bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel role of the clustered miR‐23b‐3p and miR‐27b‐3p in enhanced expression of fibrosis‐associated genes by targeting TGFBR3 in atrial fibroblasts
Authors: Yang Zhenzhen , Xiao Zhen , Guo Huiming , Fang Xianhong , Liang Jingnan , Zhu Jiening , Yang Jing , Li Hui , Pan Rong , Yuan Shujing , Dong Wenyan , Zheng Xi‐Long , Wu Shulin , Shan Zhixin
Published: February 2019

Atrial fibrillation (AF) is the most common type of arrhythmia in cardiovascular diseases. Atrial fibrosis is an important pathophysiological contributor to AF. This study aimed to investigate the role of the clustered miR‐23b‐3p and miR‐27b‐3p in atrial fibrosis. Human atrial fibroblasts (HAFs) were isolated from atrial appendage tissue of patients with sinus rhythm. A cell model of atrial fibrosis was achieved in Ang‐II‐induced HAFs. Cell proliferation and migration were detected. We found that miR‐23b‐3p and miR‐27b‐3p were markedly increased in atrial appendage tissues of AF patients and in Ang‐II‐treated HAFs. Overexpression of miR‐23b‐3p and miR‐27b‐3p enhanced the expression of collagen, type I, alpha 1 (COL1A1), COL3A1 and ACTA2 in HAFs without significant effects on their proliferation and migration. Luciferase assay showed that miR‐23b‐3p and miR‐27b‐3p targeted two different sites in 3ʹ‐UTR of transforming growth factor (TGF)‐β1 receptor 3 (TGFBR3) respectively. Consistently, TGFBR3 siRNA could increase fibrosis‐related genes expression, along with the Smad1 inactivation and Smad3 activation in HAFs. Additionally, overexpression of TGFBR3 could alleviate the increase of COL1A1, COL3A1 and ACTA2 in HAFs after transfection with miR‐23b‐3p and miR‐27b‐3p respectively. Moreover, Smad3 was activated in HAFs in response to Ang‐II treatment and inactivation of Smad3 attenuated up‐regulation of miR‐23b‐3p and miR‐27b‐3p in Ang‐II‐treated HAFs. Taken together, these results suggest that the clustered miR‐23b‐3p and miR‐27b‐3p consistently promote atrial fibrosis by targeting TGFBR3 to activate Smad3 signalling in HAFs, suggesting that miR‐23b‐3p and miR‐27b‐3p are potential therapeutic targets for atrial fibrosis.
MicroRNA‐205 is associated with diabetes mellitus‐induced erectile dysfunction via down‐regulating the androgen receptor
Authors: Wen Yan , Liu Guohui , Zhang Yun , Li Hai
Published: February 2019

As a major class of regulatory genes in majority metazoans, microRNAs (miRs) play an important role in various diseases including diabetes mellitus (DM). Lack of androgens has previously been associated with DM‐induced erectile dysfunction (DMED). In addition, the biological functioning of androgen is mediated by androgen receptor (AR). Herein, we sought to investigate whether miRs participate in AR‐associated DMED. Sprague‐Dawlay rats were employed to establish DMED models. After modelling, levels of miR‐205 and AR in their cavernous bodies were measured. The relationship between miR‐205 and AR was verified using a dual‐luciferase reporter gene assay. The underlying regulatory mechanisms of miR‐205 were investigated in concert with the treatment of mimics or inhibitors of miR‐205, or AR overexpression in the cavernous smooth muscle cells (CSMCs) isolated from rats with DMED. Meanwhile, the effects of miR‐205 and AR on cell proliferation and apoptosis were evaluated using MTT assay and flow cytometry respectively. Rats with DMED presented with increased miR‐205 and decreased AR levels in the cavernous bodies. AR was identified as a target gene of miR‐205. Down‐regulation of miR‐205 or up‐regulation of AR could increase proliferation and inhibits apoptosis of CSMCs in addition to improvements in the erectile functioning of rats with DMED. In summary, miR‐205 may contribute to the pathogenesis of DMED via down‐regulation of AR expressions.
Antibiotic prophylaxis at dental implant placement: Which is the best protocol? A systematic review and network meta‐analysis
Authors: Romandini Mario , De Tullio Ilaria , Congedi Francesca , Kalemaj Zamira , D‘Ambrosio Mattia , Laforí Andreina , Quaranta Ciro , Buti Jacopo , Perfetti Giorgio
Published: February 2019

Aim

This systematic review of randomized controlled trials (RCTs) aims to answer to the following question: “In patients undergoing dental implant placement, which is the best antibiotic prophylaxis protocol to prevent early failures?”

Materials and Methods

The MEDLINE, SCOPUS, CENTRAL and Web of Knowledge electronic databases were searched in duplicate for RCTs up to July 2017. Additional relevant literature was identified through (i) handsearching on both relevant journals and reference lists, and (ii) searching in databases for grey literature. A network meta‐analysis (NMA) was conducted, and the probability that each protocol is the “Best” was estimated.

