Designed methodology framework.
\r\n\tAbout 25 percent of all foods produced globally are lost due to microbial growth. L. monocytogenes is a microorganism ubiquitously present in the environment and affects animals and humans. L. monocytogenes can enter a factory and is able to survive in biofilms in the food processing environment. The use of adequate sanitation procedures is a prerequisite in risk prevention. Moreover, effective control measures for L. monocytogenes are very important to food operators.
\r\n\r\n\tThe safety and shelf life maximizing of food products to meet the demand of retailers and consumers is a challenge and a concern of food operators.
\r\n\r\n\tTo obtain food systems more sustainable, several developments are ongoing to ensure safe food products with an extended shelf life and a reduction of food loss and waste. The problem of antimicrobial resistance is also a great issue that must be taken into consideration.
\r\n\r\n\tThe implementation of natural antimicrobials, using food cultures, ferments, or bacteriophages, is one approach to control L. monocytogenes in food products that meet the consumer preference for clean label solutions.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art about Listeria monocytogenes in terms of occurrence in humans, animals, and food-producing plants. Its control by more natural agents allows for more sustainable food systems and points future directions to transform challenges into opportunities.
Process performance measurement tools and techniques applied to enterprise environments are essential for enterprise continuous improvement. It is the reason why the next generation of process management leads to Process Performance Management or Corporate Performance Management. The phrase Corporate Performance Management (CPM) was coined by Gartner Group to describe the combination of process, methodologies, metrics and technologies to measure, monitor and manage the performance of the business. The oft-citied phrase: “
This chapter deals with presentation way leads to establishment of efficiency system for process measurement and controlling in the manufacturing area. The process measurement can be defined as the application of the management cycle with a focus on organizational process. Muehlen present process management as the collection of planning, organizing and controlling activities for the goal-oriented management of the organization’s value chain regarding the factors quality, time, cost and customer satisfaction (Muehlen, 2004). The main goals of process management are the achievement of transparency with regard to process structure and process contribution.
\n\t\t\tThe description and practical application of process performance management system will be presented in case study. The case study also presents exploitation of data from an enterprises information system for decision–making is next point of this chapter.
\n\t\tThe process controlling has been discussed in the published books and papers in scientific journal (Shen, 2007) and (Aalst, 2007). A. Kronz presents principal tasks of process controlling in book (Scheer, 2006). He mentioned these points:
\n\t\t\tEvaluation, analysis and continues monitoring of business workflows (automatically or manually),
Map the process reality in a task-oriented manner according to the issue and task.
Result of process controlling is transparency of the process, in structural terms and for purpose of evaluation,
Results can also be used as the basepoint for process optimization.
Next author Michael zur Muehlen discusses in his book (Muhlen, 2004) of the workflow audit trail data with existing data warehouse structures and develops a reference architecture for process-oriented information system.
\n\t\t\tThe term of process controlling has been often discussed in relation to process management, because implementation of business process management is a way how to achieve of process performance management system establishment. The “Process Management and “Business Process” are contemporary terms used in the many companies. Many successful companies applied this management approach based on Hammer’s Business Process Reengineering Concept (Hammer, 1993). The authors develop the Hammer’s and Champy ideas in related works nowadays.
\n\t\t\tMany articles in journals and international conferences proceedings deal with BPM issue. High number of citations on business process management (BPM) seems to prove that BPM is a significant field of the recent research (Harmon, 2008). For example a Google.com search on „Business Process Management“ returns more than fourteen thousand pages where this phrase appears. The BPM issue is the subject of research focused on methodological or technological solution of BPM problems (Weske, 2007). The main problems are described by Wasana Bandara in article (Bandara, 2007), where fourteen global experts were interviewed for example. The problems examples show the lack of governance, lack of standards, lack of methodology, lack of tool support for process visualisation etc.
\n\t\t\tThe main principles of process measurement system are described by the authors and many authors discuss about phrase Corporate Performance Management. The phrase Corporate Performance Management (CPM) was coined by Gartner Group to describe the combination of process, methodologies, metrics and technologies to measure, monitor and manage the performance of the business. Prof A. W. Scheer discusses this issue and trends of CPM in his book (Scheer, 2006).
\n\t\t\tCPM is thus directed at continues monitoring of the effectiveness of the results of all company processes and the constant optimization thereof, i.e. its objective is a monitoring system that monitors the business performance of all pertinent business processes all the time, detects and reports weaknesses and problem situations, ideally even suggests optimization option and evaluates the success of improvement measures. Substantive recommendations for actions, including their chances of success, are needed so that the better decisions can be made more quickly. Process Performance Management may be regarded as the heart of CPM. (Scheer, 2006)
\n\t\t\tThe present trends in Corporate Performance Management are:
\n\t\t\tProcess mining for automated weak point analysis
Right time monitoring
Dynamic organizational analysis
These trends describe the purpose of application of process controlling in the manufacturing area. The application of process controlling based on process management principles for technological and diagnostics process control is one objective of our research. The main objectives of our research are design and verification of a control system based on business process management approach for control of process in the diagnostics and the electrical engineering and electronics manufacturing. In the following case study, I shall describe the practical demonstration of process controlling application.
\n\t\tDesigned methodology concept helps to implement the process performance measurement system based on process controlling. The concept has been developed into two steps:
\n\t\t\t\tAnalysis of processes and current needs of responsible managers, staffs, researchers and technicians. The designed questionnaires can be used in this step. We have obtained process attributes of key processes.
Study, selection and modification of suitable methods and tools for business process management and performance measurement.
The application of designed methodology is demonstrated on case study. Data collection for this case study was conducted these different techniques:
\n\t\t\t\tQuestionnaire – This method was used for process analyses and mapping of process attributes. The main problems were done via structured question to management and workers.
Participation/Observation – The researches were able to observe and processes in operation and validate recorded data.
Interview – This method enabled the collection information of management vision and requirements.
Methodology framework is presented by Table 1. As we can see the table presents key steps and activities in defined order. The methodology concept is based on business process and process performance management theory. It means application of Business Process
\n\t\t\t\tStep | \n\t\t\t\t\t\t\tActivities | \n\t\t\t\t\t\t\tOutput | \n\t\t\t\t\t\t
Business strategy definition | \n\t\t\t\t\t\t\tAnalysis of current situation Definition of mission, vision and strategic goals. | \n\t\t\t\t\t\t\tStrategy are defined | \n\t\t\t\t\t\t
Process design | \n\t\t\t\t\t\t\tImplementation of process modeling methodology Process models making Definition of main optimization criteria Process optimization | \n\t\t\t\t\t\t\tProcesses are designated. | \n\t\t\t\t\t\t
Process Controlling Implementation and Indicators Setup | \n\t\t\t\t\t\t\tDesign of process measurement and execution system Determination of periodicity of process measurement Implementation of tools for process measurement, execution and evaluation Design of system for correction proposal and improvement | \n\t\t\t\t\t\t\tSystem for process evaluation and execution of processes is implemented. \n\t\t\t\t\t\t\t\t Improvement system is defined. | \n\t\t\t\t\t\t
Designed methodology framework.
Management in first step. This step leads to:
\n\t\t\t\tprocess analysis and key process indicators setup
process description, modeling and optimization,
system of evaluation and process execution.
The information infrastructure can be applied for the methodology support. The information structure should be built on Service Oriented Architecture (SOA) which provides methods for systems development and integration where systems group functionality around business processes and package these as interoperable services. SOA also describes IT infrastructure which allows different applications to exchange data with one another as they participate in business processes. Service-orientation aims at a loose coupling of services with operating systems, programming languages and other technologies which underlie applications.
\n\t\t\tThe current management literature presents different methods for process performance management. Firstly, they are methods based on financial analysis of basic enterprise economic indicators (for example Economic Added Value measurement, DuPont analysis). Secondly, they are management methods used the financial and non financial indicators (typically represented by Balanced Scorecard method (BSC), EFQM model, Six Sigma, Value Based Management). The Balanced Scorecard method sophisticated presents how to define and implement the key process indicators and metrics for performance evaluation. Many companies have adopted Balanced Scorecard as a way of evaluating managerial performance.
\n\t\t\t\tThis methods supplements traditional financial measures with three additional perspectives: the customers, the internal business process and the learning and growth perspective. It is supposed to be a tool describing an organization’s overall performance across a number of measures on a regular basis.
\n\t\t\t\tThe basic idea is very straight forward. Kaplan and Norton began by arguing that "What you measure is what you get" and that "an organization\'s measurement system strongly affects the behaviour of managers and employees." They went on to say that "traditional financial accounting measures, like return-on-investment and earning-per-share, can give misleading signals for continuous improvement and innovation..." To counter the tendency to rely too heavily on financial accounting measures, Kaplan and Norton argued that senior executives should establish a scorecard that takes multiple measures into account. They proposed a Balanced Scorecard that considered four types of measures:
\n\t\t\t\tFinancial Measures: How Do We Look to Shareholders?
Internal Business Measures: What Must We Excel At?
Innovation and Learning Measures: Can We Continue to Improve and Create Value?
Customer Measures: How Do Customers See Us?
The BSC method gives a definition of strategy as hypothesis summary about causes and results. It can be declared as a sequence of “if – then”. The BSC, proposed by Kaplan and Norton, is the strategic management instrument:
\n\t\t\t\tto clarify and translate vision and strategy,
to communicate and link strategic objectives and measures,
to plan, set goals and align strategic initiatives,
to enhance strategic feedback and learning.
The case study is focused on printed circuit board production. This production is one part of our department and its customers are other universities departments and small companies from the Pilsen region. The objective was to establish the performance measurement system focused on process time measurement and real processes current status analysis. This case study also presents application of designed methodology.
