bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequentist and Bayesian Pharmacometric-Based Approaches To Facilitate Critically Needed New Antibiotic Development: Overcoming Lies, Damn Lies, and Statistics
Authors: Ambrose Paul G. , Hammel Jeffrey P. , Bhavnani Sujata M. , Rubino Christopher M. , Ellis-Grosse Evelyn J. , Drusano George L. 
Published: December 2011

ABSTRACT

Antimicrobial drug development has greatly diminished due to regulatory uncertainty about the magnitude of the antibiotic treatment effect. Herein we evaluate the utility of pharmacometric-based analyses for determining the magnitude of the treatment effect. Frequentist and Bayesian pharmacometric-based logistic regression analyses were conducted by using data from a phase 3 clinical trial of tigecycline-treated patients with hospital-acquired pneumonia (HAP) to evaluate relationships between the probability of microbiological or clinical success and the free-drug area under the concentration-time curve from time zero to 24 h (AUC
0-24
)/MIC ratio. By using both the frequentist and Bayesian approaches, the magnitude of the treatment effect was determined using three different methods based on the probability of success at free-drug AUC
0-24
/MIC ratios of 0.01 and 25. Differences in point estimates of the treatment effect for microbiological response (method 1) were larger using the frequentist approach than using the Bayesian approach (Bayesian estimate, 0.395; frequentist estimate, 0.637). However, the Bayesian credible intervals were tighter than the frequentist confidence intervals, demonstrating increased certainty with the former approach. The treatment effect determined by taking the difference in the probabilities of success between the upper limit of a 95% interval for the minimal exposure and the lower limit of a 95% interval at the maximal exposure (method 2) was greater for the Bayesian analysis (Bayesian estimate, 0.074; frequentist estimate, 0.004). After utilizing bootstrapping to determine the lower 95% bounds for the treatment effect (method 3), treatment effect estimates were still higher for the Bayesian analysis (Bayesian estimate, 0.301; frequentist estimate, 0.166). These results demonstrate the utility of frequentist and Bayesian pharmacometric-based analyses for the determination of the treatment effect using contemporary trial endpoints. Additionally, as demonstrated by using pharmacokinetic-pharmacodynamic data, the magnitude of the treatment effect for patients with HAP is large.
Antibacterial Activity of Sphingoid Bases and Fatty Acids against Gram-Positive and Gram-Negative Bacteria
Authors: Fischer Carol L. , Drake David R. , Dawson Deborah V. , Blanchette Derek R. , Brogden Kim A. , Wertz Philip W. 
Published: December 2011

ABSTRACTThere is growing evidence that the role of lipids in innate immunity is more important than previously realized. How lipids interact with bacteria to achieve a level of protection, however, is still poorly understood. To begin to address the mechanisms of antibacterial activity, we determined MICs and minimum bactericidal concentrations (MBCs) of lipids common to the skin and oral cavity—the sphingoid basesd-sphingosine, phytosphingosine, and dihydrosphingosine and the fatty acids sapienic acid and lauric acid—against four Gram-negative bacteria and seven Gram-positive bacteria. Exact Kruskal-Wallis tests of these values showed differences among lipid treatments (P< 0.0001) for each bacterial species exceptSerratia marcescensandPseudomonas aeruginosa.d-Sphingosine (MBC range, 0.3 to 19.6 μg/ml), dihydrosphingosine (MBC range, 0.6 to 39.1 μg/ml), and phytosphingosine (MBC range, 3.3 to 62.5 μg/ml) were active against all bacteria exceptS. marcescensandP. aeruginosa(MBC > 500 μg/ml). Sapienic acid (MBC range, 31.3 to 375.0 μg/ml) was active againstStreptococcus sanguinis,Streptococcus mitis, andFusobacterium nucleatumbut not active againstEscherichia coli,Staphylococcus aureus,S. marcescens,P. aeruginosa,Corynebacterium bovis,Corynebacterium striatum, andCorynebacterium jeikeium(MBC > 500 μg/ml). Lauric acid (MBC range, 6.8 to 375.0 μg/ml) was active against all bacteria exceptE. coli,S. marcescens, andP. aeruginosa(MBC > 500 μg/ml). Complete killing was achieved as early as 0.5 h for some lipids but took as long as 24 h for others. Hence, sphingoid bases and fatty acids have different antibacterial activities and may have potential for prophylactic or therapeutic intervention in infection.
Evolution of an Incompatibility Group IncA/C Plasmid Harboring
bla
CMY-16
and
qnrA6
Genes and Its Transfer through Three Clones of Providencia stuartii during a Two-Year Outbreak in a Tunisian Burn Unit
Authors: Arpin C. , Thabet L. , Yassine H. , Messadi A. A. , Boukadida J. , Dubois V. , Coulange-Mayonnove L. , Andre C. , Quentin C. 
Published: December 2011

