bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and Validation of an
In Vitro
Pharmacokinetic/Pharmacodynamic Model To Test the Antibacterial Efficacy of Antibiotic Polymer Conjugates
Authors: Azzopardi Ernest A. , Ferguson Elaine L. , Thomas David W. 
Published: December 2014

ABSTRACT

This study describes the use of a novel, two-compartment, static dialysis bag model to study the release, diffusion, and antibacterial activity of a novel, bioresponsive dextrin-colistin polymer conjugate against multidrug resistant (MDR) wild-type
Acinetobacter baumannii
. In this model, colistin sulfate, at its MIC, produced a rapid and extensive drop in viable bacterial counts (<2 log
10
CFU/ml at 4 h); however, a marked recovery was observed thereafter, with regrowth equivalent to that of control by 48 h. In contrast, dextrin-colistin conjugate, at its MIC, suppressed bacterial growth for up to 48 h, with 3 log
10
CFU/ml lower bacterial counts after 48 h than those of controls. Doubling the concentration of dextrin-colistin conjugate (to 2× MIC) led to an initial bacterial killing of 3 log
10
CFU/ml at 8 h, with a similar regrowth profile to 1× MIC treatment thereafter. The addition of colistin sulfate (1× MIC) to dextrin-colistin conjugate (1× MIC) resulted in undetectable bacterial counts after 4 h, followed by suppressed bacterial growth (3.5 log
10
CFU/ml lower than that of control at 48 h). Incubation of dextrin-colistin conjugates with infected wound exudate from a series of burn patients (
n
= 6) revealed an increasing concentration of unmasked colistin in the outer compartment (OC) over time (up to 86.3% of the initial dose at 48 h), confirming that colistin would be liberated from the conjugate by endogenous α-amylase within the wound environment. These studies confirm the utility of this model system to simulate the pharmacokinetics of colistin formation in humans administered dextrin-colistin conjugates and further supports the development of antibiotic polymer conjugates in the treatment of MDR infections.
The Novel Immunotherapeutic Oligodeoxynucleotide IMT504 Protects Neutropenic Animals from Fatal Pseudomonas aeruginosa Bacteremia and Sepsis
Authors: Chahin Abdullah , Opal Steven M. , Zorzopulos Jorge , Jobes David V. , Migdady Yazan , Yamamoto Michelle , Parejo Nicholas , Palardy John E. , Horn David L. 
Published: December 2014

ABSTRACT

IMT504 is a novel immunomodulatory oligonucleotide that has shown immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of
Pseudomonas aeruginosa
bacteremia and sepsis. This animal system recapitulates many of the pathological processes found in neutropenic patients with Gram-negative, bacterial infections. The research was conducted in the setting of an academic research laboratory. The test subjects were Sprague-Dawley rats. Animals were rendered neutropenic by administration of cyclophosphamide, colonized with
P. aeruginosa
by oral feeding, and then randomized to receive IMT504 over a range of doses and treatment regimens representing early and late therapeutic interventions. IMT504 immunotherapy conferred a significant survival advantage over the 12-day study period compared with the results seen with placebo-treated animals when the therapy was administered at the onset of neutropenia and even in the absence of antibiotics and after the onset of fever and systemic infection. Notably, even late salvage IMT504 monotherapy was highly effective (13/14 surviving rats with IMT504 therapy versus 2/14 controls,
P
= <0.001). Moreover, late salvage IMT504 monotherapy was as effective as antibiotic therapy (13/14 surviving rats versus 21/21 rats,
P
= 0.88). In addition, no antagonism or loss of therapeutic efficacy was noted with combination therapy of IMT504 plus antibiotics. IMT504 immunotherapy provides a remarkable survival advantage in bacteremia and sepsis in neutropenic animals and deserves further study as a new treatment option in patients with, or at risk for, severe Gram-negative bacterial infections and sepsis.
Comparison of the Accuracy and Precision of Pharmacokinetic Equations To Predict Free Meropenem Concentrations in Critically Ill Patients
Authors: Wong Gloria , Farkas Andras , Sussman Rachel , Daroczi Gergely , Hope William W. , Lipman Jeffrey , Roberts Jason A. 
Published: December 2014

