bluuebunny/crossref_metadata_2025 huggingface dataset:
Skeletal muscle‐derived exosomes regulate endothelial cell functions via reactive oxygen species‐activated nuclear factor‐κB signalling
Authors: Nie Yaohui , Sato Yoriko , Garner Ron T. , Kargl Christopher , Wang Chao , Kuang Shihuan , Gilpin Christopher J. , Gavin Timothy P.
Published: May 2019

New Findings

What is the central question of this study?

Capillary rarefaction is found in diabetic and aged muscle, whereas exercise increases skeletal muscle angiogenesis. The association implies a crosstalk between muscle cells and endothelial cells. The underlying mechanisms mediating the crosstalk between these cells remains to be elucidated fully.

What is the main finding and its importance?

Endothelial cell functions are regulated by skeletal muscle cell‐derived exosomes via a vascular endothelial growth factor‐independent pathway. This study reveals a new mechanism mediating the crosstalk between skeletal muscle cells and endothelial cells.

Loss of skeletal muscle capillarization, known as capillary rarefaction, is found in type 2 diabetes, chronic heart failure and healthy ageing and is associated with impaired delivery of substrates to the muscle. However, the interaction and communication of skeletal muscle with endothelial cells in the regulation of capillaries surrounding the muscle remains elusive. Exosomes are a type of secreted extracellular vesicle containing mRNAs, proteins and, especially, microRNAs that exert paracrine and endocrine effects. In this study, we investigated whether skeletal muscle‐derived exosomes (SkM‐Exo) regulate the endothelial cell functions of angiogenesis. We demonstrated that C2C12 myotube‐derived exosomes improved endothelial cell functions, assessed by the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), which were increased by 20, 23 and 40%, respectively, after SkM‐Exo exposure. The SkM‐Exo failed to activate HUVEC vascular endothelial growth factor (VEGF) signalling. The SkM‐Exo increased HUVEC reactive oxygen species and activated the nuclear factor‐κB pathway, suggesting that SkM‐Exo‐induced angiogenesis was mediated by a VEGF‐independent pathway. In addition, several angiogenic microRNAs were packaged in SkM‐Exo, with miR‐130a being particularly enriched and successfully transferred from SkM‐Exo to HUVECs. Delivery of miRNAs into endothelial cells might explain the enhancement of reactive oxygen species production and angiogenesis by SkM‐Exo. The potential angiogenic effect of SkM‐Exo could provide an effective therapy for promoting skeletal muscle angiogenesis in diseases characterized by capillary rarefaction or inadequate angiogenesis.
Issues in the determination of ‘responders’ and ‘non‐responders’ in physiological research
Authors: Atkinson Greg , Williamson Philip , Batterham Alan M.
Published: May 2019

New Findings

What is the topic for this review?

We discuss the dichotomization of continuous‐level physiological measurements into ‘responders’ and ‘non‐responders’ when interventions/treatments are examined in robust parallel‐group studies.

What advances does it highlight?

Sample responder counts are biased by pre‐to‐post within‐subject variability. Sample differences in counts may be explained wholly by differences in mean response, even without individual response heterogeneity and even if test–retest measurement error informs the choice of response threshold. A less biased and more informative approach uses the SD of individual responses to estimate the chance a new person from the population of interest will be a responder.

As a follow‐up to our 2015 review, we cover more issues on the topic of ‘response heterogeneity’, which we define as clinically important individual differences in the physiological responses to the same treatment/intervention that cannot be attributed to random within‐subject variability. We highlight various pitfalls with the common practice of counting the number of ‘responders’, ‘non‐responders’ and ‘adverse responders’ in samples that have been given certain treatments or interventions for research purposes. We focus on the classical parallel‐group randomized controlled trial and assume typical good practice in trial design. We show that sample responder counts are biased because individuals differ in terms of pre‐to‐post within‐subject random variability in the study outcome(s) and not necessarily treatment response. Ironically, sample differences in responder counts may be explained wholly by sample differences in mean response, even if there is no response heterogeneity at all. Sample comparisons of responder counts also have relatively low statistical precision. These problems do not depend on how the response threshold has been selected, e.g. on the basis of a measurement error statistic, and are not rectified fully by the use of confidence intervals for individual responses in the sample. The dichotomization of individual responses in a research sample is fraught with pitfalls. Less biased approaches for estimating the proportion of responders in a population of interest are now available. Importantly, these approaches are based on the SD for true individual responses, directly incorporating information from the control group.
Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth
Authors: Son Jun Seok , Liu Xiangdong , Tian Qiyu , Zhao Liang , Chen Yanting , Hu Yun , Chae Song Ah , de Avila Jeanene M. , Zhu Mei‐Jun , Du Min
Published: May 2019

Key points

Maternal exercise improves the metabolic health of maternal mice challenged with a high‐fat diet.

Exercise intervention of obese mothers prevents fetal overgrowth.

Exercise intervention reverses impaired placental vascularization in obese mice.

Maternal exercise activates placental AMP‐activated protein kinase, which was inhibited as a result of maternal obesity.

