bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Throughput Intracellular Antimicrobial Susceptibility Testing of Legionella pneumophila
Authors: Chiaraviglio Lucius , Kirby James E. 
Published: September 2015

ABSTRACT

Legionella pneumophila
is a Gram-negative opportunistic human pathogen that causes a severe pneumonia known as Legionnaires' disease. Notably, in the human host, the organism is believed to replicate solely within an intracellular compartment, predominantly within pulmonary macrophages. Consequently, successful therapy is predicated on antimicrobials penetrating into this intracellular growth niche. However, standard antimicrobial susceptibility testing methods test solely for extracellular growth inhibition. Here, we make use of a high-throughput assay to characterize intracellular growth inhibition activity of known antimicrobials. For select antimicrobials, high-resolution dose-response analysis was then performed to characterize and compare activity levels in both macrophage infection and axenic growth assays. Results support the superiority of several classes of nonpolar antimicrobials in abrogating intracellular growth. Importantly, our assay results show excellent correlations with prior clinical observations of antimicrobial efficacy. Furthermore, we also show the applicability of high-throughput automation to two- and three-dimensional synergy testing. High-resolution isocontour isobolograms provide
in vitro
support for specific combination antimicrobial therapy. Taken together, findings suggest that high-throughput screening technology may be successfully applied to identify and characterize antimicrobials that target bacterial pathogens that make use of an intracellular growth niche.
Old Drugs To Treat Resistant Bugs: Methicillin-Resistant Staphylococcus aureus Isolates with
mecC
Are Susceptible to a Combination of Penicillin and Clavulanic Acid
Authors: Ba Xiaoliang , Harrison Ewan M. , Lovering Andrew L. , Gleadall Nicholas , Zadoks Ruth , Parkhill Julian , Peacock Sharon J. , Holden Matthew T. G. , Paterson Gavin K. , Holmes Mark A. 
Published: September 2015

ABSTRACT

β-Lactam resistance in methicillin-resistant
Staphylococcus aureus
(MRSA) is mediated by the expression of an alternative penicillin-binding protein 2a (PBP2a) (encoded by
mecA
) with a low affinity for β-lactam antibiotics. Recently, a novel variant of
mecA
, known as
mecC
, was identified in MRSA isolates from both humans and animals. In this study, we demonstrate that
mecC
-encoded PBP2c does not mediate resistance to penicillin. Rather, broad-spectrum β-lactam resistance in MRSA strains carrying
mecC
(
mecC
-MRSA strains) is mediated by a combination of both PBP2c and the distinct β-lactamase encoded by the
blaZ
gene of strain LGA251 (
blaZ
LGA251
), which is part of
mecC
-encoding staphylococcal cassette chromosome
mec
(SCC
mec
) type XI. We further demonstrate that
mecC
-MRSA strains are susceptible to the combination of penicillin and the β-lactam inhibitor clavulanic acid
in vitro
and that the same combination is effective
in vivo
for the treatment of experimental
mecC
-MRSA infection in wax moth larvae. Thus, we demonstrate how the distinct biological differences between
mecA
- and
mecC
-encoded PBP2a and PBP2c have the potential to be exploited as a novel approach for the treatment of
mecC
-MRSA infections.
Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole
Authors: Morgand Marjolaine , Rammaert Blandine , Poirée Sylvain , Bougnoux Marie-Elisabeth , Tran Hugo , Kania Romain , Chrétien Fabrice , Jouvion Gregory , Lortholary Olivier 
Published: September 2015

ABSTRACT

Invasive aspergillosis (IA) is a severe disseminated fungal disease that occurs mostly in immunocompromised patients. However, central nervous system IA, combining meningitis and skull base involvement, does not occur only in groups with classic risk factors for IA; patients with chronic renal failure and diabetes mellitus are also at risk for more chronic forms. In both of our proven IA cases, voriconazole monotherapy was effective without surgery, and cerebrospinal fluid and serum 1,3-β-
d
-glucan test results were initially positive, in contrast to galactomannan antigen results.
Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance
Authors: Jensen Sanne B. , Serre Stéphanie B. N. , Humes Daryl G. , Ramirez Santseharay , Li Yi-Ping , Bukh Jens , Gottwein Judith M. 
Published: September 2015

