bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacotherapy for pediatric chronic intestinal pseudo‐obstruction: Nationwide survey in Japan
Authors: Hashizume Naoki , Yagi Minoru , Ushijima Kosuke , Seki Yoshitaka , Fukahori Suguru , Muto Mitsuru , Matsufuji Hiroshi , Taguchi Tomoaki
Published: November 2016

Background

Chronic intestinal pseudo‐obstruction (CIPO) is a rare disabling and life‐threatening disorder characterized by severe impairment of gastrointestinal peristalsis. While a number of pharmacotherapeutics have been developed, only a few trials have been carried out for improvement of the pathological condition of CIPO patients. This report describes the results of a nationwide survey on the pharmacotherapy used in pediatric CIPO in Japan.

Methods

In 2012, a nationwide survey was conducted to identify the clinical presentation of CIPO in Japan. Information was gathered on pharmacotherapy. Four categories were created for medicines used in pharmacotherapy: “probiotics”, “Japanese herbal medicines (Kampo medicines)”, “laxatives”, and “prokinetics”.

Results

Ninety‐two responses were collected from 47 facilities. Of the 62 patients who met the diagnostic criteria, 52 were treated with medications, while the remaining 10 were not. Thirty‐four patients were given a total of 49 probiotics; 39 were treated with a total of 50 Kampo medicines; 20 were treated with a total of 28 laxatives; and 26 were given a total of 30 prokinetics, 70% of whom were treated specifically with mosapride.

Conclusion

Traditional Japanese medicines such as Kampo medicines and mosapride are often used to treat CIPO in Japan. Two combinations, that is, probiotics and Kampo medicines; and Kampo medicines and prokinetics, were often used for pediatric CIPO in Japan.
Clinical caring science as a scientific discipline
Authors: Rehnsfeldt Arne , Arman Maria , Lindström Unni Å.
Published: November 2016

Background

Clinical caring science will be described from a theory of science perspective.

Aim

The aim of this theoretical article to give a comprehensive overview of clinical caring science as a human science‐based discipline grounded in a theory of science argumentation.

Findings

Clinical caring science seeks idiographic or specific variations of the ontology, concepts and theories, formulated by caring science. The rationale is the insight that the research questions do not change when they are addressed in different contexts. The academic subject contains a concept order with ethos concepts, core and basic concepts and practice concepts that unites systematic caring science with clinical caring science. In accordance with a hermeneutic tradition, the idea of the caring act is based on the degree to which the theory base is hermeneutically appropriated by the caregiver. The better the ethos, essential concepts and theories are understood, the better the caring act can be understood. In order to understand the concept order related to clinical caring science, an example is given from an ongoing project in a disaster context.

Comprehensive reflection

The concept order is an appropriate way of making sense of the essence of clinical caring science. The idea of the concept order is that concepts on all levels need to be united with each other. A research project in clinical caring science can start anywhere on the concept order, either in ethos, core concepts, basic concepts, practice concepts or in concrete clinical phenomena, as long as no parts are locked out of the concept order as an entity. If, for example, research on patient participation as a phenomenon is not related to core and basic concepts, there is a risqué that the research becomes meaningless.
Tenofovir stock shortages have limited impact on clinic‐ and patient‐level HIV treatment outcomes in public sector clinics in South Africa
Authors: Brennan Alana T. , Bor Jacob , Davies Mary‐Ann , Conradie Francesca , Maskew Mhairi , Long Lawrence , Sanne Ian , Fox Matthew P.
Published: November 2016

Objective

Using data from four public sector clinics in South Africa, we sought to investigate provider‐ and patient‐level outcomes, to understand how the 2012 tenofovir stock shortage affected the HIV care and monitoring of ART patients.

Methods

Prospective cohort analysis of ART‐naïve, non‐pregnant, HIV‐infected patients >18 years initiating first‐line ART between 1 July 2011–31 March 2013. Linear regression was used for all outcomes (number of ART initiates, days between pharmacy visits, transfers, single‐drug substitutions, treatment interruptions, missed pharmacy visits, loss to follow‐up and elevated viral load). We fit splines to smooth curves with knots at the beginning (1 February 2012) and end (31 August 2012) of the stock shortage and displayed results graphically by clinic. Difference‐in‐difference models were used to evaluate the effect of the stock shortage on outcomes.

Results

Results suggest a potential shift in the management of patients during the shortage, mainly fewer average days between visits during the shortage vs. before or after at all four clinics, and a significant difference in the proportion of patients missing visits during vs. before (RD: 1.2%; 95% CI: 0.5%, 2.0%). No significant difference was seen in other outcomes.