More than one‐third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high‐fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD‐induced obese mice, daily treadmill exercise during pregnancy reduced body weight gain, lowered serum glucose and lipid concentration, and improved insulin sensitivity of maternal mice. Importantly, maternal exercise prevented fetal overgrowth (macrosomia) induced by MO. To further examine the preventive effects of exercise on fetal overgrowth, placental vascularization and nutrient transporters were analysed. Vascular density and the expression of vasculogenic factors were reduced as a result of MO but were recovered by maternal exercise. On the other hand, the contents of nutrient transporters were not substantially altered by MO or exercise, suggesting that the protective effects of exercise in MO‐induced fetal overgrowth were primarily a result of the alteration of placental vascularization and improved maternal metabolism. Furthermore, exercise enhanced downstream insulin signalling and activated AMP‐activated protein kinase in HFD placenta. In sum, maternal exercise prevented fetal overgrowth induced by MO, which was associated with improved maternal metabolism and placental vascularization in obese mothers with exercise.
Metamaterial With Local Resonators Coupled by Negative Stiffness Springs for Enhanced Vibration Suppression
Authors: Hu Guobiao , Tang Lihua , Xu Jiawen , Lan Chunbo , Das Raj
Published: May 2019

In recent years, metamaterials for the applications in low-frequency vibration suppression and noise reduction have attracted numerous research interests. This paper proposes a metamaterial system with local resonators from adjunct unit cells coupled by negative stiffness springs. Frist, a lumped parameter model of the system is developed, and a stability criterion is derived. The band structure of the infinite lattice model is calculated. The result reveals the appearance of extra band gaps in the proposed metamaterial. A parametric study shows that the first extra band gap can be tuned to ultralow frequency by controlling the negative stiffness of the coupling springs. A transmittance analysis of the finite lattice model verifies the predictions obtained from the band structure analysis. Subsequently, the work is extended to a distributed parameter metamaterial beam model with the proposed configuration of coupled local resonators. The stability analysis shows that the infinitely long metamaterial beam becomes unstable as long as the stiffness of the coupling spring becomes negative. For the finitely long metamaterial beam, the stability could be achieved for negative coupling springs of given stiffnesses. The effects of the number of cells and the lattice constant on the system stability are investigated. The transmittance of the finitely long metamaterial beam is calculated. The result shows that due to the restriction on the tunability of negative stiffness for the proposed metamaterial beam, a quasistatic vibration suppression region can only be achieved when the number of cells is small.
Out-of-Plane Impact Resistance Enhancement in Plane Lattice With Curved Links
Authors: Liu Yabo , Dong Zhichao , Ge Jingran , Liang Jun
Published: May 2019

In the past decades, various novel functions (i.e., negative Poisson's ratio, zero thermal expansion) have been obtained by tailoring the microstructures of the cellular structures. Among all the microstructures, the horseshoe topology shows a J-shaped stress–strain curve, which is quite different from the conventional materials. It can be inferred that the 2D lattice structure with horseshoe microstructure will also exhibit excellent out-of-plane impact resistance since the spider silk also exhibits the J-shaped stress–strain curve. In this paper, the out-of-plane sphere impact of 2D truss lattice structure is conducted using finite element method (FEM) simulation. The point has been made that, by replacing the direct-line beam to horseshoe curved beam, the out-of-plane impact resistance has been greatly improved. The most curved beam structure is found to have the best out-of-plane performs with the maximum energy absorption and the minimum passing through velocity.
Embolus Analog Trajectory Paths Under Physiological Flowrates Through Patient-Specific Aortic Arch Models
Authors: Malone F. , McCarthy E. , Delassus P. , Buhk J. H. , Fiehler J. , Morris L.
Published: May 2019

Atrial fibrillation (AF) is the most common irregular heartbeat among the world's population and is a major contributor to cardiogenic embolisms and acute ischemic stroke (AIS). However, the role AF flow plays in the trajectory paths of cardiogenic emboli has not been experimentally investigated. A physiological simulation system was designed to analyze the trajectory patterns of bovine embolus analogs (EAs) (n = 720) through four patient-specific models, under three flow conditions: steady flow, normal pulsatile flow, and AF pulsatile flow. It was seen that EA trajectory paths were proportional to the percentage flowrate split of 25–31% along the branching vessels. Overall, AF flow conditions increased trajectories through the left- (LCCA) and right (RCCA)-common carotid artery by 25% with respect to normal pulsatile flow. There was no statistical difference in the distribution of clot trajectories when the clot was released from the right, left, or anterior positions. Significantly, more EAs traveled through the brachiocephalic trunk (BCT) than through the LCCA or the left subclavian. Yet of the EAs that traveled through the common carotid arteries, there was a greater affiliation toward the LCCA compared to the RCCA (p < 0.05).
Interlaminar Toughening of Fiber-Reinforced Polymers by Synergistic Modification of Resin and Fiber
Authors: Bian Dakai , Tsui Jason C. , Kydd Robert R. , Shim D. J. , Jones Marshall , Lawrence Yao Y.
Published: May 2019

The synergistic effect of combining different modification methods was investigated in this study to improve the interlaminar toughness and delamination resistance of fiber reinforced polymers (FRP). Epoxy-compatible polysulfone (PSU) was end-capped with epoxide group through functionalization, and the fiber surface was chemically grafted with an amino functional group to form a micron-size rough surface. Consequently, the long chain of PSU entangles into cross-linked thermoset epoxy network, additionally, epoxide group on PSU further improves the bonding through chemical connection to the epoxy network and amino group on the fiber surface. The combined modification methods can generate both strong physical and chemical bonding. The feasibility of using this method in vacuum-assisted resin transfer molding was determined by rheometer. The impact of formed chemical bonds on the cross-linking density was examined through glass transition temperatures. The chemical modifications were characterized by Raman spectroscopy to determine the chemical structures. Synergistic effect of the modification was established by mode I and mode II fracture tests, which quantify the improvement on composites delamination resistance and toughness. The mechanism of synergy was explained based on the fracture mode and interaction between the modification methods. Finally, numerical simulation was used to compare samples with and without modifications. The experiment results showed that synergy is achieved at low concentration of modified PSU because the formed chemical bonds compensate the effect of low cross-linking density and interact with the modified fiber.
Mechanism of Chip Segmentation in Orthogonal Cutting of Zr-Based Bulk Metallic Glass
Authors: Maroju Naresh Kumar , Jin Xiaoliang
Published: May 2019

