bluuebunny/crossref_metadata_2025_split huggingface dataset:
CT reconstruction techniques for improved accuracy of lung CT airway measurement
Authors: Rodriguez A. , Ranallo F. N. , Judy P. F. , Gierada D. S. , Fain S. B. 
Published: October 2014

Purpose:To determine the impact of constrained reconstruction techniques on quantitative CT (qCT) of the lung parenchyma and airways for low x‐ray radiation dose.Methods:Measurement of small airways with qCT remains a challenge, especially for low x‐ray dose protocols. Images of the COPDGene quality assurance phantom (CTP698, The Phantom Laboratory, Salem, NY) were obtained using a GE discovery CT750 HD scanner for helical scans at x‐ray radiation dose‐equivalents ranging from 1 to 4.12 mSv (12–100 mA s current–time product). Other parameters were 40 mm collimation, 0.984 pitch, 0.5 s rotation, and 0.625 mm thickness. The phantom was sandwiched between 7.5 cm thick water attenuating phantoms for a total length of 20 cm to better simulate the scatter conditions of patient scans. Image data sets were reconstructed using STANDARD (STD), DETAIL, BONE, and EDGE algorithms for filtered back projection (FBP), 100% adaptive statistical iterative reconstruction (ASIR), and Veo reconstructions. Reduced (half) display field of view (DFOV) was used to increase sampling across airway phantom structures. Inner diameter (ID), wall area percent (WA%), and wall thickness (WT) measurements of eight airway mimicking tubes in the phantom, including a 2.5 mm ID (42.6 WA%, 0.4 mm WT), 3 mm ID (49.0 WA%, 0.6 mm WT), and 6 mm ID (49.0 WA%, 1.2 mm WT) were performed with Airway Inspector (Surgical Planning Laboratory, Brigham and Women's Hospital, Boston, MA) using the phase congruency edge detection method. The average of individual measures at five central slices of the phantom was taken to reduce measurement error.Results:WA% measures were greatly overestimated while IDs were underestimated for the smaller airways, especially for reconstructions at full DFOV (36 cm) using the STD kernel, due to poor sampling and spatial resolution (0.7 mm pixel size). Despite low radiation dose, the ID of the 6 mm ID airway was consistently measured accurately for all methods other than STD FBP. Veo reconstructions showed slight improvement over STD FBP reconstructions (4%–9% increase in accuracy). The most improved ID and WA% measures were for the smaller airways, especially for low dose scans reconstructed at half DFOV (18 cm) with the EDGE algorithm in combination with 100% ASIR to mitigate noise. Using the BONE + ASIR at half BONE technique, measures improved by a factor of 2 over STD FBP even at a quarter of the x‐ray dose.Conclusions:The flexibility of ASIR in combination with higher frequency algorithms, such as BONE, provided the greatest accuracy for conventional and low x‐ray dose relative to FBP. Veo provided more modest improvement in qCT measures, likely due to its compatibility only with the smoother STD kernel.
Towards the clinical implementation of iterative low‐dose cone‐beam CT reconstruction in image‐guided radiation therapy: Cone/ring artifact correction and multiple GPU implementation
Authors: Yan Hao , Wang Xiaoyu , Shi Feng , Bai Ti , Folkerts Michael , Cervino Laura , Jiang Steve B. , Jia Xun 
Published: October 2014

