bluuebunny/crossref_metadata_2025 huggingface dataset:
An Experimental Investigation of Structured Roughness Effect on Heat Transfer During Single-Phase Liquid Flow at Microscale
Authors: Lin Ting-Yu , Kandlikar Satish G.
Published: August 2012

The effect of structured roughness on the heat transfer of water flowing through minichannels was experimentally investigated in this study. The test channels were formed by two 12.7 mm wide × 94.6 mm long stainless steel strips. Eight structured roughness elements were generated using a wire electrical discharge machining (EDM) process as lateral grooves of sinusoidal profile on the channel walls. The height of the roughness structures ranged from 18 μm to 96 μm, and the pitch was varied from 250 μm to 400 μm. The hydraulic diameter of the rectangular flow channels ranged from 0.71 mm to 1.87 mm, while the constricted hydraulic diameter (obtained by using the narrowest flow gap) ranged from 0.68 mm to 1.76 mm. After accounting for heat losses from the edges and end sections, the heat transfer coefficient for smooth channels was found to be in good agreement with the conventional correlations in the laminar entry region as well as in the laminar fully developed region. All roughness elements were found to enhance the heat transfer. In the ranges of parameters tested, the roughness element pitch was found to have almost no effect, while the heat transfer coefficient was significantly enhanced by increasing the roughness element height. An earlier transition from laminar to turbulent flow was observed with increasing relative roughness (ratio of roughness height to hydraulic diameter). For the roughness element designated as B-1 with a pitch of 250 μm, roughness height of 96 μm and a constricted hydraulic diameter of 690 μm, a maximum heat transfer enhancement of 377% was obtained, while the corresponding friction factor increase was 371% in the laminar fully developed region. Comparing different enhancement techniques reported in the literature, the highest roughness element tested in the present work resulted in the highest thermal performance factor, defined as the ratio of heat transfer enhancement factor (over smooth channels) and the corresponding friction enhancement factor to the power 1/3.
Pool Boiling Heat Transfer on the International Space Station: Experimental Results and Model Verification
Authors: Raj Rishi , Kim Jungho , McQuillen John
Published: August 2012

The relatively poor understanding of gravity effects on pool boiling heat transfer can be attributed to the lack of long duration high-quality microgravity data, g-jitter associated with ground-based low gravity facilities, little data at intermediate gravity levels, and a poor understanding of the effect of important parameters even at earth gravity conditions. The results of over 200 pool boiling experiments with n-perfluorohexane as the test fluid performed aboard the International Space Station (ISS) are presented in this paper. A flat, transparent, constant temperature microheater array was used to perform experiments over a wide range of temperatures (55 °C < Tw < 107.5 °C), pressures (0.58 atm < P < 1.86 atm), subcoolings (1 °C ≤ ΔTsub ≤ 26 °C), and heater sizes (4.2 mm ≤ Lh ≤ 7.0 mm). The boiling process was visualized from the side and bottom. Based on this high quality microgravity data (a/g<10−6), the recently reported gravity scaling parameter for heat flux, which was primarily based on parabolic flight experiments, was modified to account for these new results. The updated model accurately predicts the experimental microgravity data to within ±20%. The robustness of this framework in predicting low gravity heat transfer is further demonstrated by predicting many of the trends in the pool boiling literature that cannot be explained by any single model.
Physical Models and Design Thinking: A Study of Functionality, Novelty and Variety of Ideas
Authors: Viswanathan Vimal K. , Linsey Julie S.
Published: August 2012

