bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Patient Specifics on Mechanical Risk and Load Relief During Support of Bony Prominences
Authors: Erdemir Ahmet
Published: February 2014

Prolonged mechanical loading of tissue in between a bony prominence and a support surface can lead to pressure ulcers. Despite recent initiatives to curb down incidence rates, the health care burden of pressure ulcer prevention remains significant [1]. Etiology of pressure ulcers are commonly attributed to interface pressures. As a result, interventions, e.g., support surfaces, routinely aim to reduce contact pressures. However, the clinical effectiveness of such an objective can be questionable [2]. Recent studies have shown that internal mechanics of the tissue can be associated with pressure ulcer development [3], potentially indicating the inefficacy of interventions targeted solely at contact pressure relief. Tissue characteristics at a bony prominence, e.g., tissue thickness and material properties, also influence load distribution within and on the surface of the tissue. Given the variability in patient populations and for a bony region of interest [4], it is possible that patient specific risk and load relief (with the use of support surface) may differ widely.
Design Simulations for Droplet Generation and Particle Sorting Mimicking a Bio-Inspired Structure
Authors: Pidaparti Ramana M. , Su Guoguang
Published: February 2014

In this study, the hydrodynamic and structural aspects of the NPC are explored with respect to droplet generation and selective sorting through a design concept and several simulations were carried out to investigate the feasibility.
Finite Element Simulation of an Active Surgical Needle for Prostate Brachytherapy
Authors: Konh Bardia , Hutapea Parsaoran
Published: February 2014

In this article we present a finite element simulation of an active steerable surgical needle. The highly maneuverable actuated needle can be utilized in many cases involving diagnostic and therapeutic percutaneous procedures; for example, in prostate brachytherapy. To make the surgical needle able to navigate through the tissue accurately, avoiding sensitive organs, external bending forces are being provided by smart actuators attached to the needle body (see Fig. 1). The shape memory alloy (SMA) wires, namely Nitinol, with unique properties of super-elasticity, shape memory effect, and biocompatibility are suitable as an actuator. The attached SMA wires contract when heated due to the phase transformation and therefore bends the needle. A 3D finite element (FE) model of the SMA actuated steerable needle was developed and validated by a prototype to show the feasibility of the design and also to study the factors influencing needle deflection.
Experimental Validation of SAPIEN Transcatheter Heart Valve FEA Models
Authors: Zhao Tianwen (Tina) , Martinez Amy , Cao Hengchu
Published: February 2014

The Edwards SAPIEN transcatheter heart valve (Figure 1) is designed for heart valve replacement in patients with severe aortic stenosis without open-heart surgery. Physiological FEA analyses have been performed to provide an assessment of the fracture and fatigue resistance of the device during deployment and operation. The present study validates FEA frame models by comparing the crimping behavior of the FEA models with the results of crimping experiments.
Modeling and Simulation of High-Intensity Focused Ultrasound Therapy for Breast Cancer
Authors: Okita Kohei , Narumi Ryuta , Azuma Takashi , Takagi Shu , Matsumoto Yoichiro
Published: February 2014

Therapeutic application of ultrasound is of interest for a tumor treatment, thrombolysis, drag delivery, blood-brain barrier opening and so on. High-intensity focused ultrasound (HIFU) therapy has been developed as the noninvasive treatment deep cancers in particular. Issues as the defocusing and distortion of ultrasound in the body and the long treatment time in current HIFU should be resolved quickly. Numerical simulation is required for the early development of the advance HIFU system.
Patient-Specific Simulation of Devices-Tissues Interactions for Endovascular Aneurysm Repair
Authors: Duménil A. , Gindre J. , Kaladji A. , Haigron P. , Perrin D. , Badel P. , Avril S. , Lucas A. , Goksu C. , Gupta A. , Rochette M.
Published: February 2014

The endovascular treatment of abdominal aortic aneurysm (EVAR) consists of inserting a delivery system through intravascular pathway and deploying one or several stent-grafts at the aneurysm site in order to exclude it. This procedure has proven to have a high success rate for eligible patient population and benefits in terms of reduced blood loss, intraoperative morbidity and length of hospital stay. As the selection criteria for EVAR extend progressively due to enhancements in the devices and delivery systems, clinicians are confronted with cases becoming increasingly difficult and demanding procedures with steep learning curve (aortic dissection, branched and fenestrated stent-graft, and complex anatomy with high tortuosity or short aortic neck). In this context patient-specific Finite Element Modeling (FEM) could provide a predictive tool to support endovascular device assessment and selection as well as intervention planning. Given the lack of dedicated solutions, the aim of this study was to assess the feasibility of simulating the main steps of EVAR procedure, from guidewire insertion to stent-graft deployment.
Effect of Geometry and Blood Flow in Cooling of Upper Leg
Authors: Kalra M. , Bahrami M. , Sparrey C. J.
Published: February 2014

Systemic hypothermia has been shown to reduce neurological damage in post-cardiac arrest patients. Reducing a patient’s core temperature to 33°C over a period of 24 to 48 hours has been shown to reduce long-term neurological damage by 16% and mortality by 14% [1]. Hypothermia is frequently induced by surface cooling, either with medical devices that circulate coolant in a pad, or ice packs. However, there is a lack of knowledge about the thermal response of tissue to localized cooling. Current thermal models are designed for determining human comfort and have not been evaluated for the targeted low temperatures required for inducing hypothermia. Metabolic heat generation and tissue perfusion rate can significantly change under low temperature, which in turn affects the overall heat flux and cooling rates.
Simulation Based Prediction of the Effect of MPFL Reconstruction on Patellofemoral Mechanics
Authors: Halloran Jason , Andrish Jack , Erdemir Ahmet
Published: February 2014

