
DNA) per reaction; the estimated shelf life of the test was at least 18 months when it was stored at 4°C. The test detected
M. tuberculosis
in 99.1% of sputum extracts and 100% of sediment extracts and showed 100% concordance with the results of real-time PCR. The levels of concordance between
M. tuberculosis
and resistance-associated gene detection were 99.1% and 98.4% for sputum and sediment extracts, respectively. Genotyping results were 100% concordant between sputum and sediment extracts. Relative to the results of culture-based drug susceptibility testing, the test was 97.1% specific and 75.0% sensitive for the detection of rifampin resistance in both sputum and sediment extracts. The specificity for the detection of isoniazid (INH) resistance was 98.4% and 96.8% for sputum and sediment extracts, respectively, and the sensitivity for the detection of INH resistance was 63.6%. The amplification microarray reported the correct genotype for all discordant phenotype/genotype results. On the basis of these data, primary sputum may be considered a preferred specimen for the test. The amplification microarray design, shelf life, and analytical performance metrics are well aligned with consensus product profiles for next-generation drug-resistant
M. tuberculosis
diagnostics and represent a significant ease-of-use advantage over other hybridization-based tests for diagnosing MDR tuberculosis.
Peptide Uptake Is Essential for
Borrelia burgdorferi
Viability and Involves Structural and Regulatory Complexity of its Oligopeptide Transporter
Authors: Groshong Ashley M. , Dey Abhishek , Bezsonova Irina , Caimano Melissa J. , Radolf Justin D.
Published: January 2018

Borrelia burgdorferi
is an extreme amino acid (AA) auxotroph whose genome encodes few free AA transporters and an elaborate oligopeptide transport system (
B. burgdorferi
Opp [
Bb
Opp]).
Bb
Opp consists of five oligopeptide-binding proteins (OBPs), two heterodimeric permeases, and a heterodimeric nucleotide-binding domain (NBD). Homology modeling based on the crystal structure of liganded
Bb
OppA4 revealed that each OBP likely binds a distinct range of peptides. Transcriptional analyses demonstrated that the OBPs are differentially and independently regulated whereas the permeases and NBDs are constitutively expressed. A conditional NBD mutant failed to divide in the absence of inducer and replicated in an IPTG (isopropyl-β-
d
-thiogalactopyranoside) concentration-dependent manner. NBD mutants grown without IPTG exhibited an elongated morphotype lacking division septa, often with flattening at the cell center due to the absence of flagellar filaments. Following cultivation in dialysis membrane chambers, NBD mutants recovered from rats not receiving IPTG also displayed an elongated morphotype. The NBD mutant was avirulent by needle inoculation, but infectivity was partially restored by oral administration of IPTG to infected mice. We conclude that peptides are a major source of AAs for
B. burgdorferi
both
in vitro
and
in vivo
and that peptide uptake is essential for regulation of morphogenesis, cell division, and virulence.

IMPORTANCE
Borrelia burgdorferi
, the causative agent of Lyme disease, is an extreme amino acid (AA) auxotroph with a limited repertoire of annotated single-AA transporters. A major issue is how the spirochete meets its AA requirements as it transits between its arthropod vector and mammalian reservoir. While previous studies have confirmed that the
B. burgdorferi
oligopeptide transport (
opp
) system is capable of importing peptides, the importance of the system for viability and pathogenesis has not been established. Here, we evaluated the
opp
system structurally and transcriptionally to elucidate its ability to import a wide range of peptides during the spirochete’s enzootic cycle. Additionally, using a novel mutagenesis strategy to abrogate
opp
transporter function, we demonstrated that peptide uptake is essential for bacterial viability, morphogenesis, and infectivity. Our studies revealed a novel link between borrelial physiology and virulence and suggest that peptide uptake serves an intracellular signaling function regulating morphogenesis and division.
Comparison of Zoonotic Bacterial Agents in Fleas Collected from Small Mammals or Host-Seeking Fleas from a Ugandan Region Where Plague Is Endemic
Authors: Bai Ying , Osikowicz Lynn M. , Kosoy Michael Y. , Eisen Rebecca J. , Atiku Linda A. , Mpanga Joseph T. , Boegler Karen A. , Enscore Russell E. , Gage Kenneth L.
Published: January 2018

Fleas play critical roles in transmitting some infections among animals and from animals to humans. Detection of pathogens in fleas is important to determine human risks for flea-borne diseases and can help guide diagnosis and treatment. Our findings of high prevalence rates of
B. elizabethae
and
R. felis
in fleas in the Arua and Zombo districts of Uganda implicate these agents as potential causative agents of undiagnosed febrile illnesses in this area.
Early population-based outcomes of infants born with congenital diaphragmatic hernia
Authors: Long Anna-May , Bunch Kathryn J , Knight Marian , Kurinczuk Jennifer J , Losty Paul D
Published: January 2018

Purpose

This study aims to describe short-term outcomes of live-born infants with congenital diaphragmatic hernia (CDH) and to identify prognostic factors associated with early mortality.

