bluuebunny/crossref_metadata_2025 huggingface dataset:
Wear Characteristic of Stellite 6 Alloy Hardfacing Layer by Plasma Arc Surfacing Processes
Authors: Zhu Zhiyuan , Ouyang Chun , Qiao Yanxin , Zhou Xiaowei
Published: November 2017

The microstructure and wear resistance of Stellite 6 alloy hardfacing layer at two different temperatures (room temperature and 300°C) were investigated by plasma arc surfacing processes on Q235 Steel. Tribological test was conducted to characterize the wear property. The microstructure of Stellite 6 alloy coating mainly consists of α-Co and (Cr, Fe)7C3 phases. The friction coefficient of Stellite 6 alloys fluctuates slightly under different loads at 300°C. The oxide layer is formed on the coating surface and serves as a special lubricant during the wear test. Abrasive wear is the dominant mechanism at room temperature, and microploughing and plasticity are the key wear mechanisms at 300°C.
A Study on the Efficient Method for the Solution of the Saha Equation in the Numerical Simulation of Capillary Discharge
Authors: Liu Hengzhu , Wu Cheng , An Fengjiang , Liao Shasha
Published: November 2017

In the numerical simulation of capillary discharge for the Electrothermal (ET) or ET-chemical (ETC) launch system, one needs to solve the Saha equation to determine the composition of plasma for the transport coefficients. This would cause a relatively longer simulation runtime compared with conventional computational fluid dynamics problems. In this paper, the relatively difficult multidimensional problem of solving the Saha equation is transformed into a one-dimensional problem in the simulation of capillary discharge by constructing an iteration equation about temperature. A coefficient is introduced to ensure the convergence of this iteration equation. In order to improve the computational efficiency, this coefficient is further optimized and the methods of setting the iteration initial value dynamically are introduced. Several simulation tests are conducted to study the performance of these two methods. The results show that the simulation runtime could be significantly reduced with the methods presented in this paper.
Electromagnetic Waves Dispersion and Interaction of an Annular Beam-Ion Channel System in Plasma Waveguide
Authors: Xiao Jixiong , Wang Zhijiang , Chen Jun , Liu Changhai
Published: November 2017

A linear theory for the electromagnetic properties and interactions of an annular beam-ion channel system in plasma waveguide is presented. The dispersion relations for two families of propagating modes, including the electrostatic and transverse magnetic modes, are derived. The dependencies of the dispersion behavior and interaction for different wave modes on the thickness of the annular beam and betatron oscillation frequency are studied in detail by numerical calculations. The results show that the inner and outer radii of the beam have different influences on propagation properties of the electrostatic and electromagnetic modes with different betatron oscillation parameters. In the weak ion channel situation, the two types of electrostatic waves, that is, space charge and betatron modes, have no interaction with the transverse magnetic modes. However, in the strong ion channel situation, the transverse magnetic modes will have two branches and a low frequency mode emerged as the new branch. In this case, compared with the solid beam case, the betatron modes not only can interact with the high frequency branch at small wavenumber but also can interact with the low frequency branch at large wavenumber.
Improved Collaborative Representation Classifier Based on l2-Regularized for Human Action Recognition
Authors: Huo Shirui , Hu Tianrui , Li Ce
Published: November 2017

Human action recognition is an important recent challenging task. Projecting depth images onto three depth motion maps (DMMs) and extracting deep convolutional neural network (DCNN) features are discriminant descriptor features to characterize the spatiotemporal information of a specific action from a sequence of depth images. In this paper, a unified improved collaborative representation framework is proposed in which the probability that a test sample belongs to the collaborative subspace of all classes can be well defined and calculated. The improved collaborative representation classifier (ICRC) based on l2-regularized for human action recognition is presented to maximize the likelihood that a test sample belongs to each class, then theoretical investigation into ICRC shows that it obtains a final classification by computing the likelihood for each class. Coupled with the DMMs and DCNN features, experiments on depth image-based action recognition, including MSRAction3D and MSRGesture3D datasets, demonstrate that the proposed approach successfully using a distance-based representation classifier achieves superior performance over the state-of-the-art methods, including SRC, CRC, and SVM.
Modulatory Effect of Fermented Papaya Extracts on Mammary Gland Hyperplasia Induced by Estrogen and Progestin in Female Rats
Authors: You Zhenqiang , Sun Junying , Xie Feng , Chen Zhiqin , Zhang Sheng , Chen Hao , Liu Fang , Li Lili , Chen Guocan , Song Yisheng , Xuan Yaoxian , Zheng Gaoli , Xin Yanfei
Published: November 2017

