bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carbapenemase-Producing Enterobacteriaceae Recovered from the Environment of a Swine Farrow-to-Finish Operation in the United States
Authors: Mollenkopf Dixie F. , Stull Jason W. , Mathys Dimitria A. , Bowman Andrew S. , Feicht Sydnee M. , Grooters Susan V. , Daniels Joshua B. , Wittum Thomas E. 
Published: December 2016

ABSTRACT

Carbapenem-resistant
Enterobacteriaceae
(CRE) present an urgent threat to public health. While use of carbapenem antimicrobials is restricted for food-producing animals, other β-lactams, such as ceftiofur, are used in livestock. This use may provide selection pressure favoring the amplification of carbapenem resistance, but this relationship has not been established. Previously unreported among U.S. livestock, plasmid-mediated CRE have been reported from livestock in Europe and Asia. In this study, environmental and fecal samples were collected from a 1,500-sow, U.S. farrow-to-finish operation during 4 visits over a 5-month period in 2015. Samples were screened using selective media for the presence of CRE, and the resulting carbapenemase-producing isolates were further characterized. Of 30 environmental samples collected from a nursery room on our initial visit, 2 (7%) samples yielded 3 isolates, 2 sequence type 218 (ST 218)
Escherichia coli
and 1
Proteus mirabilis
, carrying the metallo-β-lactamase gene
bla
IMP-27
on IncQ1 plasmids. We recovered on our third visit 15 IMP-27-bearing isolates of multiple
Enterobacteriaceae
species from 11 of 24 (46%) environmental samples from 2 farrowing rooms. These isolates each also carried
bla
IMP-27
on IncQ1 plasmids. No CRE isolates were recovered from fecal swabs or samples in this study. As is common in U.S. swine production, piglets on this farm receive ceftiofur at birth, with males receiving a second dose at castration (≈day 6). This selection pressure may favor the dissemination of
bla
IMP-27
-bearing
Enterobacteriaceae
in this farrowing barn. The absence of this selection pressure in the nursery and finisher barns likely resulted in the loss of the ecological niche needed for maintenance of this carbapenem resistance gene.
A Prolonged Outbreak of KPC-3-Producing Enterobacter cloacae and Klebsiella pneumoniae Driven by Multiple Mechanisms of Resistance Transmission at a Large Academic Burn Center
Authors: Kanamori Hajime , Parobek Christian M. , Juliano Jonathan J. , van Duin David , Cairns Bruce A. , Weber David J. , Rutala William A. 
Published: December 2016

ABSTRACT

Klebsiella pneumoniae
carbapenemase (KPC)-producing
Enterobacter cloacae
has been recently recognized in the United States. Whole-genome sequencing (WGS) has become a useful tool for analysis of outbreaks and for determining transmission networks of multidrug-resistant organisms in health care settings, including carbapenem-resistant
Enterobacteriaceae
(CRE). We experienced a prolonged outbreak of CRE
E. cloacae
and
K. pneumoniae
over a 3-year period at a large academic burn center despite rigorous infection control measures. To understand the molecular mechanisms that sustained this outbreak, we investigated the CRE outbreak isolates by using WGS. Twenty-two clinical isolates of CRE, including
E. cloacae
(
n
= 15) and
K. pneumoniae
(
n
= 7), were sequenced and analyzed genetically. WGS revealed that this outbreak, which seemed epidemiologically unlinked, was in fact genetically linked over a prolonged period. Multiple mechanisms were found to account for the ongoing outbreak of KPC-3-producing
E. cloacae
and
K. pneumoniae
. This outbreak was primarily maintained by a clonal expansion of
E. cloacae
sequence type 114 (ST114) with distribution of multiple resistance determinants. Plasmid and transposon analyses suggested that the majority of
bla
KPC-3
was transmitted via an identical Tn
4401
b element on part of a common plasmid. WGS analysis demonstrated complex transmission dynamics within the burn center at levels of the strain and/or plasmid in association with a transposon, highlighting the versatility of KPC-producing
Enterobacteriaceae
in their ability to utilize multiple modes to resistance gene propagation.
High-Throughput Screening and Prediction Model Building for Novel Hemozoin Inhibitors Using Physicochemical Properties
Authors: Huy Nguyen Tien , Chi Pham Lan , Nagai Jun , Dang Tran Ngoc , Mbanefo Evaristus Chibunna , Ahmed Ali Mahmoud , Long Nguyen Phuoc , Thoa Le Thi Bich , Hung Le Phi , Titouna Afaf , Kamei Kaeko , Ueda Hiroshi , Hirayama Kenji 
Published: December 2016