Engineering idea generation is a crucial part of new product development, and physical modeling is a widely used tool. Despite the physical models’ popularity in the idea generation process, little is known about their effects on design cognition. The existing literature provides contradicting guidelines about their use in the design process. Product design firms call for the frequent use of physical models, but some studies suggest that physical models induce design fixation. The psychological literature indicates that physical representations, by supporting designers’ mental models of physical phenomena, might lead to more feasible designs. The advantages and disadvantages of physical models as idea generation tools need to be clarified to help designers decide when and where to implement them. Based on prior studies and anecdotal evidence, two hypotheses are tested: (1) physical models supplement designer’s mental models and (2) physical models induce design fixation. Two between-subject idea generation experiments with novice designers are conducted to evaluate these hypotheses. In the first pilot experiment, the participants generate ideas in three conditions: sketching only, building, and building and testing. This study is followed by a second experiment, in which a new condition called constrained sketching is added. In each condition, participants use the representation implied by the name of the condition. The percentage of ideas satisfying all design requirements indicates the physical models’ effect on the designers’ mental models. Novelty and variety are used as metrics for design fixation. The percentage of functional ideas quantified shows significant variation across the sketching and building conditions, whereas novelty and variety show no differences. These results support the argument that physical models supplement novice designer’s mental models. No evidence of fixation is observed, which contradicts the results of the prior observational studies. Hypothesized reasons for the apparently contradictory results are also presented.
Using the Pareto Set Pursuing Multiobjective Optimization Approach for Hybridization of a Plug-In Hybrid Electric Vehicle
Authors: Shahi Shashi K. , Wang G. Gary , An Liqiang , Bibeau Eric , Pirmoradi Zhila
Published: August 2012

A plug-in hybrid electric vehicle (PHEV) can improve fuel economy and emission reduction significantly compared to hybrid electric vehicles and conventional internal combustion engine (ICE) vehicles. Currently there lacks an efficient and effective approach to identify the optimal combination of the battery pack size, electric motor, and engine for PHEVs in the presence of multiple design objectives such as fuel economy, operating cost, and emission. This work proposes a design approach for optimal PHEV hybridization. Through integrating the Pareto set pursuing (PSP) multiobjective optimization algorithm and powertrain system analysis toolkit (PSAT) simulator on a Toyota Prius PHEV platform, 4480 possible combinations of design parameters (20 batteries, 14 motors, and 16 engines) were explored for PHEV20 and PHEV40 powertrain configurations. The proposed approach yielded the optimal solution in a small fraction of computational time, as compared to an exhaustive search. This confirms the efficiency and applicability of PSP to problems with discrete variables. In the design context we have found that battery, motor, and engine collectively define the optimal hybridization scheme, which also varies with the drive cycle and all electric range (AER). The proposed method and software platform could be applied to optimize other powertrain designs.
A quieting ocean: Unintended consequence of a fluctuating economy
Authors: McKenna M. F. , Katz S. L. , Wiggins S. M. , Ross D. , Hildebrand J. A.
Published: August 2012

Simultaneous long-term monitoring of underwater sound and ship traffic provided an opportunity to study how low-frequency noise correlated with ocean-based commercial shipping trends. Between 2007 and 2010 changes in regional shipping off southern California occurred as a consequence of economic and regulatory events. Underwater average noise levels measured before and during these events showed a net reduction of 12 dB. Statistical models revealed that a reduction of 1 ship transit per day resulted in 1 dB decrease in average noise. This synthesis of maritime traffic statistics with ocean noise monitoring provides an important step in understanding the magnitude and potential effects of chronic noise in marine habitats.
Elastic Pekeris waveguide normal mode solution comparisons against laboratory data
Authors: Schneiderwind Joseph D. , Collis Jon M. , Simpson Harry J.
Published: August 2012

Following the derivation presented by Press and Ewing [Geophysics 15, 426–446 (1950)], a normal mode solution for the Pekeris waveguide problem with an elastic bottom is outlined. The analytic solution is benchmarked against data collected in an experiment performed at the Naval Research Laboratory [Collis et al., J. Acoust. Soc. Am. 122, 1987–1993 (2007)]. Comparisons reveal a close match between the analytic solution and experimental data. Results are strongly dependent on the accuracy of the horizontal wavenumbers for the modes, and horizontal wavenumber spectra are compared against those from the experimental data.
Increased intensity discrimination thresholds in tinnitus subjects with a normal audiogram
Authors: Epp B. , Hots J. , Verhey J. L. , Schaette R.
Published: August 2012

