bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automatic detection of large pulmonary solid nodules in thoracic CT images
Authors: Setio Arnaud A. A. , Jacobs Colin , Gelderblom Jaap , van Ginneken Bram 
Published: September 2015

Purpose:Current computer‐aided detection (CAD) systems for pulmonary nodules in computed tomography (CT) scans have a good performance for relatively small nodules, but often fail to detect the much rarer larger nodules, which are more likely to be cancerous. We present a novel CAD system specifically designed to detect solid nodules larger than 10 mm.Methods:The proposed detection pipeline is initiated by a three‐dimensional lung segmentation algorithm optimized to include large nodules attached to the pleural wall via morphological processing. An additional preprocessing is used to mask out structures outside the pleural space to ensure that pleural and parenchymal nodules have a similar appearance. Next, nodule candidates are obtained via a multistage process of thresholding and morphological operations, to detect both larger and smaller candidates. After segmenting each candidate, a set of 24 features based on intensity, shape, blobness, and spatial context are computed. A radial basis support vector machine (SVM) classifier was used to classify nodule candidates, and performance was evaluated using ten‐fold cross‐validation on the full publicly available lung image database consortium database.Results:The proposed CAD system reaches a sensitivity of 98.3% (234/238) and 94.1% (224/238) large nodules at an average of 4.0 and 1.0 false positives/scan, respectively.Conclusions:The authors conclude that the proposed dedicated CAD system for large pulmonary nodules can identify the vast majority of highly suspicious lesions in thoracic CT scans with a small number of false positives.
Determinants of the reliability of ultrasound tomography sound speed estimates as a surrogate for volumetric breast density
Authors: Khodr Zeina G. , Sak Mark A. , Pfeiffer Ruth M. , Duric Nebojsa , Littrup Peter , Bey‐Knight Lisa , Ali Haythem , Vallieres Patricia , Sherman Mark E. , Gierach Gretchen L. 
Published: September 2015

Purpose:High breast density, as measured by mammography, is associated with increased breast cancer risk, but standard methods of assessment have limitations including 2D representation of breast tissue, distortion due to breast compression, and use of ionizing radiation. Ultrasound tomography (UST) is a novel imaging method that averts these limitations and uses sound speed measures rather than x‐ray imaging to estimate breast density. The authors evaluated the reproducibility of measures of speed of sound and changes in this parameter using UST.Methods:One experienced and five newly trained raters measured sound speed in serial UST scans for 22 women (two scans per person) to assess inter‐rater reliability. Intrarater reliability was assessed for four raters. A random effects model was used to calculate the percent variation in sound speed and change in sound speed attributable to subject, scan, rater, and repeat reads. The authors estimated the intraclass correlation coefficients (ICCs) for these measures based on data from the authors’ experienced rater.Results:Median (range) time between baseline and follow‐up UST scans was five (1–13) months. Contributions of factors to sound speed variance were differences between subjects (86.0%), baseline versus follow‐up scans (7.5%), inter‐rater evaluations (1.1%), and intrarater reproducibility (∼0%). When evaluating change in sound speed between scans, 2.7% and ∼0% of variation were attributed to inter‐ and intrarater variation, respectively. For the experienced rater's repeat reads, agreement for sound speed was excellent (ICC = 93.4%) and for change in sound speed substantial (ICC = 70.4%), indicating very good reproducibility of these measures.Conclusions:UST provided highly reproducible sound speed measurements, which reflect breast density, suggesting that UST has utility in sensitively assessing change in density.
Sustained Improvements in Dynamic Balance and Landing Mechanics After a 6-Week Neuromuscular Training Program in College Women’s Basketball Players
Authors: Pfile Kate R. , Gribble Phillip A. , Buskirk Gretchen E. , Meserth Sara M. , Pietrosimone Brian G. 
Published: September 2015