Patellofemoral complications remain the single largest reason for knee related clinical visits. Yet, robust clinical treatment remains a challenge [1]. To establish causal relationships and understand joint behavior, a complimentary approach utilizing simulation and experimentation may offer valuable insight. Simulation can be confirmed with experimental data and can also be exploited in a predictive capacity. For example, the medial patellofemoral ligament (MPFL) is a clinically relevant structure due to its role in patellofemoral stabilization [2]. MPFL reconstruction, which can be explored in a simulation framework, often utilizes a relatively stiff semitendinosus or gracilis tendon autograft [3]. The procedure is accepted to address patients with chronic patellar instability [4]. While joint stability may be achieved with such an approach, the underlying cartilage loading, and potential long term effects, are unknown. Previous simulation results found sensitivity in cartilage pressures during MPFL reconstruction [4], and these findings may be corroborated using a higher fidelity evaluation of clinically relevant factors. In the context of developing a general patellofemoral simulation framework, the goal of this study was to evaluate the effects of reconstructed MPFL zero force reference (“slack”) length on predicted joint mechanics across a range of potential values. To support the predictive simulation results, a preliminary model validation was also performed against specimen-specific in vitro joint mechanics.
Stepping Towards Subject Specific Temperature Modeling to Improve Thermal Safety in Clinical and Ultra-High Field MRI
Authors: Shrivastava Devashish , Tian Jinfeng , Hughes John , Vaughan J. T.
Published: February 2014

In vivo radiofrequency (RF) heating was simulated by solving the generic bioheat transfer model (GBHTM) in a digital pig due the power deposition from a 3T MR body coil. The simulations were validated by measuring the heating using fluoroptic probes in anesthetized swine due to the whole-body average power deposition of 2.82 W/kg for an hour in a 3T scanner. The GBHTM predicted the RF heating accurately. The simulations as well as the measurements showed that safe temperature changes, as defined by international regulatory guidelines, were exceeded <15 minutes. Thus, appropriate temperature simulations are necessary to ensure human safety in MRI. The new models and methods developed herein brings us closer towards subject specific temperature modeling to improve thermal safety of patients and research subjects in clinical as well as ultra-high field MRI.
Non-Invasive Estimation of Central Blood Pressure Waveform Using a Dual Diametric Cuff System: A Preliminary Study
Authors: Fazeli Nima , Kim Chang-Sei , Hahn Jin-Oh
Published: February 2014

Central blood pressure (BP) is clinically more relevant than peripheral BP in predicting risk factors of cardiovascular (CV) health. However, peripheral BP waveforms can be measured more easily. Thus, there has been great interest in analytically deriving central BP waveform from peripheral BP waveforms.
Surface Stiffness of Patient-Specific Arterial Segments With Varying Plaque Compositions
Authors: Bennetts Craig J. , Erdemir Ahmet , Young Melissa
Published: February 2014

Peripheral arterial disease (PAD), resulting from the accumulation of plaque, causes obstruction of blood flow in the large arteries in the arm and leg. In the United States, approximately 8.4 million people over the age of 40 have PAD [1]. If not treated, PAD can cause ischemic ulcerations and gangrene, which could eventually lead to amputation. Approximately, 25% of patients with PAD have worsening limb symptoms over 5 years, 7% requiring revascularization, and 4% requiring amputation [2].
MRI Induced Heating in a Stent: Translating Measured Ex-Vivo Heating Results to In Vivo Heating
Authors: Visaria Rachana , Shrivastava Devashish
Published: February 2014

A numerical study is performed to translate the MRI induced ex-vivo heating in a stent measured in tissue mimicking gel phantoms to heating in vivo. The in vivo heating was simulated by solving the convective energy equation in a tissue perfused with a single blood vessel embedded with a stent. Appropriate power density function was determined by matching the ex-vivo heating results in the tissue with no blood flow. The effect of the blood flow on the in vivo heating was investigated by varying the flow. Results show that ≥3% of normal, mean physiologic flow in the blood vessel reduces the maximum temperature change to < 3 °C from ∼10 °C measured ex vivo for an MRI scan of ≤ 15 minutes. Local temperature change of up to 3 °C in the trunk is considered safe by the regulatory bodies. Also, the maximum temperature change was found to be ∼1 cm away from the stent ends — and not at the stent ends.
Development, Validation and Parametric Analysis of a Finite Element Model to Simulate the Behavior of Low-Friction Cartilage Replacements
Authors: Santana Manuel E. , Blum Michelle M.
Published: February 2014

Hydrogels have many interesting biomedical applications which have led to a significant body of research in several areas including simulation [1], mechanical properties [2], and modifications to increase biocompatibility [3]. The behavior of these materials is an important mechanism to simulate because of their current and potential medical uses. In particular, soft contact lenses [4] and artificial cartilage [5] replacements are two of the research areas that will benefit from this study.
Stepwise Validated Finite Element Model of the Human Lumbar Spine
Authors: Coombs Dana , Bushelow Michael , Laz Peter , Rao Milind , Rullkoetter Paul
Published: February 2014

