bluuebunny/crossref_metadata_2025_split huggingface dataset:
A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Imidazolopiperazine KAF156 To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers
Authors: Leong F. Joel , Zhao Rong , Zeng Shuqi , Magnusson Baldur , Diagana Thierry T. , Pertel Peter 
Published: August 2014

ABSTRACT

KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg, including one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (
n
= 4; 11.1%), diarrhea (
n
= 3; 8.3%), dizziness (
n
= 3; 8.3%), and abdominal pain (
n
= 2; 5.6%) were the most common adverse events. Headache (
n
= 4; 16.7%), nausea (
n
= 3; 12.5%), upper respiratory tract infection (
n
= 3; 12.5%), and dizziness (
n
= 2; 8.3%) were the most common adverse events following multiple doses. KAF156 time to maximum concentration (
T
max
) was between 1.0 and 6.0 h. Both the area under the concentration-time curve (AUC) and maximum concentration (
C
max
) increased more than dose-proportionally in both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while mean
C
max
decreased from 778 ng/ml to 627 ng/ml and
T
max
was delayed from a median of 3.0 h under fasting conditions to 6.0 h under fed conditions. Renal elimination is a minor route.
Efficacy of a Ceftazidime-Avibactam Combination in a Murine Model of Septicemia Caused by Enterobacteriaceae Species Producing AmpC or Extended-Spectrum β-Lactamases
Authors: Levasseur Premavathy , Girard Anne-Marie , Lavallade Ludovic , Miossec Christine , Pace John , Coleman Kenneth 
Published: August 2014

ABSTRACT

Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been shown
in vitro
to inhibit class A, class C, and some class D β-lactamases. It is currently in phase 3 of clinical development in combination with ceftazidime. In this study, the efficacy of ceftazidime-avibactam was evaluated in a murine septicemia model against five ceftazidime-susceptible (MICs of 0.06 to 0.25 μg/ml) and 15 ceftazidime-resistant (MICs of 64 to >128 μg/ml) species of
Enterobacteriaceae
, bearing either TEM, SHV, CTX-M extended-spectrum, or AmpC β-lactamases. In the first part of the study, ceftazidime-avibactam was administered at ratios of 4:1 and 8:1 (wt/wt) to evaluate the optimal ratio for efficacy. Against ceftazidime-susceptible isolates of
Klebsiella pneumoniae
and
Escherichia coli
, ceftazidime and ceftazidime-avibactam demonstrated similar efficacies (50% effective doses [ED
50
] of <1.5 to 9 mg/kg of body weight), whereas against ceftazidime-resistant β-lactamase-producing strains (ceftazidime ED
50
of >90 mg/kg), the addition of avibactam restored efficacy to ceftazidime (ED
50
dropped to <5 to 65 mg/kg). In a subsequent study, eight isolates (two AmpC and six CTX-M producers) were studied in the septicemia model. Ceftazidime-avibactam was administered at a 4:1 (wt/wt) ratio, and the efficacy was compared to that of the 4:1 (wt/wt) ratio of either piperacillin-tazobactam or cefotaxime-avibactam. Against the eight isolates, ceftazidime-avibactam was the more effective combination, with ED
50
values ranging from 2 to 27 mg/kg compared to >90 mg/kg and 14 to >90 mg/kg for piperacillin-tazobactam and cefotaxime-avibactam, respectively. This study demonstrates that the potent
in vitro
activity observed with the ceftazidime-avibactam combination against ceftazidime-resistant
Enterobacteriaceae
species bearing class A and class C β-lactamases translated into good efficacy in the mouse septicemia model.
Comparison of
In Vivo
and
In Vitro
Pharmacodynamics of a Humanized Regimen of 600 Milligrams of Ceftaroline Fosamil Every 12 Hours against Staphylococcus aureus at Initial Inocula of 10
6
and 10
8
CFU per Milliliter
Authors: So Wonhee , Crandon Jared L. , Zhanel George G. , Nicolau David P. 
Published: August 2014

