bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topology-Oriented Deformation of FE-Meshes in Iterative Reverse Engineering Processes
Authors: Klaus Matthias , Holtzhausen Stefan , Schöne Christine , Stelzer Ralph 
Published: August 2013

Reverse Engineering methods are becoming more and more important in product development processes in cases without CAD models or modified physical objects. For numerical calculations of scanned components, using, for instance, the Finite Element Method (FEM) to look at strength or vibration characteristics, we need the previously scanned data, obtained via Geometric Reverse Engineering, to be converted into CAD surface data, a Finite Element-meshing and a determination of material parameters and constraints. Tremendous effort must be expended in the course of performing repeated Geometric Reverse Engineering and FE-meshing, which must be done when there are iterative, largely local changes in real geometry (such as when incorporating forming dies) or in the case of topologically similar objects, which must be scanned again and again.
This project is aimed at the generation of new calculation models using an appropriate adaption of existing FE meshes (made using a CAD model, for example) or FE meshes previously created with the help of scan data through the retention of intelligent meshing (constraints, material, element type etc.). In terms of their topology, these new meshes should adapt themselves to changes in geometry. Time-consuming Geometric Reverse Engineering, as well as re-meshing, can thus be bypassed. Product development cycles frequently proceed in an iterative manner. Repetition of process steps is intended to improve the product in order to achieve an optimum result in design and dimensioning. The goal of these research activities is to reduce the process steps from 3D scan data to FE-meshing, in particular in development cycles. The paper introduces the project’s concept, its initial results, and further steps.
Determination of lung segments in computed tomography images using the Euclidean distance to the pulmonary artery
Authors: Stoecker Christina , Welter Stefan , Moltz Jan H. , Lassen Bianca , Kuhnigk Jan‐Martin , Krass Stefan , Peitgen Heinz‐Otto 
Published: August 2013

Purpose:Computed tomography (CT) imaging is the modality of choice for lung cancer diagnostics. With the increasing number of lung interventions on sublobar level in recent years, determining and visualizing pulmonary segments in CT images and, in oncological cases, reliable segment‐related information about the location of tumors has become increasingly desirable. Computer‐assisted identification of lung segments in CT images is subject of this work.Methods:The authors present a new interactive approach for the segmentation of lung segments that uses the Euclidean distance of each point in the lung to the segmental branches of the pulmonary artery. The aim is to analyze the potential of the method. Detailed manual pulmonary artery segmentations are used to achieve the best possible segment approximation results. A detailed description of the method and its evaluation on 11 CT scans from clinical routine are given.Results:An accuracy of 2–3 mm is measured for the segment boundaries computed by the pulmonary artery‐based method. On average, maximum deviations of 8 mm are observed. 135 intersegmental pulmonary veins detected in the 11 test CT scans serve as reference data. Furthermore, a comparison of the presented pulmonary artery‐based approach to a similar approach that uses the Euclidean distance to the segmental branches of the bronchial tree is presented. It shows a significantly higher accuracy for the pulmonary artery‐based approach in lung regions at least 30 mm distal to the lung hilum.Conclusions:A pulmonary artery‐based determination of lung segments in CT images is promising. In the tests, the pulmonary artery‐based determination has been shown to be superior to the bronchial tree‐based determination. The suitability of the segment approximation method for application in the planning of segment resections in clinical practice has already been verified in experimental cases. However, automation of the method accompanied by an evaluation on a larger number of test cases is required before application in the daily clinical routine.
Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451
Authors: Yang Huiling , Robinson Margaret , Corsa Amoreena C. , Peng Betty , Cheng Guofeng , Tian Yang , Wang Yujin , Pakdaman Rowchanak , Shen Marian , Qi Xiaoping , Mo Hongmei , Tay Chin , Krawczyk Steve , Sheng X. Christopher , Kim Choung U. , Yang Chris , Delaney William E. 
Published: August 2013

ABSTRACT

GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including
in vitro
antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC
50
s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC
50
= 316 nM). Additive to synergistic
in vitro
antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ∼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of
in vitro
cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.
Spread of Carbapenem-Resistant Acinetobacter baumannii Global Clone 2 in Asia and AbaR-Type Resistance Islands
Authors: Kim Dae Hun , Choi Ji-Young , Kim Hae Won , Kim So Hyun , Chung Doo Ryeon , Peck Kyong Ran , Thamlikitkul Visanu , So Thomas Man-Kit , Yasin Rohani M. D. , Hsueh Po-Ren , Carlos Celia C. , Hsu Li Yang , Buntaran Latre , Lalitha M. K. , Song Jae-Hoon , Ko Kwan Soo 
Published: August 2013

