bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of IncA/C Plasmid Replication and Maintenance Genes and Development of a Plasmid Multilocus Sequence Typing Scheme
Authors: Hancock Steven J. , Phan Minh-Duy , Peters Kate M. , Forde Brian M. , Chong Teik Min , Yin Wai-Fong , Chan Kok-Gan , Paterson David L. , Walsh Timothy R. , Beatson Scott A. , Schembri Mark A. 
Published: November 2016

ABSTRACTPlasmids of incompatibility group A/C (IncA/C) are becoming increasingly prevalent within pathogenicEnterobacteriaceae. They are associated with the dissemination of multiple clinically relevant resistance genes, includingblaCMYandblaNDM. Current typing methods for IncA/C plasmids offer limited resolution. In this study, we present the complete sequence of ablaNDM-1-positive IncA/C plasmid, pMS6198A, isolated from a multidrug-resistant uropathogenicEscherichia colistrain. Hypersaturated transposon mutagenesis, coupled with transposon-directed insertion site sequencing (TraDIS), was employed to identify conserved genetic elements required for replication and maintenance of pMS6198A. Our analysis of TraDIS data identified roles for the replicon, includingrepA, a toxin-antitoxin system; two putative partitioning genes,parAB; and a putative gene,053. Construction of mini-IncA/C plasmids and examination of their stability withinE. coliconfirmed that the region encompassing053contributes to the stable maintenance of IncA/C plasmids. Subsequently, the four major maintenance genes (repA,parAB, and053) were used to construct a new plasmid multilocus sequence typing (PMLST) scheme for IncA/C plasmids. Application of this scheme to a database of 82 IncA/C plasmids identified 11 unique sequence types (STs), with two dominant STs. The majority ofblaNDM-positive plasmids examined (15/17; 88%) fall into ST1, suggesting acquisition and subsequent expansion of thisblaNDM-containing plasmid lineage. The IncA/C PMLST scheme represents a standardized tool to identify, track, and analyze the dissemination of important IncA/C plasmid lineages, particularly in the context of epidemiological studies.
Classical β-Lactamase Inhibitors Potentiate the Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus and Colistin against Acinetobacter baumannii
Authors: Sakoulas George , Rose Warren , Berti Andrew , Olson Joshua , Munguia Jason , Nonejuie Poochit , Sakoulas Eleanna , Rybak Michael J. , Pogliano Joseph , Nizet Victor 
Published: November 2016

ABSTRACT

We asked whether beta-lactamase inhibitors (BLIs) increased the activity of daptomycin (DAP) against methicillin-resistant
Staphylococcus aureus
(MRSA), the peptide antibiotic colistin (COL) against the emerging Gram-negative nosocomial pathogen
Acinetobacter baumannii
, and the human host defense peptide cathelicidin LL37 against either pathogen. DAP and LL37 kill curves were performed with or without BLIs against MRSA, vancomycin-intermediate
S. aureus
(VISA), and heterogeneous VISA (hVISA). COL and LL37 kill curves were performed against
A. baumannii
. Boron-dipyrromethene (BODIPY)-labeled DAP binding to MRSA grown with the BLI tazobactam (TAZ) was assessed microscopically. The combination of COL plus TAZ was studied in a murine model of
A. baumannii
pneumonia. TAZ alone lacked
in vitro
activity against MRSA or
A. baumannii
. The addition of TAZ to DAP resulted in a 2- to 5-log
10
reduction in recoverable MRSA CFU at 24 h compared to the recoverable CFU with DAP alone. TAZ plus COL showed synergy by kill curves for 4 of 5 strains of
A. baumannii
tested. Growth with 20 mg/liter TAZ resulted in 2- to 2.5-fold increases in the intensity of BODIPY-DAP binding to MRSA and hVISA strains. TAZ significantly increased the killing of MRSA and
A. baumannii
by LL37
in vitro
. TAZ increased the activity of COL in a murine model of
A. baumannii
pneumonia. Classical BLIs demonstrate synergy with peptide antibiotics. Since BLIs have scant antimicrobial activity on their own and are thus not expected to increase selective pressure toward antibiotic resistance, their use in combination with peptide antibiotics warrants further study.
Evaluation of Doravirine Pharmacokinetics When Switching from Efavirenz to Doravirine in Healthy Subjects
Authors: Yee Ka Lai , Sanchez Rosa I. , Auger Patrice , Liu Rachael , Fan Li , Triantafyllou Ilias , Lai Ming-Tain , Di Spirito Mike , Iwamoto Marian , Khalilieh Sauzanne G. 
Published: November 2016