Understanding the kinematics of the lumbosacral spine and the individual functional spinal units (FSU) is essential in assessing spine mechanics and implant performance. The lumbosacral spine and the FSU are comprised of bones and complex soft tissues such as intervertebral discs (IVD) and ligaments. Prior studies have focused on the behavior of isolated structures, but the contribution of each structure to the overall kinematics of the spine needs to be further understood. In this study, the behavior of various structural conditions was determined by experimentally dissecting each ligament in a stepwise fasion until only the IVD remained, and applying loading conditions to the FSU. The FE model was validated through optimization to match the in vitro load-deflection characteristics and contact mechanics for the various structural configurations.
Computational Growth and Remodeling Model for Evolving Tissue Engineered Vascular Grafts in the Venous Circulation
Authors: Miller Kristin S. , Udelsman Brooks V. , Lee Yong-Ung , Naito Yuji , Breuer Christopher K. , Humphrey Jay D.
Published: February 2014

The field of vascular tissue engineering continues to advance rapidly, yet there is a pressing need to understand better the time course of polymer degradation and the sequence of cell-mediated matrix deposition and organization. Mounting evidence suggests that cells respond to mechanical perturbations through a process of growth and remodeling (G&R) to establish, maintain, and restore a preferred state of homeostatic stress. Previous computational models utilizing G&R approaches have captured arterial responses to diverse changes in mechanical loading [1, 8, 9]. Recently, a G&R framework was also introduced to account for the kinetics of polymer degradation as well as synthesis and degradation of neotissue constituents [5]. Niklason et al. demonstrated that models of G&R can predict both evolving tissue composition and mechanical behavior after extended periods of in vitro culture of polymer-based tissue-engineered vascular grafts (TEVGs), thus providing insights into the timecourse of neotissue formation and polymer removal. Moreover, they suggest that models of G&R can be powerful tools for the future refinement and optimization of scaffold designs. Nevertheless, such computational models have not yet been developed for examining the formation of neotissue following the implantation of a polymeric TEVG in vivo.
Simulating the Dynamics of an Aortic Valve Prosthesis in a Pulse Duplicator: Numerical Methods and Initial Experience
Authors: Griffith Boyce E. , Flamini Vittoria , DeAnda Abe , Scotten Lawrence
Published: February 2014

Each year, approximately 50,000 aortic valve replacement operations are performed in the United States, but despite decades of development, many of the limitations of aortic valve prostheses remain consequences of the fluid dynamics induced by the replacement valve. We aim to develop detailed fluid-structure interaction (FSI) models of aortic valve prostheses mounted within a ViVitro Systems, Inc. pulse duplicator. Here, we describe numerical methods for simulating FSI with rigid structures, such as the leaflets of a mechanical heart valve, and we present initial three-dimensional simulation studies of the fluid dynamics of a St. Jude Regent bileaflet valve prosthesis.
Empirical Foundations for Computational Modeling of Medical Implants
Authors: Perry Kenneth E. , Johnson Tim J.
Published: February 2014

Validating the in vivo performance of implantable medical devices requires robust computational models that utilize appropriate loading and boundary conditions to represent in vivo conditions. Fatigue safety factors derived from computational models are most meaningful when they are based on material life data obtained from physiologically relevant test conditions of samples with similar process and deformation histories. In this paper, we present selected results that leverage novel experimental techniques that we have used to design robust implant components and develop effective test methods to guarantee they will resist fatigue.
Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer
Authors: Misale Sandra , Arena Sabrina , Lamba Simona , Siravegna Giulia , Lallo Alice , Hobor Sebastijan , Russo Mariangela , Buscarino Michela , Lazzari Luca , Sartore-Bianchi Andrea , Bencardino Katia , Amatu Alessio , Lauricella Calogero , Valtorta Emanuele , Siena Salvatore , Di Nicolantonio Federica , Bardelli Alberto
Published: February 2014

Colorectal cancers that become resistant to EGFR inhibitors through a variety of mechanisms can be effectively treated by inhibiting MEK in conjunction with EGFR.
Seeking Harmony Among Cancer Killers
Authors: Callahan Margaret K.
Published: February 2014

A rationally devised duet of apoptotic drugs and immune adjuvants boosts antitumor activity.
Dissemination of 16S rRNA Methylase ArmA-Producing Acinetobacter baumannii and Emergence of OXA-72 Carbapenemase Coproducers in Japan
Authors: Tada Tatsuya , Miyoshi-Akiyama Tohru , Shimada Kayo , Shimojima Masahiro , Kirikae Teruo
Published: February 2014

Forty-nine clinical isolates of multidrug-resistant
Acinetobacter baumannii
were obtained from 12 hospitals in 7 prefectures throughout Japan. Molecular phylogenetic analysis revealed the clonal spread of
A. baumannii
sequence type 208 (ST208) and ST455 isolates harboring the
armA
gene and ST512 harboring the
armA
and
bla
OXA-72
genes. These findings show that
A. baumannii
isolates harboring
armA
are disseminated throughout Japan, and this is the first report to show that
A. baumannii
strains harboring
bla
OXA-72
and
armA
are emerging in hospitals in Japan.
Discovery of Compounds Blocking the Proliferation of Toxoplasma gondii and Plasmodium falciparum in a Chemical Space Based on Piperidinyl-Benzimidazolone Analogs
Authors: Saïdani Nadia , Botté Cyrille Y. , Deligny Michael , Bonneau Anne-Laure , Reader Janette , Lasselin Ronald , Merer Goulven , Niepceron Alisson , Brossier Fabien , Cintrat Jean-Christophe , Rousseau Bernard , Birkholtz Lyn-Marie , Cesbron-Delauw Marie-France , Dubremetz Jean-François , Mercier Corinne , Vial Henri , Lopez Roman , Maréchal Eric
Published: February 2014