\n\t\t\tDefinition of core problem and strategy of company was first task. The core problem of visualization was effectively solved by the Current Reality Tree (CRT). This chart shows causality of relevant undesirable effects of the analyzed situation. The practical example is shown in Fig. 1. The main problem is fall of profit related to production time, capacity and quality of process. On the other hand this situation might be described by a conflict diagram (Fig. 2). The diagram describes decision and optimizing problem of manufacturing - determination of optimum batch size.
\n\t\t\t\tThe conflict exists between increasing and decreasing of the batch size. The increasing of production run (D) makes to cost reduction (B) and decreasing (D) of the batch size makes to high quality of products (C). Both described situations have negative effect on the
\n\t\t\t\tCurrent problem of causality.
Conflict diagram of company.
production plan and profit. These problems and conflict were solved by designing methodology effectively. So cost reduction, quality improvement and time reduction were the main optimizing criteria according to methodology.
\n\t\t\t\tSecondly, the business strategy and main key process indicators were developed according to Balanced Scorecard. The Table 2 shows process indicators and the strategy is describes in ARIS model (Fig. 3). From this model we can make performance dynamic execution (it is part of last step methodology implementation).
\n\t\t\t\tARIS model of Balanced Scorecard business strategy.
Process indicators | \n\t\t\t\t\t\t\tStaffs Satisfaction | \n\t\t\t\t\t\t\tInternal Productivity | \n\t\t\t\t\t\t\tCustomer Satisfaction | \n\t\t\t\t\t\t\tTraining Course | \n\t\t\t\t\t\t\tFail- ures | \n\t\t\t\t\t\t\tROI | \n\t\t\t\t\t\t\tProcess Time | \n\t\t\t\t\t\t\tProcess Costs | \n\t\t\t\t\t\t
Unit | \n\t\t\t\t\t\t\t[%] | \n\t\t\t\t\t\t\t[-] | \n\t\t\t\t\t\t\t[%] | \n\t\t\t\t\t\t\t[number] | \n\t\t\t\t\t\t\t[number] | \n\t\t\t\t\t\t\t[-] | \n\t\t\t\t\t\t\t[min] | \n\t\t\t\t\t\t\t[EUR] | \n\t\t\t\t\t\t
Minimal Value | \n\t\t\t\t\t\t\t75 | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\t80 | \n\t\t\t\t\t\t\t1 | \n\t\t\t\t\t\t\t95 | \n\t\t\t\t\t\t\t4 | \n\t\t\t\t\t\t\t24 | \n\t\t\t\t\t\t\t40 | \n\t\t\t\t\t\t
Maximal Value | \n\t\t\t\t\t\t\t100 | \n\t\t\t\t\t\t\t4 | \n\t\t\t\t\t\t\t100 | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\t100 | \n\t\t\t\t\t\t\t8 | \n\t\t\t\t\t\t\t72 | \n\t\t\t\t\t\t\t60 | \n\t\t\t\t\t\t
Tolerance | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t
Period | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t\tQ | \n\t\t\t\t\t\t
Planned Value | \n\t\t\t\t\t\t\t95 | \n\t\t\t\t\t\t\t3 | \n\t\t\t\t\t\t\t90 | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\t99 | \n\t\t\t\t\t\t\t5 | \n\t\t\t\t\t\t\t48 | \n\t\t\t\t\t\t\t50 | \n\t\t\t\t\t\t
Current Value | \n\t\t\t\t\t\t\t95 | \n\t\t\t\t\t\t\t1,5 | \n\t\t\t\t\t\t\t85 | \n\t\t\t\t\t\t\t2 | \n\t\t\t\t\t\t\t98 | \n\t\t\t\t\t\t\t5,3 | \n\t\t\t\t\t\t\t75 | \n\t\t\t\t\t\t\t75 | \n\t\t\t\t\t\t
Strategic indicators.
The process analysis and process modelling was the first important steps lead to process design. It contained following activities:
\n\t\t\t\tdefinition of the process model and attributes. It means determination of targets, key processes fragments, key performance indicators (KPI) and their dimensions,
processes fragment modelling (Fig. 5).
Core process model of PCB production.
The ARIS (Architecture of Integrated Information System) tools and process analyses were used in this part. The main problem was fall of profit related to production time, capacity and quality of the process. Due to this fact, the process controlling application based on CPM leads to this core problem minimization.
\n\t\t\t\tModel of process fragment.
We decided use the ARIS Process Performance Manager (ARIS PPM) software tool for process controlling in this case, because this tool can be implemented to any information system and structure. The information technologies make the important support for business process management nowadays. Owing to the fact that we are using tools ARIS for process modeling and optimization of processes, we decided to use the software ARIS PPM.
\n\t\t\t\tWith ARIS Process Performance Manager, IDS Scheer company offers a software solution that is a purpose-built for controlling and analyzing business processes. As a part of this solution, a patented procedure is used to collect process relevant data from the operational IT systems available for reconstructs process automatically and calculates key performance indicators online and particularly for presenting the actual process measurement in the form of event-driven process chains (eEPC).
\n\t\t\t\tARIS PPM imports all business transactions to be reviewed into the repository from one or more source systems via application-specific adapters. To begin with, depending on the source system, the process-relevant runtime information about the activities performed is highly disparate in nature (e.g. log files, vouchers, records). These are imported one after the other in chronological order by ARIS PPM and compiled into a process. A graphical illustration – the “event-driven process chain” (EPC) - containing all the individual activities (functions) are then generated automatically for each operation (process instance) – see Figure 8. As a result, even a process that extends beyond the boundaries of a single system can be represented cohesively and uniformly.
\n\t\t\t\tThe ARIS Process Performance Manager tool has these important functions for Process Performance Management:
\n\t\t\t\tVisualizing Real Process Structure
Key Performance Indicators and Analyses
Process documents
Weak Point Analysis
Process Mining: Automated Weak Point Analysis
Management Views
Offline Reports
Key process indicator | \n\t\t\t\t\t\t\tType | \n\t\t\t\t\t\t\tCategory | \n\t\t\t\t\t\t\tDescription | \n\t\t\t\t\t\t
Interval of order processing | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tProcess duration from an order acceptance till issue of an invoice. | \n\t\t\t\t\t\t
Interval of acceptance of an order | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tSub process duration: “Receipt of order”. | \n\t\t\t\t\t\t
Interval of PCB design | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tSub process duration: “Design of PCB”. | \n\t\t\t\t\t\t
Interval of manufacturing preparation | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tSub process duration: “Manufacturing data preparation”. | \n\t\t\t\t\t\t
Interval of PCB manufacturing | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tSub process duration “Manufacturing of PCB. | \n\t\t\t\t\t\t
Interval of PCB expedition | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tSub process duration: “PCB expedition”. | \n\t\t\t\t\t\t
Interval of invoice issue | \n\t\t\t\t\t\t\tProcess | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tSub process duration: “Issue invoice”. | \n\t\t\t\t\t\t
Activity process time | \n\t\t\t\t\t\t\tFunction | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tDifference between the end of current activity (process) and the end of previous activity. | \n\t\t\t\t\t\t
Processing time of an activity | \n\t\t\t\t\t\t\tFunction | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tDifference between the end of activity and the start of a particular activity. | \n\t\t\t\t\t\t
Idle time of activity | \n\t\t\t\t\t\t\tFunction | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tDifference between the start of an activity and the end of previous activity. | \n\t\t\t\t\t\t
Keeping the order term | \n\t\t\t\t\t\t\tFunction | \n\t\t\t\t\t\t\tTime | \n\t\t\t\t\t\t\tDifference between planned and real order completion date. | \n\t\t\t\t\t\t
Key process indicators definitions.
The basis for all processes controlling is a process-oriented key performance indicator system that links the process perspective to the essential controlling aspects for business. The key performance indicators must enable conclusions to be drawn regarding the effectiveness of the processes (e.g. customer satisfaction) and their efficiency (e.g. processing time, delivery reliability, process quality and costs). In addition, the process-oriented key performance indicator system is configured so that it would be possible to make statements about the actual course of the process.
\n\t\t\t\tPre-configured process key performance indicators are calculated and aggregated for each imported process stage. The ARIS PPM base system already includes a core set of key performance indicators, and these are set as default ones regardless to a connected source system. The key performance indicator types can be divided into 3 groups:
\n\t\t\t\ttime-related key performance indicators (e.g. throughput times, processing times, frequencies),
cost-related key performance indicators (e.g. process costs/rates on the basis of the performance standard) and
quality-related key performance indicators (e.g. number of processors, error rates, deadline reliability)
The process owner can use ARIS PPM to achieve the optimum balance in the ”Time-Quality-Cost” magic triangle by taking a number of key performance indicators from each of the three ranges with added weighting and thus to yield a new key performance indicator. These user-defined key performance indicators can be set in the front-end at any time during runtime. Besides the preset key performance indicators, other specific key performance indicators are configured in the ARIS PPM base system as a part of the adaptation to the customer individual environment.
\n\t\t\t\tThese are defined, for instance, by the process types to be reviewed. The key performance indicators in ARIS PPM are endowed with process-relevant decision variables - ”dimensions”. These dimensions are also imported from the source systems as features of the individual process instances. The user evaluates the efficiency of his business processes with reference to the interplay between key performance indicators and dimensions in the process analysis.
\n\t\t\t\tThe set of key performance indicators must be calculated and defined flexibly, and in such a way that it can be expanded to the need of changing requirements of the company specific processes. Besides calculating key performance indicators, it is also necessary to be able to visualize the structure of actual processes since, it is the only way to how obtain generalized explanations for their performance behaviour.
\n\t\t\t\tThe implementation of ARIS PPM tool has been formulated in project. The project main phases were:
\n\t\t\t\tImplementation for printed circuit board manufacturing.