ABSTRACT

During a 2-year period in 2005 and 2006, 64 multidrug-resistant
Providencia stuartii
isolates, including 58 strains from 58 patients and 6 strains obtained from the same tracheal aspirator, were collected in a burn unit of a Tunisian hospital. They divided into four antibiotypes (ATB1 to ATB4) and three SmaI pulsotypes (PsA to PsC), including 49 strains belonging to clone PsA (48 of ATB1 and 1 of ATB4), 11 strains to clone PsB (7 of ATB2 and 4 of ATB3), and 4 strains to clone PsC (ATB3). All strains, except for the PsA/ATB4 isolate, were highly resistant to broad-spectrum cephalosporins due to the production of the plasmid-mediated CMY-16 β-lactamase. In addition, the 15 strains of ATB2 and ATB3 exhibited decreased quinolone susceptibility associated with QnrA6. Most strains (ATB1 and ATB3) were gentamicin resistant, related to an AAC(6′)-Ib′ enzyme. All these genes were located on a conjugative plasmid belonging to the incompatibility group IncA/C
2
of 195, 175, or 100 kb. Despite differences in size and in number of resistance determinants, they derived from the same plasmid, as demonstrated by similar profiles in plasmid restriction analysis and strictly homologous sequences of

repAIncA/C
2

, unusual antibiotic resistance genes (e.g.,
aphA-6
), and their genetic environments. Further investigation suggested that deletions, acquisition of the IS
CR1
insertion sequence, and integron cassette mobility accounted for these variations. Thus, this outbreak was due to both the spread of three clonal strains and the dissemination of a single IncA/C
2
plasmid which underwent a remarkable evolution during the epidemic period.
Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings
Authors: Johnson Todd J. , Srinivasan Priya , Albright Theodore H. , Watson-Buckheit Karen , Rabe Lorna , Martin Amy , Pau Chou-Pong , Hendry R. Michael , Otten Ron , McNicholl Janet , Buckheit Robert , Smith James , Kiser Patrick F. 
Published: December 2011

ABSTRACT

The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1
0.5wt%
], PYD1
1wt%
, PYD2
4wt%
, and PYD2
14wt%
) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2
14wt%
IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 μg/ml to vaginal fluid and 1 μg/g to vaginal tissue, a level over 1,000 times the
in vitro
50% effective concentration. The
in vitro
release of PYD1 and PYD2 under nonsink conditions correlated well with
in vivo
release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release
in vitro
than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after
in vitro
release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.
Characterization of Nasal and Blood Culture Isolates of Methicillin-Resistant Staphylococcus aureus from Patients in United States Hospitals
Authors: Tenover Fred C. , Tickler Isabella A. , Goering Richard V. , Kreiswirth Barry N. , Mediavilla José R. , Persing David H. ,   for the MRSA Consortium
Published: December 2011