A piperidinyl-benzimidazolone scaffold has been found in the structure of different inhibitors of membrane glycerolipid metabolism, acting on enzymes manipulating diacylglycerol and phosphatidic acid. Screening a focus library of piperidinyl-benzimidazolone analogs might therefore identify compounds acting against infectious parasites. We first evaluated thein vitroeffects of (S)-2-(dibenzylamino)-3-phenylpropyl 4-(1,2-dihydro-2-oxobenzo[d]imidazol-3-yl)piperidine-1-carboxylate (compound 1) onToxoplasma gondiiandPlasmodium falciparum. InT. gondii, motility and apical complex integrity appeared to be unaffected, whereas cell division was inhibited at compound 1 concentrations in the micromolar range. InP. falciparum, the proliferation of erythrocytic stages was inhibited, without any delayed death phenotype. We then explored a library of 250 analogs in two steps. We selected 114 compounds with a 50% inhibitory concentration (IC50) cutoff of 2 μM for at least one species and determinedin vitroselectivity indexes (SI) based on toxicity against K-562 human cells. We identified compounds with high gains in the IC50(in the 100 nM range) and SI (up to 1,000 to 2,000) values. Isobole analyses of two of the most active compounds againstP. falciparumindicated that their interactions with artemisinin were additive. Here, we propose the use of structure-activity relationship (SAR) models, which will be useful for designing probes to identify the target compound(s) and optimizations for monotherapy or combined-therapy strategies.
Spread of NDM-1-Producing Enterobacteriaceae in a Neonatal Intensive Care Unit in Istanbul, Turkey
Authors: Poirel Laurent , Yilmaz Mesut , Istanbullu Ayse , Arslan Ferhat , Mert Ali , Bernabeu Sandrine , Nordmann Patrice
Published: February 2014

Twenty-two consecutive carbapenem-resistant enterobacterial isolates were recovered from patients hospitalized between January and April 2013 in different units at a university hospital in Istanbul, Turkey. These were
Klebsiella pneumoniae
isolates producing the carbapenemases OXA-48, NDM-1, and KPC-2,
Enterobacter cloacae
isolates producing NDM-1, and
Escherichia coli
isolates producing OXA-48. Most of the OXA-48-producing
K. pneumoniae
and all the NDM-1-producing
E. cloacae
were clonally related. The NDM-1-producing
E. cloacae
isolates recovered from a single neonatal intensive care unit corresponded to a single cluster, highlighting the spread of that clone in that setting.
Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination
Authors: Ma H. , Le Pogam S. , Fletcher S. , Hinojosa-Kirschenbaum F. , Javanbakht H. , Yan J.-M. , Jiang W.-R. , Inocencio N. , Klumpp K. , Nájera I.
Published: February 2014

Mericitabine (RG7128) is the prodrug of a highly selective cytidine nucleoside analog inhibitor (RO5855) of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. This study evaluated the effects of combining RO5855 and ribavirin on HCV replication in the HCV subgenomic replicon by using two drug-drug interaction models. The effects of RO5855 and ribavirin on the intracellular metabolism of each compound, on interferon-stimulated gene (ISG) expression, and on the viability of hepatocyte-derived cells were also investigated. RO5855 and ribavirin had additive inhibitory activities against HCV subgenomic replicon replication in drug-drug interaction analyses. RO5855 did not affect the uptake or phosphorylation of ribavirin in primary human hepatocytes, human peripheral blood mononuclear cells, or genotype 1b (G1b) replicon cells. Similarly, ribavirin did not affect the concentrations of intracellular species derived from RO5855 in primary human hepatocytes or the formation of the triphosphorylated metabolites of RO5855. Ribavirin at concentrations of >40 μM significantly reduced the viability of primary hepatocytes but not of Huh7, the G1b replicon, or interferon-cured Huh7 cells. RO5855 alone or with ribavirin did not significantly alter the viability of Huh7 or G1b replicon cells, and it did not significantly affect the viability of primary hepatocytes when it was administered alone. The viability of primary hepatocytes was reduced when they were incubated with RO5855 and ribavirin, similar to the effects of ribavirin alone. RO5855 alone or with ribavirin had no effect on ISG mRNA levels in any of the cells tested. In conclusion, RO5855 did not show any unfavorable interactions with ribavirin in human hepatocytes or an HCV subgenomic replicon system.
Trichomonas vaginalis Metronidazole Resistance Is Associated with Single Nucleotide Polymorphisms in the Nitroreductase Genes

ntr4
Tv

and

ntr6
Tv
Authors: Paulish-Miller Teresa E. , Augostini Peter , Schuyler Jessica A. , Smith William L. , Mordechai Eli , Adelson Martin E. , Gygax Scott E. , Secor William E. , Hilbert David W.
Published: February 2014

Metronidazole resistance in the sexually transmitted parasite
Trichomonas vaginalis
is a problematic public health issue. We have identified single nucleotide polymorphisms (SNPs) in two nitroreductase genes (

ntr4
Tv

and

ntr6
Tv

) associated with resistance. These SNPs were associated with one of two distinct
T. vaginalis
populations identified by multilocus sequence typing, yet one SNP (

ntr6
Tv

A238T), which results in a premature stop codon, was associated with resistance independent of population structure and may be of diagnostic value.
High Activity of Fosfomycin and Rifampin against Methicillin-Resistant Staphylococcus aureus Biofilm
In Vitro
and in an Experimental Foreign-Body Infection Model
Authors: Mihailescu Raluca , Furustrand Tafin Ulrika , Corvec Stéphane , Oliva Alessandra , Betrisey Bertrand , Borens Oliver , Trampuz Andrej
Published: February 2014