Results

Nine RCTs were included, with a total of 1,693 participants. Due to the few events reported, it was not possible to conduct a NMA for adverse events, therefore it was conducted only for implant failures (IF). The protocol with the highest probability (32.5%) of being the “Best” one to prevent IF was the single dose of 3 g of amoxicillin administered 1 hr pre‐operatively. Even if the single pre‐operative dose of 2 g of amoxicillin is the most used, it achieved only a probability of 0.2% to be the “Best” one.

Conclusions

Basing on the available RCTs, the use of antibiotic prophylaxis is protective against early implant failures. Whenever an antibiotic prophylaxis is needed, there is still insufficient evidence to confidently recommend a specific dosage. The use of post‐operative courses does not seem however to be justified by the available literature. Prospero registration number: CRD42015029708.
The Trypanosoma brucei RNA‐Binding Protein TbRRM1 is Involved in the Transcription of a Subset of RNA Pol II‐Dependent Genes
Authors: Bañuelos Carolina P. , Levy Gabriela V. , Níttolo Analía G. , Roser Leandro G. , Tekiel Valeria , Sánchez Daniel O.
Published: February 2019

It has been long thought that RNA Polymerase (Pol) II transcriptional regulation does not operate in trypanosomes. However, recent reports have suggested that these organisms could regulate RNA Pol II transcription by epigenetic mechanisms. In this paper, we investigated the role of TbRRM1 in transcriptional regulation of RNA Pol II‐dependent genes by focusing both in genes located in a particular polycistronic transcription unit (PTU) and in the monocistronic units of the SL‐RNA genes. We showed that TbRRM1 is recruited throughout the PTU, with a higher presence on genes than intergenic regions. However, its depletion leads both to the decrease of nascent RNA and to chromatin compaction only of regions located distal to the main transcription start site. These findings suggest that TbRRM1 facilitates the RNA Pol II transcriptional elongation step by collaborating to maintain an open chromatin state in particular regions of the genome. Interestingly, the SL‐RNA genes do not recruit TbRRM1 and, after TbRRM1 knockdown, nascent SL‐RNAs accumulate while the chromatin state of these regions remains unchanged. Although it was previously suggested that TbRRM1 could regulate RNA Pol II‐driven genes, we provide here the first experimental evidence which involves TbRRM1 to transcriptional regulation.
Microneedling on the external female genitalia's flaccidity in patients with Ehlers‐Danlos: Case report
Authors: Gomes Tâmara , Baqueiro Priscilla , Oliveira Caroline , Alves Rafael , Lordelo Patrícia
Published: February 2019

Introduction

The Ehlers‐Danlos Syndrome (EDS) can presentis a reduction in fibroblast proliferation and collagen production. Microneedling a minimally invasive technique that through mechanical stimulus there is incentive to the production of collagen and elastin.

Objective

Present a case study in a patient with EDS complaining of flaccidity on large genital labia, using microneedling as a therapeutic proposal.

Methodology

A 36‐year‐old female with EDS type III. The external genitalia showed tissue flaccidity associated with hyperchromia. Microneedling was performed with 0.5 mm needles and the cosmetology was used soon after the application. The level of pain was questioned to the patient through a Likert scale. The clinical response to treatment was evaluated through self‐report, visual analogue scale and analysis of photographic images. Five other people evaluated the results through before and after images.

Results

Microneedle was shown to be bearable in relation to pain and associated with cosmetology for tissue flaccidity due to EDS in the genital region proved to be very satisfactory for the patient, as well individuals who evaluated the comparative image.

Conclusion

Microneedle associated with cosmetology may be a new option for studies on skin flaccidity treatments on individuals with EDS and for treatments of genital

hyperchromias
Phytoplankton assemblages and community structure in tropical temporary freshwater ponds in sub‐Saharan Africa1
Authors: Zongo Bilassé , Zongo Frédéric , Thiombiano Adjima , Boussim Joseph I.
Published: February 2019

Anthropogenic and climatic factors are important determinants of algal distribution in aquatic systems. This study aimed to identify temporary pond‐groups of phytoplankton assemblages and to establish the interactions between environmental variables and phytoplankton structure. Phytoplankton samples were collected and preserved with 5% formalin; water samples for chemical analysis were taken in August and September 2007, 2008, and 2009 in 86 ponds randomly selected in the Sahelian sector and the Sudanian sector (protected and unprotected areas) of Burkina Faso. Plankton species were examined using light microscopy and identified using standard methods. A Fuchs‐Rosenthal chamber was used for algal cell counting. NMDS ordination, indicator species analysis and canonical analysis were performed using Pc‐Ord and CANOCO. Kruskal–Wallis and Mann–Whitney U‐tests using the software Statistica were performed to compare parameters between pond‐groups. Three pond‐groups were identified: the Sahelian pond‐group, dominated by Lyngbya martensiana and Pseudanabaena constricta; the protected area pond‐group, dominated by Euglena caudata and Trachelomonas raciborskii; and the unprotected area pond‐group, dominated by Closterium venus and Euglena proxima. At P < 0.05, species composition and abundance in algal groups were mostly associated with nitrate, pH, dissolved oxygen, and conductivity. The Sahelian and the Sudanian sectors were different in pH, water transparency, and species richness. Univariate and multivariate analyses illustrate that variations in the physicochemical properties of water and algal structure followed climatic and anthropogenic gradients. The classification of ponds into algal associations demonstrated that algal assemblages may be used as reliable indicators of habitat conditions.
Testing mechanisms of compensatory fitness of dioecy in a cosexual world
Authors: Wang Yunyun , Mazer Susan J. , Freckleton Robert P. , Yuan Zuoqiang , Wang Xugao , Du Yanjun , Lin Luxiang , Wang Xihua , Sang Weiguo , Liu Xiaojuan , Hao Zhanqing
Published: February 2019