ABSTRACT
Various protease inhibitors (PIs) currently are becoming available for treatment of hepatitis C virus (HCV). For genotype 1, substitutions at NS3 protease positions 155, 156, and 168 are the main determinants of PI resistance. For other genotypes, similar substitutions were selected during PI treatment but were not characterized systematically. To elucidate the impact of key PI resistance substitutions on genotypes 2 to 6, we engineered the substitutions R155A/E/G/H/K/Q/T, A156G/S/T/V, and D/Q168A/E/G/H/N/V into HCV recombinants expressing genotype 2 to 6 proteases. We evaluated viral fitness and sensitivity to nine PIs (telaprevir, boceprevir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, deldeprevir, and grazoprevir) in Huh7.5 cells. We found that most variants showed decreased fitness compared to that of the original viruses. Overall, R155K, A156G/S, and D/Q168A/E/H/N/V variants showed the highest fitness; however, genotype 4 position 168 variants showed strong fitness impairment. Most variants tested were resistant to several PIs. Resistance levels varied significantly depending on the specific substitution, genotype, and PI. For telaprevir and boceprevir, specific 155 and 156, but not 168, variants proved resistant. For the remaining PIs, most genotype 2, 4, 5, and 6, but not genotype 3, variants showed various resistance levels. Overall, grazoprevir (MK-5172) had the highest efficacy against original viruses and variants. This is the first comprehensive study revealing the impact of described key PI resistance substitutions on fitness and PI resistance of HCV genotypes 2 to 6. In conclusion, the studied substitutions induced resistance to a panel of clinically relevant PIs, including the newer PIs paritaprevir, deldeprevir, and grazoprevir. We discovered complex patterns of resistance, with the impact of substitutions varying from increased sensitivity to high resistance.
Escherichia coli Free Radical-Based Killing Mechanism Driven by a Unique Combination of Iron Restriction and Certain Antibiotics
Authors: Ma Li , Gao Yongjun , Maresso Anthony W. 
Published: September 2015

ABSTRACT

Bacterial resistance to antibiotics is precipitating a medical crisis, and new antibacterial strategies are being sought. Hypothesizing that a growth-restricting strategy could be used to enhance the efficacy of antibiotics, we determined the effect of FDA-approved iron chelators and various antibiotic combinations on invasive and multidrug-resistant extraintestinal pathogenic
Escherichia coli
(ExPEC), the Gram-negative bacterium most frequently isolated from the bloodstreams of hospitalized patients. We report that certain antibiotics used at sublethal concentrations display enhanced growth inhibition and/or killing when combined with the iron chelator deferiprone (DFP). Inductively coupled plasma optical emission spectrometry reveals abnormally high levels of cell-associated iron under these conditions, a response that correlates with an iron starvation response and supraphysiologic levels of reactive oxygen species (ROS). The high ROS level is reversed upon the addition of antioxidants, which restores bacterial growth, suggesting that the cells are inhibited or killed by excessive free radicals. A model is proposed in which peptidoglycan-targeting antibiotics facilitate the entry of lethal levels of iron-complexed DFP into the bacterial cytoplasm, a process that drives the generation of ROS. This new finding suggests that, in addition to restriction of access to iron as a general growth-restricting strategy, targeting of cellular pathways or networks that selectively disrupt normal iron homeostasis can have potent bactericidal outcomes.

IMPORTANCE
The prospect that common bacteria will become resistant to all antibiotics is challenging the medical community. In addition to the development of next-generation antibiotics, new bacterial targets that display cytotoxic properties when altered need to be identified. Data presented here demonstrate that combining subinhibitory levels of both iron chelators and certain antibiotics kills pathogenic
Escherichia coli
. The mechanism of this effect is the production of supraphysiologic levels of reactive oxygen species, likely powered by the excessive import of iron. These findings were consistent for both clinically relevant and no longer clinically used antibiotics and may extend to
Staphylococcus aureus
as well.
A novel non-invasive index using AFP and APTT is associated with liver fibrosis in patients with chronic hepatitis B infection: a retrospective cohort study
Authors: Feng Limin , Sun Ke , Zhang Jie , Feng Guofang , Zhao Ying 
Published: September 2015