Design

A prospective population cohort study was undertaken between April 2009 and September 2010, collecting data on live-born infants with CDH from all 28 paediatric surgical centres in the UK and Ireland using an established surgical surveillance system. Management and outcomes are described. Prognostic factors associated with death before surgery are explored.

Results

Two hundred and nineteen live-born infants with CDH were reported within the data collection period. There were 1.5 times more boys than girls (n=133, 61%). Thirty-five infants (16%) died without an operation. This adverse outcome was associated with female sex (adjusted OR (aOR) 3.96, 95% CI 1.66 to 9.47), prenatal diagnosis (aOR 4.99, 95% CI 1.31 to 18.98), and the need for physiological support in the form of inotropes (aOR 9.96, 95% CI 1.19 to 83.25) or pulmonary vasodilators (aOR 4.09, 95% CI 1.53 to 10.93). Significant variation in practice existed among centres, and some therapies potentially detrimental to infant outcomes were used, including pulmonary surfactant in 45 antenatally diagnosed infants (34%). Utilisation of extracorporeal membrane oxygenation was very low compared with published international studies (n=9/219, 4%). Postoperative 30-day survival was 98% for 182 infants with CDH who were adequately physiologically stabilised and underwent surgery.

Conclusion

This is the first British Isles population-based study reporting outcome metrics for infants born with CDH. 16% of babies did not survive to undergo surgery. Factors associated with poor outcome included female sex and prenatal diagnosis. Early postoperative survival in those who underwent surgical repair was excellent.
Volume targeting levels and work of breathing in infants with evolving or established bronchopulmonary dysplasia
Authors: Hunt Katie , Dassios Theodore , Ali Kamal , Greenough Anne
Published: January 2018

Objectives

To assess the work of breathing at different levels of volume targeting in prematurely born infants with evolving or established bronchopulmonary dysplasia (BPD).

Design

Randomised crossover study.

Setting

Tertiary neonatal intensive care unit.

Patients

Eighteen infants born at <32 weeks gestation who remained ventilated at or beyond 1 week after birth, that is, they had evolving or established BPD.

Interventions

Infants received ventilation at volume targeting levels of 4, 5, 6 and 7 mL/kg each for 20 minutes, the levels were delivered in random order. Baseline ventilation (without volume targeting) was delivered for 20 minutes between each epoch of volume-targeting.

Main outcome measures

Pressure-time product of the diaphragm (PTPdi), a measure of the work of breathing, at different levels of volume targeting.

Results

The 18 infants had a median gestational age of 26 (range 24–30) weeks and were studied at a median of 18 (range 7–60) days. The mean PTPdi was higher at 4 mL/kg than at baseline, 5 mL/kg, 6 mL/kg and 7 mL/kg (all P≤0.001). The mean PTPdi was higher at 5 mL/kg than at 6 mL/kg (P=0.008) and 7 mL/kg (P<0.001) and higher at 6 mL/kg than 7 mL/kg (P=0.003). Only at 7 mL/kg was the PTPdi significantly lower than at baseline (P=0.001).

Conclusions

Only a tidal volume target of 7 mL/kg reduced the work of breathing below the baseline and may be more appropriate for infants with evolving or established BPD who remained ventilator dependent at or beyond 7 days of age.
Are corticosteroid injections more beneficial than anaesthetic injections alone in the management of rotator cuff-related shoulder pain? A systematic review
Authors: Cook Tim , Minns Lowe Catherine , Maybury Mark , Lewis Jeremy S
Published: January 2018

Objective

To compare the effectiveness of corticosteroid injections to local anaesthetic injections in the management of rotator cuff-related shoulder pain (RCRSP).

Design

Systematic review with best evidence synthesis.

Data sources

The Cochrane, PubMed, CINAHL Plus, PEDro and EMBASE electronic databases were searched (inception until 8 June 2017). Reference lists of included articles were also hand searched.