Questions

All else being equal, populations of dioecious species with a 50:50 sex ratio have only half the effective reproductive population size of bisexual species of equal abundance. Consequently, there is a need to explain how dioecious and bisexual species coexist. Increased mean individual seed mass, fecundity, and population density have all been proposed as attributes of unisexual individuals or populations that may contribute to the persistence or resilience of dioecious species. To date, no studies have compared sympatric dioecious and cosexual species with respect to all three components of fitness. In this study, we sought evidence for these compensatory advantages (higher seed mass, greater seed production per unit basal area, and higher population density) in dioecious species.

Location

Five 20–25 ha forest dynamic plots spanning a latitudinal gradient in China, including two temperate, two subtropical, and one tropical forest.

Methods

We used a phylogenetically corrected generalized linear modelling approach to assess the phylogenetic dependence and joint evolution of sexual system, seed mass and production, and ecological abundances among 48–333 species and 32,568–136,237 individuals per forest.

Results

Across all five forests, we detected no consistent advantage for dioecious relative to sympatric cosexual species with respect to mean individual seed mass, seed production or the density of stems in any size class.

Conclusions

Our study suggests that seed traits may provide compensatory mechanisms in some forests, but most often the coexistence of sexual systems cannot be explained by advantages of dioecy related to seed quality and demographic parameters. Future investigations of the factors that promote coexistence may increase our understanding by expanding the search to include attributes such as lifespan and tolerance or resistance to herbivores.
Convergence of cell‐surface and intracellular immune receptor signalling
Authors: Adachi Hiroaki , Tsuda Kenichi
Published: February 2019

This article is a Commentary on Kadota et al., 221: 2160–2175.
Resequencing of massive pine genomes helps to unlock the genetic underpinning of quantitative traits in conifer trees
Authors: Casola Claudio
Published: February 2019

This article is a Commentary on De La Torre et al., 221: 1789–1801.
Population genomic analysis of mango (Mangifera indica) suggests a complex history of domestication
Authors: Warschefsky Emily J. , von Wettberg Eric J. B.
Published: February 2019

Humans have domesticated diverse species from across the plant kingdom, yet much of our foundational knowledge of domestication has come from studies investigating relatively few of the most important annual food crops. Here, we examine the impacts of domestication on genetic diversity in a tropical perennial fruit species, mango (Mangifera indica).

We used restriction site associated DNA sequencing to generate genomic single nucleotide polymorphism (SNP) data from 106 mango cultivars from seven geographical regions along with 52 samples of closely related species and unidentified cultivars to identify centers of mango genetic diversity and examine how post‐domestication dispersal shaped the geographical distribution of diversity.

We identify two gene pools of cultivated mango, representing Indian and Southeast Asian germplasm. We found no significant genetic bottleneck associated with the introduction of mango into new regions of the world. By contrast, we show that mango populations in introduced regions have elevated levels of diversity.

Our results suggest that mango has a more complex history of domestication than previously supposed, perhaps including multiple domestication events, hybridization and regional selection. Our work has direct implications for mango breeding and genebank management, and also builds on recent efforts to understand how woody perennial crops respond to domestication.
Older people nursing in care homes: An examination of nursing professionals' self‐assessed competence and its predictors
Authors: Kiljunen Outi , Partanen Pirjo , Välimäki Tarja , Kankkunen Päivi
Published: February 2019

Background

The need for older people nursing expertise is increasing, and every effort is required to ensure that personnel taking care of older people are capable of providing high‐quality care.

Aims

To explore care home nursing professionals' self‐rated competence in older people nursing and to identify predictors of this competence.

Design

A cross‐sectional survey design.

Method

Data were collected in August‐September 2017 via an electronic questionnaire using the newly developed Nurse Competence in Care Home Scale (NCCHS). Participants (n = 781) were recruited via nurses’ associations and social media. They were working in care homes either as licensed practical nurses (n = 680) or as registered nurse and/or in managerial position (n = 101).

Findings

Approximately 65% of the respondents had “adequate competence,” and 35% had “inadequate competence” in older people nursing based on self‐assessed overall competence. Respondents rated their competence highest in “observation, communication, interaction” and lowest in “group guidance and activities” subscale. Age and further training were predictors of licensed practical nurses' competence, and length of work experience predicted registered nurses' competence.