Recent auditory brain stem response measurements in tinnitus subjects with normal audiograms indicate the presence of hidden hearing loss that manifests as reduced neural output from the cochlea at high sound intensities, and results from mice suggest a link to deafferentation of auditory nerve fibers. As deafferentation would lead to deficits in hearing performance, the present study investigates whether tinnitus patients with normal hearing thresholds show impairment in intensity discrimination compared to an audiometrically matched control group. Intensity discrimination thresholds were significantly increased in the tinnitus frequency range, consistent with the hypothesis that auditory nerve fiber deafferentation is associated with tinnitus.
Nonlinear ultrasound: Potential of the cross-correlation method for osseointegration monitoring
Authors: Rivière Jacques , Haupert Sylvain , Laugier Pascal , Johnson Paul A.
Published: August 2012

Recently the concept of probing nonlinear elasticity at an interface prosthesis/bone has been proposed as a promising method to monitor the osseointegration/sealing of a prosthesis. However, the most suitable method to achieve this goal is a point of debate. To this purpose, two approaches termed the scaling subtraction method and the cross-correlation method are compared here. One nonlinear parameter derived from the cross-correlation method is as sensitive as a clinical device based on linear elasticity measurement. Further, this study shows that cross-correlation based methods are more sensitive than those based on subtraction/addition, such like pulse inversion and similar methods.
Formant discrimination of speech and non-speech sounds for English and Chinese listeners
Authors: Liu Chang , Tao Sha , Wang Wenjing , Dong Qi
Published: August 2012

Thresholds of formant discrimination of speech and non-speech sounds were compared for native listeners of English and Chinese. English listeners showed significantly better thresholds than Chinese listeners, not only for English vowels, but also for Chinese vowels. Thresholds for vowel-spectrum-shaped noise were comparable for the two groups. These results suggest that English listeners are more sensitive to formant frequency changes of vowel stimuli than Chinese listeners, possibly due to the denser vowel space for English than for Mandarin Chinese. However, the psychophysical capacity to discriminate formant frequency changes in non-speech sounds is similar for English and Chinese listeners.
Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy
Authors: Khairallah Ramzi J. , Shi Guoli , Sbrana Francesca , Prosser Benjamin L. , Borroto Carlos , Mazaitis Mark J. , Hoffman Eric P. , Mahurkar Anup , Sachs Fredrick , Sun Yezhou , Chen Yi-Wen , Raiteri Roberto , Lederer W. Jonathan , Dorsey Susan G. , Ward Christopher W.
Published: August 2012

Decreasing microtubule density in a mouse model of muscular dystrophy reduces contraction-induced muscle injury.
The Abluminal Endothelial Membrane in Neurovascular Remodeling in Health and Disease
Authors: Hermann Dirk M. , ElAli Ayman
Published: August 2012

Understanding brain vascular remodeling may allow effective intervention in cases of injury or disease that disrupt the blood-brain barrier.
The Inner Workings of a Clock
Authors: Ray L. Bryan
Published: August 2012

A circadian rhythm regulator acts by altering the elongation stage of gene expression.
Initiating Mitochondrial Repair
Authors: Hurtley Stella M.
Published: August 2012

When stressed, the mitochondrion reduces import of a transcription factor, which enters the nucleus instead.
Hollowing Out the Center
Authors: Gough Nancy R.
Published: August 2012

Lumen formation by mammary epithelial cells involves two distinct effects of cAMP signaling in the inner and outer cells.
Inducing Conformational Change in the Ligand
Authors: Andrianantoandro Ernesto
Published: August 2012

The structure of follicle-stimulating hormone bound to the ectodomain of its receptor reveals a possible mechanism for receptor activation.
The Outsiders: Emerging Roles of Ectonucleotidases in Inflammation
Authors: Szabo Csaba , Pacher Pal
Published: August 2012