Fermented papaya extracts (FPEs) are obtained by fermentation of papaya by Aspergillus oryzae and yeasts. In this study, we investigated the protective effects of FPEs on mammary gland hyperplasia induced by estrogen and progestogen. Rats were randomly divided into 6 groups, including a control group, an FPE‐alone group, a model group, and three FPE treatment groups (each receiving 30, 15, or 5 ml/kg FPEs). Severe mammary gland hyperplasia was induced upon estradiol benzoate and progestin administration. FPEs could improve the pathological features of the animal model and reduce estrogen levels in the serum. Analysis of oxidant indices revealed that FPEs could increase superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px) activities, decrease malondialdehyde (MDA) level in the mammary glands and serum of the animal models, and decrease the proportion of cells positive for the oxidative DNA damage marker 8‐oxo‐dG in the mammary glands. Additionally, estradiol benzoate and progestin altered the levels of serum biochemical compounds such as aspartate transaminase (AST), total bilirubin (TBIL), and alanine transaminase (ALT), as well as hepatic oxidant indices such as SOD, GSH‐Px, MDA, and 8‐oxo‐2′‐deoxyguanosine (8‐oxo‐dG). These indices reverted to normal levels upon oral administration of a high dose of FPEs. Taken together, our results indicate that FPEs can protect the mammary glands and other visceral organs from oxidative damage.
Softwarization of Mobile Network Functions towards Agile and Energy Efficient 5G Architectures: A Survey
Authors: Thembelihle Dlamini , Rossi Michele , Munaretto Daniele
Published: November 2017

Future mobile networks (MNs) are required to be flexible with minimal infrastructure complexity, unlike current ones that rely on proprietary network elements to offer their services. Moreover, they are expected to make use of renewable energy to decrease their carbon footprint and of virtualization technologies for improved adaptability and flexibility, thus resulting in green and self-organized systems. In this article, we discuss the application of software defined networking (SDN) and network function virtualization (NFV) technologies towards softwarization of the mobile network functions, taking into account different architectural proposals. In addition, we elaborate on whether mobile edge computing (MEC), a new architectural concept that uses NFV techniques, can enhance communication in 5G cellular networks, reducing latency due to its proximity deployment. Besides discussing existing techniques, expounding their pros and cons and comparing state-of-the-art architectural proposals, we examine the role of machine learning and data mining tools, analyzing their use within fully SDN- and NFV-enabled mobile systems. Finally, we outline the challenges and the open issues related to evolved packet core (EPC) and MEC architectures.
Anthropometric Measures and Frailty Prediction in the Elderly: An Easy-to-Use Tool
Authors: Closs Vera Elizabeth , Ziegelmann Patricia Klarmann , Flores João Henrique Ferreira , Gomes Irenio , Schwanke Carla Helena Augustin
Published: November 2017

Purpose. Anthropometry is a useful tool for assessing some risk factors for frailty. Thus, the aim of this study was to verify the discriminatory performance of anthropometric measures in identifying frailty in the elderly and to create an easy-to-use tool. Methods. Cross-sectional study: a subset from the Multidimensional Study of the Elderly in the Family Health Strategy (EMI-SUS) evaluating 538 older adults. Individuals were classified using the Fried Phenotype criteria, and 26 anthropometric measures were obtained. The predictive ability of anthropometric measures in identifying frailty was identified through logistic regression and an artificial neural network. The accuracy of the final models was assessed with an ROC curve. Results. The final model comprised the following predictors: weight, waist circumference, bicipital skinfold, sagittal abdominal diameter, and age. The final neural network models presented a higher ROC curve of 0.78 (CI 95% 0.74–0.82) (P<0.001) than the logistic regression model, with an ROC curve of 0.71 (CI 95% 0.66–0.77) (P<0.001). Conclusion. The neural network model provides a reliable tool for identifying prefrailty/frailty in the elderly, with the advantage of being easy to apply in the primary health care. It may help to provide timely interventions to ameliorate the risk of adverse events.
Work Interruption Experienced by Nurses during Medication Administration Process and Associated Factors, Northwest Ethiopia
Authors: Getnet Mehammed Adem , Bifftu Berhanu Boru
Published: November 2017

Background. During medication administration process, including preparation, administration, and documentation, there is high proportion of work interruption that results in medication administration errors that consequently affect the safety of patients. Thus, the main purpose of this study was to assess the prevalence of work interruption and associated factors during medication administration process.Methods. A prospective, observation-based, cross-sectional study was conducted on 278 nurses. Structure observational sheet was utilized to collect data. EPI Info version 3.5.3 and SPSS version 20 software were utilized for data entry and analysis, respectively. Binary and multivariable logistic regression were fitted to identify the associated factors using an odds ratio and 95% CI.Results. The incidence of work interruption was found to be 1,152 during medication administration process. Of this, 579 (50.3%) were major/severe work interruptions. Unit of work, day of the week, professional experience, perceived severity of work interruption, source/initiator of interruption, and secondary tasks were factors significantly associated with major work interruptions atp<0.05.Conclusion. In this study, more than half of work interruption was major/severe. Thus, the authors suggest raising the awareness of nurses regarding the severity of work interruptions, with special attention to those who have lower work experience, sources of interruption, and secondary tasks by assigning additional nurses who manage secondary tasks and supportive supervision.
Modelling and Metaheuristic for Gantry Crane Scheduling and Storage Space Allocation Problem in Railway Container Terminals
Authors: Zeng Ming , Cheng Wenming , Guo Peng
Published: November 2017