Conclusions

Self‐assessments revealed the need for competence development especially in relation to holistic support of a person's well‐being. It is recommended that care home nurses, managers, educators and curriculum developers all strive to develop care home staff's ability to support residents' well‐being holistically.

Implications for practice

Nursing personnel should consider all aspects of older people’s well‐being holistically. In care homes, it is essential to assess nursing staff competence and to provide possibilities for competence development for personnel.
A novel anti‐HIV‐1 bispecific bNAb‐lectin fusion protein engineered in a plant‐based transient expression system
Authors: Seber Kasinger Lauren E. , Dent Matthew W. , Mahajan Garima , Hamorsky Krystal Teasley , Matoba Nobuyuki
Published: February 2019

The discovery of broadly neutralizing antibodies (bNAbs) has been a major step towards better prophylactic and therapeutic agents against human immunodeficiency virus type 1 (HIV‐1). However, effective therapy will likely require a combination of anti‐HIV agents to avoid viral evasion. One possible solution to this problem is the creation of bispecific molecules that can concurrently target two vulnerable sites providing synergistic inhibitory effects. Here, we describe the production in plants and anti‐HIV activity of a novel bispecific fusion protein consisting of the antigen‐binding fragment (Fab) of the CD4 binding site‐specific bNAb VRC01 and the antiviral lectin Avaren, which targets the glycan shield of the HIV‐1 envelope (VRC01Fab‐Avaren). This combination was justified by a preliminary experiment demonstrating the synergistic HIV‐1 neutralization activity of VRC01 and Fc‐fused Avaren dimer (Avaren‐Fc). Using the GENEWARE® tobacco mosaic virus vector, VRC01Fab‐Avaren was expressed in Nicotiana benthamiana and purified using a three‐step chromatography procedure. Surface plasmon resonance and ELISA demonstrated that both the Avaren and VRC01Fab moieties retain their individual binding specificities. VRC01Fab‐Avaren demonstrated enhanced neutralizing activity against representative HIV‐1 strains from A, B and C clades, compared to equimolar combinations of VRC01Fab and Avaren. Notably, VRC01Fab‐Avaren showed significantly stronger neutralizing effects than the bivalent parent molecules VRC01 IgG and Avaren‐Fc, with IC50 values ranging from 48 to 310 pm. These results support the continued development of bispecific anti‐HIV proteins based on Avaren and bNAbs, to which plant‐based transient overexpression systems will provide an efficient protein engineering and production platform.
Alpha‐L‐fucosidase‐1 is a diagnostic marker that distinguishes mucoepidermoid carcinoma from squamous cell carcinoma
Authors: Ishida Shoko , Kayamori Kou , Sakamoto Kei , Yukimori Akane , Kugimoto Takuma , Harada Hiroyuki , Ikeda Tohru
Published: February 2019

Alpha‐L‐fucose is a component of glycans on the cell surface. Alpha‐L‐fucose is correlated with tumorigenesis and malignancy, and alpha‐L‐fucosidase‐1 (FUCA1), the enzyme that removes terminal α‐L‐fucose residues from glycoproteins, is downregulated in some high malignancy cancers. The expression profile of FUCA1 in head and neck tumors remains unknown, and we analyzed the expression profiles of FUCA1 and an upstream molecule p53 in mucoepidermoid carcinoma (MEC) and oral squamous cell carcinoma (OSCC). FUCA1 was expressed in most MECs irrespective of histopathological grading, whereas expression in OSCCs was low. High immunohistochemical intensity of p53 was detected in OSCCs at high frequency, but rarely detected in MECs. Genetic mutation analysis using next‐generation sequencing revealed no significant mutation of TP53 in MECs. We further analyzed the expression profiles of FUCA1 in normal major and minor salivary glands and found strong expression in the intercalated duct, moderate expression in mucous acinar cells and no expression in serous acinar cells. These contrasting immunohistochemical profiles and anatomical distribution in normal salivary glands suggest that FUCA1 is a useful marker to distinguish MEC from OSCC, and many MECs have similar immunohistochemical phenotypes to intercalated duct and mucous acinar cells.
Impact of sensory adapted dental environment on children with developmental disabilities
Authors: Kim Gail , Carrico Caroline , Ivey Carole , Wunsch Patrice B.
Published: February 2019

Aims

This was a pilot study assessing the impact of a sensory adapted dental environment (SADE) on children with developmental disabilities (DD) receiving routine dental care.

Methods

A crossover study of 22 children with DD, aged 6 through 21, was conducted at a University Pediatric Dental clinic. Each participant was randomized to a sequence of two dental cleanings on a 3‐ to 4‐month recall schedule, one with a regular dental environment (RDE) and one with SADE. Outcomes included physiological measures (heart rate and oxygen saturation) and cooperation (Frankl scores).

Results

Study subjects completed 36 visits. None of the physiological measures differed at either time point between the two treatment settings. The Frankl scores were significantly higher with SADE setting than RDE (P = 0.0368). Forty‐six percent of parents strongly agreed that they would prefer the SADE for their child's next visit.