CD73, an enzyme that converts AMP to adenosine, is emerging as a pharmacological target selective for sites of inflammation.
Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia
Authors: Saunders David , Khemawoot Phisit , Vanachayangkul Pattaraporn , Siripokasupkul Raveewan , Bethell Delia , Tyner Stuart , Se Youry , Rutvisuttinunt Wiriya , Sriwichai Sabaithip , Chanthap Lon , Lin Jessica , Timmermans Ans , Socheat Doung , Ringwald Pascal , Noedl Harald , Smith Bryan , Fukuda Mark , Teja-isavadharm Paktiya
Published: August 2012

Artemisinin-resistant malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral artesunate monotherapy were explored in a dose-ranging trial in an area of emerging artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated
Plasmodium falciparum
malaria in an open label study of directly observed artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in artesunate and dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable artesunate dose (4 mg/kg/day) and baseline parasitemia from the two studies. Reduced plasma drug levels with higher presentation parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated malaria. Neither
in vitro
parasite susceptibility nor plasma drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral artesunate on malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships.
Antiparasitic Effect of Vitamin B
12
on Trypanosoma cruzi
Authors: Ciccarelli Alejandra B. , Frank Fernanda M. , Puente Vanesa , Malchiodi Emilio L. , Batlle Alcira , Lombardo Maria Elisa
Published: August 2012

A nutritional characteristic of trypanosomatid protozoa is that they need a heme compound as a growth factor. Because of the cytotoxic activity of heme and its structural similarity to cobalamins, we have investigated the
in vitro
and
in vivo
effect of vitamin B
12
(or cyanocobalamin) on the different forms of
Trypanosoma cruzi
. Cyanocobalamin showed a marked antiparasitic activity against epimastigotes (50% inhibitory concentration [IC
50
], 2.42 μM), amastigotes (IC
50
, 10.69 μM), and trypomastigotes (IC
50
, 9.46 μM). Anti-epimastigote and -trypomastigote values were 1.7 to 4 times lower than those obtained with the reference drug benznidazole (Bnz). We also found that B
12
and hemin do not interact with each other in their modes of action. Our results show that B
12
increases intracellular oxidative activity and stimulates both superoxide dismutase (50%) and ascorbate peroxidase (20%) activities, while the activity of trypanothione reductase was not modified. In addition, we found that the antioxidants dithiothreitol and ascorbic acid increase the susceptibility of the parasite to the cytotoxic action of B
12
. We propose that vitamin B
12
exerts its growth-inhibitory effect through the generation of reactive oxygen species. In an
in vivo
assay, a significant reduction in the number of circulating parasites was found in
T. cruzi
-infected mice treated with cyanocobalamin and ascorbic acid. The reduction of parasitemia in benznidazole-treated mice was improved by the addition of these vitamins. According to our results, a combination of B
12
and Bnz should be further investigated due to its potential as a new therapeutic modality for the treatment of Chagas' disease.
Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen
Authors: Debnath Anjan , Tunac Josefino B. , Galindo-Gómez Silvia , Silva-Olivares Angélica , Shibayama Mineko , McKerrow James H.
Published: August 2012

Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba
Naegleria fowleri
. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species
Naegleria gruberi
. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against
Naegleria
than that of amphotericin B. Transmission electron microscopy of
N. fowleri
trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae.
In vivo
efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM.
TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections
Authors: Stryjewski Martin E. , Potgieter Peter D. , Li Yu-Ping , Barriere Steven L. , Churukian Allan , Kingsley Jeff , Corey G. Ralph ,   for the TD-1792 Investigators Group
Published: August 2012

TD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistantStaphylococcus aureusat baseline (n= 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n= 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.
Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients
Authors: Dvory-Sobol Hadas , Wong Kelly A. , Ku Karin S. , Bae Andrew , Lawitz Eric J. , Pang Phillip S. , Harris Jeanette , Miller Michael D. , Mo Hongmei
Published: August 2012

GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations were cloned into an NS3 shuttle vector, and their susceptibilities to GS-9451 and other HCV inhibitors were determined using a transient replication assay. No resistance mutations at NS3 position 155, 156, or 168 were detected in any of the baseline samples or in viruses from patients treated with 60 mg of GS-9451 once daily. Among patients who received 200 mg and 400 mg of GS-9451, viruses with mutations at position D168 (D168E/G/V) and R155 (R155K), which confer high-level resistance to GS-9451, were detected in those with GT 1b and GT 1a virus, respectively. Viruses with D168 mutations were no longer detected in any GT 1b patient at day 14 and subsequent time points. In GT 1a patients, R155K mutants were replaced by the wild type in 57% of patients at week 24. These NS3 clinical mutants were sensitive to NS5B and NS5A inhibitors, as well as alpha interferon (IFN-α) and ribavirin. The lack of cross-resistance between GS-9451 and other classes of HCV inhibitors supports the utility of combination therapy.
Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity
Authors: Rose Warren E. , Schulz Lucas T. , Andes David , Striker Rob , Berti Andrew D. , Hutson Paul R. , Shukla Sanjay K.
Published: August 2012

Antistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistant
Staphylococcus aureus
(MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. An
in vitro
pharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivity
in vivo
and resulted in clearance of persistent blood cultures. Daptomycin susceptibility
in vitro
was increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Both
in vivo
- and
in vitro
-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initial
in vivo
isolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.
Identification of a Novel Genomic Island Conferring Resistance to Multiple Aminoglycoside Antibiotics in Campylobacter coli
Authors: Qin Shangshang , Wang Yang , Zhang Qijing , Chen Xia , Shen Zhangqi , Deng Fengru , Wu Congming , Shen Jianzhong
Published: August 2012

Historically, the incidence of gentamicin resistance in
Campylobacter
has been very low, but recent studies reported a high prevalence of gentamicin-resistant
Campylobacter
isolated from food-producing animals in China. The reason for the high prevalence was unknown and was addressed in this study. PCR screening identified aminoglycoside resistance genes
aphA-3
and
aphA-7
and the
aadE–sat4–aphA-3
cluster among 41
Campylobacter
isolates from broiler chickens. Importantly, a novel genomic island carrying multiple aminoglycoside resistance genes was identified in 26 aminoglycoside resistant
Campylobacter coli
strains. Sequence analysis revealed that the genomic island was inserted between
cadF
and
COO1582
on the
C. coli
chromosome and consists of 14 open reading frames (ORFs), including 6 genes (the
aadE–sat4–aphA-3
cluster,
aacA-aphD
,
aac
, and
aadE
) encoding aminoglycoside-modifying enzymes. Analysis by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing indicated that the
C. coli
isolates carrying this unique genomic island were clonal, and the clone of PFGE subtype III and sequence type (ST) 1625 was particularly predominant among the
C. coli
isolates examined, suggesting that clonal expansion may be involved in dissemination of this resistance island. Additionally, we were able to transfer this genomic island from
C. coli
to a
Campylobacter jejuni
strain using natural transformation under laboratory conditions, and the transfer resulted in a drastic increase in aminoglycoside resistance in the recipient strain. These findings identify a previously undescribed genomic island that confers resistance to multiple aminoglycoside antibiotics. Since aminoglycoside antibiotics are used for treating occasional systemic infections caused by
Campylobacter
, the emergence and spread of this antibiotic resistance genomic island represent a potential concern for public health.
Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens
Authors: Hope William W. , Goodwin Joanne , Felton Timothy W. , Ellis Michael , Stevens David A.
Published: August 2012

There is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (
P
= 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.
Characterization of Hepatitis C Virus (HCV) Quasispecies Dynamics upon Short-Term Dual Therapy with the HCV NS5B Nucleoside Polymerase Inhibitor Mericitabine and the NS3/4 Protease Inhibitor Danoprevir
Authors: Le Pogam S. , Yan J. M. , Chhabra M. , Ilnicka M. , Kang H. , Kosaka A. , Ali S. , Chin D. J. , Shulman N. S. , Smith P. , Klumpp K. , Nájera I.
Published: August 2012