Increasing antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA). We evaluated the activity of fosfomycin alone and in combination with vancomycin, daptomycin, rifampin, and tigecycline against MRSA (ATCC 43300) in a foreign-body (implantable cage) infection model. The MICs of the individual agents were as follows: fosfomycin, 1 μg/ml; daptomycin, 0.125 μg/ml; vancomycin, 1 μg/ml; rifampin, 0.04 μg/ml; and tigecycline, 0.125 μg/ml. Microcalorimetry showed synergistic activity of fosfomycin and rifampin at subinhibitory concentrations against planktonic and biofilm MRSA. In time-kill curves, fosfomycin exhibited time-dependent activity against MRSA with a reduction of 2.5 log
10
CFU/ml at 128 × the MIC. In the animal model, planktonic bacteria in cage fluid were reduced by <1 log
10
CFU/ml with fosfomycin and tigecycline, 1.7 log
10
with daptomycin, 2.2 log
10
with fosfomycin-tigecycline and fosfomycin-vancomycin, 3.8 log
10
with fosfomycin-daptomycin, and >6.0 log
10
with daptomycin-rifampin and fosfomycin-rifampin. Daptomycin-rifampin cured 67% of cage-associated infections and fosfomycin-rifampin cured 83%, whereas all single drugs (fosfomycin, daptomycin, and tigecycline) and rifampin-free fosfomycin combinations showed no cure of MRSA cage-associated infections. No emergence of fosfomycin resistance was observed in animals; however, a 4-fold increase in fosfomycin MIC (from 2 to 16 μg/ml) occurred in the fosfomycin-vancomycin group. In summary, the highest eradication of MRSA cage-associated infections was achieved with fosfomycin in combination with rifampin (83%). Fosfomycin may be used in combination with rifampin against MRSA implant-associated infections, but it cannot replace rifampin as an antibiofilm agent.
NADPH Oxidase Promotes Neutrophil Extracellular Trap Formation in Pulmonary Aspergillosis
Authors: Röhm Marc , Grimm Melissa J. , D'Auria Anthony C. , Almyroudis Nikolaos G. , Segal Brahm H. , Urban Constantin F.
Published: February 2014

NADPH oxidase is a crucial enzyme in antimicrobial host defense and in regulating inflammation. Chronic granulomatous disease (CGD) is an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates.
Aspergillus
species are ubiquitous, filamentous fungi, which can cause invasive aspergillosis, a major cause of morbidity and mortality in CGD, reflecting the critical role for NADPH oxidase in antifungal host defense. Activation of NADPH oxidase in neutrophils can be coupled to the release of proteins and chromatin that comingle in neutrophil extracellular traps (NETs), which can augment extracellular antimicrobial host defense. NETosis can be driven by NADPH oxidase-dependent and -independent pathways. We therefore undertook an analysis of whether NADPH oxidase was required for NETosis in
Aspergillus fumigatus
pneumonia. Oropharyngeal instillation of live
Aspergillus
hyphae induced neutrophilic pneumonitis in both wild-type and NADPH oxidase-deficient (p47

phox−/−

) mice which had resolved in wild-type mice by day 5 but progressed in p47

phox
−/−

mice. NETs, identified by immunostaining, were observed in lungs of wild-type mice but were absent in p47

phox
−/−

mice. Using bona fide NETs and nuclear chromatin decondensation as an early NETosis marker, we found that NETosis required a functional NADPH oxidase
in vivo
and
ex vivo
. In addition, NADPH oxidase increased the proportion of apoptotic neutrophils. Together, our results show that NADPH oxidase is required for pulmonary clearance of
Aspergillus
hyphae and generation of NETs
in vivo
. We speculate that dual modulation of NETosis and apoptosis by NADPH oxidase enhances antifungal host defense and promotes resolution of inflammation upon infection clearance.
Metabolic and Bactericidal Effects of Targeted Suppression of NadD and NadE Enzymes in Mycobacteria
Authors: Rodionova Irina A. , Schuster Brian M. , Guinn Kristine M. , Sorci Leonardo , Scott David A. , Li Xiaoqing , Kheterpal Indu , Shoen Carolyn , Cynamon Michael , Locher Christopher , Rubin Eric J. , Osterman Andrei L.
Published: February 2014

Mycobacterium tuberculosis
remains a major cause of death due to the lack of treatment accessibility, HIV coinfection, and drug resistance. Development of new drugs targeting previously unexplored pathways is essential to shorten treatment time and eliminate persistent
M. tuberculosis
. A promising biochemical pathway which may be targeted to kill both replicating and nonreplicating
M. tuberculosis
is the biosynthesis of NAD(H), an essential cofactor in multiple reactions crucial for respiration, redox balance, and biosynthesis of major building blocks. NaMN adenylyltransferase (NadD) and NAD synthetase (NadE), the key enzymes of NAD biosynthesis, were selected as promising candidate drug targets for
M. tuberculosis
. Here we report for the first time kinetic characterization of the recombinant purified NadD enzyme, setting the stage for its structural analysis and inhibitor development. A protein knockdown approach was applied to validate bothNadD and NadE as target enzymes. Induced degradation of either target enzyme showed a strong bactericidal effect which coincided with anticipated changes in relative levels of NaMN and NaAD intermediates (substrates of NadD and NadE, respectively) and ultimate depletion of the NAD(H) pool. A metabolic catastrophe predicted as a likely result of NAD(H) deprivation of cellular metabolism was confirmed by
13
C biosynthetic labeling followed by gas chromatography-mass spectrometry (GC-MS) analysis. A sharp suppression of metabolic flux was observed in multiple NAD(P)(H)-dependent pathways, including synthesis of many amino acids (serine, proline, aromatic amino acids) and fatty acids. Overall, these results provide strong validation of the essential NAD biosynthetic enzymes, NadD and NadE, as antimycobacterial drug targets.