Verification and validation of results from implementation for PCB manufacturing.
Implementation for diagnostic process control.
Verification results and examination implementation proposal.
The first two phases were realized in following steps:
\n\t\t\t\tConceptual and technical workshop
Determination of process instance, fragments, KPI and process attributes. The results of process mapping and analysis from previous part were used in this step. The Table 3 presents used KPI.
The SW tool implementation means installation, customizing and connectivity settings. The manufacture section does not use information system now and data must be recorded on operation record cards. Due to this fact, we had to prepare the special software for CSV files generation and rewrite the data into SW ARIS PPM database using PC. Validation of results and their definition is last step of implementation.
\n\t\t\tFirst experience of PPM implementation, based on CPM idea, has shown benefits of this solution in the manufacturing area for technological process control, in this case for printed circuit board manufacturing. The SW tool ARIS PPM helps us to make analysis and processes monitoring, particularly:
\n\t\t\t\treal process course,
processes time,
comparing of the real and planned key indicators value,
type and kind of order.
The results of process mining and analysis have been used for process models correction and KPI planning. In short, the responsible management obtains quick management and performance view (see Fig. 7, 8).
\n\t\t\t\tThe solution mentioned above doesn’t use sophisticated information system. In this phase the data about process has been collected in excel files. The records from the paper sheet in manufacture section had to be rewritten to ARIS PPM database. In consequence of this we had to realize software for data converting from excel database to ARIS PPM database (CSV data format was used for this converting operation). It is obvious that this way isn’t suitable for big data volume. From this reason, the suitable information system has to be implemented in the next project phase. The structure and components of used information system presents Fig. 9.
\n\t\t\t\tManagement view.
Visualization of a process instance generated in ARIS PPM.
Information system structure.
This chapter presents an example of process controlling application. Process controlling described in this paper, comprises the following components:
\n\t\t\tEvaluation of the efficiency of business processes based on key performance indicators
Transparent representation of procedures actually performed for cause analysis.
Deduction of optimization measures.
Continuous monitoring of success developments.
Organizational analysis.
The process controlling is very important tool for process improvement in manufacturing area. The real application in manufacturing area was described in the practical case study focus on the small printed circuit board production. The case study describes way how to analyze the processes and introduces software tools, which have been applied. The benefits and results are documented in the Figures 7-8 as well.
\n\t\t\tThis solution corresponds with the new trend in process management area. Companies that are able to align their business processes to the requirements of their environment and surroundings will not only gain a competitive advantage, but they will also be able to manipulate this alignment better and faster than their competitors. The prerequisites for this solution are the supply of decision-relevant information and an ability to transform this information quickly and effectively into sustained measures for targeted alignment of business processes.
\n\t\tThis research is supported by the research plan MSM4977751310 “Diagnostic of interactive processes in electrical engineering“.
\n\t\tAntiphospholipid syndrome (APS) was first described in 1983 with steadily improving clinical and scientific refinements since that time. It was initially recognized with the discovery of lupus anticoagulant immunoglobulin that binds to phospholipids and proteins associated with the cell membrane and its association with other autoimmune conditions. Over the years, the clinical manifestations of APS were further delineated, followed by the discovery of other antiphospholipid antibodies. Currently, APS is defined as an autoimmune condition characterized by the presence of venous or arterial thrombosis and/or pregnancy-related complications in patients with antiphospholipid antibodies [1]. Notably, APS can occur as a
Clinically, APS can manifest in a variety of ways and affect multiple organ systems. Presenting symptoms can range from relatively benign to severe. One subtype (to be discussed in Section 2) termed catastrophic APS (CAPS) is defined as APS that affects >3 organs in a short period of time (<7 days) with pathologic evidence of small-vessel occlusion. The most common venous manifestation of APS is deep vein thrombosis, while stroke is the most common arterial manifestation of this disease [4]. Obstetric complications include placental insufficiency and recurrent pregnancy loss, typically after 10 weeks of gestation. There are, however, a multitude of other manifestations including cardiac valvular disease, coronary artery disease, livedo reticularis, renal small artery vasculopathy, and thrombocytopenia, which are
Antiphospholipid antibodies (aPL) are a serological marker for APS and their presence is key to the definition and classification for APS. Phospholipids are molecules found in the blood that aid in clot formation. They form complexes with other plasma proteins and are the target of aPL antibodies; thus, one may expect to clinically see a bleeding disorder when phospholipids are disrupted. However, these autoantibodies primarily cause endothelial dysfunction and disruption of coagulation factors as they compete with coagulation factors for available phospholipids, thereby leading to a procoagulant state and clot formation [6]. The pathophysiology of aPL antibodies is not fully elucidated, but the current thought is that of a “two-hit” hypothesis. The first hit being a patient-specific susceptibility, and the second hit being a trigger or inciting event. This theory is based on the idea that about 1–5% of the population may have positive aPL antibodies without any clinical manifestations, indicating the need for a trigger that leads to the pathologic state [2, 4]. In a patient carrying aPL antibodies, endothelial cell activation occurs in the setting of oxidative stress in conditions such as infection, surgery, and pregnancy. This is thought to subsequently lead to a series of events including complement activation, cytokine release, increased expression of tissue factor on endothelial cells, increased platelet adhesiveness, and impairment of thrombolysis [2, 4]. Overall, this creates a procoagulant state leading to the range of clinical manifestations as described.
aPL antibodies are a heterogeneous group of autoantibodies that primarily include
There are a variety of antiphospholipid antibodies associated with APS, as detected with different methods, some are overlapping, but each has distinct properties. Image adapted from Misita et al. [
The presence of LA alone is thought to hold the highest risk for thrombosis among all antiphospholipid antibodies. Thrombotic risk is much lower in patients who have only a positive aCL or anti-B2GPI antibody [1, 3]. The risk is thought to be much higher however in patients with multiple positive antibodies, especially those found to be “triple positive” [3]. Thrombotic risk is also much higher in patients who have secondary APS is associated with SLE and in patients with primary APS with concurrent vascular comorbidities including hypertension, hypercholesterolemia, tobacco, and oral contraceptive use [7].
The initial classification criteria for APS, called the Sapporo criteria, was first developed in 1999 and most recently updated in 2006 [1]. As shown in Table 1, the criteria currently require one clinical manifestation of thrombosis or pregnancy complication, and one laboratory criteria present on two occasions at least 12 weeks apart.
Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria that follow arc met* clinical criteria |
1. Vascular thrombosis† One or more clinical episodes‡ of arterial, venous, or small vessel thrombosis§, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. |
2. Pregnancy morbidity
|
Laboratory criteria** 1. Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies) [10, 11]. |
2. Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in scrum or plasma, present in medium or high titer (i.e. >40 GPL or MPL, or >the 99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA. |
3. Anti-β2 glycoprotein-I antibody of IgG and/or IgM isotype in scrum or plasma (in titer > the 99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures. |
The classification criteria for APS [1].
Classification of APS should be avoided if less than 12 weeks or more than 5 years separate the positive aPL test and the clinical manifestation.
Coexisting inherited or acquired factors for thrombosis arc, not reasons for excluding patients from APS trials. However, two subgroups of APS patients should be recognized, according to (a) the presence, and (b) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) such eases include: age (>55 in men, and >65 in women), and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index ≥30 kg m–2, microalbuminuria, estimated GFR < 60 ml min−1), inherited thrombophilias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus, patients who fulfill criteria should be stratified according to contributing causes of thrombosis.
A thrombotic episode in the past could be considered as a clinical criterion, provided that thrombosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of thrombosis is found.
Superficial venous thrombosis is not included in the clinical criteria.
Generally accepted features of placental insufficiency include: (i) abnormal or non-reassuring fetal surveillance test(s), e.g. a non-reactive non-stress test, suggestive of fetal hypoxemia, (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, e.g. absent end-diastolic flow in the umbilical artery, (iii) oligohydramnios, e.g. an amniotic fluid index of 5 cm or less, or (iv) a postnatal birth weight less than the 10th percentile for the gestational age.
Investigators arc strongly advised classifying APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination): IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-β2 glycoprotein-I antibody present alone.
As mentioned, there are other autoantibodies implicated in APS that are not yet included in the classification criteria. The remainder of this chapter will discuss the clinical manifestations, epidemiology, pathophysiology, diagnosis, and treatment in more detail.
APS can present as a wide range of clinical manifestations with the major clinical features consisting of arterial and venous thromboses, and obstetrical complications. The most common obstetrical manifestations of APS are recurrent early miscarriage, placental insufficiency, early pre-eclampsia, and fetal death, all of which should prompt evaluation for the presence of aPL [12].
Thrombotic events in APS may occur in virtually any vascular bed, with the cerebral circulation being the arterial territory most commonly affected, usually in the form of stroke or transient ischemic attack [13]. APS has also been associated with many other clinical features including livedo reticularis, epilepsy, thrombocytopenia, and cognitive dysfunction, however, the strength of association is not sufficiently high to include them in the syndrome definition. The clinical characteristics of a cohort of 1000 patients with APS (Euro-Phospholipid Project) are displayed in Table 2 [14].
As described in Section 1, the first set of criteria for APS was established in Sapporo, Japan in 1999 after an expert workshop [9]. This was modified, including the addition of anti-β2GPI antibodies in Sydney, Australia in 2006. The revised APS classification criteria strongly recommend investigating coexisting inherited and acquired thrombosis risk factors in patients with APS [1]. A recent assessment of the 2006 revised APS classification criteria has shown that only 59% of the patients meeting the 1999 APS Sapporo classification criteria met the revised criteria [15]. In addition, many of the older studies evaluated for only a few of the specific aPL antibodies now thought to be important in stroke risk, accepted low positive titers and many looked at only one-time point, hence it is difficult to apply the results of those studies [16]. While the purpose of the criteria was to help choose patients for clinical trials, it is the best available tool to avoid over-diagnosis of APS in clinical practice [17].