ABSTRACT
Population pharmacokinetic analyses can be applied to predict optimized dosages for individual patients. The aim of this study was to compare the prediction performance of the published population pharmacokinetic models for meropenem in critically ill patients. We coded the published population pharmacokinetic models with covariate relationships into dosing software to predict unbound meropenem concentrations measured in a separate cohort of critically ill patients. The agreements between the observed and predicted concentrations were evaluated with Bland-Altman plots. The absolute and relative bias and precision of the models were determined. The clinical implications of the results were evaluated according to whether dose adjustments were required from the predictions to achieve a meropenem concentration of >2 mg/liter throughout the dosing interval. A total of 157 free meropenem concentrations from 56 patients were analyzed. Eight published population pharmacokinetic models were compared. The models showed an absolute bias in predicting the unbound meropenem concentrations from a mean percent difference (95% confidence interval [CI]) of −108.5% (−119.9% to −97.3%) to 19.9% (7.3% to 32.7%), while absolute precision ranged from −249.1% (−263.4% to −234.8%) to 31.9% (17.6% to 46.2%) and −178.9% (−196.9% to −160.9%) to 175.0% (157.0% to 193.0%). A dose change was required in 44% to 64% of the concentration results. Seven of the eight equations evaluated underpredicted free meropenem concentrations. In conclusion, the overall accuracy of these models supports their inclusion in dosing software and application for individualizing meropenem doses in critically ill patients to increase the likelihood of achievement of optimal antibiotic exposures.
Therapeutic Responses of Plasmodium vivax Malaria to Chloroquine and Primaquine Treatment in Northeastern Myanmar
Authors: Yuan Lili , Wang Ying , Parker Daniel M. , Gupta Bhavna , Yang Zhaoqing , Liu Huaie , Fan Qi , Cao Yaming , Xiao Yuping , Lee Ming-chieh , Zhou Guofa , Yan Guiyun , Baird J. Kevin , Cui Liwang 
Published: December 2014

ABSTRACT

Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of
Plasmodium vivax
malaria. Emergence of CQ-resistant (CQR)
P. vivax
parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for
P. vivax
malaria in northeast Myanmar. We recruited 587 patients with
P. vivax
monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28-day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3α gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of
P. vivax
in northeastern Myanmar may be deteriorating.
Subinhibitory Concentrations of LFF571 Reduce Toxin Production by Clostridium difficile
Authors: Sachdeva Meena , Leeds Jennifer A. 
Published: December 2014

ABSTRACT

LFF571 is a novel semisynthetic thiopeptide antibacterial that is undergoing investigation for safety and efficacy in patients with moderate
Clostridium difficile
infections. LFF571 inhibits bacterial protein synthesis by interacting with elongation factor Tu (EF-Tu) and interrupting complex formation between EF-Tu and aminoacyl-tRNA. Given this mechanism of action, we hypothesized that concentrations of LFF571 below those necessary to inhibit bacterial growth would reduce steady-state toxin levels in
C. difficile
cultures. We investigated
C. difficile
growth and toxin A and B levels in the presence of LFF571, fidaxomicin, vancomycin, and metronidazole. LFF571 led to strain-dependent effects on toxin production, including decreased toxin levels after treatment with subinhibitory concentrations, and more rapid declines in toxin production than in inhibition of colony formation. Fidaxomicin, which is an RNA synthesis inhibitor, conferred a similar pattern to LFF571 with respect to toxin levels versus viable cell counts. The incubation of two toxigenic
C. difficile
strains with subinhibitory concentrations of vancomycin, a cell wall synthesis inhibitor, increased toxin levels in the supernatant over those of untreated cultures. A similar phenomenon was observed with one metronidazole-treated strain of
C. difficile
. These studies indicate that LFF571 and fidaxomicin generally result in decreased
C. difficile
toxin levels in culture supernatants, whereas treatment of some strains with vancomycin or metronidazole had the potential to increase toxin levels. Although the relevance of these findings remains to be studied in patients, reducing toxin levels with sub-growth-inhibitory concentrations of an antibiotic is hypothesized to be beneficial in alleviating symptoms.
Multilaboratory Testing of Antifungal Drug Combinations against Candida Species and Aspergillus fumigatus: Utility of 100 Percent Inhibition as the Endpoint
Authors: Ren Ping , Luo Ming , Lin Shao , Ghannoum Mahmoud A. , Isham Nancy , Diekema Dan J. , Pfaller Michael A. , Messer Shawn , Lockhart Shawn R. , Iqbal Naureen , Chaturvedi Vishnu 
Published: December 2014