The gantry crane scheduling and storage space allocation problem in the main containers yard of railway container terminal is studied. A mixed integer programming model which comprehensively considers the handling procedures, noncrossing constraints, the safety margin and traveling time of gantry cranes, and the storage modes in the main area is formulated. A metaheuristic named backtracking search algorithm (BSA) is then improved to solve this intractable problem. A series of computational experiments are carried out to evaluate the performance of the proposed algorithm under some randomly generated cases based on the practical operation conditions. The results show that the proposed algorithm can gain the near-optimal solutions within a reasonable computation time.
Nash Equilibrium of an Energy Saving Strategy with Dual Rate Transmission in Wireless Regional Area Network
Authors: Huo Zhanqiang , Li Xiaowei , Jin Shunfu , Wang Zhiheng
Published: November 2017

Wireless regional area network (WRAN) adopts centralized network architecture and is currently one of the most typical cognitive radio networks. In order to reduce the energy consumption of the communication networks with the constraint of spectrum resource utilization, a working sleep mechanism is introduced into the base station (BS), and a novel energy saving strategy with dual rate transmission is proposed. Combining the multiple-vacation queue and priority queue, using the quasi-birth-death process and the matrix-geometric solution method, we assess the average latency and the forced termination probability of secondary user packets, as well as the energy saving ratio and the channel utilization of system. Based on the revenue-expenditure structure, a profit function is built, and then the Nash equilibrium behavior and the socially optimal behavior are investigated. With the help of the particle swarm optimization, an intelligent optimization algorithm to search the socially optimal arrival rate of secondary user packets is presented. In order to unify the arrival rates of secondary user packets with Nash equilibrium and social optimization, a reasonable pricing policy is formulated. In addition, system experiments are carried out to verify the effectiveness of the energy saving strategy and the rationality of the pricing policy.
Natural Bioactive Compounds: Alternative Approach to the Treatment of Glioblastoma Multiforme
Authors: Desai Vilas , Bhushan Alok
Published: November 2017

Glioblastoma multiforme (GBM) is the most frequent, primary malignant brain tumor prevalent in humans. GBM characteristically exhibits aggressive cell proliferation and rapid invasion of normal brain tissue resulting in poor patient prognosis. The current standard of care of surgical resection followed by radiotherapy and chemotherapy with temozolomide is not very effective. The inefficacy of the chemotherapeutic agents may be attributed to the challenges in drug delivery to the tumor. Several epidemiological studies have demonstrated the chemopreventive role of natural, dietary compounds in the development and progression of cancer. Many of these studies have reported the potential of using natural compounds in combination with chemotherapy and radiotherapy as a novel approach for the effective treatment of cancer. In this paper, we review the role of several natural compounds individually and in combination with chemotherapeutic agents in the treatment of GBM. We also assess the potential of drug delivery approaches such as the Gliadel wafers and role of nanomaterial based drug delivery systems for the effective treatment of GBM.
Comparison of Exenatide and Metformin Monotherapy in Overweight/Obese Patients with Newly Diagnosed Type 2 Diabetes
Authors: Liu Jia , Hu Yanjin , Xu Yuan , Jia Yumei , Miao Li , Wang Guang
Published: November 2017

Aims. The present study assessed the therapeutic effect of exenatide and metformin as the initial therapy on overweight/obese patients with newly diagnosed type 2 diabetes (T2D). Methods. The prospective, nonrandomized, interventional study enrolled a total of 230 overweight or obese patients with newly diagnosed T2D who were administrated exenatide or metformin hydrochloride for 12 weeks. Results. 224/230 patients, including 106 in the exenatide group and 118 in the metformin group, completed the 12-week treatment. Both exenatide and metformin significantly decreased the HbA1c levels in overweight/obese patients with newly diagnosed T2D (all P<0.05). The reduction in HbA1c and the proportion of patients with HbA1c < 7.0% (53 mmol/mol) were higher in the exenatide group than in the metformin group (all P<0.05). The exenatide treatment caused a greater decline in the body weight and BMI as compared to the metformin treatment (all P<0.01). The exenatide treatment (β = 0.41, P<0.01) and baseline HbA1c level (β = −0.84, P<0.01) were independent influencing factors for the decrease in HbA1c level. Conclusions. For an initial therapy in overweight/obese patients with newly diagnosed T2D, exenatide causes a better glycemic control than metformin. This trial is registered with NCT03297879.
Elevated Level of Troponin but Not N-Terminal Probrain Natriuretic Peptide Is Associated with Increased Risk of Sudden Cardiac Death in Hypertrophic Cardiomyopathy Calculated According to the ESC Guidelines 2014
Authors: Rajtar-Salwa Renata , Hładij Rafał , Dimitrow Paweł Petkow
Published: November 2017