ABSTRACT

It is essential to continue the search for novel antimalarial drugs due to the current spread of resistance against artemisinin by
Plasmodium falciparum
parasites. In this study, we developed
in silico
models to predict hemozoin inhibitors as a potential first-step screening for novel antimalarials. An
in vitro
colorimetric high-throughput screening assay of hemozoin formation was used to identify hemozoin inhibitors from 9,600 structurally diverse compounds. The physicochemical properties of positive hits and randomly selected compounds were extracted from the ChemSpider database; they were used for developing prediction models to predict hemozoin inhibitors using two different approaches, i.e., traditional multivariate logistic regression and Bayesian model averaging. Our results showed that a total of 224 positive-hit compounds exhibited the ability to inhibit hemozoin formation, with 50% inhibitory concentrations (IC
50
s) ranging from 3.1 μM to 199.5 μM. The best model according to traditional multivariate logistic regression included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and number of atoms of hydrogen, while the best model according to Bayesian model averaging included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and index of refraction. Both models had a good discriminatory power, with area under the curve values of 0.736 and 0.781 for the traditional multivariate model and Bayesian model averaging, respectively. In conclusion, the prediction models can be a new, useful, and cost-effective approach for the first screen of hemozoin inhibition-based antimalarial drug discovery.
Safety and Pharmacokinetics of CD101 IV, a Novel Echinocandin, in Healthy Adults
Authors: Sandison Taylor , Ong Voon , Lee Jonathan , Thye Dirk 
Published: December 2016

ABSTRACT

CD101 IV is a novel echinocandin with distinctive pharmacokinetic properties that is being developed as a once-weekly treatment for candidemia and invasive candidiasis. CD101 has potent
in vitro
activity and
in vivo
efficacy against a broad range of
Candida
and
Aspergillus
species. The primary objective of two randomized, double-blind, placebo-controlled, dose-escalation studies in healthy adults was to determine the safety and tolerability of CD101 IV. Sequential cohorts of 8 subjects (
n
= 6, active;
n
= 2, placebo) were administered single (50, 100, 200, 400 mg) or multiple once-weekly (100 mg given once weekly for two weeks [×2], 200 mg ×2, 400 mg ×3) doses of CD101 IV infused over 1 h. There were no deaths, serious adverse events (SAEs), severe adverse events (AEs), or withdrawals from the study due to an AE. The majority of AEs were mild, and all completely resolved. There was a higher incidence of total AEs and mild transient infusion reactions in the 400-mg ×3 dose group. There were no clinically meaningful trends in postbaseline laboratory abnormalities and no safety issues related to electrocardiograms, vital signs, or physical exams. CD101 showed dose-proportional plasma exposures, minor accumulation (30% to 55%), low apparent clearance (<0.28 liter/h), long half-life (
t
1/2
) (>80 h), and minimal urine excretion. CD101 IV was safe and well tolerated at single and multiple doses of up to 400 mg given once weekly for 3 weeks and exhibited a long
t
1/2
, minimal accumulation over several weeks, negligible renal excretion, and high plasma exposures enabling once-weekly dosing.
Pharmacokinetic Evaluation of Darunavir Administered Once or Twice Daily in Combination with Ritonavir or the Three-Direct-Acting Antiviral Regimen of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Adults Coinfected with Hepatitis C and Human Immunodeficiency Viruses
Authors: King Jennifer R. , Khatri Amit , Trinh Roger , Viani Rolando M. , Ding Bifeng , Zha Jiuhong , Menon Rajeev 
Published: December 2016

ABSTRACT

The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day −1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval [CI]) for maximum concentrations (
C
max
), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC
24
), and trough plasma concentration at 24 h postdose (
C
24
) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir
C
max
, AUC
12
, and
C
12
administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (
C
trough
) associated with an HIV-1 RNA level of >40 copies/ml were above the darunavir 50% effective concentration (EC
50
) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir
C
max
and AUC, whereas the darunavir
C
trough
decreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir
C
trough
values below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.)
Genotyping and Prevalence of Pyrazinamide- and Moxifloxacin-Resistant Tuberculosis in China, 2000 to 2010
Authors: Pang Yu , Zhang Zhijian , Wang Yufeng , Wang Shengfen , Song Yuanyuan , Zhao Bing , Zhou Yang , Ou Xichao , Li Qiang , Xia Hui , Zheng Yang , Fang Xiangqun , Zhao Yanlin 
Published: December 2016