Purpose:Compressed sensing (CS)‐based iterative reconstruction (IR) techniques are able to reconstruct cone‐beam CT (CBCT) images from undersampled noisy data, allowing for imaging dose reduction. However, there are a few practical concerns preventing the clinical implementation of these techniques. On the image quality side, data truncation along the superior–inferior direction under the cone‐beam geometry produces severe cone artifacts in the reconstructed images. Ring artifacts are also seen in the half‐fan scan mode. On the reconstruction efficiency side, the long computation time hinders clinical use in image‐guided radiation therapy (IGRT).Methods:Image quality improvement methods are proposed to mitigate the cone and ring image artifacts in IR. The basic idea is to use weighting factors in the IR data fidelity term to improve projection data consistency with the reconstructed volume. In order to improve the computational efficiency, a multiple graphics processing units (GPUs)‐based CS‐IR system was developed. The parallelization scheme, detailed analyses of computation time at each step, their relationship with image resolution, and the acceleration factors were studied. The whole system was evaluated in various phantom and patient cases.Results:Ring artifacts can be mitigated by properly designing a weighting factor as a function of the spatial location on the detector. As for the cone artifact, without applying a correction method, it contaminated 13 out of 80 slices in a head‐neck case (full‐fan). Contamination was even more severe in a pelvis case under half‐fan mode, where 36 out of 80 slices were affected, leading to poorer soft tissue delineation and reduced superior–inferior coverage. The proposed method effectively corrects those contaminated slices with mean intensity differences compared to FDK results decreasing from ∼497 and ∼293 HU to ∼39 and ∼27 HU for the full‐fan and half‐fan cases, respectively. In terms of efficiency boost, an overall 3.1 × speedup factor has been achieved with four GPU cards compared to a single GPU‐based reconstruction. The total computation time is ∼30 s for typical clinical cases.Conclusions:The authors have developed a low‐dose CBCT IR system for IGRT. By incorporating data consistency‐based weighting factors in the IR model, cone/ring artifacts can be mitigated. A boost in computational efficiency is achieved by multi‐GPU implementation.
Antimicrobial Susceptibility among Clinical Nocardia Species Identified by Multilocus Sequence Analysis
Authors: McTaggart Lisa R. , Doucet Jennifer , Witkowska Maria , Richardson Susan E. 
Published: October 2014

ABSTRACT

Antimicrobial susceptibility patterns of 112 clinical isolates, 28 type strains, and 9 reference strains of
Nocardia
were determined using the Sensititre Rapmyco microdilution panel (Thermo Fisher, Inc.). Isolates were identified by highly discriminatory multilocus sequence analysis and were chosen to represent the diversity of species recovered from clinical specimens in Ontario, Canada. Susceptibility to the most commonly used drug, trimethoprim-sulfamethoxazole, was observed in 97% of isolates. Linezolid and amikacin were also highly effective; 100% and 99% of all isolates demonstrated a susceptible phenotype. For the remaining antimicrobials, resistance was species specific with isolates of
Nocardia otitidiscaviarum
,
N. brasiliensis
,
N. abscessus
complex,
N. nova
complex,
N. transvalensis
complex,
N. farcinica
, and
N. cyriacigeorgica
displaying the traditional characteristic drug pattern types. In addition, the antimicrobial susceptibility profiles of a variety of rarely encountered species isolated from clinical specimens are reported for the first time and were categorized into four additional drug pattern types. Finally, MICs for the control strains
N. nova
ATCC BAA-2227,
N. asteroides
ATCC 19247
T
, and
N. farcinica
ATCC 23826 were robustly determined to demonstrate method reproducibility and suitability of the commercial Sensititre Rapmyco panel for antimicrobial susceptibility testing of
Nocardia
spp. isolated from clinical specimens. The reported values will facilitate quality control and standardization among laboratories.
Pharmacokinetics, Safety, and Tolerability of Faldaprevir in Patients with Renal Impairment
Authors: Huang Fenglei , Moschetti Viktoria , Lang Benjamin , Halabi Atef , Petersen-Sylla Marc , Yong Chan-Loi , Elgadi Mabrouk 
Published: October 2014

ABSTRACT

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor with negligible urinary excretion. We assessed the pharmacokinetics and safety of a single oral dose of faldaprevir (480 mg) in 32 HCV-negative subjects with renal impairment or normal renal function. Compared with subjects with normal renal function, the adjusted geometric mean ratios (90% confidence intervals in parentheses) for overall exposure area under the concentration-time curve from zero to infinity (AUC
0–∞
) were 113.6% (41.6 to 310.2%), 178.3% (85.2 to 373.0%), and 169.2% (73.2 to 391.2%) for subjects with mild, moderate, and severe renal impairment, respectively. Overall, 5/8 (63%) subjects with normal renal function and 20/24 (83%) subjects with renal impairment reported adverse events, with gastrointestinal events being the most common. No severe or serious adverse events or deaths were reported. These results suggest that moderate or severe renal impairment can result in a modest increase in faldaprevir exposure. The increase in exposure may be related to decrease in the activity of the liver uptake transporter OATP1B1 as a result of renal impairment. Given this relatively slight increase in exposure, a dose adjustment in HCV patients with renal impairment is not warranted. (This study has been registered at
ClinicalTrials.gov
under registration number NCT01957657.)
Synergistic Interactions of Vancomycin with Different Antibiotics against Escherichia coli: Trimethoprim and Nitrofurantoin Display Strong Synergies with Vancomycin against Wild-Type E. coli
Authors: Zhou Alice , Kang Tina Manzhu , Yuan Jessica , Beppler Casey , Nguyen Caroline , Mao Zhiyuan , Nguyen Minh Quan , Yeh Pamela , Miller Jeffrey H. 
Published: October 2014