IMPORTANCE
To address the problems of
M. tuberculosis
drug resistance and persistence of tuberculosis, new classes of drug targets need to be explored. The biogenesis of NAD cofactors was selected for target validation because of their indispensable role in driving hundreds of biochemical transformations. We hypothesized that the disruption of NAD production in the cell via genetic suppression of the essential enzymes (NadD and NadE) involved in the last two steps of NAD biogenesis would lead to cell death, even under dormancy conditions. In this study, we confirmed the hypothesis using a protein knockdown approach in the model system of
Mycobacterium smegmatis
. We showed that induced proteolytic degradation of either target enzyme leads to depletion of the NAD cofactor pool, which suppresses metabolic flux through numerous NAD(P)-dependent pathways of central metabolism of carbon and energy production. Remarkably, bactericidal effect was observed even for nondividing bacteria cultivated under carbon starvation conditions.
An evidence-driven approach to scrum law modifications in amateur rugby played in South Africa
Authors: Hendricks Sharief , Lambert Mike I , Brown James C , Readhead Clint , Viljoen Wayne
Published: February 2014

Background

In 2012, the South African Rugby Union (SARU) approved a new set of scrum laws for amateur rugby played in the country, to be implemented at the start of the 2013 rugby season. These law changes were primarily based on the relatively high proportion of scrum-related catastrophic injury data collected as part of the BokSmart National Rugby Safety Programme (BokSmart) over the preceding 4 years (2008–2011).

Aim

To describe the scrum-related catastrophic injury data in South Africa over the past 5 years (2008–2012), and to discuss how this evidence justifies the change in the Amateur Scrum Laws to make this aspect of the game safer in South Africa.

Methods

Catastrophic injury data were collected throughBokSmartat amateur and professional levels, during training and matches over 5 years (2008–2012).

Results

The scrum phase accounted for 33% (n=20 of 60) of all catastrophic injuries between 2008 and 2012. Eighteen of the 20 scrum injuries (90%) were confirmed as acute spinal cord injuries, with 13 of these being permanent injuries. For the scrum injury mechanisms that were provided (n=19), ‘impact on the engagement’ was the most frequently reported (n=11 of 19, 58%), followed by ‘collapsed scrum’ (n=7 of 19, 37%) and ‘popping out’ (n=1 of 19, 5%).

Conclusions

Based on these scrum-related catastrophic injury data, a change in the Amateur Scrum Laws of South African Rugby was justified. The main purpose of these scrum law changes is to reduce the number of scrum-related catastrophic injuries in the country, by minimising the opportunity for impact injury and subsequent scrum collapse in amateur rugby in South Africa, thereby making this aspect of the game of rugby safer.
The smoking habit of a close friend or family member—how deep is the impact? A cross-sectional study
Authors: Saari Antti J , Kentala Jukka , Mattila Kari J
Published: February 2014

Objectives

To assess the risk of becoming a smoker in adulthood associated with parental smoking as well as the smoking of siblings and close friends.

Design

A cross-sectional study.

Setting

4 oral healthcare centres in Finland and a follow-up.

Participants

An age cohort born in 1979 (n=2586) and living in four Finnish towns. Of those reached by the 2008 follow-up, 46.9% (n=1020) responded.

Primary and secondary outcome measures

Smoking behaviour at the age of 29. Smoking behaviour at the age of 13 and smoking behaviour of family members and close friends.

Results

Smoking of a current close friend was strongly associated with participants’ own smoking (OR 5.6, 95% CI 3.6 to 8.8). The smoking of a close friend during schooldays was similarly associated (OR 2.9, 95% CI 1.8 to 4.5). Smoking among men was associated with the smoking behaviour of mothers and siblings while that among females was not.

Conclusions

The impact of a smoker as a close friend is greater than that of a smoking parent or sibling in school age when it comes to smoking behaviour in adulthood. This should be taken into consideration when attempting to prevent smoking initiation or continuation.

Trial registration

At clinicaltrials.gov (NCT01348646).
The impact of heatwaves on mortality in Australia: a multicity study
Authors: Tong Shilu , Wang Xiao Yu , Yu Weiwei , Chen Dong , Wang Xiaoming
Published: February 2014

Objectives

To assess the heterogeneity of heatwave-related impacts on mortality across different cities.

Design

A multicity time series study.

Setting

3 largest Australian cities: Brisbane, Melbourne and Sydney.

Participants

All residents living in these cities.

Main outcome measures

Non-external causes mortality data by gender and two age groups (ie, 0–75 and 75+) for these cities during the period 1988–2009 were obtained from relevant government agencies.

Results

Total mortality increased mostly within the same day (lag 0) or a lag of 1 day (lag 1) during almost all heatwaves in three cities. Using the heatwave definition (HWD) as the 95th centile of mean temperature for two or more consecutive days in the summer season, the relative risk for total mortality at lag 1 in Brisbane, Melbourne and Sydney was 1.13 (95% CI 1.08 to 1.19), 1.10 (95% CI 1.06 to 1.14) and 1.06 (95% CI 1.01 to 1.10), respectively. Using the more stringent HWD—the 99th centile of mean temperature for two or more consecutive days, the relative risk of total mortality at the lags of 0–2 days in Brisbane and Melbourne was 1.40 (95% CI 1.29 to 1.51) and 1.47 (95% CI 1.36 to 1.59), respectively. Elderly, particularly females, were more vulnerable to the impact of heatwaves.