Eligibility criteria

Two reviewers independently evaluated eligibility. Randomised controlled trials (RCTs) were included if they compared subacromial injections of corticosteroid with anaesthetic injections. Two reviewers independently extracted data regarding short-term, midterm and long-term outcomes for pain, self-reported function, range of motion and patient-perceived improvement.

Results

Thirteen RCTs (n=1013) were included. Four trials (n=475) were judged as being at low risk of bias. Three studies of low risk of bias favoured the use of corticosteroid over anaesthetic-only injections in the short term (up to 8 weeks). There was strong evidence of no significant difference between injection types in midterm outcomes (12–26 weeks). There was limited evidence of no significant difference between injection types in long-term outcomes.

Conclusion

Corticosteroid injections may have a short-term benefit (up to 8 weeks) over local anaesthetic injections alone in the management of RCRSP. Beyond 8 weeks, there was no evidence to suggest a benefit of corticosteroid over local anaesthetic injections.

Trial registration number

PROSPERO CRD42016033161.
Short-stay admissions at an inner city hospital: a cross-sectional analysis
Authors: Pope Ian , Ismail Sharif , Bloom Benjamin , Jansen Gwyneth , Burn Helen , McCoy David , Harris Tim
Published: January 2018

Objective

To investigate factors predictive of short hospital admissions and appropriate placement to inpatient versus clinical decision units (CDUs).

Method

This is a retrospective analysis of attendance and discharge data from an inner-city ED in England for December 2013. The primary outcome was admission for less than 48 hours either to an inpatient unit or CDU. Variables included: age, gender, ethnicity, deprivation score, arrival date and time, arrival method, admission outcome and discharge diagnosis. Analysis was performed by cross-tabulation followed by binary logistic regression in three models using the outcome measures above and seeking to identify factors associated with short-stay admission.

Results

There were 2119 (24%) admissions during the study period and 458 were admitted for less than 24 hours. Those who were admitted in the middle of the week or with ambulatory care sensitive conditions (ACSCs) were significantly more likely to experience short-stays. Older patients and those who arrived by ambulance were significantly more likely to have a longer hospital stay. There was no association of length of inpatient stay with being admitted in the last 10 min of a 4 hours ED stay.

Conclusion

Only a few factors were independently predictive of short stays. Patients with ACSCs were more likely to have short stays, regardless of whether they were admitted to CDU or an inpatient ward. This may be a group of patients that could be targeted for dedicated outpatient management pathways or CDU if they need admission.
Multianalysis with optical coherence tomography and vasomotion in everolimus-eluting stents and everolimus-eluting biovascular scaffolds: the MOVES trial
Authors: Arroyo Diego A , Schukraft Sara , Kallinikou Zacharenia , Stauffer Jean-Christophe , Baeriswyl Gérard , Goy Jean-Jacques , Togni Mario , Cook Stéphane , Puricel Serban
Published: January 2018

Aims

To compare endothelium-dependent vasomotor function and vascular healing 15 months after implantation of two new-generation drug-eluting stents and biovascular scaffolds (BVS).

Methods and results

A total of 28 patients previously treated with a SYNERGY stent (bioabsorbable polymer everolimus-eluting stents (BP-EES)), a PROMUS stent (persistent polymer everolimus-eluting stents (PP-EES)) or an ABSORB (BVS) underwent control coronary angiography, 15 months after implantation, coupled with optical coherence tomography imaging and supine bicycle exercise. Intracoronary nitroglycerin was administered after exercise testing. Coronary vasomotor response was assessed using quantitative coronary angiography at rest, during supine bicycle exercise and after nitroglycerin. The primary end point was the percent change in mean lumen diameter compared with baseline. Secondary end points were strut coverage and apposition.

There were no significant differences in vasomotor response between the three treatment groups. Patients with PP-EES showed significant vasoconstriction of the proximal peristent segment at maximum exercise (P=0.02). BP-EES (2.7%, 95% CI 0 to 5.5) and BVS (3.2%, 95% CI 0 to 6.7) showed less uncovered struts than PP-EES (12.1%, 95% CI 2.9 to 21.3, P=0.02 and 0.09, respectively). Complete strut apposition was more frequently seen with BP-EES (99.6%, 95% CI 99.2 to 100) than with BVS (98.9%, 95% CI 98.2 to 99.6, P=0.04) or PP-EES (95.0%, 95% CI 91.6 to 98.5, P=0.001).