ABSTRACT

Gram-negative bacteria are normally resistant to the antibiotic vancomycin (VAN), which cannot significantly penetrate the outer membrane. We used
Escherichia coli
mutants that are partially sensitive to VAN to study synergies between VAN and 10 other antibiotics representing six different functional categories. We detected strong synergies with VAN and nitrofurantoin (NTR) and with VAN and trimethoprim (TMP) and moderate synergies with other drugs, such as aminoglycosides. These synergies are powerful enough to show the activity of VAN against wild-type
E. coli
at concentrations of VAN as low as 6.25 μg/ml. This suggests that a very small percentage of exogenous VAN does enter
E. coli
but normally has insignificant effects on growth inhibition or cell killing. We used the results of pairwise interactions with VAN and the other 10 antibiotics tested to place VAN into a functional category of its own, as previously defined by Yeh et al. (P. Yeh, A. I. Tschumi, and R. Kishony, Nat Genet 28:489–494, 2006,
http://dx.doi.org/10.1038/ng1755
).
Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections
Authors: O'Dwyer Karen , Spivak Aaron T. , Ingraham Karen , Min Sharon , Holmes David J. , Jakielaszek Charles , Rittenhouse Stephen , Kwan Alan L. , Livi George P. , Sathe Ganesh , Thomas Elizabeth , Van Horn Stephanie , Miller Linda A. , Twynholm Monique , Tomayko John , Dalessandro Marybeth , Caltabiano Madelyn , Scangarella-Oman Nicole E. , Brown James R. 
Published: October 2014

ABSTRACTGSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with ≥32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing ofEscherichia coliisolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistantEscherichia coliisolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.)
A Hybrid Cationic Peptide Composed of Human β-Defensin-1 and Humanized θ-Defensin Sequences Exhibits Salt-Resistant Antimicrobial Activity
Authors: Olli Sudar , Nagaraj Ramakrishnan , Motukupally Swapna R. 
Published: October 2014

ABSTRACT

We have designed a hybrid peptide by combining sequences of human β-defensin-1 (HBD-1) and θ-defensin, in an attempt to generate a molecule that combines the diversity in structure and biological activity of two different peptides to yield a promising therapeutic candidate. HBD-1 was chosen as it is a natural defensin of humans that is constitutively expressed, but its antibacterial activity is considerably impaired by elevated ionic strength. θ-Defensins are expressed in human bone marrow as a pseudogene and are homologous to rhesus monkey circular minidefensins. Retrocyclins are synthetic human θ-defensins. The cyclic nature of the θ-defensin peptides makes them salt resistant, nonhemolytic, and virtually noncytotoxic
in vitro
. However, a nonhuman circular molecule developed for clinical use would be less viable than a linear molecule. In this study, we have fused the C-terminal region of HBD-1 to the nonapeptide sequence of a synthetic retrocyclin. Cyclization was achieved by joining the terminal ends of the hybrid peptide by a disulfide bridge. The hybrid peptide with or without the disulfide bridge exhibited enhanced antimicrobial activity against both Gram-negative and Gram-positive bacteria as well as against fungi, including clinical bacterial isolates from eye infections. The peptide retained activity in the presence of NaCl and serum and was nonhemolytic
in vitro
. Thus, the hybrid peptide generated holds potential as a new class of antibiotics.
Anti-Alpha-Toxin Monoclonal Antibody and Antibiotic Combination Therapy Improves Disease Outcome and Accelerates Healing in a Staphylococcus aureus Dermonecrosis Model
Authors: Hilliard Jamese J. , Datta Vivekananda , Tkaczyk Christine , Hamilton Melissa , Sadowska Agnieszka , Jones-Nelson Omari , O'Day Terrence , Weiss William J. , Szarka Szabolcs , Nguyen Vien , Prokai Laszlo , Suzich JoAnn , Stover C. Kendall , Sellman Bret R. 
Published: October 2014