The aim of this study was to assess the relationship between biomarkers (high-sensitive troponin I [hs-TnI], N-Terminal probrain natriuretic peptide [NT-proBNP]) and calculated 5-year percentage risk score of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). Methods. In 46 HCM patients (mean age 39 ± 7 years, 24 males and 22 females), echocardiographic examination, including the stimulating maneuvers to provoke maximized LVOT gradient, had been performed and next ECG Holter was immediately started. After 24 hours, the ECG Holter was finished and the hs-TnI and NT-proBNP have been measured. Patients were divided according to 1/value of both biomarkers (hs-TnI-positive and hs-TnI-negative subgroups) and 2/(NT-proBNP lower and higher subgroup divided by median). Results. In comparison between 19 patients (hs-TnI positive) versus 27 patients (hs-TnI negative), the calculated 5-year percentage risk of SCD in HCM was significantly greater (6.38 ± 4.17% versus 3.81 ± 3.23%, P<0.05). In comparison between higher NT-proBNP versus lower NT-proBNP subgroups, the calculated 5-year percentage risk of SCD in HCM was not significantly greater (5.18 ± 3.63% versus 4.14 ± 4.18%, P>0.05). Conclusions. Patients with HCM and positive hs-TnI test have a higher risk of SCD estimated according to SCD calculator recommended by the ESC Guidelines 2014 than patients with negative hs-TnI test.
Immunoenhancement of Edible Fungal Polysaccharides (Lentinan, Tremellan, and Pachymaran) on Cyclophosphamide‐Induced Immunosuppression in Mouse Model
Authors: Zhang Qian , Cong Renhuai , Hu Minghua , Zhu Yanhong , Yang Xiangliang
Published: November 2017

Fungal polysaccharides display a variety of important biological activities, including anti‐inflammatory, antitumor, and immune‐stimulating activities. The aim of present study was to investigate the immunomodulatory effect of fungal polysaccharides on cyclophosphamide‐induced immunosuppression in mice. Mice were pretreated orally with lentinan, tremellan, pachymaran, or a mixture of the three, respectively. The results showed that pretreatments with polysaccharides significantly increased the thymus index in cyclophosphamide‐induced immunosuppression mice. The level of the cytokine IL‐10 in sera of cyclophosphamide‐induced mice was decreased after pretreatments of polysaccharides. Flow cytometry results showed that pretreatments with polysaccharides enhanced the phagocytosis of peritoneal macrophages in mice. The increased levels of serum antibody IgG and IgM were observed in the groups pretreated with polysaccharides. Our work demonstrated that the treatment of polysaccharides elicited strong immune activity and a protective effect against cyclophosphamide‐induced immunosuppression.
Adaptive Foot in Lower-Limb Prostheses
Authors: Weerakkody Thilina H. , Lalitharatne Thilina Dulantha , Gopura R. A. R. C.
Published: November 2017

The human foot consists of complex sets of joints. The adaptive nature of the human foot enables it to be stable on any uneven surface. It is important to have such adaptive capabilities in the artificial prosthesis to achieve most of the essential movements for lower-limb amputees. However, many existing lower-limb prostheses lack the adaptive nature. This paper reviews lower-limb adaptive foot prostheses. In order to understand the design concepts of adaptive foot prostheses, the biomechanics of human foot have been explained. Additionally, the requirements and design challenges are investigated and presented. In this review, adaptive foot prostheses are classified according to actuation method. Furthermore, merits and demerits of present-day adaptive foot prostheses are presented based on the hardware construction. The hardware configurations of recent adaptive foot prostheses are analyzed and compared. At the end, potential future developments are highlighted.
Combining Extended Imperialist Competitive Algorithm with a Genetic Algorithm to Solve the Distributed Integration of Process Planning and Scheduling Problem
Authors: Zhang Shuai , Xu Yangbing , Yu Zhinan , Zhang Wenyu , Yu Dejian
Published: November 2017

Distributed integration of process planning and scheduling (DIPPS) extends traditional integrated process planning and scheduling (IPPS) by considering the distributed features of manufacturing. In this study, we first establish a mathematical model which contains all constraints for the DIPPS problem. Then, the imperialist competitive algorithm (ICA) is extended to effectively solve the DIPPS problem by improving country structure, assimilation strategy, and adding resistance procedure. Next, the genetic algorithm (GA) is adapted to maintain the robustness of the plan and schedule after machine breakdown. Finally, we perform a two‐stage experiment to prove the effectiveness and efficiency of extended ICA and GA in solving DIPPS problem with machine breakdown.
The Three-Way Pendulum of Healthcare Innovation
Authors: Horgan Denis , de Braud Filippo , Jonsson Bengt , Vallone Stefania , Jagielska Beata , Koeva Jasmina , Geanta Marius
Published: November 2017