Bulk metallic glasses (BMGs) are a series of metal alloys with an amorphous structure. The deformation of BMGs occurs in localized regions and is highly sensitive to the applied stress, strain rate, and temperature. This paper presents a coupled thermomechanical model to analyze the chip segmentation mechanism due to material shear localization in orthogonal cutting of Zr-BMG. The shear stress variation in the primary shear zone is modeled considering the tool-chip friction and large strain of the material. The constitutive property of BMG corresponding to the inhomogeneous deformation through shear transformation zones is modeled. The oscillations of shear stress, temperature, and free volume are simulated based on the cutting conditions. The predicted chip segmentation frequency is compared with the experimental result under different cutting speeds and uncut chip thicknesses. The developed model provides the fundamental mechanism of material deformation and chip formation in cutting Zr-BMG with an amorphous structure.
Asymmetry in catalysis by
Thermotoga maritima
membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor
Authors: Vidilaseris Keni , Kiriazis Alexandros , Turku Ainoleena , Khattab Ayman , Johansson Niklas G. , Leino Teppo O. , Kiuru Paula S. , Boije af Gennäs Gustav , Meri Seppo , Yli-Kauhaluoma Jari , Xhaard Henri , Goldman Adrian
Published: May 2019

Novel inhibitors of membrane-bound pyrophosphatases unlock asymmetric conformations by binding near the exit channel.
Does computer vision matter for action?
Authors: Zhou Brady , Krähenbühl Philipp , Koltun Vladlen
Published: May 2019

Controlled experiments indicate that explicit intermediate representations help action.
Mouse models of neurodegeneration: Know your question, know your mouse
Authors: Fisher Elizabeth M. C. , Bannerman David M.
Published: May 2019

There are many mouse models for studying neurodegeneration, but it is crucial to select the model that best fits the research question being asked.
Circulating exosomes derived from transplanted progenitor cells aid the functional recovery of ischemic myocardium
Authors: Saha Progyaparamita , Sharma Sudhish , Korutla Laxminarayana , Datla Srinivasa Raju , Shoja-Taheri Farnaz , Mishra Rachana , Bigham Grace E. , Sarkar Malini , Morales David , Bittle Gregory , Gunasekaran Muthukumar , Ambastha Chetan , Arfat Mir Yasir , Li Deqiang , Habertheuer Andreas , Hu Robert , Platt Manu O. , Yang Peixin , Davis Michael E. , Vallabhajosyula Prashanth , Kaushal Sunjay
Published: May 2019

Liquid biopsy of circulating exosomes can be used to monitor recovery of ischemic myocardium after transplanting cardiac progenitor cells.
Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates
Authors: Milani Michela , Annoni Andrea , Moalli Federica , Liu Tongyao , Cesana Daniela , Calabria Andrea , Bartolaccini Sara , Biffi Mauro , Russo Fabio , Visigalli Ilaria , Raimondi Andrea , Patarroyo-White Susannah , Drager Douglas , Cristofori Patrizia , Ayuso Eduard , Montini Eugenio , Peters Robert , Iannacone Matteo , Cantore Alessio , Naldini Luigi
Published: May 2019

Lentiviral vectors with high surface content of CD47 improved gene transfer efficiency to hepatocytes in nonhuman primates.
Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation
Authors: Scherschel Katharina , Hedenus Katja , Jungen Christiane , Lemoine Marc D. , Rübsamen Nicole , Veldkamp Marieke W. , Klatt Niklas , Lindner Diana , Westermann Dirk , Casini Simona , Kuklik Pawel , Eickholt Christian , Klöcker Nikolaj , Shivkumar Kalyanam , Christ Torsten , Zeller Tanja , Willems Stephan , Meyer Christian
Published: May 2019

Catheter ablation for atrial fibrillation induces intracardiac neural damage characterized by glial S100B release, which promotes nerve sprouting.
Primary cilia defects causing mitral valve prolapse
Authors: Toomer Katelynn A. , Yu Mengyao , Fulmer Diana , Guo Lilong , Moore Kelsey S. , Moore Reece , Drayton Ka’la D. , Glover Janiece , Peterson Neal , Ramos-Ortiz Sandra , Drohan Alex , Catching Breiona J. , Stairley Rebecca , Wessels Andy , Lipschutz Joshua H. , Delling Francesca N. , Jeunemaitre Xavier , Dina Christian , Collins Ryan L. , Brand Harrison , Talkowski Michael E. , del Monte Federica , Mukherjee Rupak , Awgulewitsch Alexander , Body Simon , Hardiman Gary , Hazard E. Starr , da Silveira Willian A. , Wang Baolin , Leyne Maire , Durst Ronen , Markwald Roger R. , Le Scouarnec Solena , Hagege Albert , Le Tourneau Thierry , Kohl Peter , Rog-Zielinska Eva A. , Ellinor Patrick T. , Levine Robert A. , Milan David J. , Schott Jean-Jacques , Bouatia-Naji Nabila , Slaugenhaupt Susan A. , Norris Russell A.
Published: May 2019

Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progress to mitral valve prolapse in the adult.
A sight for sore eyes (or ones with glaucoma)
Authors: Yadav Vikramaditya G.
Published: May 2019

Transduction of the exoenzyme C3 transferase gene into the trabecular meshwork reduces intraocular pressure in monkeys.
Influence of Dissolved-Aluminum Concentration on Sulfur-Oxidizing Bacterial Activity in the Biodeterioration of Concrete
Authors: Buvignier Amaury , Peyre-Lavigne Matthieu , Robin Orlane , Bounouba Mansour , Patapy Cédric , Bertron Alexandra , Paul Etienne
Published: May 2019

Biodeterioration of cement infrastructures represents 5 to 20% of observed deteriorations within the sewer network. Such biodeterioration events are mainly due to microbial sulfur-oxidizing activity which produces sulfuric acid able to dissolve cementitious material. Calcium aluminate cement materials are more resistant to biodeterioration compared to the commonly used Portland cement. Several theories have been suggested to describe this resistance, and the bacteriostatic effect of aluminum seems to be the most plausible explanation. However, results reported by the several studies on this exact topic are highly controversial. This present study provides a comprehensive analysis of the influence of dissolved aluminum on growth parameters of long-term cultures of sulfur-oxidizing bacterial consortia sampled from different origins. Kinetic and stoichiometric parameters estimated by respirometry measurements and modeling showed that total dissolved-aluminum concentrations up to 100 mM were not inhibitory, but it is more likely that a sudden increase in the ionic strength affects cell growth. Therefore, it appears that the bacteriostatic effect of aluminum on microbial growth cannot explain the better durability of aluminate based cementitious materials.
Transcriptome Analysis Provides Novel Insights into the Capacity of the Ectomycorrhizal Fungus
Amanita pantherina
To Weather K-Containing Feldspar and Apatite
Authors: Sun Qibiao , Fu Ziyu , Finlay Roger , Lian Bin
Published: May 2019

In this study, we revealed the molecular mechanism and possible strategies of
A. pantherina
with weak weathering potential in the uptake of insoluble mineral nutrients by using transcriptome sequencing (RNA-seq) technology and found that
ApHAK1
, a K transporter gene of this fungus, plays a very important role in the acquisition of K and P. Ectomycorrhizal (ECM) fungi play critical roles in the uptake of woody plant nutrients in forests that are usually characterized by nutrient limitation and in maintaining the stability of forest ecosystems. However, the regulatory mechanisms of ECM fungi in acquiring nutrients from minerals/rocks are poorly understood. This study investigated the transcriptional regulation of
A. pantherina
weathering K-containing feldspar and apatite and improves the understanding of fungal-plant interactions in promoting plant nutrition enabling increased productivity in sustainable forestry.
Horizontal Gene Transfer as an Indispensable Driver for Evolution of Neocallimastigomycota into a Distinct Gut-Dwelling Fungal Lineage
Authors: Murphy Chelsea L. , Youssef Noha H. , Hanafy Radwa A. , Couger M. B. , Stajich Jason E. , Wang Yan , Baker Kristina , Dagar Sumit S. , Griffith Gareth W. , Farag Ibrahim F. , Callaghan T. M. , Elshahed Mostafa S.
Published: May 2019

The anaerobic gut fungi (AGF) represent a distinct basal phylum lineage (Neocallimastigomycota) commonly encountered in the rumen and alimentary tracts of herbivores. Survival and growth of anaerobic gut fungi in these anaerobic, eutrophic, and prokaryote-dominated habitats necessitates the acquisition of several traits absent in other fungal lineages. We assess here the role of horizontal gene transfer as a relatively fast mechanism for trait acquisition by the Neocallimastigomycota postsequestration in the herbivorous gut. Analysis of 27 transcriptomes that represent the broad diversity of Neocallimastigomycota identified 277 distinct HGT events, with subsequent gene duplication resulting in an HGT frequency of 2 to 3.5% in AGF genomes. These HGT events have allowed AGF to survive in the herbivorous gut by expanding their substrate utilization range, augmenting their biosynthetic pathway, providing new routes for electron disposal by expanding fermentative capacities, and facilitating their adaptation to anaerobiosis. HGT in the AGF is also shown to be mainly a cross-kingdom affair, with the majority of donors belonging to the bacteria. This study represents a unique example of the role of HGT in shaping the evolution of a high-rank taxonomic eukaryotic lineage.
Bacterial Microcompartment-Mediated Ethanolamine Metabolism in Escherichia coli Urinary Tract Infection
Authors: Dadswell Katherine , Creagh Sinead , McCullagh Edward , Liang Mingzhi , Brown Ian R. , Warren Martin J. , McNally Alan , MacSharry John , Prentice Michael B.
Published: May 2019

Urinary tract infections (UTIs) are common and in general are caused by intestinal uropathogenic
Escherichia coli
(UPEC) ascending via the urethra. Microcompartment-mediated catabolism of ethanolamine, a host cell breakdown product, fuels the competitive overgrowth of intestinal
E. coli
, both pathogenic enterohemorrhagic
E. coli
and commensal strains. During a UTI, urease-negative
E. coli
bacteria thrive, despite the comparative nutrient limitation in urine.
Compensation of retinal nerve fibre layer thickness as assessed using optical coherence tomography based on anatomical confounders
Authors: Chua Jacqueline , Schwarzhans Florian , Nguyen Duc Quang , Tham Yih Chung , Sia Josh Tjunrong , Lim Claire , Mathijia Shivani , Cheung Carol , Tin Aung , Fischer Georg , Cheng Ching-Yu , Vass Clemens , Schmetterer Leopold
Published: May 2019

Background/Aims

To compensate the retinal nerve fibre layer (RNFL) thickness assessed by spectral-domain optical coherence tomography (SD-OCT) for anatomical confounders.