Conclusion

BVS and thin strut BP-EES have a reassuring vasomotion profile, suggesting minimal endothelial dysfunction 15 months after implantation.
Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease
Authors: Bond Andrew R , Iacobazzi Dominga , Abdul-Ghani Safa , Ghorbel Mohammed , Heesom Kate , Wilson Mariangela , Gillett Christopher , George Sarah J , Caputo Massimo , Suleiman Saadeh , Tulloh Robert M R
Published: January 2018

Background

The right ventricle (RV) is not designed to sustain high pressure leading to failure. There are no current medications to help RV contraction, so further information is required on adaption of the RV to such hypertension.

Methods

The Right Ventricle in Children (RVENCH) study assessed infants with congenital heart disease undergoing cardiac surgery with hypertensive RV. Clinical and echocardiographic data were recorded, and samples of RV were taken from matched infants, analysed for proteomics and compared between pathologies and with clinical and echocardiographic outcome data.

Results

Those with tetralogy of Fallot (TOF) were significantly more cyanosed than those with ventricular septal defect (median oxygen saturation 83% vs 98%, P=0.0038), had significantly stiffer RV (tricuspid E wave/A wave ratio 1.95 vs 0.84, P=0.009) and had most had restrictive physiology. Gene ontology in TOF, with enrichment analysis, demonstrated significant increase in proteins of contractile mechanisms and those of calmodulin, actin binding and others associated with contractility than inventricular septal defect. Structural proteins were also found to be higher in association with sarcomeric function: Z-disc, M-Band and thin-filament proteins. Remaining proteins associated with actin binding, calcium signalling and myocyte cytoskeletal development. Phosphopeptide enrichment led to higher levels of calcium signalling proteins in TOF.

Conclusion

This is the first demonstration that those with an RV, which is stiff and hypertensive in TOF, have a range of altered proteins, often in calcium signalling pathways. Information about these alterations might guide treatment options both in terms of individualised therapy or inotropic support for the Right ventricle when hypertensive due to pulmoanry hypertension or congenital heart disease.
Investigation of significant inputs for pavement rehabilitation design in the Pavement-ME
Authors: Harsini Iman , Haider Syed Waqar , Brink Wouter C. , Buch Neeraj , Chatti Karim
Published: January 2018

The Pavement-ME can design different flexible or rigid pavement rehabilitation scenarios. A set of quantitative and qualitative input variables are considered to characterize the new and existing pavement layers and predict the damage accumulation in these layers. To evaluate the impact of the inputs on the predicted performance for the rehabilitation options, sequential analyses were performed to assess the main and interactive effects of each input. Continuous responses surface models for interactive effects were obtained using artificial neural network. Furthermore, a normalized sensitivity index was used to quantify the significance of main and interactive effects. The following rehabilitation options were included in this paper: hot mix asphalt (HMA) over HMA, HMA over jointed plain concrete pavement (JPCP), HMA over fractured JPCP, and JPCP over JPCP. The results of the study can assist the highway agencies’ efforts to implementing the Pavement-ME, especially when the majority of pavement designs are related to rehabilitation of the existing highways.
Variety of loops generated by code loops
Authors: Grishkov Alexander , Miguel Pires Rosemary
Published: January 2018

In this work, we construct free infinitely generated Moufang loop in the variety generated by code loops and find the minimal set of identities that define this variety. We apply this construction to the study of code loops.
Low-energy meson spectrum from a QCD approach based on many-body methods
Authors: Amor-Quiroz D. A. , Yépez-Martínez T. , Hess P. O. , Civitarese O. , Weber A.
Published: January 2018

The Tamm–Dancoff Approximation (TDA) and Random Phase Approximation (RPA) many-body methods are applied to an effective Quantum Chromodynamics (QCD) Hamiltonian in the Coulomb gauge. The gluon effects in the low-energy domain are accounted for by the Instantaneous color-Coulomb Interaction between color-charge densities, approximated by the sum of a Coulomb ([Formula: see text]) and a confining linear ([Formula: see text]) potential. We use the eigenfunctions of the harmonic oscillator as a basis for the quantization of the quark fields, and discuss how suitable this basis is in various steps of the calculation. We show that the TDA results already reproduce the gross-structure of the light-flavored meson states. The pion-like state, which in the RPA description is a highly collective state, is in better agreement with the experimental value. The results are related to other nonperturbative treatments and compared to experimental data. We discuss the advantages of the present approach.
Does the Information Content of Central Bank Speeches Impact on the Level of Exchange Rate? A Comparative Study of Canadian and Australian Central Bank Communications
Authors: Masawi Becksndale , Bhattacharya Sukanto , Boulter Terry
Published: January 2018