In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.
Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Vertebral Osteomyelitis Cases Complicated by Bacteremia Treated with High-Dose Daptomycin and Trimethoprim-Sulfamethoxazole
Authors: Avery Lisa M. , Steed Molly E. , Woodruff Ashley E. , Hasan Muhammad , Rybak Michael J.
Published: August 2012

We report two cases of daptomycin (DAP)-nonsusceptible (DNS) vancomycin-intermediate
Staphylococcus aureus
(VISA) vertebral osteomyelitis cases complicated by bacteremia treated with high-dose daptomycin and trimethoprim-sulfamethoxazole. Both patients responded rapidly and favorably to this combination. The clinical isolates from the two patients were tested
post hoc
in an
in vitro
pharmacokinetic/pharmacodynamic (PK/PD) model to confirm the bactericidal activity and enhancement of daptomycin and trimethoprim-sulfamethoxazole. The combination of high-dose daptomycin and trimethoprim-sulfamethoxazole should be explored further for the treatment of DNS VISA strains.
Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)
Authors: McPhee Fiona , Sheaffer Amy K. , Friborg Jacques , Hernandez Dennis , Falk Paul , Zhai Guangzhi , Levine Steven , Chaniewski Susan , Yu Fei , Barry Diana , Chen Chaoqun , Lee Min S. , Mosure Kathy , Sun Li-Qiang , Sinz Michael , Meanwell Nicholas A. , Colonno Richard J. , Knipe Jay , Scola Paul
Published: August 2012

Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, with

K
i

values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC
50
s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC
50
, 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC
50
, >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures
in vivo
in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC
50
s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.
Herb-Drug Interaction between Echinacea purpurea and Etravirine in HIV-Infected Patients
Authors: Moltó José , Valle Marta , Miranda Cristina , Cedeño Samandhy , Negredo Eugenia , Clotet Bonaventura
Published: August 2012

The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement
Echinacea purpurea
to interact with etravirine, a nonnucleoside reverse transcriptase inhibitor of HIV. Fifteen HIV-infected patients receiving antiretroviral therapy with etravirine (400 mg once daily) for at least 4 weeks were included.
E. purpurea
root/extract-containing capsules were added to the antiretroviral treatment (500 mg every 8 h) for 14 days. Etravirine concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, 12, and 24 h after a morning dose of etravirine on day 0 and etravirine plus
E. purpurea
on day 14. Individual etravirine pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 46 years (interquartile range, 41 to 50), and the median body weight was 76 kg (interquartile range, 68 to 92). Echinacea was well tolerated, and all participants completed the study. The GMR for etravirine coadministered with
E. purpurea
relative to etravirine alone was 1.07 (90% CI, 0.81 to 1.42) for the maximum concentration, 1.04 (90% CI, 0.79 to 1.38) for the area under the concentration-time curve from 0 to 24 h, and 1.04 (90% CI, 0.74 to 1.44) for the concentration at the end of the dosing interval. In conclusion, the coadministration of
E. purpurea
with etravirine was safe and well tolerated in HIV-infected patients; our data suggest that no dose adjustment for etravirine is necessary.
Pyrazinamide May Improve Fluoroquinolone-Based Treatment of Multidrug-Resistant Tuberculosis
Authors: Chang Kwok-Chiu , Leung Chi-Chiu , Yew Wing-Wai , Leung Eric Chung-Ching , Leung Wai-Man , Tam Cheuk-Ming , Zhang Ying
Published: August 2012