Conclusion

SADE may be associated with improved behavior in children with DD.
Berkeley Moynihan – early transfusionist and blood transfusion recipient
Authors: Learoyd P.
Published: February 2019

Lord Sir Berkeley Moynihan (1865–1936) was a surgeon at the General Infirmary in Leeds (Yorkshire) from 1893, rising during his career to be one of the foremost surgeons in the UK whose reputation reached its pinnacle at the outbreak of the First World War (WW1). He was the only surgeon after Lister to be made a Baronet. In a letter to The Lancet in 1918, he claimed to have used blood transfusion on some of his patients during the 10‐year period prior to that date. If true, this statement would make him the first surgeon in England to routinely use transfusion prior to WW1. This review investigates this claim using currently available evidence from Moynihan's personal records and publications, as well as published information from his colleagues.
Management of postpartum hemorrhage in a rural hospital in Kenya: a best practice implementation project
Authors: Kinuthia Kelvin , Stephenson Matthew , Maogoto Edwin
Published: February 2019

Introduction:

Postpartum hemorrhage accounts for 34% of maternal deaths in Kenya. The World Health Organization guidelines on postpartum hemorrhage are not always followed despite being prominently promoted in hospitals.

Objectives:

The objectives of this study were to assess the current practice of health workers in the prevention and management of postpartum hemorrhage and to implement strategies to promote best practice.

Methods:

A baseline audit with five evidence-based audit criteria was conducted using the Joanna Briggs Institute Practical Application of Clinical Evidence System. Strategies to improve compliance were implemented and a follow-up audit was carried out using the same data collection methods. Results of both audits were compared.

Results:

The baseline audit showed that 90% of health workers were aware of the existence and location of the national guidelines. Almost two thirds (65%) of staff had received education on postpartum hemorrhage within the last two years. Only 30% had received specific training on the use of the guidelines and compliance with the guidelines was 0%. At the follow-up audit, the proportion of health workers who had received recent education on postpartum hemorrhage and specific training on the use of a protocol increased to 90%. The use and documentation of a protocol for postpartum hemorrhage increased to 100%. Compliance in prenatal risk assessment for postpartum hemorrhage decreased from 65% to 35%.

Conclusions:

Knowledge of the guidelines did not translate into their use during management of patients with postpartum hemorrhage. The introduction of a tool and staff education and training improved compliance.
Requiem for Rethink Robotics
Authors: Lawrence Carol
Published: February 2019

Universal Robots and Rethink Robotics burst onto the scene ten years ago with seemingly similar breakthrough products—collaborative robots, or cobots—that were safe enough to work next to people on the factory floor. Rethink Robotics, however, shut its doors in October 2018 while Denmark’s Universal has become the clear cobot leader. Why did one company succeed while the other crashed and failed? In this article, robotics experts and customers tell a complicated story of how Rethink’s designs failed to meet the needs of its target market.
Effects
of Gamma Irradiation Upon the Mechanical and Chemical Properties of 3D-Printed Samples of Polylactic
Acid
Authors: West Conrad , McTaggart Robert , Letcher Todd , Raynie Douglas , Roy Ranen
Published: February 2019

3D printing offers the opportunity to design and make replacement parts to exacting specifications when needed. This is particularly helpful for space applications where stand-alone replacement mechanisms are required. Samples of 3D-printed polylactic acid (PLA) were subjected with up to 200 kGy of gamma radiation from a Cobalt-60 irradiator. The mechanical responses to destructive testing were successfully modeled with a combination of linear and exponential functions and may be understood given the underlying chemical changes due to said radiation exposures. We find that for doses up to 50 kGy, the performance of 3D-printed PLA is largely unaffected, which is beneficial for applications in space and in medicine. At larger doses, it appears that decomposition processes win out over cross-linking, which may aid in the degradation of PLA in waste streams.
Scalable Forming and Flash Light Sintering of Polymer-Supported Interconnects for Surface-Conformal Electronics
Authors: Devaraj Harish , Malhotra Rajiv
Published: February 2019

Conformally integrating conductive circuits with rigid 3D surfaces is a key need for smart materials and structures. This paper investigates sequential thermoforming and flash light sintering (FLS) of conductive silver (Ag) nanowire (NW) interconnects printed on planar polymer sheets. The resulting interconnect–polymer assemblies are thus preshaped to the desired 3D geometry and can be robustly attached to the surface. This conformal circuit integration approach avoids interconnect delamination in manual conformation of planar flexible electronics, eliminates heating of the 3D object in direct conformal printing, and enables easy circuit replacement. The interconnect resistance increases after thermoforming, but critically, is reduced significantly by subsequent FLS. The resistance depends nonlinearly on the forming strain, interconnect thickness, and FLS fluence. The underlying physics behind these observations are uncovered by understanding interconnect morphology and temperature evolution during the process. With the optimal parameters found here, this process achieves interconnect resistance of <10 Ω/cm within 90.8 s at 100% maximum strain over a 1 square inch forming area. The application of this process for complex surfaces is demonstrated via a simple conformal LED-lighting circuit. The potential of this approach to enable surface size and material insensitivity, robust integration, and easy replaceability for conformal circuit fabrication is discussed.
Design of Planar Large-Deflection Compliant Mechanisms With Decoupled Multi-Input-Output Using Topology Optimization
Authors: Zhu Benliang , Chen Qi , Li Hai , Zhang Hongchuan , Zhang Xianmin
Published: February 2019