ObjectiveA liver biopsy is the ‘reference standard’ for diagnosing and staging liver fibrosis but with many disadvantages. Therefore, developing a non-invasive index for predicting fibrosis is very valuable. We developed and validated a novel non-invasive index for predicting significant fibrosis in patients with chronic hepatitis B infection.DesignA retrospective cohort study.SettingChronic hepatitis B virus-infected patients were recruited in the Department of Infectious Disease in the First Affiliated Hospital of Zhejiang University.ParticipantsA total of 506 patients were enrolled, and patients were randomly divided into estimation (n=253) and validation (n=253) cohorts.Primary and secondary outcome measuresChronic hepatitis B virus-infected patients were studied retrospectively using routine parameters. A novel index was developed from an estimation cohort and validated in another cohort. Liver histology was assessed for fibrosis according to the Xi'an Meeting Scoring System. The novel index using α-fetal protein (AFP) and activated partial thromboplastin time (APTT; denoted AA index) was compared with 10 other indices using receiving operating characteristics curves. Multivariate forward stepwise regression analysis revealed that AFP and APTT were significantly associated with the Xi'an Meeting Scoring System, and were used to calculate the AA index (log index=−9.164+0.114×AFP+0.236×APTT).ResultsThe AA index predicted significant fibrosis with an area under the curve of 0.822, exhibited a significantly higher area compared with the other 10 indices in the estimation cohort, and was validated in the validation cohort.ConclusionsThe AA index can be used to predict significant fibrosis, and may decrease the need for liver biopsy in patients with chronic hepatitis B infection.
Controlling crystallization process and thermal stability of a binary Cu–Zr bulk metallic glass via minor element addition
Authors: Zhang S. T. , Wang Q. , Liu T. T. , Liu J. J. 
Published: September 2015

In this paper, the effect of minor element addition on the initial structural evolution during crystallization in a simple binary Cu–Zr bulk metallic glass (BMG) forming liquid has been investigated by using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Despite no changes in the completely crystallized products, the remarkable opposite impacts on the supercooled liquid region (SLR) and crystallization reaction rate constant [Formula: see text] are observed as a result of minor selective additions of an affine element, i.e., Sn and an immiscible element, i.e., Nb into the Cu–Zr BMG alloy, respectively. Furthermore, it is demonstrated that the primary devitrification pathway and crystalline phases are simultaneously modified, which leads to significant changes in kinetics of atomic rearrangement and thus thermal stability of this material. Such a finding offers a promising way to control the type of primary crystalline phases of BMG-forming metallic supercooled liquids to synthesize novel BMGs or BMG matrix composites for structural or functional applications.
Performance of Faulty Loss Systems with Persistent Connections
Authors: Patch Brendan , Taimre Thomas , Nazarathy Yoni 
Published: September 2015

We consider a finite capacity Erlang loss system that alternates between active and inactive states according to a two state modulating Markov process. Work arrives to the system as a Poisson process but is blocked from entry when the system is at capacity or inactive. Blocked jobs cost the owner a fixed amount that depends on whether blockage was due to the system being at capacity or due to the system being inactive. Jobs which are present in the system when it becomes inactive pause processing until the system becomes active again.
A Laplace transform expression for the expected undiscounted revenue lost in [0, t] due to blocking is found. Further, an expression for the total time discounted expected lost revenue in [0,?) is provided. We also derive a second order approximation to the former that can be used when the computing power to invert the Laplace transform is not available. These expressions can be used to ascribe a value to four alternatives for improving system performance: (i) increasing capacity, (ii) increasing the service rate, (iii) increasing the repair rate, or (iv) decreasing the failure rate.
Plasma Inflammatory Markers and the Risk of Developing Hypertension in Men
Authors: Sesso Howard D. , Jiménez Monik C. , Wang Lu , Ridker Paul M. , Buring Julie E. , Gaziano J. Michael 
Published: September 2015

Background
Several cross‐sectional, but few prospective, studies suggest that inflammation may be involved in the development of hypertension. We examined markers of inflammation—high‐sensitivity C‐reactive protein, interleukin‐6, and soluble intercellular adhesion molecule‐1—and a marker of fibrinolysis, D‐dimer, for their associations with incident hypertension in the Physicians' Health Study.