CAPS is a rare and potentially fatal complication of APS. As described in Table 3, the clinical presentation is characterized by acute multi-organ failure due to thromboses of three or more organs within 1 week, associated with the presence of aPL and thrombocytopenia [16]. CAPS can be seen as the first presentation of APS or can be triggered by infection, surgery, or trauma in patients with known APS [19].
Manifestation | No. (%) of patients |
---|---|
Deep vein thrombosis | 389 (38.9%) |
Other peripheral thrombi | 248 (24.8%) |
Migraine | 202 (20.2%) |
Stroke | 198 (19.8%) |
Transient ischemic attack | 111 (11.1%) |
Epilepsy | 70 (7.0%) |
Multi-infarct dementia | 25 (2.5%) |
Chorea | 13 (1.3%) |
Acute encephalopathy | 11 (1.1%) |
Transient amnesia | 7 (0.7%) |
Cerebral venous thrombosis | 7 (0.7%) |
Cerebellar ataxia | 7 (0.7%) |
Transverse myelopathy | 4 (0.4%) |
Hemiballismus | 3 (0.3%) |
Pulmonary embolism | 141 (14.1%) |
Other pulmonary manifestations | 56 (5.6%) |
Valve thickening/dysfunction | 116 (11.6%) |
Other cardiac manifestations | 153 (15.3%) |
Renal manifestations | 27 (2.7%) |
Gastrointestinal manifestations | 42 (4.2%) |
Livedo reticularis | 241 (24.1%) |
Other cutaneous manifestations | 155 (15.5%) |
Arthralgia | 387 (38.7%) |
Other osteoarticular manifestations | 295 (29.5%) |
Amaurosis fugax | 54 (5.4%) |
Other ophthalmological manifestations | 34 (3.4%) |
8 (0.8%) | |
Thrombocytopenia | 296 (29.6%) |
Hemolytic anemia | 97 (9.7%) |
Preeclampsia | 56 (9.5%) |
Other obstetric manifestations | 41 (7.1%) |
Live birth | 753 (47.7%) |
Other fetal manifestations (fetal loss, premature births) | 827 (52.3%) |
Cumulative clinical features during the evolution of the disease in 1000 patients with APS (adapted [14]).
1. Evidence of involvement of three or more organs, systems, and/or tissues. |
2. Development of manifestations simultaneously or in less than a week. |
3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue. |
4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, and/or anti-beta2-glycoprotein I antibodies). |
Requires all four criteria |
All four criteria, except for only two organs, systems, and/or sites of tissue involvement |
All four criteria, except for the laboratory confirmation at least six weeks apart due to the early death of a patient never tested for aPL before the catastrophic APS |
Criteria 1, 2, and 4 above |
1, 3, and 4 and the development of the third event in more than a week but less than a month, despite anticoagulation. |
In the setting of pregnancy, Obstetric APS (OAPS) is diagnosed if at least one of the clinical criteria and one of the laboratory criteria are met as outlined in Table 4 [1, 20].
Clinical criteria | Laboratory criteria |
---|---|
|
|
Although up to 5% of the population might be positive for aPL antibodies, only a small fraction is diagnosed with APS as per the mentioned criteria [21]. Based on the analysis of 120 full-text papers, the overall estimated aPL frequency in stroke patients of all ages is 13.5% [22]. Sciascia et al. [7], in a systematic review of data from 5217 patients concluded that the overall aPL frequency was estimated as 17.2% for stroke and 11.7% for the transient ischemic attack, and the presence of aPL seems to confer a five-fold higher risk for stroke or TIA when compared with controls. The cumulative prevalence in the Euro-Phospholipid Project Study was 19.8% for stroke and 11.1% for TIA [14], making it the most common and severe arterial complication of APS.
Notably, it has been suggested that more than 20% of strokes in patients younger than 45 years are associated with APS [23], although this estimate may be inflated by referral bias [24]. The presence and magnitude of the ischemic stroke risk associated with aPL in the older population are more evenly split between finding an increased risk and no increased risk. This suggests that aPL may be a more important stroke mechanism in young people whereas, in older populations, other stroke risk factors take on a greater importance.
aPL associated strokes pose a higher risk for women. The Framingham cohort and offspring study found an increased risk of strokes and TIAs for women with high anticardiolipin but not in men [25]. In another study of 34 women under 45 years of age with ischemic strokes and no traditional vascular risk factors, 35% were found to have anticardiolipin antibodies [26].
Another study demonstrated that high serum concentrations of aPL, regardless of other cardiovascular risk factors, were an important predictor of the risk of future stroke and TIA in only females [27]. The presence of anti-β2GP1 antibodies in young women may increase the stroke risk 2.3-fold according to the RATIO study [28].
In terms of traditional vascular risk factors in APS patients, it is debated whether these or the circulating aPL antibodies are responsible for the accelerated atherosclerosis seen in APS. Hypertension is more prevalent in SLE and APS than in the general population. A study showed that hypertension was the only independent risk factor for arterial manifestations, mainly stroke, in APS [29]. The risk of stroke for LA-positive patients was two-fold in smokers and six-fold in smokers receiving oral contraceptives [25]. The Italian Project on Stroke in Young Adults, a prospective study of 1867 patients showed that family history of strokes, migraines with auras, aPL, discontinuation of antiplatelet or antihypertensive medications and increase in at least one traditional vascular risk factor were independent predictors for thromboembolic events [30]. Overall, this emphasizes the importance of aggressively treating all modifiable stroke risk factors like hypertension, diabetes, hypercholesterolemia, obesity, OCP use, and tobacco use to reduce additional thrombotic risks.
A summary of factors that warrant an evaluation of APS in stroke patients is listed in Table 5.
Patient age < 50 years of age |
Female gender |
Lack of traditional vascular risk factors |
Positive family history for arterial or venous thromboses |
Recurrent strokes |
Thrombocytopenia, obstetric complications, venous thromboses, or other arterial thromboses |
SLE or presence of other connective tissue diseases |
Key factors warranting evaluation of antiphospholipid syndrome.
Stroke subtypes in APS may be either thrombotic or cardioembolic depending on the location and size of the occluded vessel [31]. Intracranial stem or branch arterial occlusions and stenosis were reported in 50% of APS patients with stroke [32]. Narrowing of multiple intracranial arteries may occur in APS and indicates vasculopathy rather than vasculitis. Occasionally, there is involvement of the extracranial carotid artery. In a small case series of 17 patients, 32% had extracranial arterial abnormalities [33]. Cardioembolic strokes in APS are associated with left cardiac valvular abnormalities, including irregular thickening of leaflets, non-bacterial vegetations, and valve dysfunction [32]. Stroke subtypes in APS can also vary according to the types of antibodies [34]. Saidi et al. [35], in an analysis of 208 patients with their first stroke, reported that antiphosphatidylserine IgG was associated with cardioembolic strokes, lupus anticoagulant with lacunar strokes, and anticardiolipin IgG and IgM with lacunar, atherosclerotic and cardioembolic strokes. The severity of the thromboembolic event does not relate to the aPL antibody titer.
The type of antibodies present also appears to have an association with increased thrombotic risk. The presence of antiphosphatidylserine antibodies had the highest risk for clinical manifestations of APS, and IgG antiphosphatidylserine antibodies correlated strongly with the presence of lupus anticoagulant. The presence of antiphosphatidylserine antibodies (IgG or IgM) or anti-b2GP-1 (IgG, IgM, or IgA) antibodies improved the specificity for APS over anticardiolipin antibodies alone [36]. In another study, the positive predictive value for antiphosphatidylserine and anti-b2GP-1 antibodies was stronger for arterial thromboses than for venous thromboses [37]. Another study of pregnant women with APS reported that patients with triple aPL positivity (LA, aCL, and anti-B2GPI) and/or previous thromboembolism had an increased likelihood of poor neonatal outcomes than patients with double or single aPL positivity and no thrombosis history [38].
The recurrent risk of stroke in APS patients has been less widely studied as compared to other types of thromboses. Pezzini et al. calculated a cumulative risk of 14% for brain ischemia at 10 years [30]. Recurrent strokes and other thromboembolic events in patients with aPL antibodies have been reported both early (within the first year of an index stroke event) and late (5–10 years) [39]. The initial type of thromboembolic event (i.e. arterial, venous, miscarriage) appears to be the most likely type of event to recur in a given patient according to some studies [40]. The Euro-Phospholipid Project Group reported thrombotic events in 16.6% of patients in the first 5 years of follow-up and in 14.4% in the second 5-year follow-up period. The most common events during follow-up were strokes, TIAs, DVTs, and pulmonary emboli with survival probability at 10 years being 90.7% [14].
The first model to develop a predictive model for aPL associated thrombosis risk in SLE patients was modified in 2013 by Sciascia et al. to include data on clinical manifestations, and risk factors forming a quantitative score called the Global Antiphospholipid Syndrome Score (GAPSS) [41]. This was further modified in 2019 to form the aGAPSS (Adjusted Global Antiphospholipid Syndrome Score) as outlined in Table 6 [42]. The goal of the aGAPSS is to risk-stratify patients based on the likelihood of developing recurrent thrombosis in the setting of APS.
Factor | Point value |
---|---|
Anticardiolipin Antibody IgG/IgM | 5 |
Anti-B2-glycoprotein I IgG/IGM | 4 |
Lupus anticoagulant | 4 |
Hyperlipidemia | 3 |
Arterial hypertension | 1 |
Taken together, screening for APS is indicated in stroke patients who meet even some of the clinical and laboratory criteria and those with recurrent strokes despite maximal medical management and no clear etiology. The goal of these scoring systems is to further refine the risk of recurrent thromboses associated with APS.