ABSTRACT

Four laboratories tested three isolates of
Candida
species and two isolates of
Aspergillus fumigatus
using 96-well plates containing combinations of amphotericin B, anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, and voriconazole. The majority of summation fractional inhibitory concentration indices (ΣFICI) based on the Lowe additivity formula suggested indifferent drug interactions (ΣFICI > 0.5 and ≤4.0) and no instance of drug antagonism (ΣFICI > 4.0). The intra- and interlaboratory agreement rates were superior when MIC
100
readings were used as endpoints (at a 99% confidence interval [CI]).
Antimalarial Iron Chelator FBS0701 Blocks Transmission by Plasmodium falciparum Gametocyte Activation Inhibition
Authors: Ferrer Patricia , Vega-Rodriguez Joel , Tripathi Abhai K. , Jacobs-Lorena Marcelo , Sullivan David J. 
Published: December 2014

ABSTRACT

Reducing the transmission of the malarial parasite by
Anopheles
mosquitoes using drugs or vaccines remains a main focus in the efforts to control malaria. Iron chelators have been studied as potential antimalarial drugs due to their activities against different stages of the parasite. The iron chelator FBS0701 affects the development of
Plasmodium falciparum
early gametocytes and lowers blood-stage parasitemia. Here, we tested the effect of FBS0701 on stage V gametocyte infectivity for mosquitoes. The incubation of stage V gametocytes for up to 3 days with increasing concentrations of FBS0701 resulted in a significant dose-related reduction in mosquito infectivity, as measured by the numbers of oocysts per mosquito. The reduction in mosquito infectivity was due to the inhibition of male and female gametocyte activation. The preincubation of FBS0701 with ferric chloride restored gametocyte infectivity, showing that the inhibitory effect of FBS0701 was quenched by iron. Deferoxamine, another iron chelator, also reduced gametocyte infectivity but to a lesser extent. Finally, the simultaneous administration of drug and gametocytes to mosquitoes without previous incubation did not significantly reduce the numbers of oocysts. These results show the importance of gametocyte iron metabolism as a potential target for new transmission-blocking strategies.
Small-Molecule Xenomycins Inhibit All Stages of the Plasmodium Life Cycle
Authors: Erath Jessey , Gallego-Delgado Julio , Xu Wenyue , Andriani Grasiella , Tanghe Scott , Gurova Katerina V. , Gudkov Andrei , Purmal Andrei , Rydkina Elena , Rodriguez Ana 
Published: December 2014

ABSTRACT

Widespread resistance to most antimalaria drugs in use has prompted the search for novel candidate compounds with activity against
Plasmodium
asexual blood stages to be developed for treatment. In addition, the current malaria eradication programs require the development of drugs that are effective against all stages of the parasite life cycle. We have analyzed the antimalarial properties of xenomycins, a novel subclass of small molecule compounds initially isolated for anticancer activity and similarity to quinacrine in biological effects on mammalian cells.
In vitro
studies show potent activity of Xenomycins against
Plasmodium falciparum
. Oral administration of xenomycins in mouse models result in effective clearance of liver and blood asexual and sexual stages, as well as effective inhibition of transmission to mosquitoes. These characteristics position xenomycins as antimalarial candidates with potential activity in prevention, treatment and elimination of this disease.
Genomic, Proteomic, and Biochemical Analysis of the Organohalide Respiratory Pathway in Desulfitobacterium dehalogenans
Authors: Kruse Thomas , van de Pas Bram A. , Atteia Ariane , Krab Klaas , Hagen Wilfred R. , Goodwin Lynne , Chain Patrick , Boeren Sjef , Maphosa Farai , Schraa Gosse , de Vos Willem M. , van der Oost John , Smidt Hauke , Stams Alfons J. M. 
Published: December 2014