The role of pyrazinamide in the current treatment of multidrug-resistant (MDR) tuberculosis (TB) is uncertain. From a territory-wide registry of MDR-TB cases diagnosed between 1995 and 2009, we assembled a cohort of 194 patients with MDR pulmonary TB given fluoroquinolone-containing regimens. Stratified by pyrazinamide use and susceptibility, there were 83 users with pyrazinamide-susceptible MDR-TB (subgroup A), 24 users with pyrazinamide-resistant MDR-TB (subgroup B), 40 nonusers with pyrazinamide-susceptible MDR-TB (subgroup C), and 47 nonusers with pyrazinamide-resistant MDR-TB (subgroup D). We estimated the adjusted risk ratio (ARR) of early sputum culture conversion (ARR-culture) that occurred within 90 days posttreatment and that of cure or treatment completion (ARR-success) that occurred by 2 years posttreatment due to pyrazinamide use with susceptibility. In comparison with subgroup B, ARR-culture and ARR-success were 1.38 (95% confidence interval [CI], 0.89 to 2.12) and 1.38 (95% confidence interval [CI], 0.88 to 2.17), respectively. Corresponding findings were 0.99 (95% CI, 0.81 to 1.22) and 0.99 (95% CI, 0.78 to 1.26) in comparison with subgroup C and 1.09 (95% CI, 0.84 to 1.42) and 0.94 (95% CI, 0.74 to 1.20) in comparison with subgroup D. Early culture conversion significantly increased the incidence proportion of cure or treatment completion by 71% (95% CI, 26% to 133%). Selection bias among pyrazinamide nonusers might have underestimated the role of pyrazinamide. Comparison of pyrazinamide users showed that pyrazinamide increased the incidence proportion of early culture conversion and that of cure or treatment completion by a best estimate of 38% for both. This magnitude of change exceeded the 15 to 20% increase in the 2-month culture conversion rate of drug-susceptible TB that results from adding pyrazinamide to isoniazid and rifampin. Pyrazinamide is likely important in fluoroquinolone-based treatment of MDR-TB.
Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids
Authors: Griffin Carol E. , Hoke Jonathan M. , Samarakoon Upeka , Duan Junhui , Mu Jianbing , Ferdig Michael T. , Warhurst David C. , Cooper Roland A.
Published: August 2012

The
Cinchona
alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (−)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (−)-isomers
in vitro
and
in vivo
against
Plasmodium falciparum
malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (
P. falciparum
chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward
P. falciparum
. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the
in vitro
susceptibility of eight clonal lines of
P. falciparum
derived from the 106/1 strain, each containing a unique
pfcrt
allele, to four
Cinchona
stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the
Cinchona
alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC
50
ratio of (−)/(+) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (−) and (+) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other
Cinchona
alkaloids.
Reproductive outcomes following induced abortion: a national register-based cohort study in Scotland
Authors: Bhattacharya Siladitya , Lowit Alison , Bhattacharya Sohinee , Raja Edwin Amalraj , Lee Amanda Jane , Mahmood Tahir , Templeton Allan
Published: August 2012

Objective

To investigate reproductive outcomes in women following induced abortion (IA).

Design

Retrospective cohort study.

Setting

Hospital admissions between 1981 and 2007 in Scotland.

Participants

Data were extracted on all women who had an IA, a miscarriage or a live birth from the Scottish Morbidity Records. A total of 120 033, 457 477 and 47 355 women with a documented second pregnancy following an IA, live birth and miscarriage, respectively, were identified.

Outcomes

Obstetric and perinatal outcomes, especially preterm delivery in a second ongoing pregnancy following an IA, were compared with those in primigravidae, as well as those who had a miscarriage or live birth in their first pregnancy. Outcomes after surgical and medical termination as well as after one or more consecutive IAs were compared.

Results

IA in a first pregnancy increased the risk of spontaneous preterm birth compared with that in primigravidae (adjusted RR (adj. RR) 1.37, 95% CI 1.32 to 1.42) or women with an initial live birth (adj. RR 1.66, 95% CI 1.58 to 1.74) but not in comparison with women with a previous miscarriage (adj. RR 0.85, 95% CI 0.79 to 0.91). Surgical abortion increased the risk of spontaneous preterm birth compared with medical abortion (adj. RR 1.25, 95% CI 1.07 to 1.45). The adjusted RRs (95% CI) for spontaneous preterm delivery following two, three and four consecutive IAs were 0.94 (0.81 to 1.10), 1.06 (0.76 to 1.47) and 0.92 (0.53 to 1.61), respectively.