ABSTRACT

Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC
0–24
), maximum observed plasma concentration (
C
max
), and observed plasma concentration at 24 h postdosing (
C
24
) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC
0–24
,
C
max
, and
C
24
, respectively, by day 14 after efavirenz cessation. The doravirine
C
24
reached projected therapeutic trough concentrations, based on
in vitro
efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.
Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains
Authors: Abdelhady Wessam , Bayer Arnold S. , Gonzales Rachelle , Li Liang , Xiong Yan Q. 
Published: November 2016

ABSTRACT

We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAP
r
) methicillin-resistant
Staphylococcus aureus
(MRSA) strains. TLV treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative compared to those with the untreated control or DAP-treated animals. These results demonstrate that TLV has potent
in vivo
efficacy against DAP
r
MRSA isolates in this invasive endovascular infection model.
Pharmacokinetics of Anidulafungin in Critically Ill Intensive Care Unit Patients with Suspected or Proven Invasive Fungal Infections
Authors: Brüggemann R. J. M. , Middel-Baars V. , de Lange D. W. , Colbers A. , Girbes A. R. J. , Pickkers P. , Swart E. L. 
Published: November 2016

ABSTRACT

Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twenty-three of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 (
n
= 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC
0–24
) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg · h · liter
−1
, a median daily trough concentration (
C
24
) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum (
C
max
) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution (
V
) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters · h
−1
. Pharmacokinetic sampling on day 7 (
n
= 13) resulted in a median AUC
0–24
of 82.7 (IQR, 73.0 to 129.5) mg · h · liter
−1
, a median minimum concentration of drug in serum (
C
min
) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median
C
max
of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median
V
of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters · h
−1
. The geometric mean ratio for the AUC
day7
/AUC
day3
term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.)
Estimation of the
In Vivo
MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria
Authors: Hien Tran Tinh , White Nicholas J. , Thuy-Nhien Nguyen Thanh , Hoa Nhu Thi , Thuan Phung Duc , Tarning Joel , Nosten François , Magnusson Baldur , Jain Jay Prakash , Hamed Kamal 
Published: November 2016

ABSTRACT

The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the
in vivo
MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated
Plasmodium falciparum
malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute
P. falciparum
malaria were allocated sequentially to treatment with a single 30-mg (
n
= 6), 20-mg (
n
= 5), 10-mg (
n
= 7), or 15-mg (
n
= 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median
in vivo
MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.)
Control of Biofilm Formation: Antibiotics and Beyond
Authors: Algburi Ammar , Comito Nicole , Kashtanov Dimitri , Dicks Leon M. T. , Chikindas Michael L. 
Published: November 2016

ABSTRACT
Biofilm-associated bacteria are less sensitive to antibiotics than free-living (planktonic) cells. Furthermore, with variations in the concentration of antibiotics throughout a biofilm, microbial cells are often exposed to levels below inhibitory concentrations and may develop resistance. This, as well as the irresponsible use of antibiotics, leads to the selection of pathogens that are difficult to eradicate. The Centers for Disease Control and Prevention use the terms “antibiotic” and “antimicrobial agent” interchangeably. However, a clear distinction between these two terms is required for the purpose of this assessment. Therefore, we define “antibiotics” as pharmaceutically formulated and medically administered substances and “antimicrobials” as a broad category of substances which are not regulated as drugs. This comprehensive minireview evaluates the effect of natural antimicrobials on pathogens in biofilms when used instead of, or in combination with, commonly prescribed antibiotics.
Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence
Authors: Thomassin Jenny-Lee , Leclerc Jean-Mathieu , Giannakopoulou Natalia , Zhu Lei , Salmon Kristiana , Portt Andrea , Daigle France , Le Moual Hervé , Gruenheid Samantha 
Published: November 2016