ABSTRACT

Desulfitobacterium dehalogenans
is able to grow by organohalide respiration using 3-chloro-4-hydroxyphenyl acetate (Cl-OHPA) as an electron acceptor. We used a combination of genome sequencing, biochemical analysis of redox active components, and shotgun proteomics to study elements of the organohalide respiratory electron transport chain. The genome of
Desulfitobacterium dehalogenans
JW/IU-DC1
T
consists of a single circular chromosome of 4,321,753 bp with a GC content of 44.97%. The genome contains 4,252 genes, including six rRNA operons and six predicted reductive dehalogenases. One of the reductive dehalogenases, CprA, is encoded by a well-characterized
cprTKZEBACD
gene cluster. Redox active components were identified in concentrated suspensions of cells grown on formate and Cl-OHPA or formate and fumarate, using electron paramagnetic resonance (EPR), visible spectroscopy, and high-performance liquid chromatography (HPLC) analysis of membrane extracts. In cell suspensions, these components were reduced upon addition of formate and oxidized after addition of Cl-OHPA, indicating involvement in organohalide respiration. Genome analysis revealed genes that likely encode the identified components of the electron transport chain from formate to fumarate or Cl-OHPA. Data presented here suggest that the first part of the electron transport chain from formate to fumarate or Cl-OHPA is shared. Electrons are channeled from an outward-facing formate dehydrogenase via menaquinones to a fumarate reductase located at the cytoplasmic face of the membrane. When Cl-OHPA is the terminal electron acceptor, electrons are transferred from menaquinones to outward-facing CprA, via an as-yet-unidentified membrane complex, and potentially an extracellular flavoprotein acting as an electron shuttle between the quinol dehydrogenase membrane complex and CprA.
Random sample community-based health surveys: does the effort to reach participants matter?
Authors: Messiah Antoine , Castro Grettel , Rodríguez de la Vega Pura , Acuna Juan M 
Published: December 2014

ObjectivesConducting health surveys with community-based random samples are essential to capture an otherwise unreachable population, but these surveys can be biased if the effort to reach participants is insufficient. This study determines the desirable amount of effort to minimise such bias.DesignA household-based health survey with random sampling and face-to-face interviews. Up to 11 visits, organised by canvassing rounds, were made to obtain an interview.SettingSingle-family homes in an underserved and understudied population in North Miami-Dade County, Florida, USA.ParticipantsOf a probabilistic sample of 2200 household addresses, 30 corresponded to empty lots, 74 were abandoned houses, 625 households declined to participate and 265 could not be reached and interviewed within 11 attempts. Analyses were performed on the 1206 remaining households.Primary outcomeEach household was asked if any of their members had been told by a doctor that they had high blood pressure, heart disease including heart attack, cancer, diabetes, anxiety/ depression, obesity or asthma. Responses to these questions were analysed by the number of visit attempts needed to obtain the interview.ResultsReturn per visit fell below 10% after four attempts, below 5% after six attempts and below 2% after eight attempts. As the effort increased, household size decreased, while household income and the percentage of interviewees active and employed increased; proportion of the seven health conditions decreased, four of which did so significantly: heart disease 20.4–9.2%, high blood pressure 63.5–58.1%, anxiety/depression 24.4–9.2% and obesity 21.8–12.6%. Beyond the fifth attempt, however, cumulative percentages varied by less than 1% and precision varied by less than 0.1%.ConclusionsIn spite of the early and steep drop, sustaining at least five attempts to reach participants is necessary to reduce selection bias.
Increasing proportion of female patients with ankylosing spondylitis: a population-based study of trends in the incidence and prevalence of AS
Authors: Haroon Nisha N , Paterson J Michael , Li Ping , Haroon Nigil 
Published: December 2014