ABSTRACT

A total of 299 nares and 194 blood isolates of methicillin-resistant
Staphylococcus aureus
(MRSA), each recovered from a unique patient, were collected from 23 U.S. hospitals from May 2009 to March 2010. All isolates underwent
spa
and staphylococcal cassette chromosome
mec
element (SCC
mec
) typing and antimicrobial susceptibility testing; a subset of 84 isolates was typed by pulsed-field gel electrophoresis (PFGE) using SmaI. Seventy-six
spa
types were observed among the isolates. Overall, for nasal isolates,
spa
type t002-SCC
mec
type II (USA100) was the most common strain type (37% of isolates), while among blood isolates,
spa
type t008-SCC
mec
type IV (USA300) was the most common (39%). However, the proportion of all USA100 and USA300 isolates varied by United States census region. Nasal isolates were more resistant to tobramycin and clindamycin than blood isolates (55.9% and 48.8% of isolates versus 36.6% and 39.7%, respectively; for both,
P
< 0.05). The USA300 isolates were largely resistant to fluoroquinolones. High-level mupirocin resistance was low among all
spa
types (<5%). SCC
mec
types III and VIII, which are rare in the United States, were observed along with several unusual PFGE types, including CMRSA9, EMRSA15, and the PFGE profile associated with sequence type 239 (ST239) isolates. Typing data from this convenience sample suggest that in U.S. hospitalized patients, USA100 isolates of multiple
spa
types, while still common in the nares, have been replaced by USA300 isolates as the predominant MRSA strain type in positive blood cultures.
The deep-sea microfossil record of macroevolutionary change in plankton and its study
Authors: Lazarus David B. 
Published: December 2011

Abstract

The deep-sea planktonic microfossil record (foraminifera, coccolithophores, diatoms, radiolaria and dinoflagellates) provides a unique resource for palaeobiology. Despite some geographical gaps due to poor regional preservation, and intermittant time intervals lost to erosion, most time periods for each Cenozoic planktonic biogeographical province are preserved. Vast numbers of specimens and numerous deep-sea cores provide abundant material and the opportunity to tightly integrate macroevolutionary and palaeoenvironmental data. Current documentation of this record is mixed. Catalogues for foraminifera and coccolithophores offer nearly complete species-level clade histories, but taxonomy for siliceous microfossils is incomplete. Published occurrence data is primarily stratigraphic and covers only a fraction of the total preserved diversity. Age models for some sections are excellent (accuracy
c
. 100 kya) but for many other sections are still poor. Taxonomic errors, age model errors and reworking displace fossil occurrences in time, complicating palaeobiological analysis. With additional taxonomic work, careful collection of whole fauna/floral assemblage occurrence data, improved age models, and the development of better data filtering and analysis tools to deal with data outliers the deep-sea microfossil record can deliver its promise of providing the most complete, detailed record of macroevolutionary change available to science.

Supplementary material:

Supplementary Appendix is available at
http://www.geolsoc.org.uk/SUP18485
Collateral mammal diversity loss associated with late Quaternary megafaunal extinctions and implications for the future
Authors: Barnosky Anthony D. , Carrasco Marc A. , Graham Russell W. 
Published: December 2011

Abstract

Using data from two palaeontological databases, MIOMAP and FAUNMAP (now linked as NEOMAP), we explore how late Quaternary species loss compared in large and small mammals by determining palaeospecies-area relationships (PSARs) at 19 temporal intervals ranging from
c.
30 million to 500 years ago in 10 different biogeographical provinces in the USA. We found that mammalian diversity of both large and small mammals remained relatively stable from 30 million years ago up until both crashed near the Pleistocene–Holocene transition. The diversity crash had two components: the well-known megafaunal extinction that amounted to
c.
21% of the pre-crash species, and collateral biodiversity loss due to biogeographical range reductions. Collateral loss resulted in large mammal diversity regionally falling an additional 6–31% above extinction loss, and small mammal diversity falling 16–51%, even though very few small mammals suffered extinction. These results imply that collateral losses due to biogeographical range adjustments may effectively double the regional diversity loss during an extinction event, substantially magnifying the ecological ramifications of the extinctions themselves. This is of interest in forecasting future ecological impacts of mammal extinctions, given that
c.
8% of USA mammal species, and 22% of mammal species worldwide, are now considered ‘Threatened’ by the IUCN.
Disentangling palaeodiversity signals from a biased sedimentary record: an example from the Early to Middle Miocene of Central Paratethys Sea
Authors: Zuschin Martin , Harzhauser Mathias , Mandic Oleg 
Published: December 2011