ABSTRACT

We investigated the prevalence, trends, and risk factors for pyrazinamide (PZA) and moxifloxacin (MOX) resistance among tuberculosis (TB) cases in China and also analyzed the population structure of
Mycobacterium tuberculosis
strains. All the
M. tuberculosis
strains enrolled in this study were collected from the national TB prevalence surveys. Each strain was genotyped by analyzing the regions of RD105 and IS
6110
in the NTF region. The Bactec MGIT 960 system was used to detect the drug susceptibility of
M. tuberculosis
isolates to PZA and MOX. Based on the genotyping results, 241 (66.4%) strains were classified as Beijing genotype in 2000, which was significantly lower than in 2010 (76.2%,
P
< 0.01). The proportion of the modern Beijing genotype increased significantly from 49.6% in 2000 to 68.1% in 2010 (
P
< 0.01), while no significant difference was observed in the rate of ancient Beijing genotype between 2000 and 2010 (
P
= 0.676). In addition, we found that the proportion of PZA resistance in 2010 (15.0%) was significantly higher than that in 2000 (9.6%,
P
= 0.04). For MOX, there were more MOX-resistant isolates detected in 2010 (7.7%) than in 2000 (3.0%). In conclusion, our data demonstrate that the Beijing genotype was the predominant
M. tuberculosis
lineage during the past decade. The proportion of Beijing genotype isolates significantly increased from 2000 to 2010, largely due to an increase in the modern Beijing sublineage. In addition, resistance to PZA and MOX increased significantly in China between 2000 and 2010.
Inhibition of Antigen-Specific and Nonspecific Stimulation of Bovine T and B Cells by Lymphostatin from Attaching and Effacing Escherichia coli
Authors: Cassady-Cain Robin L. , Blackburn Elizabeth A. , Bell Charlotte R. , Elshina Elizaveta , Hope Jayne C. , Stevens Mark P. 
Published: December 2016

ABSTRACTEnterohemorrhagicEscherichia coli(EHEC) and enteropathogenicE. coli(EPEC) are enteric bacterial pathogens of worldwide importance. Most EPEC and non-O157 EHEC strains express lymphostatin (also known as LifA), a chromosomally encoded 365-kDa protein. We previously demonstrated that lymphostatin is a putative glycosyltransferase that is important in intestinal colonization of cattle by EHEC serogroup O5, O111, and O26 strains. However, the nature and consequences of the interaction between lymphostatin and immune cells from the bovine host are ill defined. Using purified recombinant protein, we demonstrated that lymphostatin inhibits mitogen-activated proliferation of bovine T cells and, to a lesser extent, proliferation of cytokine-stimulated B cells, but not NK cells. It broadly affected the T cell compartment, inhibiting all cell subsets (CD4, CD8, WC-1, and γδ T cell receptor [γδ-TCR]) and cytokines examined (interleukin 2 [IL-2], IL-4, IL-10, IL-17A, and gamma interferon [IFN-γ]) and rendered T cells refractory to mitogen for a least 18 h after transient exposure. Lymphostatin was also able to inhibit proliferation of T cells stimulated by IL-2 and by antigen presentation using aTheileria-transformed cell line and autologous T cells fromTheileria-infected cattle. We conclude that lymphostatin is likely to act early in T cell activation, as stimulation of T cells with concanavalin A, but not phorbol 12-myristate 13-acetate combined with ionomycin, was inhibited. Finally, a homologue of lymphostatin fromE. coliO157:H7 (ToxB; L7095) was also found to possess comparable inhibitory activity against T cells, indicating a potentially conserved strategy for interference in adaptive responses by attaching and effacingE. coli.
A Sulfur Oxygenase from the Haloalkaliphilic Bacterium Thioalkalivibrio paradoxus with Atypically Low Reductase Activity
Authors: Rühl Patrick , Pöll Uwe , Braun Johannes , Klingl Andreas , Kletzin Arnulf 
Published: December 2016