Methods

The Singapore Epidemiology of Eye Diseases is a population-based study, where 2698 eyes (1076 Chinese, 704 Malays and 918 Indians) with high-quality SD-OCT images from individuals without eye diseases were identified. Optic disc and macular cube scans were registered to determine the distance between fovea and optic disc centres (fovea distance) and their respective angle (fovea angle). Retinal vessels were segmented in the projection images and used to calculate the circumpapillary retinal vessel density proﬁle. Compensated RNFL thickness was generated based on optic disc (ratio, orientation and area), fovea (distance and angle), retinal vessel density, refractive error and age. Linear regression models were used to investigate the effects of clinical factors on RNFL thickness.

Results

Retinal vessel density reduced significantly with increasing age (1487±214 µm in 40–49, 1458±208 µm in 50–59, 1429±223 µm in 60–69 and 1415±233 µm in ≥70). Compensation reduced the variability of RNFL thickness, where the effect was greatest for Chinese (10.9%; p<0.001), followed by Malays (6.6%; p=0.075) and then Indians (4.3%; p=0.192). Compensation reduced the age-related RNFL decline by 55% in all participants (β=−3.32 µm vs β=−1.50 µm/10 years; p<0.001). Nearly 62% of the individuals who were initially classified as having abnormally thin RNFL (outside the 99% normal limits) were later reclassified as having normal RNFL.

Conclusions

RNFL thickness compensated for anatomical parameters reduced the variability of measurements and may improve glaucoma detection, which needs to be confirmed in future studies.
Economic evaluation of a phase III international randomised controlled trial of very early mobilisation after stroke (AVERT)
Authors: Gao Lan , Sheppard Lauren , Wu Olivia , Churilov Leonid , Mohebbi Mohammadreza , Collier Janice , Bernhardt Julie , Ellery Fiona , Dewey Helen , Moodie Marj
Published: May 2019

Objectives

While very early mobilisation (VEM) intervention for stroke patients was shown not to be effective at 3 months, 12 month clinical and economical outcomes remain unknown. The aim was to assess cost-effectiveness of a VEM intervention within a phase III randomised controlled trial (RCT).

Design

An economic evaluation alongside a RCT, and detailed resource use and cost analysis over 12 months post-acute stroke.

Setting

Multi-country RCT involved 58 stroke centres.

Participants

2104 patients with acute stroke who were admitted to a stroke unit.

Intervention

A very early rehabilitation intervention within 24 hours of stroke onset

Methods

Cost-utility analyses were undertaken according to pre-specified protocol measuring VEM against usual care (UC) based on 12 month outcomes. The analysis was conducted using both health sector and societal perspectives. Unit costs were sourced from participating countries. Details on resource use (both health and non-health) were sourced from cost case report form. Dichotomised modified Rankin Scale (mRS) scores (0 to 2 vs 3 to 6) and quality adjusted-life years (QALYs) were used to compare the treatment effect of VEM and UC. The base case analysis was performed on an intention-to-treat basis and 95% CI for cost and QALYs were estimated by bootstrapping. Sensitivity analysis were conducted to examine the robustness of base case results.

Results

VEM and UC groups were comparable in the quantity of resource use and cost of each component. There were no differences in the probability of achieving a favourable mRS outcome (0.030, 95% CI −0.022 to 0.082), QALYs (0.013, 95% CI −0.041 to 0.016) and cost (AUD1082, 95% CI -$2520 to $4685 from a health sector perspective or AUD102, 95% CI -$6907 to $7111, from a societal perspective including productivity cost). Sensitivity analysis achieved results with mostly overlapped CIs.

Conclusions

VEM and UC were associated with comparable costs, mRS outcome and QALY gains at 12 months. Compared with to UC, VEM is unlikely to be cost-effective. The long-term data collection during the trial also informed resource use and cost of care post-acute stroke across five participating countries.

Trial registration number

ACTRN12606000185561; Results.
Supporting and improving community health services—a prospective evaluation of ECHO technology in community palliative care nursing teams
Authors: White Clare , McIlfatrick Sonja , Dunwoody Lynn , Watson Max
Published: May 2019

Introduction

Project ECHO (Extension for Community Healthcare Outcomes) uses teleconferencing technology to support and train healthcare providers (HCPs) remotely, and has improved care across the USA. A 6-month pilot was trialled in a community palliative care nursing setting to determine if ECHO would be effective in the UK in providing education and support to community hospice nurses (CHN).

Methods

The pilot involved weekly 2 hour sessions of teaching and case-based discussions facilitated by hospice staff linking with nine teams of CHN using video conferencing technology. A mixed-methods prospective longitudinal cohort study was used to evaluate the pilot. Each CHN provided demographic data, and completed a written knowledge assessment and a self-efficacy tool before and after the pilot. Two focus groups were also performed after the pilot.

Results

28 CHNs completed the evaluation. Mean knowledge score improved significantly from 71.3% to 82.7%(p=0.0005) as did overall self-efficacy scores following the ECHO pilot. Pre-ECHO (p=0.036) and Retro-Pretest ECHO (p=0.0005) self-efficacy were significantly lower than post-ECHO. There was no significant difference between Pretest and Retro-Pretest ECHO self-efficacy (p=0.063). 96% recorded gains in learning, and 90% felt that ECHO had improved the care they provided for patients. 83% would recommend ECHO to other HCPs. 70% stated the technology used in ECHO had given them access to education that would have been hard to access due to geography.