ABSTRACT

In this surveillance study, we identified the genotypes, carbapenem resistance determinants, and structural variations of AbaR-type resistance islands among carbapenem-resistant
Acinetobacter baumannii
(CRAB) isolates from nine Asian locales. Clonal complex 92 (CC92), corresponding to global clone 2 (GC2), was the most prevalent in most Asian locales (83/108 isolates; 76.9%). CC108, or GC1, was a predominant clone in India. OXA-23 oxacillinase was detected in CRAB isolates from most Asian locales except Taiwan.
bla
OXA-24
was found in CRAB isolates from Taiwan. AbaR4-type resistance islands, which were divided into six subtypes, were identified in most CRAB isolates investigated. Five isolates from India, Malaysia, Singapore, and Hong Kong contained AbaR3-type resistance islands. Of these, three isolates harbored both AbaR3- and AbaR4-type resistance islands simultaneously. In this study, GC2 was revealed as a prevalent clone in most Asian locales, with the AbaR4-type resistance island predominant, with diverse variants. The significance of this study lies in identifying the spread of global clones of carbapenem-resistant
A. baumannii
in Asia.
Ex Vivo
Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers
Authors: Lim Pharath , Dek Dalin , Try Vorleak , Eastman Richard T. , Chy Sophy , Sreng Sokunthea , Suon Seila , Mao Sivanna , Sopha Chantha , Sam Baramey , Ashley Elizabeth A. , Miotto Olivo , Dondorp Arjen M. , White Nicholas J. , Su Xin-zhuan , Char Meng Chuor , Anderson Jennifer M. , Amaratunga Chanaki , Menard Didier , Fairhurst Rick M. 
Published: August 2013

ABSTRACT

In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated
Plasmodium falciparum
malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the
ex vivo
50% inhibitory concentrations (IC
50
s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC
50
s (GMIC
50
s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (
P
≤ 0.001). An increased copy number of
P. falciparum
mdr1
(
pfmdr1
), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC
50
s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The
ex vivo
IC
50
and
pfmdr1
copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR
P. falciparum
is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance.
In Vitro
Characterization of GSK2485852, a Novel Hepatitis C Virus Polymerase Inhibitor
Authors: Voitenleitner Christian , Crosby Renae , Walker Jill , Remlinger Katja , Vamathevan Jessica , Wang Amy , You Shihyun , Johnson John , Woldu Ermias , Van Horn Stephanie , Horton Joseph , Creech Katrina , Shotwell J. Brad , Hong Zhi , Hamatake Robert 
Published: August 2013

ABSTRACT

GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC
50
s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross-resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV.
Multilocus Sequence Typing Reveals Genetic Diversity of Carbapenem- or Ceftazidime-Nonsusceptible Pseudomonas aeruginosa in China
Authors: Ji Jingshu , Wang Jie , Zhou Zhihui , Wang Haiping , Jiang Yan , Yu Yunsong 
Published: August 2013

ABSTRACT

It is unclear whether the genetic background of drug-resistant
Pseudomonas aeruginosa
was disseminated from a certain clone. Thus, we performed MLST (multilocus sequence typing) of 896
P. aeruginosa
isolates that were nonsusceptible to imipenem, meropenem, or ceftazidime. This revealed 254 sequence types (STs), including 104 new STs and 34 STs with novel alleles. Thirty-three clonal complexes and 404 singletons were found. In conclusion, drug-resistant
P. aeruginosa
clones can be developed from diverse genetic backgrounds.
Nucleic Acid Polymers Inhibit Duck Hepatitis B Virus InfectionIn Vitro
Authors: Noordeen Faseeha , Vaillant Andrew , Jilbert Allison R. 
Published: August 2013