ABSTRACT

Alpha-toxin (AT) is a major virulence determinant in
Staphylococcus aureus
skin and soft tissue infection models. We previously demonstrated that prophylactic administration of 2A3, an AT-neutralizing monoclonal antibody (MAb), prevents
S. aureus
disease in a mouse dermonecrosis model by neutralizing AT-mediated tissue necrosis and immune evasion. In the present study, MEDI4893*, an affinity-optimized version of 2A3, was characterized for therapeutic activity in the dermonecrosis model as a single agent and in combination with two frontline antibiotics, vancomycin and linezolid. MEDI4893* postinfection therapy was found to exhibit a therapeutic treatment window similar to that for linezolid but longer than that for vancomycin. Additionally, when combined with either vancomycin or linezolid, MEDI4893* resulted in reduced tissue damage, increased neutrophil and macrophage infiltration and abscess formation, and accelerated healing relative to those with the antibiotic monotherapies. These data suggest that AT neutralization with a potent MAb holds promise for both prophylaxis and adjunctive therapy with antibiotics and may be a valuable addition to currently available options for the treatment of
S. aureus
skin and soft tissue infections.
Activities of Antibiotic Combinations against Resistant Strains of Pseudomonas aeruginosa in a Model of Infected THP-1 Monocytes
Authors: Buyck Julien M. , Tulkens Paul M. , Van Bambeke Françoise 
Published: October 2014

ABSTRACT

Antibiotic combinations are often used for treating
Pseudomonas aeruginosa
infections but their efficacy toward intracellular bacteria has not been investigated so far. We have studied combinations of representatives of the main antipseudomonal classes (ciprofloxacin, meropenem, tobramycin, and colistin) against intracellular
P. aeruginosa
in a model of THP-1 monocytes in comparison with bacteria growing in broth, using the reference strain PAO1 and two clinical isolates (resistant to ciprofloxacin and meropenem, respectively). Interaction between drugs was assessed by checkerboard titration (extracellular model only), by kill curves, and by using the fractional maximal effect (FME) method, which allows studying the effects of combinations when dose-effect relationships are not linear. For drugs used alone, simple sigmoidal functions could be fitted to all concentration-effect relationships (extracellular and intracellular bacteria), with static concentrations close to (ciprofloxacin, colistin, and meropenem) or slightly higher than (tobramycin) the MIC and with maximal efficacy reaching the limit of detection in broth but only a 1 to 1.5 (colistin, meropenem, and tobramycin) to 2 to 3 (ciprofloxacin) log
10
CFU decrease intracellularly. Extracellularly, all combinations proved additive by checkerboard titration but synergistic using the FME method and more bactericidal in kill curve assays. Intracellularly, all combinations proved additive only based on both FME and kill curve assays. Thus, although combinations appeared to modestly improve antibiotic activity against intracellular
P. aeruginosa
, they do not allow eradication of these persistent forms of infections. Combinations including ciprofloxacin were the most active (even against the ciprofloxacin-resistant strain), which is probably related to the fact this drug was the most effective alone intracellularly.
Evaluation of Antimalarial Resistance Marker Polymorphism in Returned Migrant Workers in China
Authors: Feng Jun , Li Jun , Yan He , Feng Xinyu , Xia Zhigui 
Published: October 2014