Methods and Results

Baseline blood values and information on hypertension‐related risk factors were collected in 1982. Incident hypertension was defined as self‐reported initiation of antihypertensive treatment, systolic blood pressure ≥140 mm Hg, or diastolic blood pressure ≥90 mm Hg during follow‐up. With use of a nested case‐control design, 396 cases of incident hypertension and controls free of hypertension were matched 1:1 on age (mean 47.4 years) and follow‐up time. In crude matched‐pair analyses, the conditional relative risks of hypertension in the second through fourth versus the lowest quartiles for plasma high‐sensitivity C‐reactive protein were 1.27, 1.73, and 1.81 (
P
trend
=0.01); for interleukin‐6, 1.22, 1.02, and 1.51 (
P
trend
=0.06); for soluble intercellular adhesion molecule‐1, 1.00, 0.80, and 1.26 (
P
trend
=0.37); and for D‐dimer, 1.61, 1.81, and 1.52 (
P
trend
=0.46). Multivariable adjustment attenuated the estimates. The multivariable relative risks of hypertension in the second through fourth compared to the lowest quartiles of high‐sensitivity C‐reactive protein were 1.24, 1.60, and 1.47 (
P
trend
=0.20); for interleukin‐6, 1.08, 0.92, and 1.36 (
P
trend
=0.16); for soluble intercellular adhesion molecule‐1, 0.89, 0.79, and 1.18 (
P
trend
=0.55); and for D‐dimer, 1.48, 1.68, and 1.38 (
P
trend
=0.63).

Conclusions
Elevated plasma inflammatory markers and D‐dimer were nonsignificantly associated with a higher risk of hypertension among initially healthy men.
Can Antihypertensive Treatment Restore the Risk of Cardiovascular Disease to Ideal Levels?
Authors: Liu Kiang , Colangelo Laura A. , Daviglus Martha L. , Goff David C. , Pletcher Mark , Schreiner Pamela J. , Sibley Christopher T. , Burke Gregory L. , Post Wendy S. , Michos Erin D. , Lloyd‐Jones Donald M. 
Published: September 2015

Background

It is unclear whether antihypertensive treatment can restore cardiovascular disease risk to the risk level of persons with ideal blood pressure (
BP
) levels.

Methods and Results

Data from the Multi‐Ethnic Study of Atherosclerosis (
MESA
) and the Coronary Artery Risk Development in Young Adults (
CARDIA
) study were analyzed. Outcomes were compared among participants without or with antihypertensive treatment at 3
BP
levels: <120/<80 mm Hg, systolic
BP
120 to 139 mm Hg or diastolic
BP
80 to 89 mm Hg (120 to 129/≤80 mm Hg for participants with diabetes), and systolic BP ≥140 or diastolic BP ≥90 mm Hg (systolic BP ≥130 or diastolic BP ≥80 mm Hg for participants with diabetes). Among
MESA
participants aged ≥50 years at baseline, those with
BP
<120/<80 mm Hg on treatment had higher left ventricular mass index, prevalence of estimated glomerular filtration rate <60 mL/min per 1.73 m
2
, prevalence of coronary calcium score >100, and twice the incident cardiovascular disease rate over 9.5 years of follow‐up than those with
BP
<120/<80 mm Hg without treatment. In
CARDIA
at year 25, persons with
BP
<120/<80 mm Hg with treatment had much longer exposure to higher
BP
and higher risk of end‐organ damage and subclinical atherosclerosis than those with
BP
<120/<80 mm Hg without treatment. An exploratory analysis suggested that when cumulative systolic BP was high (eg, >3000 mm Hg–years in 25 years), the increase in left ventricular mass index accelerated.