Conclusions

A consistent and significant increase in mortality was observed during heatwaves in the three largest Australian cities, but the impacts of heatwave appeared to vary with age, gender, the HWD and geographical area.
‘Shouting from the roof tops’: a qualitative study of how children with leukaemia are diagnosed in primary care
Authors: Clarke Rachel T , Jones Caroline HD , Mitchell Christopher D , Thompson Matthew J
Published: February 2014

Objectives

To investigate the prehospital presentation of paediatric leukaemia and identify the disease and non-disease related factors which facilitate or impede diagnosis.

Design

Thematic analysis of qualitative semistructured interviews.

Setting

One tertiary referral centre in Southern England.

Participants

21 parents and 9 general practitioners (GPs) of 18 children (<18-year-old) with a new diagnosis of acute leukaemia.

Results

The majority of children were first seen by GPs before the characteristic signs and symptoms of leukaemia had developed. In their absence, behavioural cues such as the child becoming apathetic or ‘not themselves’ often triggered parents to seek medical help. Most GPs were unclear about the nature and severity of the child's presentation: then, safety netting, thorough history-taking and examination, and reliance on contextual information about the parents or from prior hospital paediatrics experience were used to manage diagnostic uncertainty. The nature of the doctor–parent relationship helped and hindered the diagnostic pathway. GPs’ prior perceptions of parents as being ‘sensible’ or ‘worriers’ influenced how gravely they treated parental concerns, with ‘worriers’ being taken less seriously. Some parents believed GPs failed to listen to their anxieties and discounted their expert knowledge of their child. Specific delay factors included lack of continuity of GP; some GPs’ reluctance to take blood from children; and some parents feeling unable to voice effectively their concerns.

Conclusions

The presentation of paediatric leukaemia in primary care differs from that described in many hospital studies, with greater diversity and intermittency of symptoms, and the frequent absence of ‘red flags’ of serious illness. A wide range of non-disease related factors potentially delay the diagnosis of paediatric leukaemia, including tensions in the doctor–patient relationship and the doctors’ cognitive biases. The identification and attempted modification of these factors may minimise diagnostic delay more successfully than raising awareness of ‘red flags’ of disease.
CRIB—the use of cardiac rehabilitation services to aid the recovery of patients with bowel cancer: a pilot randomised controlled trial (RCT) with embedded feasibility study
Authors: Munro Julie , Adams Richard , Campbell Anna , Campbell Sandra , Donaldson Cam , Godwin Jon , Haw Sally , Kidd Lisa , Lane Chrissie , Leslie Stephen J , Mason Helen , Mutrie Nanette , O'Carroll Ronan , Taylor Cara , Treweek Shaun , Watson Angus , Hubbard Gill
Published: February 2014

Introduction

Patients with colorectal cancer report ongoing physical and psychological impairments and a high proportion of these patients are overweight, insufficiently active and high-risk drinkers, putting them at risk of poor recovery and risk of recurrence and comorbidities. A challenge is implementing sustainable and effective rehabilitation as part of routine care for this group.

Methods and analysis

A two-arm pilot randomised controlled trial (RCT) with embedded feasibility study undertaken as a phased programme of work. The intervention involves an existing cardiac rehabilitation programme for cardiac patients accepting colorectal cancer patient referrals. The intervention consists of supervised exercise sessions run by a cardiac physiotherapist and information sessions. Phase 1 will involve one research site enrolling 12 patients to assess intervention and study design processes. Semistructured interviews with patients with colorectal cancer and cardiac patients and clinicians will be used to gather data on acceptability of the intervention and study procedures. Phase 2 will involve three sites enrolling 66 patients with colorectal cancer randomised to control or intervention groups. Outcome measures will be taken preintervention and postintervention, for phases 1 and 2. The primary outcome is accelerometer measured physical activity; secondary outcomes are self-report physical activity, quality of life, anxiety, depression, symptoms including fatigue. The following variables will also be examined to determine if these factors influence adherence and outcomes: self-efficacy, risk perception and treatments.

Ethics and dissemination

Full ethical approval was granted by NRES Committees—North of Scotland (13/NS/0004; IRAS project ID: 121757) on 22 February 2013. The proposed work is novel in that it aims to test the feasibility and acceptability of using an evidence-based and theory driven existing cardiac rehabilitation service with patients with colorectal cancer. Should this model of rehabilitation prove to be clinically and cost effective we aim to conduct a randomised controlled trial of this intervention to measure effectiveness.

Trial registration reference

ISRCTN63510637; UKCRN id 14092.
Does a geographical context of deprivation affect differences in injury mortality? A multilevel analysis in South Korean adults residing in metropolitan cities
Authors: Lee JeSuk , Lee Weon-Young , Noh MaengSeok , Khang Young-Ho
Published: February 2014

Background

This study aimed to examine whether the socioeconomic context of urban areas affects differences in adult mortality from injuries in the districts of all seven South Korean metropolitan cities, after adjusting for individual demographic and socioeconomic indicators.

Methods

Two different sets of data were used in this study: (1) the National Death Registration data from 2003 to 2008; and (2) the National Census in 2005. Variables for individual characteristics were gender, age, residential area and educational level. A geographic deprivation index was calculated based on the Carstairs Index. Multilevel Poisson regression models were used to analyse the relationship between area deprivation levels and injury mortality.