ABSTRACT

Citrobacter rodentium
is a murine pathogen used to model intestinal infections caused by the human diarrheal pathogens enterohemorrhagic and enteropathogenic
Escherichia coli
. During infection, bacteria use two-component systems (TCSs) to detect changing environmental cues within the host, allowing for rapid adaptation by altering the expression of specific genes. In this study, 26 TCSs were identified in
C. rodentium
, and quantitative PCR (qPCR) analysis showed that they are all expressed during murine infection. These TCSs were individually deleted, and the
in vitro
and
in vivo
effects were analyzed to determine the functional consequences.
In vitro
analyses only revealed minor differences, and surprisingly, type III secretion (T3S) was only affected in the Δ
arcA
strain. Murine infections identified 7 mutants with either attenuated or increased virulence. In agreement with the
in vitro
T3S assay, the Δ
arcA
strain was attenuated and defective in colonization and cell adherence. The Δ
rcsB
strain was among the most highly attenuated strains. The decrease in virulence of this strain may be associated with changes to the cell surface, as Congo red binding was altered, and qPCR revealed that expression of the
wcaA
gene, which has been implicated in colanic acid production in other bacteria, was drastically downregulated. The Δ
uvrY
strain exhibited increased virulence compared to the wild type, which was associated with a significant increase in bacterial burden within the mesenteric lymph nodes. The systematic analysis of virulence-associated TCSs and investigation of their functions during infection may open new avenues for drug development.
How old is Kīlauea Volcano (Hawai‘i)? Insights from 40Ar/39Ar dating of the 1.7-km-deep SOH-1 core
Authors: Garcia Michael O. , Jicha Brian R. , Marske Jared P. , Pietruszka Aaron J. 
Published: November 2016

Abstract
Reliable estimates for lava accumulation rates are essential for interpreting magma fluxes to intraplate volcanoes and inferring the thermal and compositional structure of mantle plumes. Kīlauea Volcano’s (Hawai‘i) 1.7-km-deep SOH-1 scientific drill hole provides an opportunity to assess the lava accumulation rate and duration of the early shield stage for Hawaiian volcanoes. New 40Ar/39Ar ages were determined for four SOH-1 tholeiitic samples. Combining these results with two previous 40Ar/39Ar ages and the age of the drill-site surface flow, and correcting sample depth to remove intervening dikes, yields a good correlation (R2 = 0.97) for a 4.4 m/k.y. accumulation rate, which may have increased to 5.9 m/k.y. during the last 50 k.y. These rates contrast with a predicted 40% decrease during the last 200 k.y. from a simple shield volcano growth model. Mauna Loa, a massive shield volcano that buttresses the north flank of Kīlauea, may have contributed to this nearly constant lava accumulation rate. Extending the correlation to the base of the SOH-1 core indicates that Kīlauea’s tholeiitic volcanism probably started by 240 ka. Assuming an ∼400 k.y. duration for the preshield stage, Kīlauea is much older than some previous estimates (ca. 600 ka versus 150–275 ka) and has been vigorously erupting tholeiitic lavas for at least the past 200 k.y. During this period, it has been competing with Mauna Loa for the higher-temperature output of the Hawaiian mantle plume, which is contrary to previous models. New models that assess the magmatic output and thermal history of the Hawaiian mantle plume need to consider a steep increase in magma supply during the transition from preshield to shield stages to explain the near-constant lava accumulation rate during early shield growth.
Preservation or piracy: Diagnosing low-relief, high-elevation surface formation mechanisms
Authors: Whipple Kelin X. , DiBiase Roman A. , Ouimet William B. , Forte Adam M. 
Published: November 2016

Abstract
Absent clear lithologic control, the presence of elevated, low-relief topography in upland landscapes has traditionally been interpreted as a signature of relative surface uplift and incision of a paleo-landscape. Such interpretations are commonly supported and quantified using analyses of river longitudinal profiles under the assumption of a static drainage network topology. Drainage networks, however, are not static, and it has been proposed recently that divide migration and drainage capture can lead to the generation of low-relief upland topography that mimics that of incised paleo-landscapes and that might be falsely interpreted as recording surface uplift and/or the onset of accelerated incision. Indeed, the interpretation of the incised southeastern Tibetan Plateau, and thus the associated geodynamic implications, have been called into question. Here we use theory and one- and two-dimensional landscape evolution models to develop a set of morphometric criteria to distinguish these alternative mechanisms of low-relief upland formation. Application to the southeastern Tibetan Plateau illustrates the utility of these metrics and demonstrates that the topography is in no way consistent with the drainage network dynamics mechanism and is fully consistent with incision into an elevated, preexisting low-relief landscape.
Water concentration profiles in natural mantle orthopyroxenes: A geochronometer for long annealing of xenoliths within magma
Authors: Tian Zhen-Zhen , Liu Jia , Xia Qun-Ke , Ingrin Jannick , Hao Yan-Tao , Christophe Depecker 
Published: November 2016