Conclusions

This study supports the use of Project ECHO for CHNs in the UK by demonstrating how a 6-month pilot improved knowledge and self-efficacy. As a low-cost high-impact model, ECHO provides an affordable solution to addressing growing need.
Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance
Authors: Xiang Dai-Min , Sun Wen , Zhou Tengfei , Zhang Cheng , Cheng Zhuo , Li Shi-Chao , Jiang Weiqi , Wang Ruoyu , Fu Gongbo , Cui Xiuliang , Hou Guojun , Jin Guang-Zhi , Li Hengyu , Hou Caiying , Liu Hui , Wang Hongyang , Ding Jin
Published: May 2019

Background and aims

The unique expression pattern makes oncofetal proteins ideal diagnostic biomarkers and therapeutic targets in cancer. However, few oncofetal proteins have been identified and entered clinical practice.

Methods

Fetal liver, adult liver and hepatocellular carcinoma (HCC) tissues were employed to assess the expression of hepatic leukaemia factor (HLF). The impact of HLF on HCC onset and progression was investigated both in vivo and in vitro. The association between HLF and patient prognosis was determined in patient cohorts. The correlation between HLF expression and sorafenib benefits in HCC was further evaluated in patient cohorts and patient-derived xenografts (PDXs).

Results

HLF is a novel oncofetal protein which is reactivated in HCC by SOX2 and OCT4. Functional studies revealed that HLF transactivates c-Jun to promote tumour initiating cell (TIC) generation and enhances TIC-like properties of hepatoma cells, thus driving HCC initiation and progression. Consistently, our clinical investigations elucidated the association between HLF and patient prognosis and unravelled the close correlation between HLF levels and c-Jun expression in patient HCCs. Importantly, HLF/c-Jun axis determines the responses of hepatoma cells to sorafenib treatment, and interference of HLF abrogated c-Jun activation and enhanced sorafenib response. Analysis of patient cohorts and PDXs further suggests that HLF/c-Jun axis might serve as a biomarker for sorafenib benefits in HCC patients.

Conclusions

Our findings uncovered HLF as a novel oncofetal protein and revealed the crucial role of the HLF/c-Jun axis in HCC development and sorafenib response, rendering HLF as an optimal target for the prevention and intervention of HCC.
Republished: Transradial approach in the treatment of a sacral dural arteriovenous fistula: a technical note
Authors: Orru Emanuele , Tsang Chun On Anderson , Klostranec Jesse M , Pereira Vitor M
Published: May 2019

Sacral dural arteriovenous fistulas (SDAVFs) are rare, constituting no more than 10% of all spinal dural fistulas. They are most commonly fed by the lateral sacral artery (LSA), a branch of the internal iliac artery (IIA). Catheterization of this vessel requires either a crossover at the aortic bifurcation in cases of right femoral access or retrograde catheterization from the ipsilateral common femoral artery. We present the case of a 79-year-old man with tethered cord syndrome and a symptomatic SDAVF fed by two feeders from the left LSA. Spinal diagnostic angiography was made exceptionally challenging by an aorto-bi-iliac endograft, and selective catheterization of the left IIA was not possible. The patient could not undergo surgery due to multiple comorbidities, therefore embolization was considered the best approach. The procedure was carried out through a transradial access (TRA) with Onyx and n-butyl cyanoacrylate. The SDAVF was successfully treated and the patient made a full neurological recovery.
Dural puncture epidural analgesia for labor: a randomized comparison between 25-gauge and 27-gauge pencil point spinal needles
Authors: Contreras Felipe , Morales Juan , Bravo Daniela , Layera Sebastián , Jara Álvaro , Riaño Carlos , Pizarro Rodrigo , De La Fuente Natalia , Aliste Julián , Finlayson Roderick J , Tran De Q
Published: May 2019

Background

This double-blind, randomized trial compared dural puncture epidural analgesia (DPEA) for labor using 25-gauge and 27-gauge pencil point spinal needles. We hypothesized that both needle sizes would result in similar onset time (equivalence margin=2.5 min) and therefore designed the study as an equivalence trial.

Methods

One hundred and forty patients undergoing labor were randomized to DPEA with 25-gauge (n=70) or 27-gauge (n=70) pencil point spinal needles. After the placement of the epidural catheter, a bolus of 20 mL of bupivacaine 0.125% and fentanyl 2 µg/mL was administered to all subjects. Thereafter, patients received boluses of 12 mL of bupivacaine 0.125% every 2 hours as needed.

A blinded investigator recorded the onset time (defined as the temporal interval required to achieve a pain score ≤1 on a 0–10 scale), S2 block, sensory block height (30 min after the initial bolus of local anesthetic), presence of motor block (30 min after the initial bolus of local anesthetic), number of top-up doses required during labor and incidence of postural headache.

Results

Out of the 140 recruited patients, 135 were retained for analysis. Compared with their 27-gauge counterparts, 25-gauge pencil point spinal needles provided a 1.6 min shorter DPEA onset (95% CI of the difference of the means: −3.2 to −0.1 min). However, there were no intergroup differences in terms of S2 block, sensory block height, motor block, number of top-up doses and incidence of postural headache.