ABSTRACT

Sequence comparisons showed that the sulfur oxygenase reductase (SOR) of the haloalkaliphilic bacterium
Thioalkalivibrio paradoxus
Arh 1 (
Tp
SOR) is branching deeply within dendrograms of these proteins (29 to 34% identity). A synthetic gene encoding
Tp
SOR expressed in
Escherichia coli
resulted in a protein 14.7 ± 0.9 nm in diameter and an apparent molecular mass of 556 kDa. Sulfite and thiosulfate were formed from elemental sulfur in a temperature range of 10 to 98°C (optimum temperature ≈ 80°C) and a pH range of 6 to 11.5 (optimum pH ≈ 9; 308 ± 78 U/mg of protein). Sulfide formation had a maximum specific activity of 0.03 U/mg, or <1% of the corresponding activity of other SORs. Hence, reductase activity seems not to be an integral part of the reaction mechanism.
Tp
SOR was most active at NaCl or glycine betaine concentrations of 0 to 1 M, although 0.2% of the maximal activity was detected even at 5 M NaCl and 4 M betaine. The melting point of
Tp
SOR was close to 80°C, when monitored by circular dichroism spectroscopy or differential scanning fluorimetry; however, the denaturation kinetics were slow: 55% of the residual activity remained after 25 min of incubation at 80°C. Site-directed mutagenesis showed that the active-site residue Cys
44
is essential for activity, whereas alanine mutants of the two other conserved cysteines retained about 0.5% residual activity. A model of the sulfur metabolism in
T. paradoxus
is discussed.
IMPORTANCE
Sulfur oxygenase reductases (SORs) are the only enzymes catalyzing an oxygen-dependent disproportionation of elemental sulfur and/or polysulfides to sulfite, thiosulfate, and hydrogen sulfide. SORs are known from mesophilic and extremophilic archaea and bacteria. All SORs seem to form highly thermostable 24-subunit hollow spheres. They carry a low-potential mononuclear nonheme iron in the active site and an indispensable cysteine; however, their exact reaction mechanisms are unknown. Typically, the reductase activity of SORs is in the range of 5 to 50% of the oxygenase activity, but mutagenesis studies had so far failed to identify residues crucial for the reductase reaction. We describe here the first SOR, which is almost devoid of the reductase reaction and which comes from a haloalkaliphilic bacterium.
An urban collection of modern-day large micrometeorites: Evidence for variations in the extraterrestrial dust flux through the Quaternary
Authors: Genge M.J. , Larsen J. , Van Ginneken M. , Suttle M.D. 
Published: December 2016

Abstract
We report the discovery of significant numbers (500) of large micrometeorites (&gt;100 μm) from rooftops in urban areas. The identification of particles as micrometeorites is achieved on the basis of their compositions, mineralogies, and textures. All particles are silicate-dominated (S type) cosmic spherules with subspherical shapes that form by melting during atmospheric entry and consist of quench crystals of magnesian olivine, relict crystals of forsterite, and iron-bearing olivine within glass. Four particles also contain Ni-rich metal-sulfide beads. Bulk compositions are chondritic apart from depletions in the volatile, moderately volatile, and siderophile elements, as observed in micrometeorites from other sources. The reported particles are likely to have fallen on Earth in the past 6 yr and thus represent the youngest large micrometeorites collected to date. The relative abundance ratio of barred olivine to cryptocrystalline spherule types in the urban particles of 1.45 is shown to be higher than a Quaternary average of ∼0.9, suggesting variations in the extraterrestrial dust flux over the past 800 k.y. Changes in the entry velocities of dust caused by quasi-periodic gravitational perturbation during transport to Earth are suggested to be responsible. Variations in cosmic spherule abundance within the geologic column are thus unavoidable and can be a consequence of dust transport as well as major dust production events.
Overbank sedimentation from the historic A.D. 2011 flood along the Lower Mississippi River, USA
Authors: Heitmuller Franklin T. , Hudson Paul F. , Kesel Richard H. 
Published: December 2016