ABSTRACTNucleic acid polymers (NAPs) utilize the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) to target protein interactions involved in viral replication. NAPs are broadly active against a diverse range of enveloped viruses that use type I entry mechanisms. The antiviral activity of NAPs against hepatitis B virus (HBV) infection was assessedin vitroin duck hepatitis B virus (DHBV)-infected primary duck hepatocytes (PDH). NAPs efficiently entered PDH in the absence of any transfection agent and displayed antiviral activity at concentrations of 0.01 to 10 μM, measured by their ability to prevent the intracellular accumulation of DHBV surface antigen, which was independent of their nucleotide sequence and was specifically dependent on phosphorothioation. Higher levels of antiviral activity were observed with NAPs 40 nucleotides in length or longer. The fully degenerate NAP (REP 2006) was active during DHBV infection or when added 12 h after infection. In contrast, an acidic-pH-sensitive NAP (REP 2031) that was broadly active against other viruses displayed antiviral activity when present during DHBV infection but no activity when added 12 h after infection, suggesting that NAPs exert their postentry effect in an acidic environment unique to DHBV infection. Both REP 2006 and REP 2031 displayed negligible cytotoxicity in PDH at concentrations of up to 10 μM, as assessed using an XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] cytotoxicity assay. The antiviral activity of NAPs against DHBVin vitrowas strictly dependent on their amphipathic character, suggesting that NAPs interact with amphipathic target(s) that are important for DHBV entry and postentry mechanisms required for infection.
Nucleic Acid Polymers Prevent the Establishment of Duck Hepatitis B Virus Infection
In Vivo
Authors: Noordeen Faseeha , Vaillant Andrew , Jilbert Allison R. 
Published: August 2013

ABSTRACT

Nucleic acid polymers (NAPs) are novel, broad-spectrum antiviral compounds that use the sequence-independent properties of phosphorothioate oligonucleotides (PS-ONs) as amphipathic polymers to block amphipathic interactions involved in viral entry. Using the duck hepatitis B virus (DHBV) model of human hepatitis B virus infection, NAPs have been shown to have both entry and postentry antiviral activity against DHBV infection
in vitro
in primary duck hepatocytes (PDH). In the current study, various NAPs were assessed for their prophylactic activity
in vivo
against DHBV infection in ducks. The degenerate NAP REP 2006 prevented the development of widespread and persistent DHBV infection in 14-day-old ducks, while the acidic-pH-sensitive NAP REP 2031 had little or no prophylactic effect. REP 2006 displayed significant toxicity in ducks, which was attributed to CpG-mediated proinflammation, while REP 2031 (which has no CpG motifs) displayed no toxicity. A third NAP, REP 2055, which was designed to retain amphipathic activity at acidic pH and contained no CpG motifs, was well tolerated and displayed prophylactic activity against DHBV infection at doses as low as 1 mg/kg of body weight/day. These studies suggest that NAPs can be easily and predictably tailored to retain anti-DHBV activity and to have minimal toxic effects
in vivo
. Future studies are planned to establish the therapeutic efficacy of NAPs against persistent DHBV infection.
Transduction of Staphylococcal Cassette Chromosome
mec
Elements between Strains of Staphylococcus aureus
Authors: Scharn Caitlyn R. , Tenover Fred C. , Goering Richard V. 
Published: August 2013

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) is a well-known public health concern. However, the means by which methicillin resistance genes are transferred among staphylococci in nature remains unknown. Older scientific literature suggests transduction as a means of
mecA
transfer, but the optimal conditions are reported to require plasmids and potentially a lysogenic phage. These reports preceded discovery of the staphylococcal cassette chromosome
mec
(SCC
mec
) elements. We undertook studies to confirm and clarify the conditions promoting transduction of SCC
mec
in
S. aureus
populations using well-characterized donor and recipient strains primarily of the USA300 lineage. Both bacteriophages 80α and 29 were capable of transducing SCC
mec
type IV and SCC
mec
type I to recipient strains of
S. aureus
. Pulsed-field gel electrophoresis and
mec
-associated
dru
typing were used to confirm the identity of the transductants. Transfer of
mecA
via transduction occurred at low frequency and required extended selection times for
mecA
gene expression and the presence of a penicillinase plasmid in the recipient. However, interference with the process by clavulanic acid and the necessity of lysogeny with ϕ11 in the recipient or the presence of a small (4-kb) tetracycline resistance plasmid, as previously reported, were not confirmed. SCC
mec
transduction was occasionally associated with substantial deletions or truncation of SCC
mec
and the arginine catabolic metabolic element in USA300 recipients. Overall, these data clarify the conditions required for SCC
mec
transduction and document that rearrangements may occur during the process.
In Vitro
and
In Vivo
Activities of Antibiotic PM181104
Authors: Mahajan Girish , Thomas Becky , Parab Rajashri , Patel Zarine E. , Kuldharan Sandip , Yemparala Vijayaphanikumar , Mishra Prabhu Dutt , Ranadive Prafull , D'Souza Lisette , Pari Koteppa , Sivaramkrishnan H. 
Published: August 2013