Cerebral venous sinus thrombosis (CVST) usually presents with headaches, nausea, vomiting, often associated with seizures, and focal neurological deficits. Papilledema, coma, and death also occasionally contribute to the clinical manifestation of CVST. In patients with CVST, reported frequency of aCL positivity ranges from 7 to 22% [43], and predisposes to CVST at a relatively younger age and to a more extensive cerebral venous involvement [44]. In addition, a higher rate of post-cerebral venous sinus thrombosis headache and more infarctions on brain imaging studies are seen in patients with aPL antibodies than in those without them [45].
While intracranial hemorrhage (ICH) is not a common manifestation of APS, there have been reports of reversible vasoconstriction syndrome (RCVS) [46] which is characterized by thunderclap headaches (severe pain peaking in seconds), and focal neurologic deficits.
Moyamoya disease, a progressive narrowing of cerebral vasculature with collateralization, has also been reported to have associations with APS. Of the 16 cases reported in a small series of moyamoya and aPL, 21% fulfilled APS criteria [47].
Sneddon syndrome is a rare entity that may be considered during workup for APS. It is a chronic disorder, usually non-inflammatory, notable for generalized livedo racemosa (which may be confused with livedo reticularis seen in APS), and recurrent strokes [48]. Livedo racemosa is characterized by a violaceous netlike patterning of the skin similar to the familiar livedo reticularis, although it differs by its location (more generalized and widespread, found not only on the limbs but also on the trunk and/or buttocks). Approximately 40–50% of patients with Sneddon’s syndrome present aPL antibodies, suggesting that some patients should be classified as APS [49].
Cognitive dysfunction has been reported 19–40% in aPL-positive patients [50]. While many believe that the cognitive decline is due to multiple subcortical infarcts, there have been theories that it is multifactorial, with genetic predisposition, antibody specificity, and direct antibody effects as potential contributors [51].
Migraines are the most prevalent neurologic manifestation in APS, estimated prevalence of around 20% [52].
Other rare clinical manifestations of APS include seizures, acute ischemic encephalopathy, transverse myelitis, amaurosis fugax, optic neuropathy, and other neuropsychiatric disorders.
APS has been a recognized cause of cerebrovascular events (CVE) especially in those without classic cardiovascular risk factors. Traditionally, it has been estimated that one in five strokes in patients younger than 45 could be associated with APS, but there have been concerns that this is an over-estimate due to referral bias [53]. Systematic reviews have provided much of our current knowledge on the prevalence of aPL in patients with vascular events, however broad population studies are lacking. One large study evaluating stroke, pregnancy morbidity, myocardial infarction, and deep vein thrombosis estimated that aPL antibodies were present in ∼14% of stroke patients [22].
APS, either primary or secondary, garners consideration especially in young patients with CVE. To address events in the young, the previous study [21] was repeated for those less than 50 years of age and positive aPL was found in 17.4% of cases [54]. Regardless of diagnosis, the presence of any aPL increased the risk of CVE by 5.48-fold for those under the age of 50, and the risk of thrombosis progressively increases with the increasing number of positive antibodies [54]. It has also been reported that patients with stroke and aPL positivity are younger and more likely to be female than patients with strokes who are aPL negative [51]. A similar risk for CVE has been recently reported in another study, where persistently positive aPL increased the risk of CVE by 4.62-fold and where the positive criteria and non-criteria aPL was found in 20/89 (22%) CVE patients [55].
The Euro-Phospholipid Project cataloged the largest group of patients with APS. At the initiation of this study, prevalence data were obtained with 13.1% of patients having a stroke as their presenting manifestation [52]. Stroke was the fourth most common presenting symptom behind deep vein thrombosis, thrombocytopenia, and livedo reticularis. Of the 1000 patients, 204 (about 20%) experienced a stroke at some point during their disease course [52]. Cervera et al. [52] made a delineation regarding age-of-onset, defining “older-onset” APS as diagnosis after the age of 50. Comparatively, the over-50 patients were more likely to have strokes (30%) and were more likely to be male (34%), and were more likely to experience angina pectoris (9%) [52]. These patients were followed over a 10-year time period, and over that time period, 5.3% of the patients experienced a stroke. Stroke was the most prevalent thrombotic event. It was also the 4th leading cause of death in these patients following bacterial infection, myocardial infarction, and malignancy [14].
Patients with APS hospitalized with a stroke also have increased mortality compared to patients without APS [55]. APS has also been identified as an independent risk factor for hemorrhagic transformation of ischemic stroke (OR 2.57, 95%CI 1.14–5.81, p = 0.0228) and extended hospital length of stay [56].
One of the unique aspects of APS is the diversity of types of vasculature involved—arteries and veins, small vessels, and large vessels. Multiple mechanisms of the prothrombotic state have been theorized and will be discussed in Section 4 of this chapter. APS has been implicated in multiple stroke etiologic subtypes including large-artery atherosclerosis, cardio-embolism, and small-vessel occlusion. However, the percentage breakdown between these etiologies has not been consistently reported.
As previously stated, APS is responsible for venous events as well as arterial events. In the cerebrovascular system, these include CVST. APS has been implicated in 6–17% of all cases of CVST and tends to predispose to CVST at a relatively younger age [44].
Vasculopathies, described in detail in Section 2, including Moyamoya and Sneddon’s syndrome, overlap with APS at a rate of 21% and 50% respectively. Reversible cerebral vasoconstriction syndrome (RCVS) has also been described in patients with APS [46].
Other neurologic manifestations of the antiphospholipid syndrome include headache (20%), seizures (8%), and chorea (1.3–4.5%), with less frequent neurological manifestations including parkinsonism (especially progressive supranuclear palsy), dystonia, ballismus, myoclonus, cerebella ataxia, transverse myelitis, cognitive impairments, psychiatric symptoms, and peripheral neuropathy [4, 57].
As outlined in Table 7, some aPL are associated with a higher risk of ischemic stroke than others. Isolated LA positivity induces the greatest individual antibody risk for ischemic stroke [58]. Anti- β2-GPI were also associated with increased risk but to a lesser degree [58]. aCL and antiprothrombin antibodies have been reported variably with some studies showing no increased risk as an independent risk factor [27] while others reported to be independent risk when considering young patients exclusively [58]. As mentioned, triple positivity with positive LA, β2-GPI antibodies and aCL antibodies confers the highest risk [58].
High risk | Moderate risk | Low risk |
---|---|---|
Triple positivity (LA + aCL + anti-β2-GPI) | Isolated aCL when persistently positive in patients with SLE | Isolated anti-β2-GPI positivity |
Isolated LA positivity | Inconsistent and low titer isolated aCL positivity |
Risk for cerebrovascular event based on serologic profile. Adapted [58].
Traditional cardiovascular risk factors also play a role in outcomes for patients with APS. Studies reveal that hypertension and smoking are the risk factors most associated with repeat thrombotic arterial events [59]. Combinations of risk factors have also been shown to increase the risk of repeat events [60]. Prospective studies evaluating the results of risk factor control have yet to be reported.
The RATIO study (Risk of Arterial Thrombosis In relation to Oral contraceptives) identified that the use of oral contraceptives (OCPs) and smoking carried an extremely high risk for women with APS in terms of risk for myocardial infarction and ischemic stroke [28]. The data revealed that the relative risk for ischemic stroke was higher in those who were smoking and in women with OCPs. The odds ratio for ischemic stroke was 43.1 (95%CI 12.2–152.0), which increased to 201.0 (95%CI 22.1–1828.0) in women who used oral contraceptives and 87.0 (14.5–523.0) in those who smoked. In women who had anti- β2-GPI, the risk of ischemic stroke was 2.3 (95%CI 1.4–3.7), but the risk of myocardial infarction was not increased (OR 0.9, 95%CI 0.5–1.6). Neither aCL nor anti-prothrombin antibodies affected the risk of myocardial infarction or ischemic stroke [28].
Vascular thrombosis in APS can affect a wide variety of organ systems, but cerebrovascular thrombosis leading to stroke and transient ischemic attack is the most prevalent and perhaps the most consequential arterial event [61]. In a retrospective study of 135 APS patients, the highest morbidity was linked to neurologic involvement especially due to arterial thrombosis [62]. APS is also an important cause of stroke in the young, but as described can also affect older individuals [60]. The mechanisms of stroke in APS are diverse and include thrombosis in arteries, veins, and the microvasculature, as well as cardioembolism from non-bacterial thrombotic endocarditis.
The pathophysiology of vascular thrombosis in APS is not completely understood, but several studies suggest multiple converging pathways involving not only antibodies but also endothelial cells, platelets, monocytes, coagulation cascade proteins, and complements [63] producing a systemic thrombo-inflammatory state. The presence of aPL is not the sole cause for the significant clinical manifestations of APS as there can be asymptomatic “carriers” [17, 60]. Therefore, as previously mentioned, a “two-hit” hypothesis has been theorized, where the first-hit involves the presence of circulating aPL and associated endothelial dysfunction, and the second-hit presents an inflammatory insult such as trauma, surgery, or infection, leading to upregulation of β2GPI receptors on endothelial cells, as schematically demonstrated in Figure 2.