ABSTRACT

In light of the
in vivo
/
in vitro
discordance among beta-lactams against Gram-negative pathogens, we compared the
in vivo
pharmacodynamics of humanized ceftaroline against 9
Staphylococcus aureus
strains (MICs of 0.13 to 1 mg/liter) from published
in vitro
studies using standard and high inocula in the murine thigh infection model. Consistent with the
in vitro
findings, mean reductions of ≥1 log
10
CFU were observed for ceftaroline against all strains using both standard and high inocula. These results suggest
in vivo
/
in vitro
concordance with no observed inoculum effect.
Role of PBPD1 in Stimulation of Listeria monocytogenes Biofilm Formation by Subminimal Inhibitory β-Lactam Concentrations
Authors: Nguyen Uyen T. , Harvey Hanjeong , Hogan Andrew J. , Afonso Alexandria C. F. , Wright Gerard D. , Burrows Lori L. 
Published: August 2014

ABSTRACT

Disinfectant-tolerant
Listeria monocytogenes
biofilms can colonize surfaces that come into contact with food, leading to contamination and, potentially, food-borne illnesses. To better understand the process of
L. monocytogenes
biofilm formation and dispersal, we screened 1,120 off-patent FDA-approved drugs and identified several that modulate
Listeria
biofilm development. Among the hits were more than 30 β-lactam antibiotics, with effects ranging from inhibiting (≤50%) to stimulating (≥200%) biofilm formation compared to control. Most β-lactams also dispersed a substantial proportion of established biofilms. This phenotype did not necessarily involve killing, as >50% dispersal could be achieved with concentrations as low as 1/20 of the MIC of some cephalosporins. Penicillin-binding protein (PBP) profiling using a fluorescent penicillin analogue showed similar inhibition patterns for most β-lactams, except that biofilm-stimulatory drugs did not bind PBPD1, a low-molecular-weight
d
,
d
-carboxypeptidase. Compared to the wild type, a
pbpD1
mutant had an attenuated biofilm response to stimulatory β-lactams. The cephalosporin-responsive CesRK two-component regulatory system, whose regulon includes PBPs, was not required for the response. The requirement for PBPD1 activity for β-lactam stimulation of
L. monocytogenes
biofilms shows that the specific set of PBPs that are inactivated by a particular drug dictates whether a protective biofilm response is provoked.
Characterization of Wheat Germ Agglutinin Lectin-Reactive Glycosylated OmpA-Like Proteins Derived from Porphyromonas gingivalis
Authors: Murakami Yukitaka , Hasegawa Yoshiaki , Nagano Keiji , Yoshimura Fuminobu 
Published: August 2014

ABSTRACT

Glycosylation is one of the common posttranslational modifications in eukaryotes. Recently, glycosylated proteins have also been identified in prokaryotes. A few glycosylated proteins, including gingipains, have been identified in
Porphyromonas gingivalis
, a major pathogen associated with chronic periodontitis. However, no other glycosylated proteins have been found. The present study identified glycoproteins in
P. gingivalis
cell lysates by lectin blotting. Whole-cell lysates reacted with concanavalin A (ConA),
Lens culinaris
agglutinin (LCA),
Phaseolus vulgaris
erythroagglutinin (PHA-E4), and wheat germ agglutinin (WGA), suggesting the presence of mannose-,
N
-acetylgalactosamine-, or
N
-acetylglucosamine (GlcNAc)-modified proteins. Next, glycoproteins were isolated by ConA-, LCA-, PHA-E4-, or WGA-conjugated lectin affinity chromatography although specific proteins were enriched only by the WGA column. Mass spectrometry analysis showed that an OmpA-like, heterotrimeric complex formed by Pgm6 and Pgm7 (Pgm6/7) was the major glycoprotein isolated from
P. gingivalis
. Deglycosylation experiments and Western blotting with a specific antibody indicated that Pgm6/7 was modified with
O
-GlcNAc. When whole-cell lysates from
P. gingivalis
mutant strains with deletions of Pgm6 and Pgm7 were applied to a WGA column, homotrimeric Pgm7, but not Pgm6, was isolated. Heterotrimeric Pgm6/7 had the strongest affinity for fibronectin of all the extracellular proteins tested, whereas homotrimeric Pgm7 showed reduced binding activity. These findings suggest that the heterotrimeric structure is important for the biological activity of glycosylated WGA-binding OmpA-like proteins in
P. gingivalis
.
Early Innate Immunity to Bacterial Infection in the Lung Is Regulated Systemically by the Commensal Microbiota via Nod-Like Receptor Ligands
Authors: Clarke Thomas B. 
Published: August 2014