Conclusion

While South Africa has made great strides to extend access to ART and increase the quality of the health services provided, patient care can be affected when stock shortages/outs occur. While our results show little effect on treatment outcomes, this most likely reflects the clinics’ ability to mitigate the crisis by continuing to keep patient care and treatment as consistent as possible.
A two‐step screening approach for the identification of blood donors with highly and broadly neutralizing capacities against human cytomegalovirus
Authors: Falk Jessica J. , Winkelmann Martina , Schrezenmeier Hubert , Stöhr Dagmar , Sinzger Christian , Lotfi Ramin
Published: November 2016

BACKGROUND

Hyperimmunoglobulins are frequently applied for prophylaxis and treatment of human cytomegalovirus (HCMV) infections but were only marginally effective in meta‐analyses of clinical studies. This might be partially due to selection of donors rather for total anti‐HCMV titers than for neutralizing capacities. To improve efficacy against HCMV infection, we aimed at developing a high‐throughput screening method for identification of blood donors with highly and broadly neutralizing capacities.

STUDY DESIGN AND METHODS

Using a Gaussia luciferase‐expressing reporter virus, 1000 HCMV immunoglobulin (Ig)G‐positive plasma samples with known anti‐HCMV immunoglobulin titers were analyzed regarding their neutralization titers against fibroblast and endothelial cell infection. Based on these results, a high‐throughput screening was designed. Highly neutralizing plasma samples were further tested 1) by an enzyme‐linked immunosorbent assay‐based neutralization assay regarding efficiency against different HCMV strains and 2) for their efficiency compared to commercially available hyperimmunoglobulins.

RESULTS

Total anti‐HCMV immunoglobulin titers did not correlate with neutralization. Mean neutralization capacities were 15‐fold higher in endothelial cells compared to fibroblasts. All plasma samples neutralizing fibroblast infection were at least equally effective against infection of endothelial cells, providing the possibility to simplify our screening method by testing only fibroblasts as target cells with a plasma dilution of 1 in 400. Of the nine tested top HCMV neutralizers, four were broadly effective against different HCMV strains. All nine were significantly superior to hyperimmunoglobulins.

CONCLUSION

Donors with highly and broadly neutralizing capacities can be identified by a two‐step high‐throughput screening approach. This may provide a basis for improved antibody‐based treatment or prophylaxis of HCMV infections.
Human anti‐pig NK cell and CD8+ T‐cell responses in the presence of regulatory dendritic cells
Authors: Madelon Natacha , Puga Yung Gisella L. , Seebach Jörg D.
Published: November 2016

Background

Dendritic cells (DC) play a major role in natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activation leading to cell‐mediated xenogeneic responses. In contrast, the use of in vitro differentiated regulatory DC may represent an attractive approach to protect porcine endothelial cells (pEC) from human cell‐mediated immune responses. In this study, we evaluated the potential of human regulatory DC to reduce xenogeneic NK cell and CTL responses to pEC.

Methods

Human monocytes were differentiated into DC with GM‐CSF and IL‐4 in the absence or presence of rapamycin or IL‐10. The effect of regulatory DC on xenogeneic NK cell and CTL responses was evaluated by analyzing phenotype, IFNγ production, degranulation, and cytotoxicity by flow cytometry and cytotoxicity assays.

Results

Upon maturation with LPS, Rapa‐DC and IL‐10‐DC displayed different phenotypes and cytokine production profiles. In contrast to untreated DC, both Rapa‐DC and IL‐10‐DC induced significantly less IFNγ production and NK cell degranulation in response to pEC, but did not affect NK cell‐mediated pEC lysis. Low production of IL‐18 by Rapa‐DC, and of IL‐12 by IL‐10‐DC were linked to the deficient IFNγ production by NK cells as shown by partial reversion of IFNγ production upon cytokine reconstitution. In contrast to untreated DC efficiently generating xenoantigen‐specific CTL, priming of CTL in the presence of IL‐10‐DC was impaired as shown by lower IFNγ production and cytotoxicity of CTL in response to pEC.

Conclusion

Both Rapa‐DC and IL‐10‐DC controlled human anti‐porcine NK cell responses, in particular IFNγ production, whereas IL‐10‐DC presented stronger regulatory properties of anti‐porcine CTL responses. These in vitro findings indicate that regulatory DC could be a useful tool to promote xenograft tolerance in vivo.
Effects of topical medications on radial artery spasm in patients undergoing transradial coronary procedures: a systematic review protocol
Authors: Curtis Elizabeth , Fernandez Ritin , Lee Astin
Published: November 2016

Review objective:

The objective is to identify the effectiveness of topical medications in reducing radial artery spasm in patients undergoing transradial coronary procedures.
Effectiveness of assertive communication training programs for health professionals and students: a systematic review protocol
Authors: Omura Mieko , Maguire Jane , Levett-Jones Tracy , Stone Teresa Elizabeth
Published: November 2016

Review question/objective:

The objective of this systematic review is to identify, appraise and synthesize the best available evidence related to the effectiveness of assertive communication training programs in healthcare.