ABSTRACT

Drug resistance has become a global threat that, if not addressed, may return us to the preantibiotic era. A way to overcome the problem of growing incidence of global antibiotic resistance is to introduce compounds belonging to classes that are new to the clinic. During a screening of the marine microbial extract library for new antibiotics, one of the extracts showed promising antibacterial activity against Gram-positive organisms. Bioactivity-guided isolation and characterization of active metabolites led to the discovery of a novel thiazolyl cyclic-peptide antibiotic, PM181104. It was isolated and characterized from a marine sponge-associated actinobacterium strain of the genus
Kocuria
(MTCC 5269). The compound exhibited a potent
in vitro
antibacterial activity against a broad range of Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus
(MRSA) and vancomycin-resistant enterococci (VRE). The MIC values evaluated for the compound were found to be in the single-digit nanomolar range. In
in vivo
studies of PM181104 in a BALB/c murine septicemia model, the compound displayed 100% effective dose (ED
100
) values of 2.5 and 5.0 mg/kg of body weight against MRSA and 10.0 mg/kg against VRE. In this report,
in vitro
and
in vivo
studies of PM181104 are described.
Mutations of the
ompK36
Porin Gene and Promoter Impact Responses of Sequence Type 258, KPC-2-Producing Klebsiella pneumoniae Strains to Doripenem and Doripenem-Colistin
Authors: Clancy Cornelius J. , Chen Liang , Hong Jae H. , Cheng Shaoji , Hao Binghua , Shields Ryan K. , Farrell Annie N. , Doi Yohei , Zhao Yanan , Perlin David S. , Kreiswirth Barry N. , Nguyen M. Hong 
Published: August 2013

ABSTRACT

Doripenem-colistin exerts synergy against some, but not all,
Klebsiella pneumoniae
carbapenemase (KPC)-producing
K. pneumoniae
strains
in vitro
. We determined if doripenem MICs and/or
ompK36
porin gene mutations impacted the responses of 23 sequence type 258 (ST258), KPC-2-producing strains to the combination of doripenem (8 μg/ml) and colistin (2 μg/ml) during time-kill assays. The median doripenem and colistin MICs were 32 and 4 μg/ml. Doripenem MICs did not correlate with KPC-2 expression levels. Five and 18 strains had wild-type and mutant
ompK36
, respectively. The most common mutations were IS
5
promoter insertions (
n
= 7) and insertions encoding glycine and aspartic acid at amino acid (aa) positions 134 and 135 (ins aa134-135 GD;
n
= 8), which were associated with higher doripenem MICs than other mutations or wild-type
ompK36
(all
P
values ≤ 0.04). Bactericidal activity (24 h) was achieved by doripenem-colistin against 12%, 43%, and 75% of ins aa134-135 GD, IS
5
, and wild-type/other mutants, respectively (
P
= 0.04). Doripenem-colistin was more active in time-kill studies than colistin at 12 and 24 h if the doripenem MIC was ≤8 μg/ml (
P
= 0.0007 and 0.09, respectively), but not if the MIC was >8 μg/ml (
P
= 0.10 and 0.16). Likewise, doripenem-colistin was more active at 12 and 24 h against the wild type/other mutants than ins aa134-135 GD or IS
5
mutants (
P
= 0.007 and 0.0007). By multivariate analysis, the absence of ins aa134-135 GD or IS
5
mutations was the only independent predictor of doripenem-colistin responses at 24 h (
P
= 0.002). In conclusion,
ompK36
genotypes identified ST258 KPC-
K. pneumoniae
strains that were most likely to respond to doripenem-colistin.
Systematic Review and Meta-Analysis of Antimicrobial Treatment Effect Estimation in Complicated Urinary Tract Infection
Authors: Singh Krishan P. , Li Gang , Mitrani-Gold Fanny S. , Kurtinecz Milena , Wetherington Jeffrey , Tomayko John F. , Mundy Linda M. 
Published: August 2013

ABSTRACT
Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations.