bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effectiveness of terminal feedback delivery to improve the clinical skills of pre-registration health professional students in simulated environments: A systematic review
Authors: Stanhope Jessica , Gill Robyn 
Published: April 2015

Aim: To determine whether terminal feedback is effective in improving the practical, clinical skills of pre-registration health professional students in simulated environments, and how it is best delivered. Methods: Eight databases were searched systematically to identify studies addressing our aim. Eligible studies were published 2004–2014, in English language, within peer- reviewed journals. Study designs were determined and assigned to the National Health and Medical Research Council hierarchy of evidence, with the PEDro scale used to appraise ≥Level III_1 studies. Data regarding the country, participant characteristics, sample size, task critiqued, prior experience with the task, feedback delivered, follow-up time, outcome measures, methods of statistical analysis and the results were extracted and reported descriptively. Results: Eight studies (Levels II–V) were included. Most investigated medical students performing laparoscopic and/or knot tying tasks. PEDro scale scores ranged from 18–54%. Results were mixed when comparing terminal verification feedback and no feedback (n=3), and comparing different types of feedback (n=3). Overall, it would appear that, in terms of terminal feedback, elaborative feedback is more effective in improving the practical, clinical skills of pre-registration health professional students (n=4). Discussion: Whilst there is some indication that elaborative feedback may be more effective than no feedback, the small number of studies and poor methodological quality of the included studies precludes any strong conclusions from being drawn. There are a number of gaps in the current literature, particularly investigating non-medical professions, that should be addressed in future research. Furthermore, larger-scale, well-designed studies in the area are required to guide clinical teaching.
Motion mitigation for lung cancer patients treated with active scanning proton therapy
Authors: Grassberger Clemens , Dowdell Stephen , Sharp Greg , Paganetti Harald 
Published: April 2015

Purpose:Motion interplay can affect the tumor dose in scanned proton beam therapy. This study assesses the ability of rescanning and gating to mitigate interplay effects during lung treatments.Methods:The treatments of five lung cancer patients [48 Gy(RBE)/4fx] with varying tumor size (21.1–82.3 cm3) and motion amplitude (2.9–30.6 mm) were simulated employing 4D Monte Carlo. The authors investigated two spot sizes (σ ∼ 12 and ∼3 mm), three rescanning techniques (layered, volumetric, breath‐sampled volumetric) and respiratory gating with a 30% duty cycle.Results:For 4/5 patients, layered rescanning 6/2 times (for the small/large spot size) maintains equivalent uniform dose within the target >98% for a single fraction. Breath sampling the timing of rescanning is ∼2 times more effective than the same number of continuous rescans. Volumetric rescanning is sensitive to synchronization effects, which was observed in 3/5 patients, though not for layered rescanning. For the large spot size, rescanning compared favorably with gating in terms of time requirements, i.e., 2x‐rescanning is on average a factor ∼2.6 faster than gating for this scenario. For the small spot size however, 6x‐rescanning takes on average 65% longer compared to gating. Rescanning has no effect on normal lung V20 and mean lung dose (MLD), though it reduces the maximum lung dose by on average 6.9 ± 2.4/16.7 ± 12.2 Gy(RBE) for the large and small spot sizes, respectively. Gating leads to a similar reduction in maximum dose and additionally reduces V20 and MLD. Breath‐sampled rescanning is most successful in reducing the maximum dose to the normal lung.Conclusions:Both rescanning (2–6 times, depending on the beam size) as well as gating was able to mitigate interplay effects in the target for 4/5 patients studied. Layered rescanning is superior to volumetric rescanning, as the latter suffers from synchronization effects in 3/5 patients studied. Gating minimizes the irradiated volume of normal lung more efficiently, while breath‐sampled rescanning is superior in reducing maximum doses to organs at risk.
Biomechanical modeling constrained surface‐based image registration for prostate MR guided TRUS biopsy
Authors: van de Ven Wendy J. M. , Hu Yipeng , Barentsz Jelle O. , Karssemeijer Nico , Barratt Dean , Huisman Henkjan J. 
Published: April 2015

Purpose:Adding magnetic resonance (MR)‐derived information to standard transrectal ultrasound (TRUS) images for guiding prostate biopsy is of substantial clinical interest. A tumor visible on MR images can be projected on ultrasound (US) by using MR‐US registration. A common approach is to use surface‐based registration. The authors hypothesize that biomechanical modeling will better control deformation inside the prostate than a regular nonrigid surface‐based registration method. The authors developed a novel method by extending a nonrigid surface‐based registration algorithm with biomechanical finite element (FE) modeling to better predict internal deformations of the prostate.Methods:Data were collected from ten patients and the MR and TRUS images were rigidly registered to anatomically align prostate orientations. The prostate was manually segmented in both images and corresponding surface meshes were generated. Next, a tetrahedral volume mesh was generated from the MR image. Prostate deformations due to the TRUS probe were simulated using the surface displacements as the boundary condition. A three‐dimensional thin‐plate spline deformation field was calculated by registering the mesh vertices. The target registration errors (TREs) of 35 reference landmarks determined by surface and volume mesh registrations were compared.Results:The median TRE of a surface‐based registration with biomechanical regularization was 2.76 (0.81–7.96) mm. This was significantly different than the median TRE of 3.47 (1.05–7.80) mm for regular surface‐based registration without biomechanical regularization.Conclusions:Biomechanical FE modeling has the potential to improve the accuracy of multimodal prostate registration when comparing it to a regular nonrigid surface‐based registration algorithm and can help to improve the effectiveness of MR guided TRUS biopsy procedures.
Dynamic contrast‐enhanced MR microscopy identifies regions of therapeutic response in a preclinical model of colorectal adenocarcinoma
Authors: Subashi Ergys , Qi Yi , Johnson G. Allan 
Published: April 2015

Purpose:A typical dynamic contrast‐enhanced (DCE)‐MRI study often compares the derived pharmacokinetic parameters on manually selected tumor regions or over the entire tumor volume. These measurements include domains where the interpretation of the biomarkers may be unclear (such as in necrotic areas). Here, the authors describe a technique for increasing the sensitivity and specificity of DCE‐MRI by identifying tumor regions with a variable response to therapy.Methods:Two cohorts (n = 8/group) of nu/nu mice with LS‐174T implanted in the mammary fat pad were imaged at five time points over four weeks. The treatment/control group received bevacizumab/saline at a dose of 5 mg/kg or 5 ml/kg twice weekly; imaging experiments were performed weekly. MR images were acquired at an isotropic resolution of 156 μm3(2.4 nl) and with a sampling rate of 9.9 s. The histogram of the time‐to‐peak (TTP) was used to identify two (fast‐ and slow‐enhancing) regions based on a threshold of TTP = 1000 s. The regions were correlated with histology, and the effect of therapy was locally examined.Results:Tumors in the treatment group had a significantly longer doubling time. The regions defined by thresholding the TTP histogram identified two distinct domains correlating significantly with tumor permeability and microvessel density. In the fast‐enhancing region, the mean permeability constant (Ktrans) was significantly lower in the treatment group at day 9; in the slow‐enhancing region, Ktrans was not different between the control and treatment groups. At day 9, the relative volume of the fast‐enhancing region was significantly lower in the treatment group, while that of the slow‐enhancing region was significantly higher.Conclusions:Two regions with distinct kinetic parameters were identified based on the histogram of TTP. The effect of bevacizumab, as measured by a decrease in Ktrans, was confined to one of these regions. High spatiotemporal resolution MR studies may contribute unique insights into the response of the tumor microenvironment to therapy.
Treatment with the Smallpox Antiviral Tecovirimat (ST-246) Alone or in Combination with ACAM2000 Vaccination Is Effective as a Postsymptomatic Therapy for Monkeypox Virus Infection
Authors: Berhanu Aklile , Prigge Jonathan T. , Silvera Peter M. , Honeychurch Kady M. , Hruby Dennis E. , Grosenbach Douglas W. 
Published: April 2015

ABSTRACT
The therapeutic efficacies of smallpox vaccine ACAM2000 and antiviral tecovirimat given alone or in combination starting on day 3 postinfection were compared in a cynomolgus macaque model of lethal monkeypox virus infection. Postexposure administration of ACAM2000 alone did not provide any protection against severe monkeypox disease or mortality. In contrast, postexposure treatment with tecovirimat alone or in combination with ACAM2000 provided full protection. Additionally, tecovirimat treatment delayed until day 4, 5, or 6 postinfection was 83% (days 4 and 5) or 50% (day 6) effective.
Antifungal Susceptibility Profiles of Bloodstream Yeast Isolates by Sensititre YeastOne over Nine Years at a Large Italian Teaching Hospital
Authors: Posteraro Brunella , Spanu Teresa , Fiori Barbara , De Maio Flavio , De Carolis Elena , Giaquinto Alessia , Prete Valentina , De Angelis Giulia , Torelli Riccardo , D'Inzeo Tiziana , Vella Antonietta , De Luca Alessio , Tumbarello Mario , Ricciardi Walter , Sanguinetti Maurizio 
Published: April 2015

ABSTRACT

Sensititre YeastOne (SYO) is an affordable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method for antifungal susceptibility testing. In this study, the MICs of yeast isolates from 1,214 bloodstream infection episodes, generated by SYO during hospital laboratory activity (January 2005 to December 2013), were reanalyzed using current CLSI clinical breakpoints/epidemiological cutoff values to assign susceptibility (or the wild-type [WT] phenotype) to systemic antifungal agents. Excluding
Candida albicans
(57.4% of all isolates [
n
= 1,250]), the most predominant species were
Candida parapsilosis
complex (20.9%),
Candida tropicalis
(8.2%),
Candida glabrata
(6.4%),
Candida guilliermondii
(1.6%), and
Candida krusei
(1.3%). Among the non-
Candida
species (1.9%), 7 were
Cryptococcus neoformans
and 17 were other species, mainly
Rhodotorula
species. Over 97% of
Candida
isolates were susceptible (WT phenotype) to amphotericin B and flucytosine. Rates of susceptibility (WT phenotype) to fluconazole, itraconazole, and voriconazole were 98.7% in
C. albicans
, 92.3% in the
C. parapsilosis
complex, 96.1% in
C. tropicalis
, 92.5% in
C. glabrata
, 100% in
C. guilliermondii
, and 100% (excluding fluconazole) in
C. krusei
. The fluconazole-resistant isolates consisted of 6
C. parapsilosis
complex isolates, 3
C. glabrata
isolates, 2
C. albicans
isolates, 2
C. tropicalis
isolates, and 1
Candida
lusitaniae
isolate. Of the non-
Candida
isolates, 2
C. neoformans
isolates had the non-WT phenotype for susceptibility to fluconazole, whereas
Rhodotorula
isolates had elevated azole MICs. Overall, 99.7% to 99.8% of
Candida
isolates were susceptible (WT phenotype) to echinocandins, but 3 isolates were nonsusceptible (either intermediate or resistant) to caspofungin (
C. albicans
,
C. guilliermondii
, and
C. krusei
), anidulafungin (
C. albicans
and
C. guilliermondii
), and micafungin (
C. albicans
). However, when the intrinsically resistant non-
Candida
isolates were included, the rate of echinocandin nonsusceptibility reached 1.8%. In summary, the SYO method proved to be able to detect yeast species showing antifungal resistance or reduced susceptibility.
Histone Deacetylase Inhibitor Romidepsin InhibitsDe NovoHIV-1 Infections
Authors: Jønsson Kasper L. , Tolstrup Martin , Vad-Nielsen Johan , Kjær Kathrine , Laustsen Anders , Andersen Morten N. , Rasmussen Thomas A. , Søgaard Ole S. , Østergaard Lars , Denton Paul W. , Jakobsen Martin R. 
Published: April 2015

ABSTRACTAdjunct therapy with the histone deacetylase inhibitor (HDACi) romidepsin increases plasma viremia in HIV patients on combination antiretroviral therapy (cART). However, a potential concern is that reversing HIV latency with an HDACi may reactivate the virus in anatomical compartments with suboptimal cART concentrations, leading tode novoinfection of susceptible cells in these sites. We tested physiologically relevant romidepsin concentrations known to reactivate latent HIV in order to definitively address this concern. We found that romidepsin significantly inhibited HIV infection in peripheral blood mononuclear cells and CD4+T cells but not in monocyte-derived macrophages. In addition, romidepsin impaired HIV spreading in CD4+T cell cultures. When we evaluated the impact of romidepsin on quantitative viral outgrowth assays with primary resting CD4+T cells, we found that resting CD4+T cells exposed to romidepsin exhibited reduced proliferation and viability. This significantly lowered assay sensitivity when measuring the efficacy of romidepsin as an HIV latency reversal agent. Altogether, our data indicate that romidepsin-based HIV eradication strategies are unlikely to reseed a latent T cell reservoir, even under suboptimal cART conditions, because romidepsin profoundly restrictsde novoHIV infections.
Influence of Linker Length and Composition on Enzymatic Activity and Ribosomal Binding of Neomycin Dimers
Authors: Watkins Derrick , Kumar Sunil , Green Keith D. , Arya Dev P. , Garneau-Tsodikova Sylvie 
Published: April 2015

ABSTRACT
The human and bacterial A site rRNA binding as well as the aminoglycoside-modifying enzyme (AME) activity against a series of neomycin B (NEO) dimers is presented. The data indicate that by simple modifications of linker length and composition, substantial differences in rRNA selectivity and AME activity can be obtained. We tested five different AMEs with dimeric NEO dimers that were tethered via triazole, urea, and thiourea linkages. We show that triazole-linked dimers were the worst substrates for most AMEs, with those containing the longer linkers showing the largest decrease in activity. Thiourea-linked dimers that showed a decrease in activity by AMEs also showed increased bacterial A site binding, with one compound (compound 14) even showing substantially reduced human A site binding. The urea-linked dimers showed a substantial decrease in activity by AMEs when a conformationally restrictive phenyl linker was introduced. The information learned herein advances our understanding of the importance of the linker length and composition for the generation of dimeric aminoglycoside antibiotics capable of avoiding the action of AMEs and selective binding to the bacterial rRNA over binding to the human rRNA.
Role of Pseudomonas aeruginosa Low-Molecular-Mass Penicillin-Binding Proteins in AmpC Expression, β-Lactam Resistance, and Peptidoglycan Structure
Authors: Ropy Alaa , Cabot Gabriel , Sánchez-Diener Irina , Aguilera Cristian , Moya Bartolome , Ayala Juan A. , Oliver Antonio 
Published: April 2015

ABSTRACT

This study aimed to characterize the role of
Pseudomonas aeruginosa
low-molecular-mass penicillin-binding proteins (LMM PBPs), namely, PBP4 (DacB), PBP5 (DacC), and PBP7 (PbpG), in peptidoglycan composition, β-lactam resistance, and
ampC
regulation. For this purpose, we constructed all single and multiple mutants of
dacB
,
dacC
,
pbpG
, and
ampC
from the wild-type
P. aeruginosa
PAO1 strain. Peptidoglycan composition was determined by high-performance liquid chromatography (HPLC),
ampC
expression by reverse transcription-PCR (RT-PCR), PBP patterns by a Bocillin FL-binding test, and antimicrobial susceptibility by MIC testing for a panel of β-lactams. Microscopy and growth rate analyses revealed no apparent major morphological changes for any of the mutants compared to the wild-type PAO1 strain. Of the single mutants, only
dacC
mutation led to significantly increased pentapeptide levels, showing that PBP5 is the major
dd
-carboxypeptidase in
P. aeruginosa
. Moreover, our results indicate that PBP4 and PBP7 play a significant role as
dd
-carboxypeptidase only if PBP5 is absent, and their
dd
-endopeptidase activity is also inferred. As expected, the inactivation of PBP4 led to a significant increase in
ampC
expression (around 50-fold), but, remarkably, the sequential inactivation of the three LMM PBPs produced a much greater increase (1,000-fold), which correlated with peptidoglycan pentapeptide levels. Finally, the β-lactam susceptibility profiles of the LMM PBP mutants correlated well with the
ampC
expression data. However, the inactivation of
ampC
in these mutants also evidenced a role of LMM PBPs, especially PBP5, in intrinsic β-lactam resistance. In summary, in addition to assessing the effect of
P. aeruginosa
LMM PBPs on peptidoglycan structure for the first time, we obtained results that represent a step forward in understanding the impact of these PBPs on β-lactam resistance, apparently driven by the interplay between their roles in AmpC induction, β-lactam trapping, and
dd
-carboxypeptidase/β-lactamase activity.
Transcriptomic Analysis of Yersinia enterocolitica Biovar 1B Infecting Murine Macrophages Reveals New Mechanisms of Extracellular and Intracellular Survival
Authors: Bent Zachary W. , Poorey Kunal , Brazel David M. , LaBauve Annette E. , Sinha Anupama , Curtis Deanna J. , House Samantha E. , Tew Karen E. , Hamblin Rachelle Y. , Williams Kelly P. , Branda Steven S. , Young Glenn M. , Meagher Robert J. 
Published: April 2015