More specifically, the objective of this systematic review is to determine the effectiveness of assertive communication interventions for health professionals and students on levels of assertiveness, communication competence and impact on clinician behaviors compared to alternative or no interventions.
Effectiveness of interventions for preventing occupational irritant hand dermatitis: a quantitative systematic review protocol
Authors: Papadatou Zoi , Cooper Kay , Klein Susan , MacDuff Colin , Steiner Markus
Published: November 2016

Review question/objective:

The objective of this quantitative systematic review is to identify, appraise and synthesize the best available evidence on the effectiveness of moisturizers, barrier creams, protective gloves, skin protection education and complex interventions (a combination of two or more of the interventions listed) in preventing occupational irritant hand dermatitis (OIHD) in wet workers. These interventions will be compared to an alternative intervention or to usual care (workers regular skin care regime). The specific review question is: “What is the effectiveness of moisturizers, barrier creams, protective gloves, skin protection education and complex interventions in preventing OIHD in wet workers?”
In-hospital communication experiences of Aboriginal and Torres Strait Islander people: a systematic review protocol
Authors: Kelly Janet , Dowling Anna , McBride Katharine , Keech Wendy , Brown Alex
Published: November 2016

Review question/objective.

The objective of this systematic review is to identify and synthesize available qualitative evidence to understand the in-hospital communication experiences of Aboriginal and Torres Strait Islander adults, their family members and hospital staff, and the factors that impact on these experiences.

Specifically, the review questions are as follows:

What are the communication experiences of Australian Aboriginal and Torres Strait Islander adults and their family members when they interact with hospital staff?

What are the communication experiences of hospital staff when they interact with Australian Aboriginal and Torres Strait Islander adults and their family members?

What are the factors that influence these communication experiences?
Retracted: Mathematical relationships and their consequences between rat pulse waveform parameters and blood pressure during decreasing NO bioavailability
Authors: Misak Anton , Kristek Frantisek , Tomasova Lenka , Grman Marian , Ondriasova Elena , Krizanova Olga , Ondrias Karol
Published: November 2016

New Findings

What is the central question of this study?

We wanted to find out whether the relationship between rat arterial pulse waveform (APW) parameters and blood pressure could be described by known mathematical functions and find mathematical parameters for conditions of hypertension resulting from decreased NO bioavailability.

What is the main finding and its importance?

We found mathematical functions and their parameters that approximate the relationships of 12 APW parameters to systolic and diastolic blood pressure in conditions of decreased NO bioavailability. The results may assign APW parameters to decreased NO bioavailability, which may have predictive or diagnostic value.

Information obtained from the arterial pulse waveform (APW) is useful for characterization of the cardiovascular system in particular (patho)physiological conditions. Our goal was to find out whether the relationships between rat APW parameters could be described by simple mathematical functions and to find mathematical parameters for conditions of hypertension resulting from decreased NO bioavailability. Therefore, we explored details of 14 left carotid APW parameters of anaesthetized male Wistar rats and mathematically characterized their relationship to systolic and diastolic blood pressure (BP) in conditions of a gradual reduction in NO bioavailability after administration of l‐NAME. The right jugular vein of anaesthetized Wistar rats was cannulated for l‐NAME administration. The left carotid artery was cannulated to detect the APW at high resolution. Here, we show the time‐dependent parallel changes of 14 APW parameters before and after i.v. administration of l‐NAME and present mathematical functions that approximate the relationships of 12 APW parameters to systolic and diastolic BP. Some APW parameters had minor (e.g. heart rate) or biphasic dependence on BP (e.g. relative level of the maximum rate of ventricular pressure decrease (dP/dtmin)), but all relationships, within a particular range of BP, could be approximated by known regression functions, as a linear function (e.g. pulse BP), exponential decay (e.g. relative level of the maximum rate of ventricular pressure increase (dP/dtmax)), exponential growth (systolic area), exponential rise to a maximum (relative augmentation index) or sigmoid function (e.g. increase of relative level of dP/dtmin). The mathematical functions may assign APW parameters to decreased NO bioavailability. This may have predictive or diagnostic value.
Plasma enhanced atomic layer deposition of zinc sulfide thin films
Authors: Kuhs Jakob , Dobbelaere Thomas , Hens Zeger , Detavernier Christophe
Published: November 2016

Zinc sulfide thin films were deposited by plasma enhanced atomic layer deposition (PE-ALD) using diethylzinc and H2S/Ar plasma. The growth characteristics were studied in situ with spectroscopic ellipsometry and ex situ with x-ray reflectometry. The growth was linear and self-limited. Furthermore, it was demonstrated that the growth per cycle was less temperature dependent for the PE-ALD process compared to the thermal process. ZnS thin film properties were investigated ex situ using x-ray photoelectron spectroscopy, x-ray diffraction, ultraviolet/visible optical spectroscopy, and atomic force microscopy. The as-deposited films were crystalline with a transmittance of >90% and a band gap of 3.49 eV. ZnS films deposited by PE-ALD were smoother than films deposited by thermal ALD. The plasma enhanced ALD process may have an advantage for ALD of ternary compounds where different temperature windows have to be matched or for applications where a smooth interface is required.
Evaluating the compressive stress generated during fabrication of Si doubly clamped nanobeams with AFM
Authors: Lorenzoni Matteo , Llobet Jordi , Gramazio Federico , Sansa Marc , Fraxedas Jordi , Perez-Murano Francesc
Published: November 2016

In this work, the authors employed Peak Force tapping and force spectroscopy to evaluate the stress generated during the fabrication of doubly clamped, suspended silicon nanobeams with rectangular section. The silicon beams, released at the last step of fabrication, present a curved shape that suggests a bistable buckling behavior, typical for structures that retain a residual compressive stress. Both residual stress and Young's modulus were extracted from experimental data using two different methodologies: analysis of beam deflection profiles and tip-induced mechanical bending. The results from the two methods are compared, providing an insight into the possible limitations of both methods.
Evolution of microstructure and macrostress in sputtered hard Ti(Al,V)N films with increasing energy delivered during their growth by bombarding ions
Authors: Musil Jindřich , Jaroš Martin , Čerstvý Radomír , Haviar Stanislav
Published: November 2016

This letter reports on the effect of the energy Ebi, delivered to the sputtered Ti(Al,V)N film by bombarding ions, on its microstructure, macrostress σ, mechanical properties, and resistance to cracking. The films were deposited by reactive magnetron sputtering. Interrelationships between these parameters were investigated in detail. It was shown that (1) the increase of the energy Ebi makes it possible to convert (1) the film microstructure from columnar to dense, noncolumnar, (2) the macrostress σ from tensile (σ > 0) to compressive (σ < 0), (3) the brittle hard film with low ratio H/E* < 0.1 and low elastic recovery We < 60% to the flexible hard film with high ratio H/E* ≥ 0.1 and high elastic recovery We ≥ 60%, (2) the flexible hard Ti(Al,V)N films with high ratio H/E* ≥ 0.1, high elastic recovery We ≥ 60%, and compressive macrostress can be formed not only in the transition zone (zone T in which the films exhibit a dense, voids-free microstructure) of the Thornton's structural zone model (SZM) but also in zone 1 in which the films exhibit a columnar microstructure and (3) the line corresponding to the films with zero macrostress (σ = 0) in the SZM lies in zone 1 corresponding to the columnar microstructure; here, H is the film hardness and E* = E(1 − ν2) is the effective Young's modulus, E is the Young's modulus, and ν is the Poisson's ratio.
Strategies for CT tissue segmentation for Monte Carlo calculations in nuclear medicine dosimetry
Authors: Braad P. E. N. , Andersen T. , Hansen S. B. , Høilund‐Carlsen P. F.
Published: November 2016

Purpose:

CT images are used for patient specific Monte Carlo treatment planning in radionuclide therapy. The authors investigated the impact of tissue classification, CT image segmentation, and CT errors on Monte Carlo calculated absorbed dose estimates in nuclear medicine.

Methods:

CT errors as a function of patient size, CT reconstruction, and tube current modulation methods were assessed in a phantom experiment on a clinical CT system. The impact of tissue segmentation methods and CT number variations on EGSnrc Monte Carlo calculated absorbed dose distributions was assessed for 99mTc and 131I in the ICRP/ICRU male phantom and in a patient PET/CT‐scanned with 124I prior to radioiodine therapy.

Results:

CT number variations <20 HU were obtained for whole‐body CT examinations at effective CT doses ∼2 mSv. Monte Carlo calculated absorbed doses depended on both the number of media types and accurate calibration of the CT number‐to‐density conversion ramp. Tissue segmentation by a 13‐tissue CT conversion ramp, calibrated by a stoichiometric method, resulted in low (<4%) dose errors in selected organs for both isotopes.

Conclusions:

A calibrated CT scanner specific conversion ramp is required for accurate patient specific dosimetry in nuclear medicine. Accurate dosimetry was obtained with a 13‐tissue ramp that included five different bone types.
An efficient method to determine double Gaussian fluence parameters in the eclipse™ proton pencil beam model
Authors: Shen Jiajian , Liu Wei , Stoker Joshua , Ding Xiaoning , Anand Aman , Hu Yanle , Herman Michael G. , Bues Martin
Published: November 2016

Purpose:

To find an efficient method to configure the proton fluence for a commercial proton pencil beam scanning (PBS) treatment planning system (TPS).

Methods:

An in‐water dose kernel was developed to mimic the dose kernel of the pencil beam convolution superposition algorithm, which is part of the commercial proton beam therapy planning software, eclipse™ (Varian Medical Systems, Palo Alto, CA). The field size factor (FSF) was calculated based on the spot profile reconstructed by the in‐house dose kernel. The workflow of using FSFs to find the desirable proton fluence is presented. The in‐house derived spot profile and FSF were validated by a direct comparison with those calculated by the eclipse TPS. The validation included 420 comparisons of the FSFs from 14 proton energies, various field sizes from 2 to 20 cm and various depths from 20% to 80% of proton range.

Results:

The relative in‐water lateral profiles between the in‐house calculation and the eclipse TPS agree very well even at the level of 10−4. The FSFs between the in‐house calculation and the eclipse TPS also agree well. The maximum deviation is within 0.5%, and the standard deviation is less than 0.1%.

Conclusions:

The authors’ method significantly reduced the time to find the desirable proton fluences of the clinical energies. The method is extensively validated and can be applied to any proton centers using PBS and the eclipse TPS.
A robust automatic birdsong phrase classification: A template-based approach
Authors: Kaewtip Kantapon , Alwan Abeer , O'Reilly Colm , Taylor Charles E.
Published: November 2016

Automatic phrase detection systems of bird sounds are useful in several applications as they reduce the need for manual annotations. However, birdphrase detection is challenging due to limited training data and background noise. Limited data occur because of limited recordings or the existence of rare phrases. Background noise interference occurs because of the intrinsic nature of the recording environment such as wind or other animals. This paper presents a different approach to birdsong phrase classification using template-based techniques suitable even for limited training data and noisy environments. The algorithm utilizes dynamic time-warping (DTW) and prominent (high-energy) time-frequency regions of training spectrograms to derive templates. The performance of the proposed algorithm is compared with the traditional DTW and hidden Markov models (HMMs) methods under several training and test conditions. DTW works well when the data are limited, while HMMs do better when more data are available, yet they both suffer when the background noise is severe. The proposed algorithm outperforms DTW and HMMs in most training and testing conditions, usually with a high margin when the background noise level is high. The innovation of this work is that the proposed algorithm is robust to both limited training data and background noise.
A longer spending freeze
Authors: Mervis Jeffrey
Published: November 2016

Spending freeze could be extended or replaced with final numbers.
The Loop 2 Region of Ribosomal Protein uS5 Influences Spectinomycin Sensitivity, Translational Fidelity, and Ribosome Biogenesis
Authors: Kamath Divya , Gregory Steven T. , O'Connor Michael
Published: November 2016

Ribosomal protein uS5 is an essential component of the small ribosomal subunit that is involved in subunit assembly, maintenance of translational fidelity, and the ribosome's response to the antibiotic spectinomycin. While many of the characterized uS5 mutations that affect decoding map to its interface with uS4, more recent work has shown that residues distant from the uS4-uS5 interface can also affect the decoding process. We targeted one such interface-remote area, the loop 2 region (residues 20 to 31), for mutagenesis in
Escherichia. coli
and generated 21 unique mutants. A majority of the loop 2 alterations confer resistance to spectinomycin and affect the fidelity of translation. However, only a minority show altered rRNA processing or ribosome biogenesis defects.
Echinocandin Resistance in Candida Species Isolates from Liver Transplant Recipients
Authors: Prigent Gwénolé , Aït-Ammar Nawel , Levesque Eric , Fekkar Arnaud , Costa Jean-Marc , El Anbassi Sarra , Foulet Françoise , Duvoux Christophe , Merle Jean-Claude , Dannaoui Eric , Botterel Françoise
Published: November 2016

Liver transplant recipients are at risk of invasive fungal infections, especially candidiasis. Echinocandin is recommended as prophylactic treatment but is increasingly associated with resistance. Our aim was to assess echinocandin drug resistance in
Candida
spp. isolated from liver transplant recipients treated with this antifungal class. For this, all liver-transplanted patients in a University Hospital (Créteil, France) between January and June of 2013 and 2015 were included. Susceptibilities of
Candida
isolates to echinocandins were tested by Etest and the EUCAST reference method. Isolates were analyzed by
FKS
sequencing and genotyped based on microsatellites or multilocus sequence typing (MLST) profiles. Ninety-four patients were included, and 39 patients were colonized or infected and treated with echinocandin. Echinocandin resistance appeared in 3 (8%) of the treated patients within 1 month of treatment. One patient was colonized by resistant
Candida glabrata
, one by resistant
Candida dubliniensis
, and one by resistant
Candida albicans
. Molecular analysis found three mutations in
FKS2
HS1 (F659S, S663A, and D666E) for
C. glabrata
and one mutation in
FKS1
HS1 (S645P) for
C. dubliniensis
and
C. albicans
. Susceptible and resistant isolates belonged to the same genotype. To our knowledge, this is the first study on echinocandin resistance in
Candida
spp. in a liver transplant population. Most resistant isolates were found around/in digestive sites, perhaps due to lower diffusion of echinocandin in these sites. This work documents the risk of emergence of resistance to echinocandin, even after short-term treatment.
High Prevalence of Pneumocystis jirovecii Dihydropteroate Synthase Gene Mutations in Patients with a First Episode of Pneumocystis Pneumonia in Santiago, Chile, and Clinical Response to Trimethoprim-Sulfamethoxazole Therapy
Authors: Ponce Carolina A. , Chabé Magali , George Claudio , Cárdenas Alejandra , Durán Luisa , Guerrero Julia , Bustamante Rebeca , Matos Olga , Huang Laurence , Miller Robert F. , Vargas Sergio L.
Published: November 2016

Mutations in the dihydropteroate synthase (DHPS) gene of
Pneumocystis jirovecii
are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for
Pneumocystis
pneumonia (PCP). The prevalence of
Pneumocystis
DHPS mutations was examined in
Pneumocystis
isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.
Emergence of Colistin Resistance Gene
mcr-1
in Cronobacter sakazakii Producing NDM-9 and in Escherichia coli from the Same Animal
Authors: Liu Bao-Tao , Song Feng-Jing , Zou Ming , Hao Zhi-Hui , Shan Hu
Published: November 2016

We report the presence of
mcr-1
in
Escherichia coli
and carbapenem-resistant
Cronobacter sakazakii
from the same diseased chicken. The
mcr-1
gene linked with IS
Apl1
was located on two different IncI2 plasmids, including one multidrug plasmid in
E. coli
, whereas
fosA3-bla
NDM-9
was on an IncB/O plasmid in
C. sakazakii
. The development of the
fosA3-bla
NDM-9
resistance region was mediated by IS
26
. The colocation of
mcr-1
or
bla
NDM-9
with other resistance genes will accelerate the dissemination of the two genes.
Chromosomal Amplification of the
bla
OXA-58
Carbapenemase Gene in a Proteus mirabilis Clinical Isolate
Authors: Girlich Delphine , Bonnin Rémy A. , Bogaerts Pierre , De Laveleye Morgane , Huang Daniel T. , Dortet Laurent , Glaser Philippe , Glupczynski Youri , Naas Thierry
Published: November 2016

Horizontal gene transfer may occur between distantly related bacteria, thus leading to genetic plasticity and in some cases to acquisition of novel resistance traits
. Proteus mirabilis
is an enterobacterial species responsible for human infections that may express various acquired β-lactam resistance genes, including different classes of carbapenemase genes. Here we report a
Proteus mirabilis
clinical isolate (strain 1091) displaying resistance to penicillin, including temocillin, together with reduced susceptibility to carbapenems and susceptibility to expanded-spectrum cephalosporins. Using biochemical tests, significant carbapenem hydrolysis was detected in
P. mirabilis
1091. Since PCR failed to detect acquired carbapenemase genes commonly found in
Enterobacteriaceae
, we used a whole-genome sequencing approach that revealed the presence of
bla
OXA-58
class D carbapenemase gene, so far identified only in
Acinetobacter
species. This gene was located on a 3.1-kb element coharboring a
bla
AmpC
-like gene. Remarkably, these two genes were bracketed by putative XerC-XerD binding sites and inserted at a XerC-XerD site located between the terminase-like small- and large-subunit genes of a bacteriophage. Increased expression of the two
bla
genes resulted from a 6-time tandem amplification of the element as revealed by Southern blotting. This is the first isolation of a clinical
P. mirabilis
strain producing OXA-58, a class D carbapenemase, and the first description of a XerC-XerD-dependent insertion of antibiotic resistance genes within a bacteriophage. This study revealed a new role for the XerC-XerD recombinase in bacteriophage biology.
Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection
Authors: Antwi Sampson , Yang Hongmei , Enimil Anthony , Sarfo Anima M. , Gillani Fizza S. , Ansong Daniel , Dompreh Albert , Orstin Antoinette , Opoku Theresa , Bosomtwe Dennis , Wiesner Lubbe , Norman Jennifer , Peloquin Charles A. , Kwara Awewura
Published: November 2016

Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC
0–8
), maximum concentration (
C
max
), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age
Z
scores (
P
< 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC
0–8
values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC
0–8
for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)
β-(1,3)-Glucan Unmasking in Some Candida albicans Mutants Correlates with Increases in Cell Wall Surface Roughness and Decreases in Cell Wall Elasticity
Authors: Hasim Sahar , Allison David P. , Retterer Scott T. , Hopke Alex , Wheeler Robert T. , Doktycz Mitchel J. , Reynolds Todd B.
Published: November 2016