The pathophysiology of vascular thrombosis in APS is not completely understood, but a 2-hit hypothesis is widely proposed. The first hit involves the presence of circulating aPL and endothelial injury, while the second hit requires an inflammatory insult such as trauma, surgery, or infection, leading to upregulation of beta-2 glycoprotein 1 (β2-GP1) receptors on endothelial cells. The aPLs-β2-GP1 receptor interaction unleashes multiple converging downstream pathways culminating in a thrombo-inflammatory state. VEGF: vascular endothelial growth factor; neutrophil extracellular traps (NETosis); GP: glycoprotein; TF: tissue factor (adapted [
Even though aPL can be detected either by clotting tests, such as LA, or by an ELISA, such as aCL and anti-β2GPI, they are predominantly directed against β2GPI [17] and prothrombin [64]. Other important antigens recognized by aPL are annexin V, phosphatidylethanolamine, and phosphatidylserine [65]. Mechanistically these autoantibodies target phospholipid-binding plasma proteins bound to the surface of vascular endothelial cells and thrombocytes [60]. Plasma proteins predominantly bind to phosphatidylserine [17]. Normally located in the inner surface of cell membranes, phosphatidylserine becomes externalized when endothelial cells, platelets, and monocytes are activated. The avidity with which β2GPI binds to phosphatidylserine is further enhanced by the ‘β2GPI’- ‘β2GPI antibody dimerization’ [66]. The downstream effect of β2GPI antibodies on endothelial cells and monocytes includes increased expression of tissue factor and thromboxane A2 which trigger the extrinsic coagulation pathway [64, 67]. Furthermore, the antibody binding inhibits the tissue factor pathway inhibitor and protein C activity [64, 67]. Taken together, the net effect is the synergistic production of a prothrombotic state. Endothelial cells, upon stimulation with aPL, also downregulate their nitric oxide production and increase the surface expression of adhesion molecules such as E-selectin leading to pro-inflammatory and pro-coagulation endothelial phenotype [17, 57, 67, 68]. This antibody-induced endothelial injury can lead to intimal hyperplasia, micro-vasculopathy, and accelerated atherosclerosis [69]. Activated platelets increase their surface expression of GPIIb-IIIa, synthesis of thromboxane A2 and platelet factor-4a, all acting to facilitate thrombosis [67]. Activation of neutrophils with accompanying release of Neutrophil Extracellular Traps (NETosis) and IL-8 may also play a role [67]. Annexin V, a natural anticoagulant, binds to phosphatidylserine (a procoagulant) forming an anticoagulant shield in the physiologic state in APS, this shield is disrupted tipping the system in favor of coagulation [70]. Upregulation in the mTOR (mechanistic target of rapamycin) pathway on endothelial cells may partly explain the microvascular thrombosis seen in APS.
In addition to vascular thrombosis, up to one-third of patients with APS develop non-bacterial thrombotic endocarditis (NBTE) in which there is a deposition of sterile platelet thrombi on heart valves, particularly the mitral and aortic valves, which can be a source of cardioembolic strokes [66].
Population and family studies, as well as animal studies, have suggested genetic disposition may be relevant to the development of APS. Like many autoimmune disorders, predisposition to APS has been mapped to genes in the major histocompatibility complex (MHC), among others. Also, epigenetic phenomena such as altered microRNA biogenesis in neutrophils, leading to accelerated atherosclerosis, have been implicated in APS [63].
The initial workup for stroke in the setting of APS is consistent with that of other stroke etiologies. Specifically, a multisystem approach evaluating from “
What raises the suspicion for APS in stroke? When should it be considered that more information and studies are needed besides the typical workup usually undertaken? The most pertinent situation would be when a younger patient (<50 years) presented with a thrombotic stroke without identified classic risk factors for ischemic/embolic stroke [71]. Initial workup may reveal exam and laboratory findings that may raise the concern for APS as listed in Table 8. Notably, subtle renal, cardiac, hematologic, and dermatologic system alterations can be indicative. Further, a family history of early-onset stroke, clotting, or other systemic features should be queried. Absence of typical risk factors including hypertension, diabetes, atrial fibrillation, or known history of coagulopathy (e.g. protein C deficiency, protein S deficiency, antithrombin III), among others, further increases the consideration for APS. Notably, as many as 17% of cardiovascular events in those under 50 reveal aPL antibodies and up to 22% including anticardiolipin antibodies [54].
1. Hematologic |
2. Neurologic
|
3. Dermatologic
|
4. Cardiac
|
5. Renal
|
Other important clinical signs of APS not noted in Sapporo criteria, by body system. Adapted [63].
Of note, without suggestion of underlying coagulopathy or clinical findings (see Table 8) a young patient without classic risk factors, testing for many coagulopathies is not routinely performed. When performed, there is also the question of whether this workup needs to occur in the inpatient setting, during the patient’s admission for stroke, or if it can be done post-discharge. When considering this, the most important question is: Will any findings acutely change management? It should also be noted that for a positive diagnosis APS testing needs to occur multiple times over a 3 month or longer time period. If considering the APS diagnosis, formal hematology and/or rheumatology consult is recommended. In general, the recommendation for inpatient vs. outpatient is that some workup may be deferred if necessary, to the outpatient setting, either under the care of the patient’s primary physician/provider, neurologist, hematologist, or rheumatologist.
Consistent with all stroke patients, every patient should receive standard stroke workup testing including brain imaging (CT brain, MRI brain), vessel imaging of the head, neck, and great vessels of the chest (CTA, MRA), cardiac imaging including a transthoracic echocardiogram (TTE) and laboratory testing (CMP, CBC, PT/INR, aPTT, TSH, HgbA1C, lipid profile). A bubble study with the TTE should be considered if a paradoxical embolus from a DVT is on the differential. It is also recommended to obtain basic inflammatory markers such as sedimentation rate (ESR) and C-reactive protein (CRP) to evaluate for suggestion of diffuse inflammatory disease [24].
Transesophageal echocardiogram (TEE) should also be considered if the etiology remains uncertain, this is due to the increased frequency of valvular abnormalities in the setting of APS that may include irregular nodules/vegetations most commonly on the atrial side of the mitral valve or vascular side of the aortic valve, or if thickening of the valves is noted on TTE. Most commonly, the left side of the heart is the affected side with the mitral valve more commonly affected compared to the aortic valve. These cardiac changes are postulated to be due to immune complex damage and fibrosis [72].
If APS is being considered, it is recommended that while inpatient with the acute stroke the patient should have all antiphospholipid antibodies checked, according to the revised Sapporo laboratory criteria (see Table 1). Notably, this includes ELISA IgM/IgG for anticardiolipin (aCL) with a positive test showing medium to high titers (>40 GPL/MPL units or >99th percentile), which will need to be confirmed on at least two or more occasions, 12-weeks apart. Lupus anticoagulant (LA) should also be checked by two tests including dilute Russell viper venom time (dRVVT) and LA-sensitive PTT (PTT-LA)), again conformed on at least two occasions, 12-weeks apart. Lastly, an ELISA IgM/IgG for anti-beta2-glycoprotein I (β2GPI) should also be tested, with a positive value determined by titer in the 99th percentile, and again, should be tested on at least two occasions 12-weeks apart.
At least one clinical criterion (in the context of this chapter, most likely stroke) and one laboratory criterion should be met to diagnosis APS. As described, these tests are done 12-weeks apart, so the first set of lab tests will be performed inpatient and then the second 12-weeks later, typically performed in the outpatient setting. As outlined in Table 8, if the patient does not meet revised Sapporo criteria, APS may still be diagnosed if clinical suspicion remains high based on multi-system abnormalities and if further etiologies are not identified [64].
If a patient inconsistently tests positive for APS, it may be warranted to also check for other autoimmune diseases, namely systemic lupus erythematosus (SLE), as up to 36% of those with APS will be positive for SLE. Having both APS and SLE increases the risk for stroke beyond having only one or the other [31].
As described above, there are 3 primary antibody tests for APS including aCL, LA, and β2GPI. Anticardiolipin (aCL) testing was first developed as a test for syphilis in the 1900s [71]. The aCL antibody was found not to be specific to just syphilis, thus its utility as a test for APS was also found after many false-positive syphilis tests showed an increased risk for thrombotic events. The tests presently use tissue derived from bovine tissue. Both IgG and IgM are evaluated by ELISA for the presence of aCL antibodies. Notably, due to cross-reactivity as discussed with syphilis, the presence of aCL does not alone confirm APS.
Lupus anticoagulant (LA) is a test for immunoglobulins that while associated with thrombosis, are associated with preventing coagulation in vivo. The process for testing LA is three tests including screening (usually with aPTT or dRVVT, clotting of phospholipid factors), mixing (correct with normal plasma), and confirmation (shortening prolongation with added phospholipid) [67]. Once again, LA by itself cannot confirm APS due to cross-reactivity. LA testing is outlined in Figure 3.
Testing for lupus anticoagulant (Adapted [
Anti-β2 glycoprotein I (β2GPI) enzyme-linked immunosorbent assay (ELISA) testing is the last of the trio of tests for APS. There are 5 main domains of the β2GPI, labeled DI through DV. Anti-β2GPI largely targets domain I (DI). When this domain is targeted, it has been shown an association with thrombosis. The other domains DII through DV being targeted have not been shown to have as strong a connection for promoting thrombosis. Of note, there are some more rare entities that may also raise anti-β2GPI levels, such as leishmaniasis, leptospirosis, or leprosy. For APS, the associated antibodies are against the IgG form, whereas other elevates of anti-β2GPI may be directed towards the IgM variety [73].
Unless the patient presents with a prior history of APS, the diagnosis of APS will likely be in question during the acute and subacute stroke window. This is because APS by laboratory criteria needs to be performed 12-weeks apart with two positive tests to confirm. That said, a patient that presents with a stroke and has one or more laboratory results that are concerning for APS (positive LA, aCL, anti-β2GPI), there is a question if confirming APS would change acute management. Oftentimes, the answer is yes; this even in the setting of likely APS, because thrombosis can be multifactorial and can progress between confirmatory APS testing [67]. As such, management should focus on appropriate treatment for the source of the stroke. For example, if the source is cardioembolic, the timing of initiation of anticoagulation should be considered, weighing the risk of a second embolic event while not on indicated therapy versus the risk of hemorrhagic conversion of the primary infarct.
Once the workup for APS is complete, and if positive, the next logical step is to address treatment. However, prior to addressing treatment, let us first consider if APS is a primary risk factor for stroke risk. Numerous studies have been performed to address this question, culminating with a meta-analysis evaluating 15 different studies in aggregate [54]. In this evaluation, 13 of the 15 studies reported a significant association between a CVE and aPL antibodies with a cumulative odds ratio of 5.48 [54]. While this study provides insight into primary event risk, a follow-up question relates to the risk of APS with recurrent stroke. A second meta-analysis was completed looking at 8 studies to answer this question, demonstrating no statistically significant risk of recurrent ischemic stroke among APS patients [74]. Understanding why one meta-analysis demonstrated a link between aPL antibodies and single ischemic events, while another did not show a link with recurrent events remains challenging to understand. One hypothesis used to explain these incongruent findings is that clinical events do not occur frequently occur despite the presence of the antibodies, suggesting that treatment and/or lifestyle modifications after a first stroke affect the chance of a second event [74, 75]. Therefore, an understanding that APS is associated with the single cerebral vascular event, and that treatment affects the chance of a second event, indicates that secondary prevention is highly warranted.
Knowing that therapy is indicated, we can now evaluate various treatments on the risk of thrombosis in the setting of APS. In those individuals without any other risk factors, the risk of thrombosis is less than 1% per year [76, 77]. In this group, when they do present with a thrombus, it is normally in the setting of another thrombotic risk factor, such as cancer, surgery, pregnancy, estrogen use, acute infection, smoking, and hypertension. On the other hand, the risk of thrombosis can be as high as 5% per year in individuals with a persistent moderate high-risk profile including aPL antibodies and a systemic autoimmune disease [78]. Therefore, with the risk of thrombosis being so variable, sometimes as low as 1% or other times as high as 5%, the question of optimal prevention strategies can be challenging.
Regarding primary prevention (before a stroke or vascular event) the answer remains controversial with only scant data based on prospective trials [79]. Some of these trials have demonstrated a decrease in thrombosis with the use of aspirin. For example, a meta-analysis of 11 mostly observational studies demonstrated a 2-fold risk reduction in the first thrombotic event with a more significant effect in those with arterial thrombosis [79]. Post subgroup analysis of only prospective trials demonstrated there was no significant difference between aspirin and those not treated [79]. Therefore, with conflicting data on aspirin, one may ask could there be a benefit with the use of anticoagulation as well as aspirin for primary prevention. While the data was limited, one primary prevention study evaluated the use of aspirin alone vs. aspirin plus anticoagulation in 166 patients, demonstrating no significant difference in terms of the amount of thrombotic events between groups, with an increased risk of bleeding in the aspirin plus warfarin arm [80]. Therefore, given the increased bleeding risk, the use of aspirin and warfarin in combination is not recommended for primary prevention, with the question of aspirin use in isolation remaining. Many agencies have weighed in on this subject including the 13th International Congress on Antiphospholipid Antibodies as well as the European League Against Rheumatism making recommendations suggesting the use of aspirin in high-risk antiphospholipid profiles, those with other thrombotic risk factors, as well as those with SLE [58, 81]. Even with these recommendations, one must also consider the risk of bleeding with the use of aspirin. One meta-analysis looking at six randomized control trials showed an association of increased annual risk of major bleeding in those patients using aspirin with hypertension, age > 65, diabetes, and male sex being the most significant associated risk factors [82].
In summary, the decision to use primary prevention remains an individualized choice based on a patient-centric decision. Overall, though one should consider the use of primary prevention with aspirin in those with cardiac risk factors, high risk antiphospholipid antibody profile, presence of other thrombotic risk factors and in the presence of other autoimmune disease always ensuring a thorough risk benefit analysis is done with concern for bleeding. See Figure 4 for breakdown of treatment option algorithm.
Treatment options algorithm (adapted [
Knowing the indications for the use of primary prophylaxis we now consider secondary prophylaxis. Data regarding the need for secondary prophylaxis specifically in previous arterial thrombi remains scant without any consensus. For example, one study demonstrated the use of warfarin with a goal INR of 1.4–2.8 was not superior to full dose aspirin 325 mg alone for stroke prevention, with concerns that this study was flawed due to transient positivity of aPL antibodies [27]. Another study evaluating 20 patients with ischemic stroke demonstrated that the use of low-dose aspirin and warfarin with a goal INR of 2–3 was superior to low-dose aspirin alone in the prevention of further arterial thrombi [11]. While two other studies demonstrated that for older patients with stroke, and a single test showing low titers of anticardiolipin antibodies, that aspirin may be as effective as warfarin [27, 83]. With this conflicting data, there remains no consensus statement on secondary prophylaxis with many agencies weighing in on this subject. For example, the 13th International Congress on Antiphospholipid Antibodies as well as the European League Against Rheumatism both recommended secondary prophylaxis with high-intensity warfarin with an INR > 3 or low dose aspirin combined with moderate-intensity warfarin with an INR from 2 to 3 [58, 81]. Both agencies decided on using a goal INR of >3 for warfarin because in previous studies evaluating different doses of warfarin in treating thrombi, relatively few patients with arterial thrombi were enrolled [84, 85]. Overall, data remains scarce and guidelines are based upon a consensus of expert opinion. In those with recurrent arterial events, some recommend increasing target INR level and or switching to low molecular weight heparin with the addition of other adjective therapies to include statins [86].
In summary, the decision on which patient to treat and which agent to use for secondary prophylaxis with arterial thrombi remains a patient-centric decision. Those with high-risk aPL profiles, presence of other systemic autoimmune diseases, and or other risk factors for thrombus would likely benefit from treatment with either aspirin and warfarin with a goal 2–3 or warfarin alone with a goal INR 3–4. Those with recurrent events would likely benefit from increasing the INR goal or if not feasible switching to low molecular weight heparin. Moving forward it would be beneficial to validate a risk stratification model to identify those with arterial thrombosis who would benefit from more aggressive treatment [67]. See Figure 5 demonstrates a treatment options algorithm.
Arterial versus venous thrombus treatment options algorithm (adapted [
Now knowing the indications and treatment options for the use in secondary arterial prophylaxis we now move on to secondary venous prophylaxis, which in the case of stroke would be beneficial in treating paradoxical emboli. Much different from that in arterial secondary prophylaxis, there is more of a consensus regarding the treatment of secondary venous prophylaxis using warfarin with a goal INR of 2–3 showing a decrease in recurrent venous events of 80–90% [57, 87]. Some studies have evaluated the use of higher intensity anticoagulation with a goal INR of 3.1–4.5 showing no reduced risk in thrombosis, but a significant excess of minor bleeding [84, 85].
Therefore, with the above data, we can safely say in summary for secondary prevention for venous thrombi in those with a chance of paradoxical emboli treatment with warfarin with a goal INR of 2–3 is indicated. See Figure 5 for a treatment options algorithm.
Following the basics of both primary and secondary prevention, one may question other anticoagulation options as adjuvant therapies. Regarding the use of direct oral anticoagulants (DOACs) there remains insufficient evidence with data suggesting an increased risk of thrombosis [88]. For example, two studies demonstrated no difference in the rate of venous thromboembolism and an increased risk of arterial thrombotic with the use of rivaroxaban over warfarin [89, 90]. Looking at this data more closely, a meta-analysis of these two studies did not find an increased risk of thrombosis in patients treated with rivaroxaban over warfarin at a 6 month follow up, however for unclear reasons, almost 3/4 of the thrombi occurred post the 6 months follow up [39]. Given the lack of prospective data, the utility of DOACs in the treatment of thrombus formation remains uncertain.
Beyond DOACs, other adjuvant therapies have been studied including statins and hydroxychloroquine. With statins being a mainstay of treatment post-stroke, it would not be unreasonable to think that they may be beneficial in APS, potentially exhibiting pleiotropic effects including anti-inflammatory, antithrombotic, and as well as the expected lipid-lowering potential [13]. To date, there have been no randomized controlled trials looking at the efficacy in this group of patients. One study however did look at the levels of pro-inflammatory and prothrombotic markers post use of Fluvastatin, which were significantly decreased suggesting their benefit in APS [91]. At this time without a randomized control trial, the 15th International Congress on Antiphospholipid Antibodies has recommended the use of statins in those with high cardiovascular risks and or recurrent thrombosis despite adequate AC [88]. Regarding the use of hydroxychloroquine, similar to statins in addition to its immunomodulatory effect, it also has antithrombotic properties making it a good candidate as adjunctive therapy [88]. Two studies have been performed demonstrating differing results regarding treatment with hydroxychloroquine plus aspirin vs. aspirin alone. The first demonstrated no difference between rates of thrombosis between both groups [92]. The other demonstrated a significantly lower thrombotic rate compared to standard of care alone, in addition to down-trending antibody titers [93]. These data suggest that both statins and hydroxychloroquine could be beneficial as adjunctive therapies in specific situations, although more data is needed for consensus.