We are, understandably, forever hearing about the high cost of bringing innovative new drugs and treatments to the healthcare market, especially medicines for smaller subgroups, and the fact that member state health systems often baulk at the prices. This article will argue that such a bypassing and blocking of innovative medicines and treatments is not only counterproductive when it comes to the health of Europe's patients, but actually fails to take into account the economic arguments. The article seeks to show that the long-term benefit to patients and the economy (health means wealth) will outweigh initial costs down the line. Couple this with a smarter use of information technologies and other resources and it will be possible to get much closer to building sustainable healthcare systems in a Europe struggling under the burden of an ageing population.
Prevention, Early Dialogue and Education in the Personalised Healthcare Era
Authors: Horgan Denis , Pazzagli Mario
Published: November 2017

In the EU, the “portrait” of healthcare has undergone many changes down the years, with many adaptations as the EU has evolved. The role of patients has become much more significant as they have gained greater knowledge; there have been giant leaps in innovation, while societal changes and issues (such as the ageing population) have led to different priorities. Today's portrait of healthcare features many perspectives, schools of thought and approaches coming from different stakeholders, different Member States and even different regions within those Member States. One thing that has become very clear is that a one-size-fits-all approach to treatment is outmoded, wasteful and often counterproductive to the health of patients. This includes, in these days of increasing co-morbidities, treating one disease separately, rather than looking at the patient's health issues as a whole. Meanwhile, citizens are being bombarded with often contradictory messages regarding what is “good” or “bad” for them, often in a patronising manner, while the realities of extremely effective preventative measures are often obscured, with a lack of emphasis on screening and early diagnosis. The authors argue that, among other matters, better communication and education are key to improving healthcare in Europe.
Making Change Happen in Health
Authors: Horgan Denis , Smand Carin , Negrouk Anastassia , Lacombe Denis
Published: November 2017

Integrating personalised medicine into Europe's healthcare systems will undoubtedly need to draw upon diverse talents via a multi-stakeholder approach taking expertise from academia, industry, healthcare organisations, government, policymakers and, of course, patient groups. It will also need a long-term budget commitment geared towards stimulating research and innovation in order to succeed. The role of HTA also needs to be boosted, while EU engagement in health needs to increase, not decrease, and requires a long-term strategy to provide a structure, a framework, and a consensus. Health equals wealth and the authors argue here that investment in research and innovation, alongside laws and rules that are fit-for-purpose and reflect the swiftly changing world of medicine, are vital. Europe needs to grasp these points at every level for the benefit of the millions of potential patients spread across the soon-to-be 27 Member States.
Ensuring Consistent European-Wide Urological Care by the Use of Evidence-Based Clinical Practice Guidelines: Can We Do Better
Authors: Smith Emma Jane , MacLennan Steven , Bjartell Anders , Briganti Alberto , Knoll Thomas , Loch Tillmann , Ribal Maria J. , Sylvester Richard , Van Poppel Hein , N'Dow James
Published: November 2017

The European Association of Urology (EAU) annually updates 21 clinical practice guidelines in which summaries of the evidence base and best practice recommendations are made. The methodology applied to achieve this and integrate stakeholder opinion is continuously improving. However, there is evidence to suggest wide variation in clinical practice indicating that many patients receive suboptimal and heterogeneous care. Studies from certain countries suggest that 2 out of 5 patients do not receive care according to the current scientific evidence, and in 1 out of 4 cases the care provided is potentially harmful. Clearly, the harmonisation of care in alignment with evidence-based best practice recommendations is something to strive for. Development of robust methods to disseminate and implement guideline recommendations and measure their impact is an objective the EAU is committed to improving. An important strategy for achieving harmonisation in urological care across Europe is to ensure the availability of high-quality clinical practice guidelines and to actively promote their implementation by clinicians and healthcare providers.
The “Molecularly Unstratified” Patient: A Focus for Moral, Psycho-Social and Societal Research
Authors: Hordern Joshua , Maughan Tim , Feiler Therese , Morrell Liz , Horne Rob , Sullivan Richard
Published: November 2017

The biomedical paradigm of personalised precision medicine - identification of specific molecular targets for treatment of an individual patient - offers great potential for treatment of many diseases including cancer. This article provides a critical analysis of the promise, the hype, and the pitfalls attending this approach. In particular, we focus on “molecularly unstratified” patients - those who, for various reasons, are not eligible for a targeted therapy. For these patients, hope-laden therapeutic options are closed down, leaving them left out, and left behind, bobbing untidily about in the wake of technological and scientific “advance.” This process creates a distinction between groups of patients on the basis of biomarkers and challenges our ability to provide equitable access to care for all patients. In broadening our consideration of these patients to include the research ecosystem that shapes their experience, we hypothesise that the combination of immense promise with significant complexity creates particular individual and organisational challenges for researchers. The novelty and complexity of their research consumes high levels of resource, possibly in parallel with undervaluing other “low hanging fruit,” and may be challenging current regulatory thinking. We outline future research to consider the societal, psycho-social and moral issues relating to “molecularly unstratified” patients, and the impact of the drive towards personalisation on the research, funding, and regulatory ecosystem.
Research Choices: Time for Europe to Decide
Authors: Horgan Denis , Harfelach Torsten , Ciliberto Gennaro
Published: November 2017