ABSTRACT

The commensal microbiota is a major regulator of the immune system. The majority of commensal bacteria inhabit the gastrointestinal tract and are known to regulate local mucosal defenses against intestinal pathogens. There is growing appreciation that the commensal microbiota also regulates immune responses at extraintestinal sites. Currently, however, it is unclear how this influences host defenses against bacterial infection outside the intestine. Microbiota depletion caused significant defects in the early innate response to lung infection by the major human pathogen
Klebsiella pneumoniae
. After microbiota depletion, early clearance of
K. pneumoniae
was impaired, and this could be rescued by administration of bacterial Nod-like receptor (NLR) ligands (the NOD1 ligand MurNAcTri
DAP
and NOD2 ligand muramyl dipeptide [MDP]) but not bacterial Toll-like receptor (TLR) ligands. Importantly, NLR ligands from the gastrointestinal, but not upper respiratory, tract rescued host defenses in the lung. Defects in early innate immunity were found to be due to reduced reactive oxygen species-mediated killing of bacteria by alveolar macrophages. These data show that bacterial signals from the intestine have a profound influence on establishing the levels of antibacterial defenses in distal tissues.
Lipopolysaccharides Belonging to Different Salmonella Serovars Are Differentially Capable of Activating Toll-Like Receptor 4
Authors: Chessa Daniela , Spiga Luisella , De Riu Nicola , Delaconi Paola , Mazzarello Vittorio , Ganau Giulia , Rubino Salvatore 
Published: August 2014

ABSTRACT

Salmonella enterica
subsp.
enterica
serovar (serotype) Abortusovis is a member of the
Enterobacteriaceae
. This serotype is naturally restricted to ovine species and does not infect humans. Limited information is available about the immune response of sheep to
S
. Abortusovis.
S
. Abortusovis, like
Salmonella enterica
subsp.
enterica
serovar Typhi, causes a systemic infection in which, under natural conditions, animals are not able to raise a rapid immune response. Failure to induce the appropriate response allows pathogens to reach the placenta and results in an abortion. Lipopolysaccharides (LPSs) are pathogen-associated molecular patterns (PAMPs) that are specific to bacteria and are not synthesized by the host. Toll-like receptors (TLRs) are a family of receptors that specifically recognize PAMPs. As a first step, we were able to identify the presence of Toll-like receptor 4 (TLR4) on the ovine placenta by using an immunohistochemistry technique. To our knowledge, this is the first work describing the interaction between
S
. Abortusovis LPS and TLR4. Experiments using an embryonic cell line (HEK293) transfected with human and ovine TLR4s showed a reduction of interleukin 8 (IL-8) production by
S
. Abortusovis and
Salmonella enterica
subsp.
enterica
serovar Paratyphi upon LPS stimulation compared to
Salmonella enterica
subsp.
enterica
serovar Typhimurium. Identical results were observed using heat-killed bacteria instead of LPS. Based on data obtained with TLR4
in vitro
stimulation, we demonstrated that the serotype
S
. Abortusovis is able to successfully evade the immune system whereas
S
. Typhimurium and other serovars fail to do so.
Contributions of NanI Sialidase to Caco-2 Cell Adherence by Clostridium perfringens Type A and C Strains Causing Human Intestinal Disease
Authors: Li Jihong , McClane Bruce A. 
Published: August 2014

ABSTRACT

Previous studies showed that
Clostridium perfringens
type D animal disease strain CN3718 uses NanI sialidase for adhering to enterocyte-like Caco-2 cells. The current study analyzed whether NanI is similarly important when type A and C human intestinal disease strains attach to Caco-2 cells. A PCR survey determined that the
nanI
gene was absent from typical type A food poisoning (FP) strains carrying a chromosomal enterotoxin (CPE) gene or the genetically related type C Darmbrand (Db) strains. However, the
nanI
gene was present in type A strains from healthy humans, type A strains causing CPE-associated antibiotic-associated diarrhea (AAD) or sporadic diarrhea (SD), and type C Pig-Bel strains. Consistent with NanI sialidase being the major
C. perfringens
sialidase when produced, FP and Db strains had little supernatant sialidase activity compared to other type A or C human intestinal strains. All type A and C human intestinal strains bound to Caco-2 cells, but NanI-producing strains had higher attachment levels. When produced, NanI can contribute to host cell attachment of human intestinal disease strains, since a
nanI
null mutant constructed in type A SD strain F4969 had lower Caco-2 cell adhesion than wild-type F4969 or a complemented strain. Further supporting a role for NanI in host cell attachment, sialidase inhibitors reduced F4969 adhesion to Caco-2 cells. Collectively, these results suggest that NanI may contribute to the intestinal attachment and colonization needed for the chronic diarrhea of CPE-associated AAD and SD, but this sialidase appears to be dispensable for the acute pathogenesis of type A FP or type C enteritis necroticans.
Relationship between Buckling of Acupuncture Needles and the Handle Type
Authors: Zhang Claire Shuiqing , Pannirselvan Muthu , Xue Charlie Changli , Xie Yi Min 
Published: August 2014

Background Most popular single-use acupuncture needles consist of a stainless steel shaft with a handle made of copper coil or plastic stick. Objectives To determine the strengths and weaknesses of these two handle types for needle buckling. Methods The buckling load for acupuncture needles with these two different handle types was determined using a digital scale, and the stiffness of stainless steel wires used in different types of acupuncture needles was measured using a Dynamic Mechanical Analysis machine. Results This study showed that an acupuncture needle with a copper coil handle was far more susceptible to buckling than a needle with a plastic stick handle. The average buckling force of acupuncture needles with plastic stick handles was 46.7% higher than that with copper coil handles for needles of 0.25 mm×30 mm, and 30.8% higher for needles of 0.25 mm×60 mm. Replacing a copper coil handle with a plastic stick handle could save about 100 tonnes of copper wires and 20 million metres of medical grade stainless steel wire a year worldwide. Conclusions The results from this study suggest that the common practice of using coiled copper for handles on acupuncture needles should be re-evaluated. Replacing a copper coil handle with a plastic stick handle would significantly reduce needle buckling and improve patient comfort and safety. This would also reduce the consumption of copper and medical grade stainless steel wire considerably.
Evaluation of hospital factors associated with hospital postoperative venous thromboembolism imaging utilisation practices
Authors: Chung Jeanette W , Ju Mila H , Kinnier Christine V , Haut Elliott R , Baker David W , Bilimoria Karl Y 
Published: August 2014

BackgroundRecent research suggests that hospital rates of postoperative venous thromboembolism (VTE) are subject to surveillance bias: the more hospitals ‘look for’ VTE, the more VTE they find. However, little is known about what drives variation in hospital VTE imaging rates. We conducted an observational study to examine hospital and market characteristics that were associated with hospital-level rates of postoperative VTE imaging, focusing on hospitals with particularly high rates.MethodsFor Medicare beneficiaries undergoing 11 major operations (2009–2010) at 2820 hospitals, hospital-level postoperative VTE imaging use rates were calculated. Hospital characteristics associated with hospital VTE imaging use rates were examined including case severity, size, ownership, VTE process measure adherence, accreditations, staffing, malpractice environment, and county market factors. Associations between explanatory variables and VTE imaging rates were assessed using quantile regressions at the 25th, median, 75th and 90th quantiles.ResultsMean postoperative VTE imaging rates ranged from 85.26 (SD=67.38) per 1000 discharges in the lowest quartile of hospitals ranked by VTE imaging rates to 168.86 (SD=76.70) in the highest quartile. Drivers of high imaging rates at the 90th quantile were high resident-to-bed ratio (coefficient=51.35, p<0.01), Joint Commission accreditation (coefficient=19.05, p<0.01), presence of other hospitals in the same market with high imaging rates (coefficient=15.29, p<0.01), average case severity (coefficient=11.97, p<0.01), local malpractice costs (coefficient=11.29, p<0.01), and market competition (coefficient=11.03, p<0.01).ConclusionsHospital teaching status, resident-to-bed ratio, malpractice environment and local market factors drive hospital postoperative VTE imaging use, suggesting that non-clinical forces predominantly drive hospital VTE imaging practices.
Republished: Creating a safe, reliable hospital at night handover: a case study in implementation science
Authors: McQuillan Annette , Carthey Jane , Catchpole Ken , McCulloch Peter , Ridout Deborah A , Goldman Allan P 
Published: August 2014

Abstract

Background
We developed protocols to handover patients from day to hospital at night (H@N) teams.

Setting
NHS paediatric specialist hospital.