Candida albicans
is among the most common human fungal pathogens, causing a broad range of infections, including life-threatening systemic infections. The cell wall of
C. albicans
is the interface between the fungus and the innate immune system. The cell wall is composed of an outer layer enriched in mannosylated glycoproteins (mannan) and an inner layer enriched in β-(1,3)-glucan and chitin. Detection of
C. albicans
by Dectin-1, a C-type signaling lectin specific for β-(1,3)-glucan, is important for the innate immune system to recognize systemic fungal infections. Increased exposure of β-(1,3)-glucan to the immune system occurs when the mannan layer is altered or removed in a process called unmasking. Nanoscale changes to the cell wall during unmasking were explored in live cells with atomic force microscopy (AFM). Two mutants, the
cho1
Δ/Δ and
kre5
Δ/Δ mutants, were selected as representatives that exhibit modest and strong unmasking, respectively. Comparisons of the
cho1
Δ/Δ and
kre5
Δ/Δ mutants to the wild type reveal morphological changes in their cell walls that correlate with decreases in cell wall elasticity. In addition, AFM tips functionalized with Dectin-1 revealed that the forces of binding of Dectin-1 to all of the strains were similar, but the frequency of binding was highest for the
kre5
Δ/Δ mutant, decreased for the
cho1
Δ/Δ mutant, and rare for the wild type. These data show that nanoscale changes in surface topology are correlated with increased Dectin-1 adhesion and decreased cell wall elasticity. AFM, using tips functionalized with immunologically relevant molecules, can map epitopes of the cell wall and increase our understanding of pathogen recognition by the immune system.
NADPH Oxidase Contributes to Resistance against Aggregatibacter actinomycetemcomitans-Induced Periodontitis in Mice
Authors: Bast Antje , Kubis Helen , Holtfreter Birte , Ribback Silvia , Martin Heiner , Schreiner Helen C. , Dominik Malte J. , Breitbach Katrin , Dombrowski Frank , Kocher Thomas , Steinmetz Ivo
Published: November 2016

Aggregatibacter actinomycetemcomitans
is a Gram-negative commensal bacterium of the oral cavity which has been associated with the pathogenesis of periodontitis with severe alveolar bone destruction. The role of host factors such as reactive oxygen and nitrogen intermediates in periodontal
A. actinomycetemcomitans
infection and progression to periodontitis is still ill-defined. Therefore, this study aimed to analyze the role of NADPH oxidase and inducible nitric oxide synthase (iNOS) in a murine model of
A. actinomycetemcomitans
-induced periodontitis. NADPH oxidase-deficient (gp91
phox
knockout [KO]), iNOS-deficient (iNOS KO), and C57BL/6 wild-type mice were orally infected with
A. actinomycetemcomitans
and analyzed for bacterial colonization at various time points. Alveolar bone mineral density and alveolar bone volume were quantified by three-dimensional micro-computed tomography, and the degree of tissue inflammation was calculated by histological analyses. At 5 weeks after infection,
A. actinomycetemcomitans
persisted at significantly higher levels in the murine oral cavities of infected gp91
phox
KO mice than in those of iNOS KO and C57BL/6 mice. Concomitantly, alveolar bone mineral density was significantly lower in all three infected groups than in uninfected controls, but with the highest loss of bone density in infected gp91
phox
KO mice. Only infected gp91
phox
KO mice revealed significant loss of alveolar bone volume and enhanced inflammatory cell infiltration, as well as an increased number of osteoclasts. Our results indicate that NADPH oxidase is important to control
A. actinomycetemcomitans
infection in the murine oral cavity and to prevent subsequent alveolar bone destruction and osteoclastogenesis.
Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus
Authors: Chan Liana C. , Chaili Siyang , Filler Scott G. , Miller Lloyd S. , Solis Norma V. , Wang Huiyuan , Johnson Colin W. , Lee Hong K. , Diaz Luis F. , Yeaman Michael R.
Published: November 2016

Staphylococcus aureusis the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due toS. aureus, including methicillin-resistantS. aureus(MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type andrag1−/−mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type andrag1−/−mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type andrag1−/−mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mβD-3. Priming also protectedrag1−/−mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mβD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.
Spot 42 Small RNA Regulates Arabinose-Inducible
araBAD
Promoter Activity by Repressing Synthesis of the High-Affinity Low-Capacity Arabinose Transporter
Authors: Chen Jiandong , Gottesman Susan
Published: November 2016

The
l
-arabinose-inducible
araBAD
promoter (P
BAD
) enables tightly controlled and tunable expression of genes of interest in a broad range of bacterial species. It has been used successfully to study bacterial sRNA regulation, where P
BAD
drives expression of target mRNA translational fusions. Here we report that in
Escherichia coli
, Spot 42 sRNA regulates P
BAD
promoter activity by affecting arabinose uptake. We demonstrate that Spot 42 sRNA represses
araF
, a gene encoding the AraF subunit of the high-affinity low-capacity arabinose transporter AraFGH, through direct base-pairing interactions. We further show that endogenous Spot 42 sRNA is sufficient to repress
araF
expression under various growth conditions. Finally, we demonstrate this posttranscriptional repression has a biological consequence, decreasing the induction of P
BAD
at low levels of arabinose. This problem can be circumvented using strategies reported previously for avoiding all-or-none induction behavior, such as through constitutive expression of the low-affinity high-capacity arabinose transporter AraE or induction with a higher concentration of inducers. This work adds
araF
to the set of Spot 42-regulated genes, in agreement with previous studies suggesting that Spot 42, itself negatively regulated by the cyclic AMP (cAMP) receptor protein-cAMP complex, reinforces the catabolite repression network.