Conclusions

The risk of preterm birth after IA is lower than that after miscarriage but higher than that in a first pregnancy or after a previous live birth. This risk is not increased further in women who undergo two or more consecutive IAs. Surgical abortion appears to be associated with an increased risk of spontaneous preterm birth in comparison with medical termination of pregnancy. Medical termination was not associated with an increased risk of preterm delivery compared to primigravidae.
Poor uptake of primary healthcare registration among recent entrants to the UK: a retrospective cohort study
Authors: Stagg Helen R , Jones Jane , Bickler Graham , Abubakar Ibrahim
Published: August 2012

Objectives

Uptake of healthcare among migrants is a complex and controversial topic; there are multiple recognised barriers to accessing primary care. Delays in presentation to healthcare services may result in a greater burden on costly emergency care, as well as increased public health risks. This study aimed to explore some of the factors influencing registration of new entrants with general practitioners (GPs).

Design

Retrospective cohort study.

Setting

Port health screening at Heathrow and Gatwick airports, primary care.

Participants

252 559 new entrants to the UK, whose entry was documented by the port health tuberculosis screening processes at Heathrow and Gatwick. 191 had insufficient information for record linkage.

Primary outcome measure

Registration with a GP practice within the UK, as measured through record linkage with the Personal Demographics Service (PDS) database.

Results

Only 32.5% of 252 368 individuals were linked to the PDS, suggesting low levels of registration in the study population. Women were more likely to register than men, with a RR ratio of 1.44 (95% CI 1.41 to 1.46). Compared with those from Europe, individuals of nationalities from the Americas (0.43 (0.39 to 0.47)) and Africa (0.74 (0.69 to 0.79)) were less likely to register. Similarly, students (0.83 (0.81 to 0.85)), long-stay visitors (0.82 (0.77 to 0.87)) and asylum seekers (0.46 (0.42 to 0.51)) were less likely to register with a GP than other migrant groups.

Conclusions

Levels of registration with GPs within this selected group of new entrants, as measured through record linkage, are low. Migrant groups with the lowest proportion registered are likely to be those with the highest health needs. The UK would benefit from a targeted approach to identify the migrants least likely to register for healthcare and to promote access among both users and service providers.
AN EFFICIENT BANDWIDTH ALLOCATION STRATEGY FOR SCALE-FREE NETWORKS
Authors: JIANG ZHONG-YUAN , LIANG MAN-GUI , ZHANG SHUAI , WANG SHU-JUAN , GUO DONG-CHAO
Published: August 2012

Traffic capacity is critical for various networks and strongly depends on the distribution of link's bandwidth resources. In this paper, we propose a betweenness-based bandwidth allocation strategy in which the bandwidth of each link lij is allocated proportionally to the product (1 + Bi)α(1 + Bj)α, where α is a tunable parameter, and Bi and Bj are the betweenness of node i and node j, respectively. The optimal value of α is achieved by extensive simulations and slightly increases with the network size. Our new bandwidth allocation strategy achieves the highest traffic capacity when compared with the average bandwidth allocation strategy and the previously proposed degree-based bandwidth allocation strategy. Our work will be beneficial for network service providers to improve the traffic capacity by efficiently allocating or reallocating the overall finite link's bandwidth resources of networks such as the Internet, urban transport networks and airway networks.
A NOVEL METHOD TO ANALYZE PHASE DIAGRAMS FOR TRAFFICS ON THE CROSSROAD
Authors: LI QI-LANG , JIANG RUI , WANG BING-HONG , LIU MU-REN
Published: August 2012

Traffic flow at a single crossroad consisting of two perpendicular one-lane roads, treated earlier by Ishibashi and Fukui [J. Phys. Soc. Jpn.70, 2793 (2001); 70, 3747 (2001)], has been studied on the basis of the local occupation probability method. However, in this work, based on the novel theoretical analysis and computer simulations, we have studied this crossroad traffic model again and presented the same phase diagrams of traffic flow in the case of various maximum vehicle velocities. We have also derived the flow formulas in all regions in the phase diagrams, which are in good agreement with computer simulation results. Compared with the previous local occupation probability method, our analytical way is simpler and may be widely used for other traffic bottlenecks research.