ObjectiveWith the introduction of MRI in diagnosis and tumour necrosis factor inhibitors for treatment, the field of ankylosing spondylitis (AS) has undergone significant changes. We carried out a population-based study of the trends in incidence and prevalence of AS over the past 15 years.MethodsThis is a retrospective analysis of provincial health administrative databases. Residents of Ontario, Canada aged 15 years or older diagnosed with AS between 1995 and 2010 were included in the study. Crude as well as age-standardised and sex-standardised incidence and prevalence of AS between 1995 and 2010 were calculated. Trends in prevalence and incidence of male and female patients with AS were separately analysed.ResultsWe identified 24 976 Ontarians with AS. Age/sex-standardised AS prevalence increased from 79/100 000 in 1995 to 213/100 000 in 2010. Men had higher prevalence than women, but the male/female prevalence ratio decreased from 1.70 in 1995 to 1.21 by 2010. A higher proportion of male compared with female patients with AS were diagnosed in the 15–45 age group. Annual incidence rates revealed increasing diagnosis of AS among women after 2003.ConclusionsThe prevalence of AS in Ontario has nearly tripled over the past two decades. The proportion of women with new diagnosis of AS is increasing, a trend that began around the year 2003. A higher proportion of male compared with female patients with AS are diagnosed at an earlier age.
The relationship between gasoline price and patterns of motorcycle fatalities and injuries
Authors: Zhu He , Wilson Fernando A , Stimpson Jim P 
Published: December 2014

ObjectiveEconomic factors such as rising gasoline prices may contribute to the crash trends by shaping individuals’ choices of transportation modalities. This study examines the relationship of gasoline prices with fatal and non-fatal motorcycle injuries.MethodsData on fatal and non-fatal motorcycle injuries come from California's Statewide Integrated Traffic Records System for 2002–2011. Autoregressive integrated moving average (ARIMA) regressions were used to estimate the impact of inflation-adjusted gasoline price per gallon on trends of motorcycle injuries.ResultsMotorcycle fatalities and severe and minor injuries in California were highly correlated with increasing gasoline prices from 2002 to 2011 (r=0.76, 0.88 and 0.85, respectively). In 2008, the number of fatalities and injuries reached 13 457—a 34% increase since 2002, a time period in which inflation-adjusted gasoline prices increased about $0.30 per gallon every year. The majority of motorcycle riders involved in crashes were male (92.5%), middle-aged (46.2%) and non-Hispanic white (67.9%). Using ARIMA modelling, we estimated that rising gasoline prices resulted in an additional 800 fatalities and 10 290 injuries from 2002 to 2011 in California.ConclusionsOur findings suggest that increasing gasoline prices led to more motorcycle riders on the roads and, consequently, more injuries. Aside from mandatory helmet laws and their enforcement, other strategies may include raising risk awareness of motorcyclists and investment in public transportation as an alternative transportation modality to motorcycling. In addition, universally mandated training courses and strict licensing tests of riding skills should be emphasised to help reduce the motorcycle fatal and non-fatal injuries.
Classification of left ventricular size: diameter or volume with contrast echocardiography?
Authors: Gibson Patrick H , Becher Harald , Choy Jonathan B 
Published: December 2014

BackgroundLeft ventricular (LV) size is an important clinical variable, commonly assessed at echocardiography by measurement of the internal diameter in diastole (IDD). However, this has recognised limitations and volumetric measurement from apical views is considered superior, particularly with the use of echocardiographic contrast. We sought to determine the agreement in classification of LV size by different measures in a large population of patients undergoing echocardiography.Methods and resultsData were analysed retrospectively from consecutive patients (n=2008, 61% male, median 62 years) who received echocardiographic contrast for LV opacification over 3 years in a single institution. Repeat studies were not included. LVIDD was measured, and LV end-diastolic volume (LVEDV) calculated using Simpson's biplane method. Both measures were indexed (i) to body surface area and categorised according to the American Society of Echocardiography (ASE) guidelines as normal, mild, moderate or severely dilated. Of 320 patients with a severely dilated LVEDVi, only 95 (30%) were similarly classified by LVIDD, with 86 patients (27%) measuring in the normal range. LVIDDi agreement was poorer, with only 43 patients (13%) classified as being severely dilated, and 173 (54%) measuring in the normal range.ConclusionsCurrently recommended echocardiographic measures of LV size show limited agreement when classified according to currently recommended cut-offs. LV diameter should have a limited role in the assessment of LV size, particularly where a finding of LV dilation has important diagnostic or therapeutic implications.