Conclusion

Dural puncture epidural analgesia with 25-gauge pencil point spinal needles provides a 1.6 min shorter onset time than DPEA with 27-gauge spinal needles. Although statistically significant, such a difference may not be clinically relevant. Further investigation is required to compare 25-gauge and 27-gauge spinal needles for DPEA in the setting of different local anesthetic infusion strategies.

Trial registration number

NCT03389945.
Development of one general and six country-specific algorithms to assess societal health utilities based on ASAS HI
Authors: Essers Ivette , Hiligsmann Mickael , Kiltz Uta , Bansback Nick , Braun Juergen , van der Heijde Desirée , Boonen Annelies
Published: May 2019

Objective

Health utilities represent preference values that persons attach to health states. This study aims to develop one general and six country-specific algorithms to calculate societal preference values for health of patients with spondyloarthritis (SpA), as assessed by the disease-specific Assessment of SpondyloArthritis international Society Health Index (ASAS HI).

Methods

A survey was performed in random population samples from six European countries. In a best-worst choice experiment, subjects were asked to indicate repeatedly which of 4 random aspects of the 17-item ASAS HI was were most and least important. Bayesian analysis provided the relative importance of each of the 17 items. To rescale the relative importance scores on the absolute utility scale between 0 and 1, participants additionally completed two lead time trade-off experiments, one for ‘severe SpA’ and one for ‘best health’ without SpA. Six country-specific algorithms and one general algorithm were derived. The general algorithm was tested in 199 patients with axial SpA (axSpA).

Results

3039 subjects, mean age 47 years (SD 15) and 52% female completed the experiments. The population’s health utility value for SpA varied between − 0.24 for ‘worst’ SpA (country range −0.35 to 0.03), and 0.88 for ‘best’ health (country range 0.81 to 0.90). Among 199 patients with axSpA, the mean utility was 0.36 (SD 0.30, range −0.24 to 0.88) and discriminated well between patients having high (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4) or low (BASDAI < 4) disease activity (0.18 (SD 0.24) vs 0.51(SD 0.27), p<0.01).

Conclusion

One general and six country-specific algorithms are available to convert scores from the ASAS HI into disease-specific societal utility values.
DNA methylation and regulation of DNA methyltransferases in a freeze-tolerant vertebrate
Authors: Zhang Jing , Hawkins Liam J. , Storey Kenneth B.
Published: May 2019

The wood frog is one of the few freeze-tolerance vertebrates. This is accomplished in part by the accumulation of cryoprotectant glucose, metabolic rate depression, and stress response activation. These may be achieved by mechanisms such as DNA methylation, which is typically associated with transcriptional repression. Hyperglycemia is also associated with modifications to epigenetic profiles, indicating an additional role that the high levels of glucose play in freeze tolerance. We sought to determine whether DNA methylation is affected during freezing exposure, and whether this is due to the wood frog’s response to hyperglycemia. We examined global DNA methylation and DNA methyltransferases (DNMTs) in the liver and muscle of frozen and glucose-loaded wood frogs. The results showed that levels of 5-methylcytosine (5mC) increased in the muscle, suggesting elevated DNA methylation during freezing. DNMT activities also decreased in muscle during thawing, glucose loading, and in vitro glucose experiments. Liver DNMT activities were similar to muscle; however, a varied response to DNMT levels and a decrease in 5mC highlight the metabolic role the liver plays during freezing. Glucose was also shown to decrease DNMT activity levels in the wood frog, in vitro, elucidating a potentially novel regulatory mechanism. Together these results suggest an interplay between freeze tolerance and hyperglycemic regulation of DNA methylation.
Analysis of settlements in piled raft systems founded in soft soil under consolidation process
Authors: Rodriguez Rincón Edgar , Cunha Renato Pinto da , Caicedo Hormaza Bernardo
Published: May 2019

In piled raft systems (PRSs), the piles are used to support load or to control settlements. These systems, when founded in soft soils that are then consolidated by loads or subsidence processes, can induce negative friction in the piles and other phenomena related to variations in the distribution of load or settlements. This paper presents the results of physical modeling in a geotechnical centrifuge capable of different distributions of piles under a raft. As a result, the influence of consolidation and extraction of water from a deep soil layer on the behavior of the PRS model was analyzed. It was determined that the processes associated with the extraction of water from the deep soil layer induce larger settlements. A separation between the raft and the soil is possible, as well as a change in the behavior of the PRS.
VALUE CO-CREATION FOR MARKETING INNOVATION: COMPARATIVE STUDY IN THE SME COMMUNITY
Authors: WIDJOJO HANDYANTO , FONTANA AVANTI , GAYATRI GITA , SOEHADI AGUS W.
Published: May 2019

The study of value co-creation for marketing innovation in the small–medium enterprise (SME) community is still overlooked despite its contribution to economic development. This study offers a platform of value co-creation model for marketing innovation and compares its application to the green and business-as-usual SME communities. Structural equation modelling is conducted to test the hypotheses of both model applications. Key persons in the community were interviewed to enrich the quantitative results. The result shows the relationships between collaborative networks and dynamic interactions with resource integration as well as their impact on marketing innovation. Collaborative networks and dynamic interactions demonstrate significantly positive influences on marketing innovation in the business-as-usual SME community, whereas the green SME community only engages in internal dynamic interactions to build internal value co-creation. Policymakers may adopt this model to evaluate SMEs’ business performance by measuring the value co-creation effect on the community’s capacity development.
The Association Between Age and Clinical and Radiological Activity in Axial Spondyloarthritis
Authors: Li Philip Hei , Chung Ho Yin , Wong Chun Sing , Tsang Helen Hoi Lun , Lau Vince Wing Hang , Ho Grace , Xu Xiaopei , Lau Chak Sing , Ma Kai Yiu
Published: May 2019

Objective: To investigate the associations between age and clinical and radiological disease activities in axial SpA.