Traditionally, central banks have used direct intervention in currency markets when the exchange rate has moved away from equilibrium or when the volatility has been excessive and the literature on the effects of indirect intervention is sparse. We examine whether indirect intervention has any impact on the exchange rate levels by examining the central bank verbal communications in Australia and Canada. We find evidence that the Bank of Canada’s (BOC’s) speeches reduce the mean exchange rate returns but not the Reserve Bank of Australia’s (RBA’s) speeches. Our results show that the socio-economic similarities between countries do not guarantee a similar impact of indirect intervention.
A Method to Personalize the Lumped Parameter Model of Coronary Artery
Authors: Li Bao , Wang Wenxin , Mao Boyan , Liu Youjun
Published: January 2018

A method which can personalize the lumped parameter model of coronary artery and cardiovascular system based on the non-invasive physiological parameters has been developed. The parameters of system were determined by different physiological parameters. The heart module was determined by aortic pressure and heart rate; the systemic circulation module was determined by cardiac output, height and cardio-ankle vascular index (CAVI), while the CAVI was determined by age and aortic pressure; the coronary module was determined by the target waveforms of coronary flow rate predicted from cardiac output. The considerable results proved that this method could be applied to each patient.
EMPLOYMENT CONTRACT AND SMES’ INNOVATION IN DEVELOPING AND TRANSITION ECONOMIES: THE CASE OF VIETNAM
Authors: DUNG NGO VI , THANG NGUYEN NGOC , JANSSEN FRANK , HINE DAMIAN
Published: January 2018

Although the job/employment security is critical to the implementation of high performance management practices (Pfeffer and Veiga, 1999), its impact on innovation remains understudied, especially in the context of small and medium-size enterprises (SMEs) in emerging and transition economies (ETEs). This paper uses the institution-based view in entrepreneurship and strategic management to (i) analyze the relationships between the formality of an employment contract and the firm’s innovation (i.e., product innovation, product improvement, process innovation and intention of innovation); and (ii) indentify potential antecedents of the contractual formality. Based on a sample of 865 private, domestic SMEs operating in the manufacturing sector in an ETE — namely Vietnam — and by using multivariable regression techniques, we find that the formality of the employment contract significantly and positively influences some aspects of the firm’s innovation (i.e., product improvement and process innovation). Furthermore, the major factors that determine the employment contract’s degree of formality are the manager’s regulatory knowledge, the degree of industrial competition and the existence of a labor representative within the firm. Implications for policy makers, managers and future research are suggested.
REGIONAL FLOOD IMPACTS AND ADAPTATION IN A FEDERAL SETTING: A SPATIAL COMPUTABLE GENERAL EQUILIBRIUM ANALYSIS FOR SWITZERLAND
Authors: HOFFMANN CHRISTIN , STEPHAN GUNTER
Published: January 2018

Climate change, a growing population and inappropriate land use may lead to a significant increase in the frequency, intensity and the duration of water-related extreme events. We aim (1) to gain a better understanding of the direct and indirect economic impacts of floods, (2) to analyze the issue of efficient flood adaption as well as the issue of financing adaptation in a federalist system, where local and national governmental authorities interplay in the provision of local public good adaptation. Our numerical thought experiments are based on a dynamic, spatial differentiated Ramsey type Computable General Equilibrium Model. Regions are determined by exposure and vulnerability to floods and are not identical with territorial units. Our results indicate: (1) general equilibrium effects caused by flood damages in vulnerable regions lead in regions of low vulnerability also to considerable welfare and GDP losses. (2) Providing local public good adaptation can at low economic costs significantly reduce negative impacts on welfare, GDP as well as the allocation of resources between regions and sectors. (3) Funding adaptation by imposing a regional land tax should be preferred to a national output tax or a combination of both with transfers from national to regional governments.
High Explosive Detonation–Confiner Interactions
Authors: Short Mark , Quirk James J.
Published: January 2018