Context:Epidemiological data demonstrate the need for lower-extremity injury-prevention training. Neuromuscularcontrol (NMC) programs are immediately effective at minimizing lower-extremity injury risk and improving sport-related performance measures. Research investigating lasting effects after an injury-prevention program is limited.Objective:To determine whether dynamic balance, landing mechanics, and hamstring and quadriceps strength could be improved after a 6-wk NMC intervention and maintained for a season.Design:Prospective case series.Setting:Controlled laboratory.Participants:11 Division I women’s basketball players (age 19.40 ± 1.35 y, height 178.05 ± 7.52 cm, mass 72.86 ± 10.70 kg).Interventions:Subjects underwent testing 3 times, completing the Star Excursion Balance Test (SEBT), Landing Error Scoring System (LESS), and isometric strength testing for the hamstrings and quadriceps muscles. Pretest and posttest 1 occurred immediately before and after the intervention, respectively, and posttest 2 at the end of the competitive season, 9 mo after posttest 1. Subjects participated in eighteen 30-min plyometric and NMC-training sessions over a 6-wk period.Main Outcome Measures:The normalized SEBT composite score, normalized peak isometric hamstrings:quadriceps (H:Q) ratio, and the LESS total score.Results:The mean composite reach significantly improved over time (F2,10 = 6.96, P = .005) where both posttest scores were significantly higher than pretest (70.41% ± 4.08%) (posttest 1 73.48% ± 4.19%, t10 = –3.11, P = .011) and posttest 2 (74.2% ± 4.77%, t10 = –3.78, P = .004). LESS scores significantly improved over time (F2,10 = 6.29, P = .009). The pretest LESS score (7.30 ± 3.40) was higher than posttest 1 (4.9 ± 1.20, t10 = 2.71, P = .024) and posttest 2 (5.44 ± 1.83, t10 = 2.58, P = .030). There were no statistically significant differences (P > .05) over time for the H:Q ratio when averaging both legs (F2,10 = 0.83, P = .45).Conclusions:A 6-wk NMC program improved landing mechanics and dynamic balance over a 9-mo period in women’s basketball players. NMC adaptations can be retained without an in-season maintenance program.
Factors Impacting Unbound Vancomycin Concentrations in Different Patient Populations
Authors: Oyaert Matthijs , Spriet Isabel , Allegaert Karel , Smits Anne , Vanstraelen Kim , Peersman Nele , Wauters Joost , Verhaegen Jan , Vermeersch Pieter , Pauwels Steven 
Published: September 2015

ABSTRACT

The unbound drug hypothesis states that only unbound drug concentrations are active and available for clearance, and highly variable results regarding unbound vancomycin fractions have been reported in the literature. We have determined the unbound vancomycin fractions in four different patient groups by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method and identified factors that modulate vancomycin binding. We have further developed and validated a prediction model to estimate unbound vancomycin concentrations. Vancomycin (unbound and total) concentrations were measured in 90 patients in four different hospital wards (hematology [
n
= 33 samples], intensive care unit [ICU] [
n
= 51], orthopedics [
n
= 44], and pediatrics [age range, 6 months to 14 years;
n
= 18]) by a validated LC-MS/MS method. Multiple linear mixed model analysis was performed to identify patient variables that were predictive of unbound vancomycin fractions and concentrations. The variables included in the model were patient age, ward, number of coadministered drugs with high protein binding, kidney function (estimated glomerular filtration rate [determined by Chronic Kidney Disease Epidemiology Collaboration formula]), alpha-1-acid glycoprotein, albumin, total bilirubin, IgA, IgM, urea, and total vancomycin concentrations. In the pediatric cohort, the median unbound vancomycin fraction was 81.3% (range, 61.9 to 95.9%), which was significantly higher (
P
< 0.01) than the unbound fraction found in the three adult patient cohorts (hematology, 60.6% [48.7 to 90.6%]; ICU, 61.7% [47.0 to 87.6%]; orthopedics, 56.4% [45.9 to 78.0%]). The strongest significant predictor of the unbound vancomycin concentration was the total drug concentration, completed by albumin in the pediatric cohort and albumin and IgA in the adult cohorts. Validation of our model was performed with data from 13 adult patients. A mean difference of 0.3 mg/liter (95% confidence interval [CI], −1.3 to 0.7 mg/liter;
R
2
= 0.99 [95% CI, 0.95 to 0.99]) between measured and calculated unbound vancomycin concentrations demonstrated that the predictive performance of our model was favorable. Unbound vancomycin fractions vary significantly between pediatric and adult patients. We developed a formula to estimate the unbound fraction derived from total vancomycin, albumin, and IgA concentrations in adult patients.
Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock: Does Standard Dosing Result in Therapeutic Plasma Concentrations?
Authors: Öbrink-Hansen Kristina , Juul Rasmus Vestergaard , Storgaard Merete , Thomsen Marianne Kragh , Hardlei Tore Forsingdal , Brock Birgitte , Kreilgaard Mads , Gjedsted Jakob 
Published: September 2015

ABSTRACT

Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (
T
>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for
Pseudomonas aeruginosa
(16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50%
fT
>4×MIC and 100%
fT
>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.)
The Makes Caterpillars Floppy (MCF)-Like Domain of Vibrio vulnificus Induces Mitochondrion-Mediated Apoptosis
Authors: Agarwal Shivangi , Zhu Yeuming , Gius David R. , Satchell Karla J. F. 
Published: September 2015