Abstract
Changes in molluscan diversity across the 3rd order sequence boundary from the Lower to the Middle Miocene of the Paratethys were evaluated in the context of environmental bias. Taken at face value, quantitative data from nearshore and sublittoral shell beds suggest a transition from low-diversity Karpatian (Upper Burdigalian) to highly diverse Badenian (Langhian and Lower Serravallian) assemblages, but environmental affiliation of samples reveals a strong facies shift across the sequence boundary. Ordination methods show that benthic assemblages of the two stages, including 4 biozones and four 3rd order depositional sequences over less than four million years, are developed along the same depth-related environmental gradient. Almost all samples are from highstand systems tracts, but Karpatian faunas are mostly from nearshore settings, and Badenian faunas are strongly dominated by sublittoral assemblages. This study emphasizes the importance of highly resolved stratigraphic and palaeoenvironmental frameworks for deciphering palaeodiversity patterns at regional scales and highlights the effort required to reach the asymptote of the collector's curve. Abundance data facilitate the recognition of ecological changes in regional biota and it is suggested that in second and higher order sequences the facies covered within systems tracts will drive observed diversity patterns.
Molecular Ontogeny of Donor-Derived Follicular Lymphomas Occurring after Hematopoietic Cell Transplantation
Authors: Weigert Oliver , Kopp Nadja , Lane Andrew A. , Yoda Akinori , Dahlberg Suzanne E. , Neuberg Donna , Bahar Anita Y. , Chapuy Bjoern , Kutok Jeffery L. , Longtine Janina A. , Kuo Frank C. , Haley Terry , Salois Maura , Sullivan Timothy J. , Fisher David C. , Fox Edward A. , Rodig Scott J. , Antin Joseph H. , Weinstock David M. 
Published: December 2011

Abstract
The relative timing of genetic alterations that contribute to follicular lymphoma remains unknown. We analyzed a donor–recipient pair who both developed grade 2/3A follicular lymphoma 7 years after allogeneic transplantation and donor lymphocyte infusions. Both patients harbored identical BCL2/IGH rearrangements also present in 1 in 2,000 cells in the donor lymphocyte infusion, and the same V(D)J rearrangement, which underwent somatic hypermutation both before and after clonal divergence. Exome sequencing of both follicular lymphomas identified 15 shared mutations, of which 14 (including alterations in EP300 and KLHL6) were recovered from the donor lymphocyte infusion by ultra-deep sequencing (average read coverage, 361,723), indicating acquisition at least 7 years before clinical presentation. Six additional mutations were present in only one follicular lymphoma and not the donor lymphocyte infusion, including an ARID1A premature stop, indicating later acquisition during clonal divergence. Thus, ultrasensitive sequencing can map clonal evolution within rare subpopulations during human lymphomagenesis in vivo.
Significance: For the first time, we define the molecular ontogeny of follicular lymphoma during clonal evolution in vivo. By using ultrasensitive mutation detection, we mapped the time-course of somatic alterations after passage of a malignant ancestor by hematopoietic cell transplantation. Cancer Discovery; 2(1); 47–55. ©2011 AACR.
This article is highlighted in the In This Issue feature, p. 1
Peculiarities of Immature Individuals Developing from Both Resting and Subitaneous Eggs of Polyphemus pediculus (Cladocera, Onychopoda)
Authors: Butorina L. G. 
Published: December 2011