Results

Greater mortality risks of traffic accidents, falls, suicide and all injuries were found in the elderly, the less educated and men, compared with their counterparts. The most deprived districts were at greater risks of death due to traffic accidents (risk ratio (RR)=1.34; 95% CI 1.05 to 1.73), falls (RR=1.63; 95% CI 1.20 to 2.20), suicide (RR=1.09; 95% CI 1.01 to 1.17) and all injuries (RR=1.14; 95% CI 1.07 to 1.22) compared with the least deprived districts, even after individual level socioeconomic variables were controlled for. However, area level deprivation did not show cross level interactions with the individual level education in estimating fatal injury risks.

Conclusions

Both contextual and compositional effects of socioeconomic status on injury mortality among urban areas in South Korea should be considered in allocating resources for injury prevention.
Feminisation of UK General Practice: a challenge for the Defence Medical Services?
Authors: Withnall Richard D J , Graham D J M , Morris L E , Wallace M
Published: February 2014

Background

The Defence Medical Services (DMS) primarily recruits its trained General Practitioners (GPs) from the NHS and since 1970, the number of men entering medicine has doubled whereas the number of women has increased 10-fold; female GPs will outnumber their male counterparts by 2017. This study performs a quantitative assessment of the potential impact of feminisation of UK General Practice upon the DMS recruitment and workforce planning.

Methods

General Medial Council General Practice Certificate of Completion of Training (GMC GP CCT) data were analysed to identify any change in the percentage of male and female GP Specialty Training Registrars successfully completing GP vocational training between 2007 and 2012, thus becoming potentially recruitable into the DMS as independent GPs.

Results

A 3% increase was seen in the number of women achieving GMC GP CCT between 2007 and 2012 (p=0.015). The percentage of DMS GP Specialty Training Registrars (GPStRs) gaining their GMC GP CCT in 2012 who were women (25%) was about half that seen nationally (59%). A lack of 2007 by-sex GMC GP CCT data for DMS GPStRs prevented a comparison with 2012.

Conclusions

The national increase of only 3% infers feminisation of UK General Practice is not an immediate challenge for the DMS. Nevertheless, as feminisation of the UK GP workforce is expected to continue, the future cohort from whom the DMS will recruit its GPs is likely to contain increasing numbers of women. With the return to contingency, the DMS may wish to consider the implications of increasing numbers of female GPs upon service delivery in the UK and overseas, and explore more flexible medical employment models.
Vitamin D levels and left ventricular diastolic function
Authors: Pandit Anil , Mookadam Farouk , Boddu Sailaja , Aryal Pandit Aashrayata , Tandar Anwar , Chaliki Hari , Cha Stephen , Lee Howard R
Published: February 2014

Objective

To determine the association between serum vitamin D level and left ventricular (LV) diastolic dysfunction.

Background

Vitamin D deficiency has been shown in observational and prospective studies to be associated with cardiovascular diseases including coronary artery disease, LV hypertrophy and systolic heart failure. Even though diastolic LV dysfunction is an early manifestation of cardiac disease, there is no study that examines whether a deficiency of vitamin D is associated with LV diastolic dysfunction.

Method

A retrospective observational review of 1011 patients (679 women) was conducted to examine if low 25-OH-vitamin D levels were associated with LV diastolic dysfunction.

Results

All the LV diastolic dysfunction parameters: left atrial volume index, E/e', e' velocity, LV mass index and deceleration time were not significantly different between patients with 25-OH vitamin D level ≤20 ng/mL vs 25-OH vitamin D level >20 ng/mL.

Conclusions

Despite growing medical literature suggesting vitamin D deficiency is associated with cardiovascular disease, in this present study there is no significant association of vitamin D levels and LV diastolic performance, including left atrial volume index.
Preventive PCI versus culprit lesion stenting during primary PCI in acute STEMI: a systematic review and meta-analysis
Authors: Pandit Anil , Aryal Madan Raj , Aryal Pandit Aashrayata , Hakim Fayaz Ahmad , Giri Smith , Mainali Naba Raj , Sharma Prashant , Lee Howard R , Fortuin F David , Mookadam Farouk
Published: February 2014

Aim

The benefit of preventive percutaneous coronary intervention (PCI) in ST elevation myocardial infarction (STEMI) has been shown in randomised trials. However, all the randomised trials are underpowered to detect benefit in cardiac death. We aim to systematically review evidence on the cardiac mortality benefit of preventive PCI in patients presenting with acute STEMI in randomised patient populations.

Methods

PubMed, Scopus, Cochrane and clinicaltrials.gov databases were searched for studies published until 30 September 2013. The studies were limited to randomised clinical trials. Independent observers abstracted the data on outcomes, characteristics and qualities of studies included. Fixed effect model was employed for meta-analysis. Heterogeneity of studies included was analysed using I2statistics.

Results

In three randomised clinical trials published, involving 748 patients with acute STEMI and multivessel disease, 416 patients were randomised to preventive PCI and 332 to culprit-only PCI. Patients undergoing preventive PCI had significant lower risk of cardiovascular deaths (pooled OR 0.39, 95% CI 0.18 to 0.83, p=0.01, I2=0%), repeat revascularisation (pooled OR 0.28, 95% CI 0.18 to 0.44, p=0.00001, I2=0%) and non-fatal myocardial infarction (pooled OR 0.38, 95% CI 0.20 to 0.75, p=0.005, I2=0%) compared with culprit-only revascularisation.

Conclusions

In patients presenting with acute STEMI and significant multivessel coronary artery disease, based on our data, preventive PCI is associated with lower risk of cardiovascular mortality compared with primary PCI of only the culprit artery. This finding needs to be confirmed in larger adequately powered randomised clinical trials.