Taking real advantage of Europe's excellence in research to improve citizens' lives presents challenges that Europe's policymakers have not yet fully met. The EU has shown some clarity of assessment in recognising the needs, and some laudable determination to improve the situation, and it has intermittently taken some real steps to deliver on its ambitions to turn its research into valuable innovations. But Europe still faces harsh choices about whether it is actually going to do what it has so often discussed. The EU has to make some firm decisions about what research deserves support - and where. It must turn words into deeds to promote effective links between research and innovation. That requires a sharper focus on developing and retaining the right skill sets in Europe, on funding innovation, on creating an encouraging regulatory environment, and on building greater public understanding and engagement. Here, among other issues, the authors discuss where resources should be deployed, how to maximise the potential of personalised medicine, the time it takes for search to be turned into products ready for market, education, and the EU's regulatory role.
Pulling the Strands Together: MEGA Steps to Drive European Genomics and Personalised Medicine
Authors: Horgan Denis , Romao Mario , Hastings Rob
Published: November 2017

The increasing understanding of the genome is recognised as being one of the main determinants of future improvement in healthcare. The availability of genetic data from a large number of individuals increases the ability to investigate questions across many rare and common diseases and in different populations, and also provides more information for understanding clinical care outcomes for an individual. A number of large scale genome sequencing initiatives have been launched in the last few years to try and capitalise on this potential. Within Europe, the UK has led the way with the 100,000 Genomes Project. This project looks at the genome sequences of patients with rare diseases or cancer. More recently France announced plans to invest EUR 670 million in a genomics and personalised medicine programme. In the US, the Precision Medicine Initiative aims at large-scale research by gathering one million or more volunteers to extend precision medicine to all diseases. Meanwhile, China has announced plans to invest nearly USD 10 billion in its own precision medicine initiative. These projects demonstrate the commitment at a national level and raise the question “What benefits would be realised by undertaking a million genome initiative in a coordinated effort across European countries?” A coordinated, pan-European MEGA project would garner crucial genetic information that could have an immeasurable benefit when it comes to the health of current and future EU citizens.
The Long and the Short of Missing Medicines
Authors: Horgan Denis , Doeswijk Robin
Published: November 2017

Who would have thought that in the most recent decade of the 21st century, shortages of medicines would be on the rise? As the authors will show, it is not simply about price, but involves other factors such as sudden outbreaks of a disease or diseases, a lack of raw materials, manufacturing issues and high demand. Shortages of medicines can lead to higher costs and lower quality and safety of care, while unavailable medicines tend to be substituted with often less effective medicines, which can even be more costly. Possible solutions involve a monitoring of supply chains and “early warning” systems as well as Member States getting together to purchase medicines as a group. There is no single answer, and there is much work to be done.
The FDA Changed Everything
Authors: Geantă Marius , Cioroboiu Cosmina
Published: November 2017

On May 23, 2017, the FDA approved the first cancer treatment (pembrolizumab) for any solid tumor with a specific genetic biomarker: microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). For the first time in history, a solid cancer treatment was approved based on the genetic makeup of tumor not on the location in the body where the cancer originated, for example lung or breast cancer (TNM staging). This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer that has progressed following treatment with certain chemotherapeutics. All cancer drug approvals in the last 30 years were grounded on TNM staging independent of the therapy type (chemotherapy, monoclonal antibodies, TKI inhibitors, immune therapies or targeted therapies) and despite the huge and fast advances in understanding tumor biology. In fact, the FDA previously approved pembrolizumab taking into consideration the TNM staging, for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma. The archaic TNM staging will probably be changed under the disruptive wave of molecular biology. The recent FDA approval could be considered the certificate of birth for a truly new dimension of personalized medicine in cancer. We recommend European Union to follow the FDA approach of tissue-agnostic cancer drugs in order to speed up the development of next-generation oncologic therapies and to increase the access of patients to truly personalized medicine.
Keeping the Person in Personalised Healthcare
Authors: Horgan Denis
Published: November 2017

Proponents of personalised medicine believe that the involvement of the patients, including in “risk-sharing agreements,” will result in cost savings, the use of the genetic makeup of an individual patient as the starting point will save resources and, indirectly, there will be great potential for startups and new business in many areas. But how can Europe ensure that the “person” is central stage and allow us to focus on the development of personalised medicine for his or her ultimate benefit? The EU has a clear role to play, argues the author. One way for this to happen is for the EU to focus investment in guidelines for governance. This will go a long way to ensuring that the citizen is the principal factor when it comes to utilising the new wealth of innovation in health. The citizen must always come first when innovation is harnessed.
Long-Term Survival with Regorafenib in KRAS-Mutated Metastatic Rectal Cancer
Authors: Amram Marie-Laure , Montet Xavier , Roth Arnaud D.
Published: November 2017