This paper presents a method for topology optimization of large-deflection compliant mechanisms with multiple inputs and outputs by considering the coupling issue. First, the objectives of the design problem are posed by modeling the output loads using several springs to enable control of the input–output behavior. Second, a scheme is proposed to obtain a completely decoupled mechanism. Both input coupling and output coupling are considered. Third, with the implementation of an energy interpolation scheme to stabilize the numerical simulations, the geometrical nonlinearity is considered to appropriately capture the large displacements of compliant mechanisms. Finally, several numerical examples are presented to demonstrate the validity of the proposed method. Comparison studies with the obtained results without considering the coupling issues are also presented.
Modeling the Bending Behavior of Fiber-Reinforced Pneumatic Actuators Using a Pseudo-Rigid-Body Model
Authors: Satheeshbabu Sreeshankar , Krishnan Girish
Published: February 2019

Fiber reinforced elastomeric enclosures (FREEs) are soft pneumatic representative elements that can form the basis for building soft self-actuating structures/mechanisms. When placed in different configurations, they exhibit unique stroke amplification characteristics that can be leveraged to create interesting deformation patterns. Such deformations occur as a combination of axial and bending deflection due to internal pressurization and external forces. This paper presents a lumped reduced-order model that enables quick and accurate analysis of mechanisms made from FREEs grouped as a system. The model proposed is a modified four-spring pseudo-rigid-body (PRB) model that effectively captures the axial and bending stiffnesses of contracting FREEs. Parametric estimation of the model is performed using a multistart optimization routine to fit the PRB model with results from experiments and finite element analysis (FEA). The model is also generalized and statistically verified for FREEs with different fiber angles, length-to-diameter ratios, and different actuation pressures. Finally, efficacy of the approach is validated through three case studies that involve a planar arrangement of FREEs at different orientations.
Numerical and Experimental Investigation of the Impact of Mixed Flow Turbine Inlet Cone Angle and Inlet Blade Angle
Authors: Leonard Thomas , Spence Stephen , Starke Andre , Filsinger Dietmar
Published: February 2019

Mixed flow turbines (MFTs) offer potential benefits for turbocharged engines when considering off-design performance and engine transient behavior. Although the performance and use of MFTs are described in the literature, little is published on the combined impact of the cone angle and the inlet blade angle, which are the defining features of such turbines. Numerical simulations were completed using a computational fluid dynamics (CFD) model that was validated against experimental measurements for a baseline geometry. The mechanical impact of the design changes was also analyzed. Based on the results of the numerical study, two rotors of different blade angle and cone angle were selected and manufactured. These rotors were tested using the Queen's University Belfast (QUB) low-temperature turbine test rig, which allowed for accurate and wide-range mapping of the turbine performance to low values of the velocity ratio. The performance results from these additional rotors were used to further validate the numerical findings. The numerical model was used to understand the underlying physical reasons for the measured performance differences through detailed consideration of the flow field at the rotor inlet and to document how the loss mechanisms and secondary flow structures developed with varying rotor inlet geometry. It was observed that large inlet blade cone angles resulted in strong separation and flow blockage near the hub at off-design conditions, which greatly reduced efficiency. However, the significant rotor inertia benefits achieved with the large blade cone angles were shown to compensate for the efficiency penalties and could be expected to deliver improved transient performance in downsized automotive engine applications.
Heat-Transfer Enhancement Incorporating Fin-Like Structures Inside Droplet on Hydrophobic Surface
Authors: Al-Sharafi Abdullah , Yilbas Bekir S. , Al-Zahrani Abdullah
Published: February 2019

Enhancement of droplet heat transfer on a hydrophobic surface is examined via introducing the fin-like structures inside the droplet without altering the wetting state of the surface. A solution crystallization of polycarbonate surface is carried out and the functionalized silica particles are deposited onto the crystallized surface to create the hydrophobic surface characteristics. The ferrous particles (Fe2O3) are locally spread onto the hydrophobic surface and, later, manipulated by an external magneto-static force generating various configurations of fin-like structures inside the droplet. The droplet with fin-like structures is heated from the hydrophobic surface through introducing a constant temperature heat source. Flow and temperature fields inside the droplet are simulated in line with the experimental conditions. It is found that changing the configuration of the fin-like structures in the droplet modifies significantly the flow and temperature fields inside the droplet. The Bond number remains less than unity for all configurations of the fin-like structures while demonstrating the importance of the Marangoni current over the buoyancy current in the flow field. The presence of the fin-like structures lowers the difference between the fluid bulk and the minimum temperatures inside the droplet and improves considerably the heat transfer rates and the Nusselt number.
NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages
Authors: Liu Zhiyong , Wu Cheng , Pan Yueyun , Liu Huan , Wang Xiumei , Yang Yuting , Gu Meidi , Zhang Yuanyuan , Wang Xiaojian
Published: February 2019

NDR2 functions as an antiviral molecule via regulating TRIM25-mediated RIG-I activation.
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study
Authors: An Guohua , Murry Daryl J. , Gajurel Kiran , Bach Thanh , Deye Greg , Stebounova Larissa V. , Codd Ellen E. , Horton John , Gonzalez Armando E. , Garcia Hector H. , Ince Dilek , Hodgson-Zingman Denice , Nomicos Effie Y. H. , Conrad Thomas , Kennedy Jessie , Jones Walt , Gilman Robert H. , Winokur Patricia
Published: February 2019

Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of
Taenia solium
and has potential to be developed as an effective therapy for neurocysticercosis.
Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus
Authors: Tesini Brenda L. , Kanagaiah Preshetha , Wang Jiong , Hahn Megan , Halliley Jessica L. , Chaves Francisco A. , Nguyen Phuong Q. T. , Nogales Aitor , DeDiego Marta L. , Anderson Christopher S. , Ellebedy Ali H. , Strohmeier Shirin , Krammer Florian , Yang Hongmei , Bandyopadhyay Sanjukta , Ahmed Rafi , Treanor John J. , Martinez-Sobrido Luis , Golding Hana , Khurana Surender , Zand Martin S. , Topham David J. , Sangster Mark Y.
Published: February 2019

Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.
Measles Virus Bearing Measles Inclusion Body Encephalitis-Derived Fusion Protein Is Pathogenic after Infection via the Respiratory Route
Authors: Mathieu Cyrille , Ferren Marion , Jurgens Eric , Dumont Claire , Rybkina Ksenia , Harder Olivia , Stelitano Debora , Madeddu Silvia , Sanna Giuseppina , Schwartz Dayna , Biswas Sudipta , Hardie Diana , Hashiguchi Takao , Moscona Anne , Horvat Branka , Niewiesk Stefan , Porotto Matteo
Published: February 2019

Measles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.
Subacromial decompression surgery for adults with shoulder pain: a clinical practice guideline
Authors: Vandvik Per Olav , Lähdeoja Tuomas , Ardern Clare , Buchbinder Rachelle , Moro Jaydeep , Brox Jens Ivar , Burgers Jako , Hao Qiukui , Karjalainen Teemu , van den Bekerom Michel , Noorduyn Julia , Lytvyn Lyubov , Siemieniuk Reed A C , Albin Alexandra , Shunjie Sean Chua , Fisch Florian , Proulx Laurie , Guyatt Gordon , Agoritsas Thomas , Poolman Rudolf W
Published: February 2019

Clinical question

Do adults with atraumatic shoulder pain for more than 3 months diagnosed as subacromial pain syndrome (SAPS), also labelled as rotator cuff disease, benefit from subacromial decompression surgery? This guideline builds on to two recent high quality trials of shoulder surgery.

Current practice

SAPS is the common diagnosis for shoulder pain with several first line treatment options, including analgesia, exercises, and injections. Surgeons frequently perform arthroscopic subacromial decompression for prolonged symptoms, with guidelines providing conflicting recommendations.

Recommendation

The guideline panel makes a strong recommendation against surgery.

How this guideline was created

A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines and the GRADE system. The recommendation is based on two linked systematic reviews on (a) the benefits and harms of subacromial decompression surgery and (b) the minimally important differences for patient reported outcome measures. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of surgery in multilayered evidence summaries and decision aids available in MAGIC (www.magicapp.org) to support shared decisions and adaptation.

The evidence

Surgery did not provide important improvements in pain, function, or quality of life compared with placebo surgery or other options. Frozen shoulder may be more common with surgery.

Understanding the recommendation

The panel concluded that almost all informed patients would choose to avoid surgery because there is no benefit but there are harms and it is burdensome. Subacromial decompression surgery should not be offered to patients with SAPS. However, there is substantial uncertainty in what alternative treatment is best.
Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study)
Authors: Gay-Escoda Cosme , Hanna Magdi , Montero Antonio , Dietrich Thomas , Milleri Stefano , Giergiel Ewa , Zoltán Tóth Bagi , Varrassi Giustino
Published: February 2019

Objectives

To compare efficacy/safety of oral tramadol 75 mg/dexketoprofen 25 mg (TRAM/DKP) and TRAM 75 mg/paracetamol 650 mg (TRAM/paracetamol) in moderate to severe pain following surgical removal of impacted lower third molar.

Design

Multicentre, randomised, double-blind, placebo-controlled, phase IIIb study.

Participants

Healthy adult patients scheduled for surgical extraction of at least one fully/partially impacted lower third molar requiring bone manipulation. 654 patients were randomised and 653 were eligible for analysis.