The primary purpose of a detonation in a high explosive (HE) is to provide the energy to drive a surrounding confiner, typically for mining or munitions applications. The details of the interaction between an HE detonation and its confinement are essential to achieving the objectives of the explosive device. For the high pressures induced by detonation loading, both the solid HE and confiner materials will flow. The structure and speed of a propagating detonation, and ultimately the pressures generated in the reaction zone to drive the confiner, depend on the induced flow both within the confiner and along the HE–confiner material interface. The detonation–confiner interactions are heavily influenced by the material properties and, in some cases, the thickness of the confiner. This review discusses the use of oblique shock polar analysis as a means of characterizing the possible range of detonation–confiner interactions. Computations that reveal the fluid mechanics of HE detonation–confiner interactions for finite reaction-zone length detonations are discussed and compared with the polar analysis. This includes cases of supersonic confiner flow; subsonic, shock-driven confiner flow; subsonic, but shockless confiner flow; and sonic flow at the intersection of the detonation shock and confiner material interface. We also summarize recent developments, including the effects of geometry and porous material confinement, on detonation–confiner interactions.
T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma—Implications for Adoptive Cell Therapy
Authors: Andersen Rikke , Westergaard Marie Christine Wulff , Kjeldsen Julie Westerlin , Müller Anja , Pedersen Natasja Wulff , Hadrup Sine Reker , Met Özcan , Seliger Barbara , Kromann-Andersen Bjarne , Hasselager Thomas , Donia Marco , Svane Inge Marie
Published: January 2018

In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8+ TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8+ T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4+ T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8+ RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. Cancer Immunol Res; 6(2); 222–35. ©2018 AACR.
Longitudinal Analysis of Drusen Volume in Intermediate Age-Related Macular Degeneration Using Two Spectral-Domain Optical Coherence Tomography Scan Patterns
Authors: Thiele Sarah , Nadal Jennifer , Fleckenstein Monika , Fang Petra P. , Pfau Maximilian , Schmid Matthias , Hua Rui , Holz Frank G. , Schmitz-Valckenberg Steffen ,   MODIAMD-Study Group
Published: January 2018

Purpose: To evaluate two different spectral-domain optical coherence tomography (SD-OCT) scan patterns in eyes with intermediate age-related macular degeneration (AMD) for the longitudinal assessment of drusen volume. Methods: The data of 38 eyes of 38 AMD patients (age 69.97 ± 6.08 years) were included. The longitudinal drusen volume over 4 years was analyzed by annual SD-OCT raster scanning (field size 20 × 15°). Two raster scan patterns (A/B) differed in the distance between neighboring B-scans (240 vs. 30 µm) and in the number of averaged frames (4 vs. 15). Results: The mean drusen volume at baseline was 0.213 ± 0.100 mm3 (pattern A) and 0.219 ± 0.103 mm3 (pattern B) (p = 0.937). Linear mixed-effect models showed no significant difference for the change within 4 years for both pattern A (p = 0.8) and pattern B (p = 0.8). Conclusions: The results indicate that the performance of interpolation algorithms may be sufficient to balance for less dense raster scanning with regard to quantification of longitudinal drusen volume, which can be used as a surrogate marker for AMD progression in future clinical trials.
Clinically Observed Estrogen Receptor Alpha Mutations within the Ligand-Binding Domain Confer Distinguishable Phenotypes
Authors: Jia Shanhang , Miedel Mark T. , Ngo Marilyn , Hessenius Ryan , Chen Ning , Wang Peilu , Bahreini Amir , Li Zheqi , Ding Zhijie , Shun Tong Ying , Zuckerman Daniel M. , Taylor D. Lansing , Puhalla Shannon L. , Lee Adrian V. , Oesterreich Steffi , Stern Andrew M.
Published: January 2018

Objective: Twenty to fifty percent of estrogen receptor-positive (ER+) metastatic breast cancers express mutations within the ER ligand-binding domain. While most studies focused on the constitutive ER signaling activity commonly engendered by these mutations selected during estrogen deprivation therapy, our study was aimed at investigating distinctive phenotypes conferred by different mutations within this class. Methods: We examined the two most prevalent mutations, D538G and Y537S, employing corroborative genome-edited and lentiviral-transduced ER+ T47D cell models. We used a luciferase-based reporter and endogenous phospho-ER immunoblot analysis to characterize the estrogen response of ER mutants and determined their resistance to known ER antagonists. Results: Consistent with their selection during estrogen deprivation therapy, these mutants conferred constitutive ER activity. While Y537S mutants showed no estrogen dependence, D538G mutants demonstrated an enhanced estrogen-dependent response. Both mutations conferred resistance to ER antagonists that was overcome at higher doses acting specifically through their ER target. Conclusions: These observations provide a tenable hypothesis for how D538G ESR1-expressing clones can contribute to shorter progression-free survival observed in the exemestane arm of the BOLERO-2 study. Thus, in those patients with dominant D538G-expressing clones, longitudinal analysis for this mutation in circulating free DNA may prove beneficial for informing more optimal therapeutic regimens.
Is There a Preferred Stroke Prevention Strategy for Diabetic Patients with Non-Valvular Atrial Fibrillation? Comparing Warfarin, Dabigatran and Rivaroxaban
Authors: Hsu Chih-Cheng , Hsu Pai-Feng , Sung Shih-Hsien , Tu Shih-Te , Yu Ben-Hui , Huang Chi-Jung , Cheng Hao-Min
Published: January 2018