Throughout this section, we have addressed the need for primary and secondary prevention, but one question left unanswered is safety as associated with therapy cessation. Unfortunately, there remains a multitude of answers to this question, hence each case should be considered independently. In those with a history of arterial thrombotic events, the risk of repeat thrombus formation off anticoagulation is too high and therefore indefinite anticoagulation is warranted [94]. In those with a history of transient positivity of antiphospholipid antibodies who eventually become negative based on two separate studies, one can consider stopping anticoagulation [95, 96]. Specifically, this would be associated with those who only have primary APS with persistently negative antibodies where if there was a thrombotic event it occurred in association with a transient risk factor including pregnancy or immobilization as examples [96]. In these cases, it is thought that the antibodies do not play a pathogenic role, but rather are a “phenomenon”. Therefore, some have recommended a 3–6-month course of anticoagulation with consideration to look for residual thrombus, which has been shown to increase the rate of recurrence by 50% [94]. Notably, the data and recommendations regarding stopping anticoagulation are based upon two small case series. Therefore, with such insufficient data, unless the risk of anticoagulation outweighs the benefit it would not be recommended to stop anticoagulation in those that become persistently negative.
Throughout this section we have addressed both preventions of stroke in APS, but what if someone should fail prevention and come in with an acute stroke. The answer to this question unlike many of the other is simple. Acute management is no different than those with or without APS [97]. Lastly, as described, APS often requires treatment with anticoagulant medications such as heparin to reduce the risk of further episodes of thrombosis and improve the prognosis of pregnancy. Warfarin (brand name Coumadin) should not be used during pregnancy because it crosses the placenta and is teratogenic. Unfractionated heparin (UFH) and low molecular weight heparin do not cross the placenta and are safe for the fetus, but long-term treatment with UFH is problematic because of its inconvenient administration, the need to monitor anticoagulant activity, and because of its potential side effects, such as heparin-induced thrombocytopenia and osteoporosis [98].
Thromboses of the cerebral arterial and venous systems are a common manifestation of APS leading to ischemic and/or hemorrhagic stroke. APS has been a recognized cause of CVE especially in those without classic cardiovascular risk factors. It has been estimated that one in five strokes and patients younger than 45 could be associated with APS and some newer studies show that APL antibodies are present in approximately 14% of stroke patients. Persistently elevated APL seems to increase the risk for CV by at least fourfold. Stroke is the fourth most common presenting symptom behind deep venous thrombosis, thrombocytopenia, and livedo reticularis. The recurrent risk of stroke in APS patients has been less widely studied as compared to other types of thromboses, however, cumulative risk of 14% for brain ischemia at 10 years has been reported. APS increases stroke risk via many mechanisms including hypercoagulability, inflammation, accelerated atherosclerosis, and cardiac manifestations, among others. Mechanistically these lead to in-situ clot formation and/or embolic phenomena. Physicians must carefully consider all these potential mechanisms when evaluating and treating stroke patients to achieve both optimal short- and long-term outcomes. While the exact underlying pathophysiology of APS remains uncertain, underlying genetics in the setting of a triggering event (e.g., surgery, trauma, infection) is believed to play a key role in the development of the disease. While primary and secondary prevention recommendations continue to evolve, each case should be considered independently to achieve optimal results. Results from more randomized control trials are needed to further infer upon the ever-evolving consensus guidelines. For the time being, the decision to use primary and/or secondary prevention therapies, and of which type, will continue to be an individualized patient-centric decision requiring careful interpretation of test results with multispecialty (neurology, hematology, rheumatology) input.
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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We herein focus on how parasites (protozoans and helminths) and their derived products have the capability of stimulating or evading the host response by triggering or inhibiting TLR activation. Parasites often develop successful survival strategies that imply interference with the host immune response. Accordingly, many of these organisms have molecules that modulate inflammation and other aspects of host immunity. Taking advantage of such mechanisms, there are some anti-inflammatory therapies based on human infection with helminths. Helminths and protozoans influence the activity of various TLRs, especially TLR2, TLR4, and TLR9. A better understanding of the role of TLRs and their parasite-derived ligands should certainly provide new therapeutic tools for combatting various parasitic and inflammatory diseases.",book:{id:"8805",slug:"toll-like-receptors",title:"Toll-like Receptors",fullTitle:"Toll-like Receptors"},signatures:"M. Magdalena Aguirre-García, Araceli Rojas-Bernabé, A. 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Pamela Gómez-García"}]},{id:"66687",title:"TLR Signaling on Protozoan and Helminthic Parasite Infection",slug:"tlr-signaling-on-protozoan-and-helminthic-parasite-infection",totalDownloads:1161,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Toll-like receptors (TLRs), a major component of innate immune system, are expressed as membrane or cytosolic receptors on neutrophils, monocytes, macrophages, dendritic cells (DCs), B lymphocytes, Th1, Th2, and regulatory T lymphocytes. It recognizes pathogen-associated molecular patterns (PAMPs) and Toll-interleukin1 (IL-1) receptor (TIR) of various invading pathogens. Downstream signaling of TLRs activates NF-κB, which acts as a transcription factor of pro-inflammatory cytokines, chemokines, and costimulatory molecules. A balance between pro- and anti-inflammatory cytokine protects host body from infectious agents and also induces the healing process. Some of parasitic infections by protozoans and helminths such as Malaria, Leishmaniasis, Trypanosomiasis, Toxoplasmosis, Amoebiasis, Filariasis, Schistosomiasis, Ascariasis, Taeniasis, and Fasciolosis are the leading cause of death and economic loss in both developing and developed nations. Frequent exposure to parasites, immigration, refugee resettlement, increasing immunodeficiency, climate change, drug resistance, lack of vaccination, etc. are the major cause of emerging and re-emerging of the above-stated diseases. However, TLR activation by parasites could stimulate antigen presenting cells and ultimately clear the pathogens by phagocytosis. So, a better understanding of host-parasite interaction in relation to TLR signaling pathway will improve the controlling method of these pathogens in immunotherapy.",book:{id:"8805",slug:"toll-like-receptors",title:"Toll-like Receptors",fullTitle:"Toll-like Receptors"},signatures:"Chandrani Fouzder, Alpana Mukhuty, Snehasis Das and Dipanjan Chattopadhyay",authors:[{id:"278297",title:"MSc.",name:"Alpana",middleName:null,surname:"Mukhuty",slug:"alpana-mukhuty",fullName:"Alpana Mukhuty"},{id:"286872",title:"Ms.",name:"Chandrani",middleName:null,surname:"Fouzder",slug:"chandrani-fouzder",fullName:"Chandrani Fouzder"},{id:"286873",title:"Mr.",name:"Snehasis",middleName:null,surname:"Das",slug:"snehasis-das",fullName:"Snehasis Das"},{id:"286874",title:"Mrs.",name:"Dipanjan",middleName:null,surname:"Chattopadhyay",slug:"dipanjan-chattopadhyay",fullName:"Dipanjan Chattopadhyay"}]},{id:"66447",title:"Precipitation of Detergent-Containing Samples for Top-Down and Bottom-Up Proteomics",slug:"precipitation-of-detergent-containing-samples-for-top-down-and-bottom-up-proteomics",totalDownloads:1275,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Prior to proteome analysis by mass spectrometry (MS), protein mixtures must first be subject to various sample preparation steps. The goal is to isolate proteins in high yield, and with high purity. Liquid chromatography (LC) separation is also integral to comprehensive proteome characterization, and so a key component of sample preparation is simply to solubilize the proteome in LC-MS compatible solvents. Hydrophobic proteins (membrane proteins) represent a greater challenge to maintain protein solubility during sample preparation. Sodium dodecyl sulfate (SDS) is a favored detergent to solubilize proteins, and also is used to impart mass-based fractionation (i.e., SDS PAGE, GELFrEE). However, SDS is incompatible with downstream LC-MS analysis. Fortunately, effective strategies for SDS removal do exist, which permits the use of this surfactant in proteomics workflows. Here we highlight an approach that is grounded in the classic technique—protein precipitation. The technique has been updated and has recently seen a revival as a strategy permitting high protein recovery, with exceptional purity. Moreover, with aid of simple disposable spin cartridges, protein precipitation can meet the needs of high throughput, automated, and reproducible proteome purification, enabling the analysis of SDS-containing samples in both top-down and bottom-up formats.",book:{id:"6914",slug:"proteomics-technologies-and-applications",title:"Proteomics Technologies and Applications",fullTitle:"Proteomics Technologies and Applications"},signatures:"Alan Doucette and Andrew Crowell",authors:null},{id:"67051",title:"2D Gel Electrophoresis to Address Biological Issues",slug:"2d-gel-electrophoresis-to-address-biological-issues",totalDownloads:1283,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Two-dimensional (2D) gel electrophoresis is a high-resolution technique for the study of proteome. This chapter describes how it can be applied to characterize specific differences in the proteome profile of breast cancer cells following gene target interference. The proteome is the complete set of proteins encoded by a genome, and proteomic analysis consists in profiling the whole proteins expressed in a given cell, tissue, organ, or organism. Proteomic expression has the main purpose of qualitatively and quantitatively comparing proteins expressed under physiological and/or pathological conditions. Although it is not the unique approach used in modern proteomics, two-dimensional electrophoresis (2DE) is unrivaled allowing simultaneous separation of thousands of proteins and the detection of post-translational modification, not predictable through genome analysis. 2DE combines two physical principles to separate complex protein mixtures: the isoelectric point and the molecular weight. The result is a gel map in which each protein isoform present in the sample can be visualized as a spot, analyzed, quantified, and identified by mass spectrometry analysis. Here we outline features and advantages of the 2DE-based proteomic approach and we describe how 2DE meets biochemistry and molecular biology to address specific issues.",book:{id:"6914",slug:"proteomics-technologies-and-applications",title:"Proteomics Technologies and Applications",fullTitle:"Proteomics Technologies and Applications"},signatures:"Domenica Scumaci and Giovanni Cuda",authors:null}],onlineFirstChaptersFilter:{topicId:"386",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. Barderas",slug:"oxidative-stress-in-cardiovascular-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}}]},overviewPagePublishedBooks:{paginationCount:33,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. 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He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"23",type:"subseries",title:"Computational Neuroscience",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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