Regorafenib, an oral multikinase inhibitor, was approved in September 2012 by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer progressing on standard therapies. Here, we describe the clinical history of a 63-year-old male patient who was treated with regorafenib in the pivotal CORRECT trial. The patient was initially diagnosed in November 2008 with nonmetastatic KRAS-mutated (exon 2, codon 12) rectal cancer. He underwent successful surgery and was treated with 5 cycles of adjuvant chemotherapy. In 2010, lung metastases (KRAS-mutated) were detected and the patient received 6 cycles of FOLFIRI plus bevacizumab. By January 2011, the metastases had progressed. The patient, who was asymptomatic with an Eastern Cooperative Oncology Group performance status of 0, was enrolled onto the CORRECT trial and received best supportive care plus regorafenib (160 mg once daily for 3 weeks of a 4-week cycle) over a period of 2 years, during which time the disease remained stable and the patient remained asymptomatic. Grade 1 anemia and thrombocytopenia were the only treatment-emergent adverse events reported. After receiving 26 cycles of regorafenib, a majority of the lung lesions progressed, and third-line palliative 5-fluorouracil, leucovorin, and oxaliplatin chemotherapy was administered. The patient died in May 2016.
Identification Systems and Their Legitimacy in the New Legislation on the Protection of Personal Data
Authors: Benes Vlastimil , Neuwirt Karel , Dostal Otto
Published: November 2017

In the new digital environment, citizens have the right to use tools to effectively control the usage of personal information related to them. Data protection is one of the fundamental rights in the EU guaranteed by the Charter of Fundamental Rights of the European Union. The article deals with the requirements that electronic identification system operators will have to take into account to ensure that the system in operation meets the requirements for the protection of personal data.
Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Calkins Hugh , Corrado Domenico , Marcus Frank
Published: November 2017

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. Although structural abnormalities of the right ventricle predominate, it is well recognized that left ventricular involvement is common, particularly in advanced disease, and that left-dominant forms occur. The pathological characteristic of ARVC is myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982, significant advances have been made in understanding this disease. Once the diagnosis of ARVC is established, the single most important clinical decision is whether a particular patient’s sudden cardiac death risk is sufficient to justify placement of an implantable cardioverter-defibrillator. The importance of this decision reflects the fact that ARVC is a common cause of sudden death in young people and that sudden death may be the first manifestation of the disease. This decision is particularly important because these are often young patients who are expected to live for many years. Although an implantable cardioverter-defibrillator can save lives in individuals with this disease, it is also well recognized that implantable cardioverter-defibrillator therapy is associated with both short- and long-term complications. Decisions about the placement of an implantable cardioverter-defibrillator are based on an estimate of a patient’s risk of sudden cardiac death, as well as their preferences and values. The primary purpose of this article is to provide a review of the literature that concerns risk stratification in patients with ARVC and to place this literature in the framework of the 3 authors’ considerable lifetime experiences in caring for patients with ARVC. The most important parameters to consider when determining arrhythmic risk include electric instability, including the frequency of premature ventricular contractions and sustained ventricular arrhythmia; proband status; extent of structural disease; cardiac syncope; male sex; the presence of multiple mutations or a mutation in TMEM43; and the patient’s willingness to restrict exercise and to eliminate participation in competitive or endurance exercise.
Evidence for a Role of Vascular Endothelium in the Control of Arterial Wall Viscosity in Humans
Authors: Roca Frederic , Iacob Michele , Remy-Jouet Isabelle , Bellien Jeremy , Joannides Robinson
Published: November 2017

Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO-synthase (
N
G
-monomethyl-
l
-arginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination. AWV was estimated from the relative viscosity expressed as the ratio of the area of the hysteresis loop of the pressure–diameter relationship to the area under the loading phase. Arterial tone was assessed by measuring change in wall stiffness and midwall stress.
N
G
-monomethyl-
l
-arginine paradoxically reduced relative viscosity (34.9±8.9%–28.9±8.6%). Conversely, relative viscosity was not modified by fluconazole (33.5±15.5%–32.0±13.6%) but increased by tetraethylammonium (31.7±6.6%–35.7±8.0%). This increase was more marked with
N
G
-monomethyl-
l
-arginine+fluconazole (31.1±10.7%–43.3±13.2%) and
N
G
-monomethyl-
l
-arginine+tetraethylammonium (29.5±2.3%–41.5±11.1%) compared with inhibitors alone. Sodium nitroprusside decreased AWV (35.4±2.9%–28.7±2.0%). These effects were associated with parallel change in tone but of different magnitude for similar variations in viscosity, suggesting tone-dependent and independent mechanisms. In conclusion, this is the first demonstration that the endothelial factors, NO and epoxyeicosatrienoic acids, regulate AWV in humans and support the role of arterial tone in this regulation.