Conclusions

The data suggest that based on the current approach, antihypertensive treatment cannot restore cardiovascular disease risk to ideal levels. Emphasis should be placed on primordial prevention of
BP
increases to further reduce cardiovascular disease morbidity and mortality.
Investigation of Urban Air Temperature and Humidity Patterns during Extreme Heat Conditions Using Satellite-Derived Data
Authors: Hu Leiqiu , Monaghan Andrew J. , Brunsell Nathaniel A. 
Published: September 2015

AbstractExtreme heat is a leading cause of weather-related human mortality. The urban heat island (UHI) can magnify heat exposure in metropolitan areas. This study investigates the ability of a new MODIS-retrieved near-surface air temperature and humidity dataset to depict urban heat patterns over metropolitan Chicago, Illinois, during June–August 2003–13 under clear-sky conditions. A self-organizing mapping (SOM) technique is used to cluster air temperature data into six predominant patterns. The hottest heat patterns from the SOM analysis are compared with the 11-summer median conditions using the urban heat island curve (UHIC). The UHIC shows the relationship between air temperature (and dewpoint temperature) and urban land-use fraction. It is found that during these hottest events 1) the air temperature and dewpoint temperature over the study area increase most during nighttime, by at least 4 K relative to the median conditions; 2) the urban–rural temperature/humidity gradient is decreased as a result of larger temperature and humidity increases over the areas with greater vegetation fraction than over those with greater urban fraction; and 3) heat patterns grow more rapidly leading up to the events, followed by a slower return to normal conditions afterward. This research provides an alternate way to investigate the spatiotemporal characteristics of the UHI, using a satellite remote sensing perspective on air temperature and humidity. The technique has potential to be applied to cities globally and provides a climatological perspective on extreme heat that complements the many case studies of individual events.
Applications of Evolving Robotic Technology for Head and Neck Surgery
Authors: Sharma Arun , Albergotti W. Greer , Duvvuri Umamaheswar 
Published: September 2015

Objective: Assess the use and potential benefits of a new robotic system for transoral radical tonsillectomy, transoral supraglottic laryngectomy, and retroauricular thyroidectomy in a cadaver dissection. Methods: Three previously described robotic procedures (transoral radical tonsillectomy, transoral supraglottic laryngectomy, and retroauricular thyroidectomy) were performed in a cadaver using the da Vinci Xi Surgical System. Surgical exposure and access, operative time, and number of collisions were examined objectively. Results: The new robotic system was used to perform transoral radical tonsillectomy with dissection and preservation of glossopharyngeal nerve branches, transoral supraglottic laryngectomy, and retroauricular thyroidectomy. There was excellent exposure without any difficulties in access. Robotic operative times (excluding set-up and docking times) for the 3 procedures in the cadaver were 12.7, 14.3, and 21.2 minutes (excluding retroauricular incision and subplatysmal elevation), respectively. No robotic arm collisions were noted during these 3 procedures. The retroauricular thyroidectomy was performed using 4 robotic ports, each with 8 mm instruments. Conclusions: The use of updated and evolving robotic technology improves the ease of previously described robotic head and neck procedures and may allow surgeons to perform increasingly complex surgeries.
Introducing a 3‐dimensionally Printed, Tissue‐Engineered Graft for Airway Reconstruction
Authors: Goldstein Todd A. , Smith Benjamin D. , Zeltsman David , Grande Daniel , Smith Lee P. 
Published: September 2015

Objective:To use 3‐dimensional (3D) printing and tissue engineering to create a graft for laryngotracheal reconstruction (LTR).Study Design:In vitro and in vivo pilot animal study.Setting:Large tertiary care academic medical center.Subjects and Methods:A 3D computer model of an anterior LTR graft was designed. That design was printed with polylactic acid on a commercially available 3D printer. The scaffolds were seeded with mature chondrocytes and collagen gel and cultured in vitro for up to 3 weeks. Scaffolds were evaluated in vitro for cell viability and proliferation. Anterior graft LTR was performed on 9 New Zealand white rabbits with the newly created scaffolds. Three animals were sacrificed at each time point (4, 8, and 12 weeks). The in vivo graft sites were assessed via bronchoscopy and histology.Results:The in vitro cell proliferation assay demonstrated initial viability of 87.5%. The cells proliferated during the study period, doubling over the first 7 days. Histology revealed that the cells retained their cartilaginous properties during the 21‐day study period. In vivo testing showed that all animals survived for the duration of the study. Bronchoscopy revealed a well‐mucosalized tracheal lumen with no evidence of scarring or granulation tissue. Histology indicated the presence of newly formed cartilage in the region where the graft was present.Conclusions:Our results indicate that it is possible to produce a custom‐designed, 3D‐printed, tissue‐engineered graft for airway reconstruction.