Abstract
Both mantle-derived clinopyroxene and orthopyroxene are generally homogeneous in water concentration, while water content in the coexisting olivine is affected by partial or complete loss during the ascent of the hosting magma. Here, we report the first record of water content profiles (higher water in the cores than in the rims) in natural orthopyroxene grains in peridotite xenoliths hosted by Cenozoic alkali basalts in Tianchang volcano, eastern China. The water contents of the coexisting clinopyroxene grains are homogeneous and are twice that measured in the cores of orthopyroxene grains, confirming previous chemical equilibrium between the two pyroxenes. The olivines (ol) are nearly dry (∼0 ppm). These observations demonstrate that H diffusion in mantle orthopyroxene (opx) is faster than in clinopyroxene (cpx), and the relative mobility of H in each mineral phase could be quantified as: (where is the chemical diffusion coefficient of hydrogen). Combining this with experimental diffusion coefficients from the literature, we infer that (1) the xenoliths remained in contact with the magma below 900 °C for several months, and (2) clinopyroxene remains the more reliable recorder of water from depth, and orthopyroxene should be used more cautiously but can be considered with olivine for tracing slow transport and cooling of magma.
Validation of the German Diabetes Risk Score among the general adult population: findings from the German Health Interview and Examination Surveys
Authors: Paprott Rebecca , Mühlenbruch Kristin , Mensink Gert B M , Thiele Silke , Schulze Matthias B , Scheidt-Nave Christa , Heidemann Christin 
Published: November 2016

ObjectiveTo evaluate the German Diabetes Risk Score (GDRS) among the general adult German population for prediction of incident type 2 diabetes and detection of prevalent undiagnosed diabetes.MethodsThe longitudinal sample for prediction of incident diagnosed type 2 diabetes included 3625 persons who participated both in the examination survey in 1997–1999 and the examination survey in 2008–2011. Incident diagnosed type 2 diabetes was defined as first-time physician diagnosis or antidiabetic medication during 5 years of follow-up excluding potential incident type 1 and gestational diabetes. The cross-sectional sample for detection of prevalent undiagnosed diabetes included 6048 participants without diagnosed diabetes of the examination survey in 2008–2011. Prevalent undiagnosed diabetes was defined as glycated haemoglobin ≥6.5% (48 mmol/mol). We assessed discrimination as area under the receiver operating characteristic curve (ROC-AUC (95% CI)) and calibration through calibration plots.ResultsIn longitudinal analyses, 82 subjects with incident diagnosed type 2 diabetes were identified after 5 years of follow-up. For prediction of incident diagnosed diabetes, the GDRS yielded an ROC-AUC of 0.87 (0.83 to 0.90). Calibration plots indicated excellent prediction for low diabetes risk and overestimation for intermediate and high diabetes risk. When considering the entire follow-up period of 11.9 years (ROC-AUC: 0.84 (0.82 to 0.86)) and including incident undiagnosed diabetes (ROC-AUC: 0.81 (0.78 to 0.84)), discrimination decreased somewhat. A previously simplified paper version of the GDRS yielded a similar predictive ability (ROC-AUC: 0.86 (0.82 to 0.89)). In cross-sectional analyses, 128 subjects with undiagnosed diabetes were identified. For detection of prevalent undiagnosed diabetes, the ROC-AUC was 0.84 (0.81 to 0.86). Again, the simplified version yielded a similar result (ROC-AUC: 0.83 (0.80 to 0.86)).ConclusionsThe GDRS might be applied for public health monitoring of diabetes risk in the German adult population. Future research needs to evaluate whether the GDRS is useful to improve diabetes risk awareness and prevention among the general population.