Background The prevalence of diabetes is growing, and diabetes is an independent risk factor for both atrial fibrillation (AF) and stroke. However, the relative effectiveness and safety of different oral anticoagulants for diabetic patients with non-valvular AF remain unclear. We aimed to compare thromboembolic events, bleeding and mortality in diabetic AF patients treated with rivaroxaban, dabigatran and warfarin.

Methods and Results Diabetic AF patients taking dabigatran (n = 322), rivaroxaban (n = 320) or warfarin (n = 1,899) were identified from the nationwide diabetes pay-for-performance program (n = 814,465) in Taiwan. Outcomes and comorbidities were evaluated by linking with Taiwan National Health Insurance Research Database. Propensity score weighting method was used to balance covariates across study groups. Patients were followed up until the first occurrence of any study outcome or the study end date. Compared with warfarin, dabigatran significantly decreased the risk of all-cause mortality (hazard ratio [HR] = 0.348, 95% confidence interval [CI] = 0.157–0.771) and gastrointestinal bleeding (HR = 0.558, 95% CI = 0.327–0.955). Relative effectiveness and safety outcomes between rivaroxaban and warfarin were comparable. Compared with rivaroxaban, dabigatran significantly decreased the risk of all-cause mortality (HR = 0.310, 95% CI = 0.121–0.798) and was associated with a borderline reduced risk for composite safety end points (HR = 0.670, 95% CI = 0.421–1.067).

Conclusion In diabetic AF patients, dabigatran and rivaroxaban showed a superior or non-inferior effectiveness and safety profile compared with warfarin. Dabigatran was associated with a significantly lower risk of mortality than rivaroxaban.
Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins
Authors: Vogt Katja , Mahajan-Thakur Shailaja , Wolf Robert , Bröderdorf Susanne , Vogel Conny , Böhm Andreas , Ritter Christoph , Gräler Markus , Oswald Stefan , Greinacher Andreas , Kroemer Heyo , Jedlitschky Gabriele , Rauch Bernhard
Published: January 2018

Sphingosine-1-phosphate (S1P) is a potent lipid mediator released from activated platelets by an adenosine triphosphate (ATP)-dependent export mechanism. A candidate transport protein is the multidrug resistance protein 4 (MRP4/ABCC4), an ATP-dependent transporter highly expressed in platelets. Furthermore, several statins are known to affect platelet functions and exhibit antithrombotic properties. This study determines the involvement of MRP4 in the transport of S1P and a possible interference by statins. Transport studies in membrane vesicles of Sf9 cells containing recombinant human MRP4 revealed that MRP4 mediates ATP-dependent transport of fluorescein- and tritium-labelled S1P. Also, ATP-dependent S1P transport in platelet membrane vesicles containing endogenous MRP4 was inhibited by the MRP inhibitor MK571 and the MRP4-selective compound Ceefourin-1. Confocal microscopy using fluorescein-labelled S1P as well as boron-dipyrromethene (BODIPY)-labelled sphingosine indicated association of S1P and MRP4 in human platelets. In MRP4-deficient mice, agonist-induced S1P secretion was reduced compared with matched wild-type C57Bl/6 mice and platelet S1P concentrations were lower. Fluvastatin and rosuvastatin interfered with MRP4 function inhibiting ATP-dependent cGMP (cyclic guanosine monophosphate) uptake into MRP4-containing vesicles, inhibited MRP4-mediated S1P transport in vitro and significantly attenuated endogenous S1P release from agonist-activated platelet ex vivo. These data suggest that release of S1P from platelets depends on MRP4 and statins can interfere with this transport process. Potentially, this may be relevant for the pleiotropic anti-inflammatory effects of statins and their effect on modulating atherothrombosis.
Passivating Injured Endothelium with Kinexins in Thrombolytic Therapy
Authors: Ma Yunn-Hwa , Huang Chao-Wei , Wen Chih-Jen , Lu Yi-Ching , Wey Shiaw-Pyng , Wun Tze-Chein
Published: January 2018