AbstractJuveniles of Polyphemus pediculus (Linnaeus, 1761) emerge into the aquatic environment from resting eggs at an earlier stage of development, compared to those that hatch from subitaneous eggs. They become sexually mature after five moults, while individuals originating from subitaneous eggs become mature after four moults. The numbers of moults under both circumstances are strictly stable. Morphometric characteristics, body length, and the ratio of the entire body and its parts change with every moult, but the intensity of these changes is different in individuals originating from different types of eggs. Newborns originating from resting eggs, are larger, but have less setae on antennae I-II and on the third endopodal segments of thoracic limbs I-III. Morphometrically they are closer to sexually mature individuals of Polyphemus exiguus Sars, 1897, than to immature individuals of P. pediculus originating from subitaneous eggs. Their morphometric correspondence to mature individuals of the freshwater form of their own species, P. pediculus is even less. As a consequence, the numbers of setae on the first segments of the endopodites of the thoracic limbs can not be used as a systematic character for the species of the genus Polyphemus.
Human–Human Reliance in the Context of Automation
Authors: Lyons Joseph B. , Stokes Charlene K. 
Published: December 2011

Objective: The current study examined human–human reliance during a computer-based scenario where participants interacted with a human aid and an automated tool simultaneously. Background: Reliance on others is complex, and few studies have examined human–human reliance in the context of automation. Past research found that humans are biased in their perceived utility of automated tools such that they view them as more accurate than humans. Prior reviews have postulated differences in human–human versus human–machine reliance, yet few studies have examined such reliance when individuals are presented with divergent information from different sources. Method: Participants ( N = 40) engaged in the Convoy Leader experiment. They selected a convoy route based on explicit guidance from a human aid and information from an automated map. Subjective and behavioral human–human reliance indices were assessed. Perceptions of risk were manipulated by creating three scenarios (low, moderate, and high) that varied in the amount of vulnerability (i.e., potential for attack) associated with the convoy routes. Results: Results indicated that participants reduced their behavioral reliance on the human aid when faced with higher risk decisions (suggesting increased reliance on the automation); however, there were no reported differences in intentions to rely on the human aid relative to the automation. Conclusion: The current study demonstrated that when individuals are provided information from both a human aid and automation, their reliance on the human aid decreased during high-risk decisions. Application: This study adds to a growing understanding of the biases and preferences that exist during complex human–human and human–machine interactions.
Cognitive Neurophysiologic Synchronies
Authors: Stevens Ronald H. , Galloway Trysha L. , Wang Peter , Berka Chris 
Published: December 2011

Objective: Cognitive neurophysiologic synchronies (NS) are low-level data streams derived from electroencephalography (EEG) measurements that can be collected and analyzed in near real time and in realistic settings. The objective of this study was to relate the expression of NS for engagement to the frequency of conversation between team members during Submarine Piloting and Navigation (SPAN) simulations. Background: If the expression of different NS patterns is sensitive to changes in the behavior of teams, they may be a useful tool for studying team cognition. Method: EEG-derived measures of engagement (EEG-E) from SPAN team members were normalized and pattern classified by self-organizing artificial neural networks and hidden Markov models. The temporal expression of these patterns was mapped onto team events and related to the frequency of team members’ speech. Standardized models were created with pooled data from multiple teams to facilitate comparisons across teams and levels of expertise and to provide a framework for rapid monitoring of team performance. Results: The NS expression for engagement shifted across task segments and internal and external task changes. These changes occurred within seconds and were affected more by changes in the task than by the person speaking. Shannon entropy measures of the NS data stream showed decreases associated with periods when the team was stressed and speaker entropy was high. Conclusion: These studies indicate that expression of neurophysiologic indicators measured by EEG may complement rather than duplicate communication metrics as measures of team cognition. Application: Neurophysiologic approaches may facilitate the rapid determination of the cognitive status of a team and support the development of novel adaptive approaches to optimize team function.