ABSTRACT

Imported malaria has been a great challenge for public health in China due to decreased locally transmitted cases and frequent exchange worldwide.
Plasmodium falciparum
has been mainly responsible for the increasing impact. Currently, artesunate plus amodiaquine, one of the artemisinin combination therapies recommended by the World Health Organization, has been mainly used against uncomplicated
P. falciparum
malaria in China. However, drug resistance marker polymorphism in returning migrant workers has not been demonstrated. Here, we have evaluated the prevalence of
pfmdr1
and
pfcrt
polymorphisms, as well as the K13 propeller gene, a molecular marker of artemisinin resistance, in migrant workers returned from Ghana to Shanglin County, Guangxi Province, China, in 2013. A total of 118 blood samples were randomly selected and used for the assay. Mutations of the
pfmdr1
gene that covered codons 86, 184, 1034, and 1246 were found in 11 isolates. Mutations at codon N86Y (9.7%) were more frequent than at others, and Y
86
Y
184
S
1034
D
1246
was the most prevalent (63.6%) of the four haplotypes. Mutations of the
pfcrt
gene that covered codons 74, 75, and 76 were observed in 17 isolates, and M
74
N
75
T
76
was common (70.6%) in three haplotypes. Eight different genotypes of the K13 propeller were first observed in 10 samples in China, 2 synonymous mutations (V487V and A627A) and 6 nonsynonymous mutations. C580Y was the most prevalent (2.7%) in all the samples. The data presented might be helpful for enrichment of molecular surveillance of antimalarial resistance and will be useful for developing and updating antimalarial guidance in China.
The R262K Substitution Combined with H51Y in HIV-1 Subtype B Integrase Confers Low-Level Resistance against Dolutegravir
Authors: Cutillas Vincent , Mesplede Thibault , Anstett Kaitlin , Hassounah Said , Wainberg Mark A. 
Published: October 2014

ABSTRACT
Clinical studies have shown that integrase strand transfer inhibitors (INSTIs) can be used effectively against HIV-1 infection. To date, no resistance substitution has been found in INSTI-naive patients treated with the new integrase inhibitor dolutegravir (DTG). In a recent selection study with DTG, using a virus bearing the H51Y substitution in integrase, the emergence of an R to K substitution at position 262 (R262K) was observed. We characterized this double mutant with respect to integrase strand transfer activity and susceptibility to DTG both biochemically and in tissue culture. We showed that the addition of R262K to H51Y decreased recombinant integrase strand transfer activity but improved integrase DNA-binding affinity, compared to wild-type or H51Y-containing enzymes. The defect in strand transfer activity did not translate into a decrease in HIV-1 infectivity. The combination of H51Y and R262K substitutions slightly decreased susceptibility to DTG (fold change = 1.87) in cell-based resistance assays. Although viral replication was not affected and enzyme efficiency was impaired by the addition of R262K to H51Y, there was an overall increase in the level of biochemical drug resistance against DTG. Our findings suggest that the R at position 262 plays an important role in DNA binding.
Intestinal Alkaline Phosphatase Deficiency Leads to Lipopolysaccharide Desensitization and Faster Weight Gain
Authors: Yang Ye , Millán José Luis , Mecsas Joan , Guillemin Karen 
Published: October 2014

ABSTRACT

Animals develop in the presence of complex microbial communities, and early host responses to these microbes can influence key aspects of development, such as maturation of the immune system, in ways that impact adult physiology. We previously showed that the zebrafish intestinal alkaline phosphatase (ALPI) gene
alpi.1
was induced by Gram-negative bacterium-derived lipopolysaccharide (LPS), a process dependent on myeloid differentiation primary response gene 88 (MYD88), and functioned to detoxify LPS and prevent excessive host inflammatory responses to commensal microbiota in the newly colonized intestine. In the present study, we examined whether the regulation and function of ALPI were conserved in mammals. We found that among the mouse ALPI genes,
Akp3
was specifically upregulated by the microbiota, but through a mechanism independent of LPS or MYD88. We showed that disruption of
Akp3
did not significantly affect intestinal inflammatory responses to commensal microbiota or animal susceptibility to
Yersinia pseudotuberculosis
infection. However, we found that
Akp3
−/−
mice acquired LPS tolerance during postweaning development, suggesting that
Akp3
plays an important role in immune education. Finally, we demonstrated that inhibiting LPS sensing with a mutation in
CD14
abrogated the accelerated weight gain in
Akp3
−/−
mice receiving a high-fat diet, suggesting that the weight gain is caused by excessive LPS in
Akp3
−/−
mice.