Without conjunctive administration of an anticoagulant, endothelial injury-induced thrombosis is resistant to thrombolysis and prone to re-thrombosis. We hypothesized that co-delivery of recombinant tissue plasminogen activator (rtPA) with annexin V–containing anticoagulants that specifically target the injured endothelium may passivate the thrombogenic elements of the vascular injury site and enhance rtPA-induced thrombolysis. In this study, the effects of conjunctive administration of Kinexins (Kunitz inhibitor–annexin V fusion proteins) with rtPA on thrombolysis were determined in vitro and in vivo. Thromboelastometry showed that both TAP-A (tick anticoagulant peptide–annexin V fusion protein; an inhibitor of factor Xa [FXa] and prothrombinase) and A-6L15 (annexin V-6L15 fusion protein; an inhibitor of tissue factor/FVIIa) exerted concentration-dependent (10–100 nM) effects on clot formation, with TAP-A being several folds more potent than A-6L15 in whole blood. Combination of TAP-A or A-6L15 with rtPA (1 μg/mL) led to decrease in lysis index, suggesting conjunctive enhancement of thrombolysis by combined use of rtPA with TAP-A or A-6L15. In a rat cremaster muscle preparation subjected to photochemical injury, conjunctive administration of rtPA and TAP-A significantly restored tissue perfusion to 56%, which is approximately two fold of that by rtPA or TAP-A alone. Near-infrared fluorescence images demonstrated local retention of a fluorescent A-6L15-S288 at the injury site, suggesting a targeting effect of the fusion protein. Pharmacokinetic analysis showed that 123I-labelled TAP-A and A-6L15 had initial distribution half-lives (T1/2α) of approximately 6 minutes and elimination half-lives (T1/2β) of approximately 2.3 hours. In conclusion, Kinexins were potentially useful adjunctive agents with rtPA thrombolytic therapy especially for thrombosis induced by endothelial injury.
Comparative Performance of Clinical Risk Assessment Models for Hospital-Acquired Venous Thromboembolism in Medical Patients
Authors: Blondon Marc , Spirk David , Kucher Nils , Aujesky Drahomir , Hayoz Daniel , Beer Jürg , Husmann Marc , Frauchiger Beat , Korte Wolfgang , Wuillemin Walter , Bounameaux Henri , Righini Marc , Nendaz Mathieu
Published: January 2018

Background Improved thromboprophylaxis for acutely ill medical patients relies on valid predictions of thrombotic risks. Our aim was to compare the performance of the Improve and Geneva clinical risk assessment models (RAMs), and to simplify the current Geneva RAM.

Methods Medical inpatients from eight Swiss hospitals were prospectively followed during 90 days, for symptomatic venous thromboembolism (VTE) or VTE-related death. We compared discriminative performance and calibration of the RAMs, using time-to-event methods with competing risk modelling of non-VTE death.

Results In 1,478 patients, the 90-day VTE cumulative incidence was 1.6%. Discrimination of the Improve and Geneva RAM was similar, with a 30-day AUC (areas under the curve) of 0.78 (95% CI [confidence interval]: 0.65–0.92) and 0.81 (0.73–0.89), respectively. According to the Improve RAM, 68% of participants were at low risk (0.8% VTE at 90 days), and 32% were at high risk (4.7% VTE), with a sensitivity of 73%. According to the Geneva RAM, 35% were at low risk (0.6% VTE) and 65% were at high risk (2.8% VTE), with a sensitivity of 90%. Among patients without thromboprophylaxis, the sensitivity was numerically greater in the Geneva RAM (85%) than in the Improve RAM (54%). We derived a simplified Geneva RAM with comparable discrimination and calibration as the original Geneva RAM.

Conclusions We found comparably good discrimination of the Improve and Geneva RAMs. The Improve RAM classified more patients as low risk, but with possibly lower sensitivity and greater VTE risks, suggesting that a lower threshold for low risk (<2) should be used. The simplified Geneva RAM may represent an alternative to the Geneva RAM with enhanced usability.