Method
We observed four handover protocols (baseline, Phases 1, 2 and 3) over 2 years. A mixed-method study (observation, interviews, task analysis, prospective risk assessment, document and case note review) explored the impact of different protocols on performance.

Intervention
In Phase 1, a handover protocol was introduced to resolve problems with the baseline H@N handover. Following this intervention, two further revisions to the handover occurred, driven by staff feedback (Phases 2 and 3).

Results
Variations in performance between handover protocols on three process measures, start time efficiency, total length of handover, and number of distractions and interruptions, were identified. Univariate regression analysis showed statistically significant differences between handover protocols on two surrogate outcome measures: number of flagging omissions and the number of out of hours deteriorations (p=0.04 for Phase 3 vs Phase 1 for both measures (CI 1.04 to 4.08; CI 1.03 to 4.33), and for Phase 3 vs Phase 2 (p=0.006 and p=0.001 (CI 1.22 to 5.15; CI 1.62 to 9.0)), respectively). The Phase 1 and 2 handover protocols were effective at identifying patients whose clinical condition warranted review overnight. Performance on both surrogate outcome measures, length of handover and distractions, deteriorated in Phase 3.

Conclusions
A carefully designed prioritisation process within the H@N handover can be effective at flagging acutely unwell patients. However, the protocol we introduced was unsustainable. In a complex healthcare system, sustainable implementation of new processes may be threatened by conflicting goals.
Demographic characteristics of doctors who intend to follow clinical academic careers: UK national questionnaire surveys
Authors: Smith Fay , Lambert Trevor W , Goldacre Michael J 
Published: August 2014

Abstract

Objectives
It is well recognised that women are underrepresented in clinical academic posts. Our aim was to determine which of a number of characteristics—notably gender, but also ethnicity, possession of an intercalated degree, medical school attended, choice of specialty—were predictive of doctors’ intentions to follow clinical academic careers.

Design
Questionnaires to all UK-trained medical graduates of 2005 sent in 2006 and again in 2010, graduates of 2009 in 2010 and graduates of 2012 in 2013.

Results
At the end of their first year of medical work, 13.5% (368/2732) of men and 7.3% (358/4891) of women specified that they intended to apply for a clinical academic training post; and 6.0% (172/2873) of men and 2.2% (111/5044) of women specified that they intended to pursue clinical academic medicine as their eventual career. A higher percentage of Asian (4.8%) than White doctors (3.3%) wanted a long-term career as a clinical academic, as did a higher percentage of doctors who did an intercalated degree (5.6%) than others (2.2%) and a higher percentage of Oxbridge graduates (8.1%) than others (2.8%). Of the graduates of 2005, only 30% of those who in 2006 intended a clinical medicine career also did so when re-surveyed in 2010 (men 44%, women 12%).

Conclusions
There are noteworthy differences by gender and other demographic factors in doctors’ intentions to pursue academic training and careers. The gap between men and women in aspirations for a clinical academic career is present as early as the first year after qualification.
Epigenetic States of Cells of Origin and Tumor Evolution Drive Tumor-Initiating Cell Phenotype and Tumor Heterogeneity
Authors: Chow Kin-Hoe , Shin Dong-Mi , Jenkins Molly H. , Miller Emily E. , Shih David J. , Choi Seungbum , Low Benjamin E. , Philip Vivek , Rybinski Brad , Bronson Roderick T. , Taylor Michael D. , Yun Kyuson 
Published: August 2014

Abstract
A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, particularly in tumor-initiating cells (TIC), within clinically identical tumors. Here, we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)+/− mice, we identified three distinct tumor subtypes. Through cell type–specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes. Moreover, TICs in each subtype had distinct molecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs from different subtypes were differentially sensitive to SHH or AKT pathway inhibitors, highlighting new mechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels. Cancer Res; 74(17); 4864–74. ©2014 AACR.
Matching Wits with Melanoma Brain Metastases: From Biology to Therapeutics
Authors: Tawbi Hussein 
Published: August 2014

Abstract
Melanoma brain metastases (MBM) present a significant clinical challenge. Molecular profiling of MBM is useful to identify molecular pathways, such as the PI3K pathway, that are specifically and differentially altered in MBM. Therapeutic studies should recruit patients with MBM and prospective tissue collection will lay the foundation for further advances. Clin Cancer Res; 20(21); 5346–8. ©2014 AACR.