ABSTRACT

The multifunctional-autoprocessing repeats-in-toxin (MARTX
Vv
) toxin of
Vibrio vulnificus
plays a significant role in the pathogenesis of this bacterium through delivery of up to five effector domains to the host cells. Previous studies have established that the MARTX
Vv
toxin is linked to
V. vulnificus
dependent induction of apoptosis, but the region of the large multifunction protein essential for this activity was not previously identified. Recently, we showed that the Makes Caterpillar Floppy-like MARTX effector domain (MCF
Vv
) is an autoproteolytic cysteine protease that induces rounding of various cell types. In this study, we demonstrate that cell rounding induced by MCF
Vv
is coupled to reduced metabolic rate and inhibition of cellular proliferation. Moreover, delivery of MCF
Vv
into host cells either as a fusion to the N-terminal fragment of anthrax toxin lethal factor or when naturally delivered as a
V. vulnificus
MARTX toxin led to loss of mitochondrial membrane potential, release of cytochrome
c
, activation of Bax and Bak, and processing of caspases and poly-(ADP-ribose) polymerase (PARP-γ). These studies specifically link the MCF
Vv
effector domain to induction of the intrinsic apoptosis pathway by
V. vulnificus
.
Beyond the Crystal Structure: Insight into the Function and Vaccine Potential of TbpA Expressed by Neisseria gonorrhoeae
Authors: Cash Devin R. , Noinaj Nicholas , Buchanan Susan K. , Cornelissen Cynthia Nau 
Published: September 2015

ABSTRACT

Neisseria gonorrhoeae
, the causative agent of the sexually transmitted infection gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. However, the transferrin (Tf) receptor system, composed of TbpA and TbpB, is an ideal target for novel therapeutics and vaccine development. Using a three-dimensional structure of gonococcal TbpA, we investigated two hypotheses, i.e., that loop-derived antibodies can interrupt ligand-receptor interactions in the native bacterium and that the loop 3 helix is a critical functional domain. Preliminary loop-derived antibodies, as well as optimized second-generation antibodies, demonstrated similar modest ligand-blocking effects on the gonococcal surface but different effects in
Escherichia coli
. Mutagenesis of loop 3 helix residues was employed, generating 11 mutants. We separately analyzed the mutants' abilities to (i) bind Tf and (ii) internalize Tf-bound iron in the absence of the coreceptor TbpB. Single residue mutations resulted in up to 60% reductions in ligand binding and up to 85% reductions in iron utilization. All strains were capable of growing on Tf as the sole iron source. Interestingly, in the presence of TbpB, only a 30% reduction in Tf-iron utilization was observed, indicating that the coreceptor can compensate for TbpA impairment. Complete deletion of the loop 3 helix of TbpA eliminated the abilities to bind Tf, internalize iron, and grow with Tf as the sole iron source. Our studies demonstrate that while the loop 3 helix is a key functional domain, its function does not exclusively rely on any single residue.
Refined Live Attenuated Salmonella enterica Serovar Typhimurium and Enteritidis Vaccines Mediate Homologous and Heterologous Serogroup Protection in Mice
Authors: Tennant Sharon M. , Schmidlein Patrick , Simon Raphael , Pasetti Marcela F. , Galen James E. , Levine Myron M. 
Published: September 2015

ABSTRACTInvasive nontyphoidalSalmonella(NTS) infections constitute a major health problem among infants and toddlers in sub-Saharan Africa; these infections also occur in infants and the elderly in developed countries. We genetically engineered aSalmonella entericaserovar Typhimurium strain of multilocus sequence type 313, the predominant genotype circulating in sub-Saharan Africa. We evaluated the capacities ofS. Typhimurium andSalmonella entericaserovar Enteritidis ΔguaBAΔclpXlive oral vaccines to protect mice against a highly lethal challenge dose of the homologous serovar and determined protection against other group B and D serovars circulating in sub-Saharan Africa. The vaccinesS. Typhimurium CVD 1931 andS. Enteritidis CVD 1944 were immunogenic and protected BALB/c mice against 10,000 50% lethal doses (LD50) ofS. Typhimurium orS. Enteritidis, respectively.S. Typhimurium CVD 1931 protected mice against the group B serovarSalmonella entericaserovar Stanleyville (91% vaccine efficacy), andS. Enteritidis CVD 1944 protected mice against the group D serovarSalmonella entericaserovar Dublin (85% vaccine efficacy). High rates of survival were observed when mice were infected 12 weeks postimmunization, indicating that the vaccines elicited long-lived protective immunity. Whereas CVD 1931 did not protect againstS. Enteritidis R11, CVD 1944 did mediate protection againstS. Typhimurium D65 (81% efficacy). These findings suggest that a bivalent (S. Typhimurium andS. Enteritidis) vaccine would provide broad protection against the majority of invasive NTS infections in sub-Saharan Africa.
STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans
Authors: Leopold Wager Chrissy M. , Hole Camaron R. , Wozniak Karen L. , Olszewski Michal A. , Mueller Mathias , Wormley Floyd L. 
Published: September 2015

ABSTRACTCryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals,C. neoformanscan lead to life-threatening meningoencephalitis. Studies using a virulent strain ofC. neoformansengineered to produce gamma interferon (IFN-γ), denoted H99γ, demonstrated that protection against pulmonaryC. neoformansinfection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-C. neoformansactivity remains unknown. The current studies demonstrate that infection withC. neoformansstrain H99γ in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-C. neoformansactivity via the production of NO.
Antimicrobial Peptide Conformation as a Structural Determinant of Omptin Protease Specificity
Authors: Brannon John R. , Thomassin Jenny-Lee , Gruenheid Samantha , Le Moual Hervé 
Published: September 2015

ABSTRACT

Bacterial proteases contribute to virulence by cleaving host or bacterial proteins to promote survival and dissemination. Omptins are a family of proteases embedded in the outer membrane of Gram-negative bacteria that cleave various substrates, including host antimicrobial peptides, with a preference for cleaving at dibasic motifs. OmpT, the enterohemorrhagic
Escherichia coli
(EHEC) omptin, cleaves and inactivates the human cathelicidin LL-37. Similarly, the omptin CroP, found in the murine pathogen
Citrobacter rodentium
, which is used as a surrogate model to study human-restricted EHEC, cleaves the murine cathelicidin-related antimicrobial peptide (CRAMP). Here, we compared the abilities of OmpT and CroP to cleave LL-37 and CRAMP. EHEC OmpT degraded LL-37 and CRAMP at similar rates. In contrast,
C. rodentium
CroP cleaved CRAMP more rapidly than LL-37. The different cleavage rates of LL-37 and CRAMP were independent of the bacterial background and substrate sequence specificity, as OmpT and CroP have the same preference for cleaving at dibasic sites. Importantly, LL-37 was α-helical and CRAMP was unstructured under our experimental conditions. By altering the α-helicity of LL-37 and CRAMP, we found that decreasing LL-37 α-helicity increased its rate of cleavage by CroP. Conversely, increasing CRAMP α-helicity decreased its cleavage rate. This structural basis for CroP substrate specificity highlights differences between the closely related omptins of
C. rodentium
and
E. coli
. In agreement with previous studies, this difference in CroP and OmpT substrate specificity suggests that omptins evolved in response to the substrates present in their host microenvironments.

IMPORTANCE
Omptins are recognized as key virulence factors for various Gram-negative pathogens. Their localization to the outer membrane, their active site facing the extracellular environment, and their unique catalytic mechanism make them attractive targets for novel therapeutic strategies. Gaining insights into similarities and variations between the different omptin active sites and subsequent substrate specificities will be critical to develop inhibitors that can target multiple omptins. Here, we describe subtle differences between the substrate specificities of two closely related omptins, CroP and OmpT. This is the first reported example of substrate conformation acting as a structural determinant for omptin activity between OmpT-like proteases.
Finding Regulators Associated with the Expression of the Long Polar Fimbriae in Enteropathogenic Escherichia coli
Authors: Hu Jia , Ross Brittany N. , Cieza Roberto J. , Torres Alfredo G. 
Published: September 2015

ABSTRACT

Enteropathogenic
Escherichia coli
(EPEC) is a human pathogen that requires initial adhesion to the intestine in order to cause disease. Multiple adhesion factors have been identified in
E. coli
strains, among them the long polar fimbriae (Lpf), a colonization factor associated with intestinal adhesion. The conditions of Lpf expression are well understood in enterohemorrhagic
E. coli
(EHEC); however, the expression of EPEC
lpf
has been found to be repressed under any
in vitro
condition tested. Therefore, we decided to identify those factors silencing expression of EPEC
lpf
. Because histone-like nucleoid structuring protein (H-NS) is a known repressor of EHEC
lpf
, we tested it and found that H-NS is a repressor of EPEC
lpf
. We also found that the adhesion of the EPEC Δ
hns
strain was significantly enhanced compared to the wild-type strain. Because
lpf
expression was modestly increased in the
hns
mutant, transposon mutagenesis was performed to find a strain displaying higher
lpf
expression than EPEC Δ
hns
. One Tn
5
insertion was identified within the
yhjX
gene, and further
in vitro
characterization revealed increased
lpf
expression and adhesion to Caco-2 cells compared with EPEC Δ
hns
. However, in a murine model of intestinal infection, the EPEC Δ
hns
and EPEC Δ
hns
Tn
5
mutants had only a slight change in colonization pattern compared to the wild-type strain. Our data showed that EPEC Lpf is transcribed, but its role in EPEC intestinal colonization requires further analysis.

IMPORTANCE
Data are presented demonstrating that the long polar fimbriae (
lpf
) operon in enteropathogenic
E. coli
(EPEC) is highly regulated; however, derepression occurs by mutagenizing two proteins associated with its control. The study demonstrates that the EPEC
lpf
operon can be expressed and, therefore, participates in the EPEC adherence phenotype.