IMPORTANCE
The bacterial arabinose-inducible system is widely used for titratable control of gene expression. We demonstrate here that a posttranscriptional mechanism mediated by Spot 42 sRNA contributes to the functionality of the P
BAD
system at subsaturating inducer concentrations by affecting inducer uptake. Our finding extends the inputs into the known transcriptional control for the P
BAD
system and has implications for improving its usage for tunable gene expression.
Effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C reactive protein in overweight or obese adults: results from the OmniCarb trial
Authors: Juraschek Stephen P , Miller Edgar R , Selvin Elizabeth , Carey Vincent J , Appel Lawrence J , Christenson Robert H , Sacks Frank M
Published: November 2016

Objective

The glycemic index (GI) of dietary carbohydrate is thought to affect glucose homeostasis. Recently, the Effect of Amount and Type of Dietary Carbohydrates on Risk for Cardiovascular Heart Disease and Diabetes Study (OmniCarb) trial reported that a low-GI diet did not improve insulin sensitivity. We conducted this ancillary study of the OmniCarb trial to determine the effects of GI and carbohydrate content on glucose homeostasis and inflammation.

Research design and methods

OmniCarb was a randomized cross-over feeding study conducted in overweight or obese adults without diabetes (N=163). Participants were fed each of 4 diets for 5 weeks with 2-week washout periods. Weight was held constant. Diets were: high GI (GI≥65) with high carbohydrate (58% kcal), low GI (GI≤45) with low carbohydrate (40% kcal), low GI with high carbohydrate, and high GI with low carbohydrate. We measured glycated albumin (GA), fructosamine, and high sensitivity C reactive protein (CRP) at baseline and following each dietary period. These biomarkers were compared within-person between diets.

Results

The study population was 52% female and 50% black. Mean age was 53 (SD, 11) years; mean body mass index was 32 (SD 6) kg/m2. Reducing GI had no effect on GA or fructosamine, but increased fasting glucose in the setting of a high-carbohydrate diet (+2.2 mg/dL; p=0.02). Reducing carbohydrate content decreased GA in the setting of a high-GI diet (−0.2%; p=0.03) and decreased fructosamine in the setting of a low-GI diet (−4 µmol/L; p=0.003). Reducing carbohydrate while simultaneously increasing GI significantly reduced both GA (−0.2%; p=0.04) and fructosamine (−4 µmol/L; p=0.009). Neither reducing GI nor amount of carbohydrate affected insulin or CRP.

Conclusions

Reducing carbohydrate, regardless of high or low GI, decreased GA and fructosamine. This suggests that reducing carbohydrate content, rather than GI, is a better strategy for lowering glycemia in adults at risk for diabetes.

Trial registration number

NCT00608049.
A critical appraisal of the methodology and quality of evidence of systematic reviews and meta-analyses of traditional Chinese medical nursing interventions: a systematic review of reviews
Authors: Jin Ying-Hui , Wang Guo-Hao , Sun Yi-Rong , Li Qi , Zhao Chen , Li Ge , Si Jin-Hua , Li Yan , Lu Cui , Shang Hong-Cai
Published: November 2016

Objective

To assess the methodology and quality of evidence of systematic reviews and meta-analyses of traditional Chinese medical nursing (TCMN) interventions in Chinese journals. These interventions include acupressure, massage, Tai Chi, Qi Gong, electroacupuncture and use of Chinese herbal medicines—for example, in enemas, foot massage and compressing the umbilicus.

Design

A systematic literature search for systematic reviews and meta-analyses of TCMN interventions was performed. Review characteristics were extracted. The methodological quality and the quality of the evidence were evaluated using the Assessment of Multiple Systematic Reviews (AMSTAR) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) approaches.

Result

We included 20 systematic reviews and meta-analyses, and a total of 11 TCMN interventions were assessed in the 20 reviews. The compliance with AMSTAR checklist items ranged from 4.5 to 8 and systematic reviews/meta-analyses were, on average, of medium methodological quality. The quality of the evidence we assessed ranged from very low to moderate; no high-quality evidence was found. The top two causes for downrating confidence in effect estimates among the 31 bodies of evidence assessed were the risk of bias and inconsistency.

Conclusions

There is room for improvement in the methodological quality of systematic reviews/meta-analyses of TCMN interventions published in Chinese journals. Greater efforts should be devoted to ensuring a more comprehensive search strategy, clearer specification of the interventions of interest in the eligibility criteria and identification of meaningful outcomes for clinicians and patients (consumers). The overall quality of evidence among reviews remains suboptimal, which raise concerns about their roles in influencing clinical practice. Thus, the conclusions in reviews we assessed must be treated with caution and their roles in influencing clinical practice should be limited. A critical appraisal of systematic reviews/meta-analyses of TCMN interventions is particularly important to provide sound guidance for TCMN.