Abstract
In this study, we document sedimentary characteristics of overbank flood deposits associated with the epic A.D. 2011 flood along the Lower Mississippi River (southern USA) and directly compare the findings to sedimentation from a comparable flood event in 1973, with the general purpose of understanding how extreme floods contribute to floodplain depositional patterns and accretion rates of embanked fluvial systems. The thicknesses of the 2011 flood deposits averaged 138 mm along natural levee crests, 9 mm on meander scrolls, and 3 mm in backswamps. These thicknesses are considerably less than those documented for the 1973 flood, sampled at the same locations. We contend that less sedimentation in 2011 occurred because the flood was not supplied with much upstream sediment from the Missouri River. Further, the 2011 sediments are coarser than in 1973, indicating that the higher 2011 flood levels were associated with more energetic overbank flows that flushed fine-grained sediments downstream within the narrow embanked floodplain corridor. The largest recorded flood in North American history is only marginally preserved in the embanked floodplain stratigraphy of the alluvial valley of Earth’s third largest fluvial system.
Nocturnal antihypertensive treatment in patients with type 1 diabetes with autonomic neuropathy and non-dipping: a randomised, placebo-controlled, double-blind cross-over trial
Authors: Hjortkjær Henrik Øder , Jensen Tonny , Kofoed Klaus F , Mogensen Ulrik M , Sigvardsen Per Ejlstrup , Køber Lars , Hilsted Karen Lisa , Corinth Helle , Theilade Simone , Hilsted Jannik 
Published: December 2016

ObjectivesCardiovascular autonomic neuropathy (CAN) and abnormal circadian blood pressure (BP) rhythm are independent cardiovascular risk factors in patients with diabetes and associations between CAN, non-dipping of nocturnal BP and coronary artery disease have been demonstrated. We aimed to test if bedtime dosing (BD) versus morning dosing (MD) of the ACE inhibitor enalapril would affect the 24-hour BP profile in patients with type 1 diabetes (T1D), CAN and non-dipping.SettingSecondary healthcare unit in Copenhagen, Denmark.Participants24 normoalbuminuric patients with T1D with CAN and non-dipping were included, consisting of mixed gender and Caucasian origin. Mean±SD age, glycosylated haemoglobin and diabetes duration were 60±7 years, 7.9±0.7% (62±7 mmol/mol) and 36±11 years.InterventionsIn this randomised, placebo-controlled, double-blind cross-over study, the patients were treated for 12 weeks with either MD (20 mg enalapril in the morning and placebo at bedtime) or BD (placebo in the morning and 20 mg enalapril at bedtime), followed by 12 weeks of switched treatment regimen.Primary and secondary outcome measuresPrimary outcome was altered dipping of nocturnal BP. Secondary outcomes included a measurable effect on other cardiovascular risk factors than BP, including left ventricular function (LVF).ResultsSystolic BP dipping increased 2.4% (0.03–4.9%; p=0.048) with BD compared to MD of enalapril. There was no increase in mean arterial pressure dipping (2.2% (−0.1% to 4.5%; p=0.07)). No difference was found on measures of LVF (p≥0.15). No adverse events were registered during the study.ConclusionsWe demonstrated that patients with T1D with CAN and non-dipping can be treated with an ACE inhibitor at night as BD as opposed to MD increased BP dipping, thereby diminishing the abnormal BP profile. The potentially beneficial effect on long-term cardiovascular risk remains to be determined.Trial registration numberEudraCT2012-002136-90; Post-results.
Distinguishing between those dying suddenly or not suddenly from coronary heart disease: long-term prospective results from the Northwick Park Heart Study
Authors: Meade Tom , Clayton Tim , Chamberlain Douglas 
Published: December 2016

AimTo establish whether ECG findings are associated with subsequent risk of sudden death from coronary heart disease (CHD).Methods and resultsPotential risk factors for CHD were measured at entry to the first Northwick Park Heart Study of 2167 men. ECG findings were coded as high or low risk for CHD according to definitions in the Minnesota code. Sudden or non-sudden deaths were defined as occurring in less than or more than 24 hours, respectively. The only factor independently associated with sudden death among the 262 men dying of CHD was high-risk ECG. Of 184 sudden CHD deaths, 34 men (18.5%) had had high-risk ECGs at entry to the study compared with 5 (6.4%) of 78 men who experienced non-sudden deaths (adjusted OR 3.94 (95% CI 1.33 to 11.67)) (p=0.006). Findings were also compared among all 2167 men, where high-risk ECGs were again associated with sudden death. T-wave changes were the main abnormalities associated with a high risk of sudden death.ConclusionsIn a group of men who had not previously experienced major episodes of CHD but who subsequently died from it, there was strong evidence that high-risk ECG changes, mainly T-wave abnormalities, differentiated between those who later died sudden deaths and those who survived for >24 hours.