Clinical Trial Registration—

URL:
https://eudract.ema.europa.eu
. Unique identifier: RCB2007-A001-10-53.
Confirmatory Tests for the Diagnosis of Primary Aldosteronism
Authors: Song Ying , Yang Shumin , He Wenwen , Hu Jinbo , Cheng Qingfeng , Wang Yue , Luo Ting , Ma Linqiang , Zhen Qianna , Zhang Suhua , Mei Mei , Wang Zhihong , Qing Hua , Bruemmer Dennis , Peng Bin , Li Qifu
Published: November 2017

The diagnosis of primary aldosteronism typically requires at least one confirmatory test. The fludrocortisone suppression test is generally accepted as a reliable confirmatory test, but it is cumbersome. Evidence from accuracy studies of the saline infusion test (SIT) and the captopril challenge test (CCT) has provided conflicting results. This prospective study aimed to evaluate the diagnostic accuracy of the SIT and CCT using fludrocortisone suppression test as the reference standard. One hundred thirty-five patients diagnosed with primary aldosteronism and 101 patients diagnosed with essential hypertension who completed the 3 confirmatory tests were included for the diagnostic accuracy analysis. The areas under the receiver–operator characteristics curves of the CCT and SIT were 0.96 (95% confidence interval [CI], 0.92–0.98) and 0.96 (95% CI, 0.92–0.98), respectively, using post-test plasma aldosterone concentration (PAC) for diagnosis. However, the areas under the receiver–operator characteristics curves of the CCT decreased to 0.71 (95% CI, 0.65–0.77) when the PAC suppression percentage was used to diagnose primary aldosteronism. The optimal cutoff of PAC post-CCT was set at 11 ng/dL, resulting in a sensitivity of 0.90 (95% CI, 0.84–0.95) and a specificity of 0.90 (95% CI, 0.83–0.95), which were not significantly different from those of SIT (with PAC post-SIT set at 8 ng/dL, sensitivity: 0.85 [95% CI, 0.78–0.91],
P
=0.192; specificity: 0.92 [95% CI, 0.85–0.97],
P
=0.551). In conclusion, both CCT and SIT are accurate alternatives to the more complex fludrocortisone suppression test. Because CCT is safe and much easier to perform, it may serve as a more feasible alternative. When interpreting the results of CCT, PAC post-CCT is highly recommended.
Cerebrovascular Reactivity and Vascular Activation in Postmenopausal Women With Histories of Preeclampsia
Authors: Barnes Jill N. , Harvey Ronée E. , Miller Kathleen B. , Jayachandran Muthuvel , Malterer Katherine R. , Lahr Brian D. , Bailey Kent R. , Joyner Michael J. , Miller Virginia M.
Published: November 2017

Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell–cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63±4 versus 73±3 cm/s;
P
=0.047) and during hypercapnia (
P
=0.013–0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1±1.3 versus 2.9±1.1 cm·s·mm Hg;
P
=0.009). Globally, the association of the 7 identified principal components with preeclampsia (
P
=0.107) and with baseline middle cerebral artery velocity (
P
=0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR (
P
=0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes (
P
=0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements.
Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor–Binding Protein)
Authors: Tassi Elena , Lai En Yin , Li Lingli , Solis Glenn , Chen Yifan , Kietzman William E. , Ray Patricio E. , Riegel Anna T. , Welch William J. , Wilcox Christopher S. , Wellstein Anton
Published: November 2017

Fibroblast growth factors (FGFs) participate in organ development and tissue maintenance, as well as the control of vascular function. The paracrine-acting FGFs are stored in the extracellular matrix, and their release is controlled by a secreted FGF-binding protein (FGF-BP, FGFBP1, and BP1) that modulates FGF receptor signaling. A genetic polymorphism in the human
FGFBP1
gene was associated with higher gene expression and an increased risk of familial hypertension. Here, we report on the effects of inducible BP1 expression in a transgenic mouse model. Induction of BP1 expression in adult animals leads to a sustained rise in mean arterial pressure by >30 mm Hg. The hypertensive effect of BP1 expression is prevented by candesartan, an angiotensin II (AngII) receptor antagonist, or by tempol, an inhibitor of reactive oxygen species. In vivo, BP1 expression sensitizes peripheral resistance vessels to AngII constriction by 20-fold but does not alter adrenergic vasoconstriction. FGF receptor kinase inhibition reverses the sensitization to AngII. Also, constriction of isolated renal afferent arterioles by AngII is enhanced after BP1 expression and blocked by FGF receptor kinase inhibition. Furthermore, AngII-mediated constriction of renal afferent arterioles is abolished in FGF2
−/−
mice but can be restored by add-back of FGF2 plus BP1 proteins. In contrast to AngII, adrenergic constriction is not affected in the FGF2
−/−
model. Proteomics and gene expression analysis of kidney tissues after BP1 induction show that MAPK (mitogen-activated protein kinase) signaling via MKK4 (MAPK kinase 4), p38, and JNK (c-Jun N-terminal kinase) integrates the crosstalk of the FGF receptor and AngII pathways and thus impact vascular tone and blood pressure.