Interventions

Surgery was performed under local anaesthetic. No sedation was permitted. Patients rated pain intensity (PI) using an 11-Numerical Rating Scale (NRS) (0 no pain; 10 worst pain). Participants experiencing moderate/severe pain (≥4) within 4 hours of surgery were randomised (2:2:1 ratio) to a single oral dose of TRAM/DKP 75/25 mg, TRAM/paracetamol 75/650 mg or placebo.

Main outcome measures

Efficacy was based patients’ electronic diaries. Analgesia and pain were recorded as follows: pain relief (PAR) on a 5-point Verbal Rating Scale (0=‘no relief’, 1=‘a little (perceptible) relief’, 2=‘some (meaningful) relief’, 3=‘lot of relief’, 4=‘complete relief’) at the predefined postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour and t8 hour and PI on the 11-point NRS at t0 and at the same predefined postdose time points. Onset of analgesia documented using double stopwatch method over a 2-hour period. Primary endpoint was total pain relief over 6 hours (TOTPAR6). Rescue medication was available during the treatment period.

Results

TRAM/DKP was superior to TRAM/paracetamol and placebo at the primary endpoint TOTPAR6 (p<0.0001). Mean (SD) TOTPAR6 in the TRAM/DKP group was 13 (6.97), while those in the active control and placebo groups were 9.2 (7.65) and 1.9 (3.89), respectively. Superiority of TRAM/DKP over active comparator and placebo was observed at all secondary endpoints. Incidence of adverse events was comparable between active groups.

Conclusions

TRAM/DKP (75/25 mg) is effective and superior to TRAM/paracetamol (75/650 mg) in relieving moderate to severe acute pain following surgical removal of impacted lower third molar, with a faster onset of action, greater and durable analgesia, together with a favourable safety profile.

Trial registration number

EudraCT 2015-004152-22 andNCT02777970.
A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2)
Authors: Geven Christopher , Blet Alice , Kox Matthijs , Hartmann Oliver , Scigalla Paul , Zimmermann Jens , Marx Gernot , Laterre Pierre-François , Mebazaa Alexandre , Pickkers Peter
Published: February 2019

Introduction

Sepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist. Adrenomedullin (ADM) is a vasoactive peptide. High plasma concentrations of ADM correlate with worse outcome in sepsis patients. Preclinical work with the non-neutralising ADM-binding antibody adrecizumab showed promising effects in animal models of septic shock, including improved vascular barrier function, reduced vasopressor demand and organ dysfunction and increased survival. Therapeutic use of adrecizumab may therefore improve outcome in critically ill patients with septic shock and high ADM plasma concentrations. Phase I studies in healthy volunteers did not reveal any safety concerns. In this biomarker-guided trial, the safety and efficacy of adrecizumab will be investigated in patients with septic shock.

Methods and analysis

We describe a phase II, randomised, double-blind, placebo-controlled, biomarker-guided, proof-of-concept and dose-finding clinical trial in patients with early septic shock and high concentration of circulating ADM. A total of 300 patients will be enrolled at approximately 30 sites within the European Union. Patients are randomised to receive active treatment (2 and 4 mg/kg adrecizumab) or placebo, in a 1:1:2 ratio. Patient selection is guided by clinical parameters, and biomarker-guided by measurement of circulating biologically active ADM concentration at admission. Primary endpoint is safety and tolerability of adrecizumab over a 90-day period. A key secondary endpoint is the Sepsis Severity Index over a 14-day period.

Ethics and dissemination

This study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.

Trial registration number

NCT03085758; Pre-results.
Significance of the metasomatized lithospheric mantle in the formation of early basalts and Cu – platinum group element sulfide mineralization in the Coldwell Complex, Midcontinent Rift, Canada
Authors: Good David J. , Lightfoot Peter C.
Published: February 2019

A diverse suite of tholeiitic to alkaline basalt and gabbroic intrusions located in the Coldwell Complex on the northern margin of the Midcontinent Rift exhibit unusual trace element signatures that show enriched large ion lithophile elements and light rare earth elements with negative Nb and Zr anomalies. These features are not typical of magmas derived by partial melting within or above a rising mantle plume, as might be expected in an early Midcontinent Rift magmatic event. In this paper, we provide a detailed geochemical study of a 500 m thick sequence of metabasalt that represents the earliest stage of magmatism in the Coldwell Complex. We show that contamination or crystallization processes or subsequent metasomatism cannot explain the trace element variations. Instead, we propose partial melting in a metasomatized Subcontinental Lithospheric Mantle source to explain the decoupled behavior of large ion lithophile elements from light rare earth elements and heavy rare earth elements and rare earth elements from high field strength elements and the enriched Nd isotope signature of metabasalt. Similar features occur in unit 5b of the Mamainse Point Volcanic Group located at the northern margin of the Rift. An objective of this paper is to relate Two Duck Lake gabbro, host rock for low-sulfur, high precious metal sulfide mineralization at the Marathon deposit, to the metabasalt sequence. The excellent match of trace element abundances in Two Duck Lake gabbro to metabasalt unit 3 confirms an early Coldwell Complex age for metabasalt and a Subcontinental Lithospheric Mantle source for Cu – platinum group element mineralized gabbros.