ABSTRACT

Yersinia enterocolitica
is typically considered an extracellular pathogen; however, during the course of an infection, a significant number of bacteria are stably maintained within host cell vacuoles. Little is known about this population and the role it plays during an infection. To address this question and to elucidate the spatially and temporally dynamic gene expression patterns of
Y. enterocolitica
biovar 1B through the course of an
in vitro
infection, transcriptome sequencing and differential gene expression analysis of bacteria infecting murine macrophage cells were performed under four distinct conditions. Bacteria were first grown in a nutrient-rich medium at 26°C to establish a baseline of gene expression that is unrelated to infection. The transcriptomes of these bacteria were then compared to bacteria grown in a conditioned cell culture medium at 37°C to identify genes that were differentially expressed in response to the increased temperature and medium but not in response to host cells. Infections were then performed, and the transcriptomes of bacteria found on the extracellular surface and intracellular compartments were analyzed individually. The upregulated genes revealed potential roles for a variety of systems in promoting intracellular virulence, including the Ysa type III secretion system, the Yts2 type II secretion system, and the Tad pilus. It was further determined that mutants of each of these systems had decreased virulence while infecting macrophages. Overall, these results reveal the complete set of genes expressed by
Y. enterocolitica
in response to infection and provide the groundwork for future virulence studies.
Anti-Pseudomonas aeruginosa IgY Antibodies Induce Specific Bacterial Aggregation and Internalization in Human Polymorphonuclear Neutrophils
Authors: Thomsen K. , Christophersen L. , Bjarnsholt T. , Jensen P. Ø. , Moser C. , Høiby N. 
Published: April 2015

ABSTRACT

Polymorphonuclear neutrophils (PMNs) are essential cellular constituents in the innate host response, and their recruitment to the lungs and subsequent ubiquitous phagocytosis controls primary respiratory infection. Cystic fibrosis pulmonary disease is characterized by progressive pulmonary decline governed by a persistent, exaggerated inflammatory response dominated by PMNs. The principal contributor is chronic
Pseudomonas aeruginosa
biofilm infection, which attracts and activates PMNs and thereby is responsible for the continuing inflammation. Strategies to prevent initial airway colonization with
P. aeruginosa
by augmenting the phagocytic competence of PMNs may postpone the deteriorating chronic biofilm infection. Anti-
P. aeruginosa
IgY antibodies significantly increase the PMN-mediated respiratory burst and subsequent bacterial killing of
P. aeruginosa
in vitro
. The mode of action is attributed to IgY-facilitated formation of immobilized bacteria in aggregates, as visualized by fluorescence microscopy and the induction of increased bacterial hydrophobicity. Thus, the present study demonstrates that avian egg yolk immunoglobulins (IgY) targeting
P. aeruginosa
modify bacterial fitness, which enhances bacterial killing by PMN-mediated phagocytosis and thereby may facilitate a rapid bacterial clearance in airways of people with cystic fibrosis.
AP-1 Transcription Factor Serves as a Molecular Switch between Chlamydia pneumoniae Replication and Persistence
Authors: Krämer S. , Crauwels P. , Bohn R. , Radzimski C. , Szaszák M. , Klinger M. , Rupp J. , van Zandbergen G. 
Published: April 2015

ABSTRACT

Chlamydia pneumoniae
is a Gram-negative bacterium that causes acute or chronic respiratory infections. As obligate intracellular pathogens, chlamydiae efficiently manipulate host cell processes to ensure their intracellular development. Here we focused on the interaction of chlamydiae with the host cell transcription factor activator protein 1 (AP-1) and its consequence on chlamydial development. During
Chlamydia pneumoniae
infection, the expression and activity of AP-1 family proteins c-Jun, c-Fos, and ATF-2 were regulated in a time- and dose-dependent manner. We observed that the c-Jun protein and its phosphorylation level significantly increased during
C. pneumoniae
development. Small interfering RNA knockdown of the c-Jun protein in HEp-2 cells reduced the chlamydial load, resulting in smaller inclusions and significantly lower chlamydial recovery. Furthermore, inhibition of the c-Jun-containing AP-1 complexes using tanshinone IIA changed the replicative infection phenotype into a persistent one. Tanshinone IIA-dependent persistence was characterized by smaller, aberrant inclusions, a strong decrease in the chlamydial load, and significantly reduced chlamydial recovery, as well as by the reversibility of the reduced recovery after the removal of tanshinone IIA. Interestingly, not only was tanshinone IIA treatment accompanied by a significant decrease of ATP levels, but fluorescence live cell imaging analysis by two-photon microscopy revealed that tanshinone IIA treatment also resulted in a decreased fluorescence lifetime of protein-bound NAD(P)H inside the chlamydial inclusion, indicating that chlamydial reticulate bodies have decreased metabolic activity. In all, these data demonstrate that the AP-1 transcription factor is involved in
C. pneumoniae
development, with tanshinone IIA treatment resulting in persistence.