Methods: One hundred and twenty-one patients fulfilling the Assessment of SpondyloArthritis International Society Classification Criteria for axial SpA were included in analyses. Patient demographics, disease activity and radiographic scores, as well as magnetic resonance imaging (MRI) with diffusion weighted imaging derived apparent diffusion coefficient values (DWI(ADC)), were compared between patients aged > 40 and [Formula: see text] 40 years at a cross-sectional level. Variables with significant differences in univariate analyses were used as dependent variables in multivariate linear regression models adjusted for potential confounding/contributing factors.

Results: Multivariate analysis showed that increasing age was significantly associated with higher Bath Ankylosing Spondylitis Functional Index (B = 0.04, p < 0.01) and Bath Ankylosing Spondylitis Metrology Index scores (B = 0.04, p < 0.01); as well as higher modified Stoke Ankylosing Spondylitis Spine Score (B = 0.41, p < 0.01). On MRI, increasing age was associated with a lower DWI(ADC) (B = (-0.01), p < 0.01) of the SI joints, but higher DWI(ADC) values of the axial spine (B = 0.01, p = 0.01).

Conclusion: Increasing age in SpA was associated with greater functional impairment and structural damage, more inflammation of the axial spine, but less inflammation of the SI joints. Our findings are consistent with the traditional belief that SpA is an “ascending disease” and highlights the importance of different modalities of MRI in the diagnosis and disease monitoring of SpA.
Insulin-like growth factor II receptor-α is a novel stress-inducible contributor to cardiac damage underpinning doxorubicin-induced oxidative stress and perturbed mitochondrial autophagy
Authors: Pandey Sudhir , Kuo Wei-Wen , Shen Chia-Yao , Yeh Yu-Lan , Ho Tsung-Jung , Chen Ray-Jade , Chang Ruey-Lin , Pai Pei-Ying , Viswanadha Vijaya Padma , Huang Chih-Yang , Huang Chih-Yang
Published: May 2019

Doxorubicin (DOX) is an anthracycline antibiotic commonly employed for the treatment of various cancers. However, its therapeutic uses are hampered by side effects associated with cumulative doses during the course of treatment. Whereas deregulation of autophagy in the myocardium has been involved in a variety of cardiovascular diseases, the role of autophagy in DOX-induced cardiomyopathy remains debated. Our earlier studies have shown that DOX treatment in a rat animal model leads to increased expression of the novel stress-inducible protein insulin-like growth factor II receptor-α (IGF-IIRα) in cardiac tissues, which exacerbated the cardiac injury by enhancing oxidative stress and p53-mediated mitochondria-dependent cardiac apoptosis. Through this study, we investigated the contribution of IGF-IIRα to dysregulation of autophagy in heart using both in vitro H9c2 cells (DOX treated, 1 µM) and in vivo transgenic rat models (DOX treated, 5 mg/kg ip for 6 wk) overexpressing IGF-IIRα specifically in the heart. We found that IGF-IIRα primarily localized to mitochondria, causing increased mitochondrial oxidative stress that was severely aggravated by DOX treatment. This was accompanied by a significant perturbation in mitochondrial membrane potential and increased leakage of cytochrome c, causing increased cleaved caspase-3 activity. There were significant alterations in phosphorylated AMP-activated protein kinase (p-AMPK), phosphorylated Unc-51 like kinase-1 (p-ULK1), PARKIN, PTEN-induced kinase 1 (PINK1), microtubule-associated protein 1 light chain 3 (LC3), and p62 proteins, which were more severely disrupted under the combined effect of IGF-IIRα overexpression plus DOX. Finally, LysoTracker Red staining showed that IGF-IIRα overexpression causes lysosomal impairment, which was rescued by rapamycin treatment. Taken together, we found that IGF-IIRα leads to mitochondrial oxidative stress, decreased antioxidant levels, disrupted mitochondrial membrane potential, and perturbed mitochondrial autophagy contributing to DOX-induced cardiomyopathy.
Cyclic compression increases F508 Del CFTR expression in ciliated human airway epithelium
Authors: Marozkina Nadzeya , Bosch Jürgen , Cotton Calvin , Smith Laura , Seckler James , Zaman Khalequz , Rehman Shagufta , Periasamy Ammasi , Gaston Herbert , Altawallbeh Ghaith , Davis Michael , Jones David R. , Schilz Robert , Randell Scott H. , Gaston Benjamin
Published: May 2019

The mechanisms by which transepithelial pressure changes observed during exercise and airway clearance can benefit lung health are challenging to study. Here, we have studied 117 mature, fully ciliated airway epithelial cell filters grown at air-liquid interface grown from 10 cystic fibrosis (CF) and 19 control subjects. These were exposed to cyclic increases in apical air pressure of 15 cmH2O for varying times. We measured the effect on proteins relevant to lung health, with a focus on the CF transmembrane regulator (CFTR). Immunoflourescence and immunoblot data were concordant in demonstrating that air pressure increased F508Del CFTR expression and maturation. This effect was in part dependent on the presence of cilia, on Ca2+ influx, and on formation of nitrogen oxides. These data provide a mechanosensory mechanism by which changes in luminal air pressure, like those observed during exercise and airway clearance, can affect epithelial protein expression and benefit patients with diseases of the airways.