**6. Conclusions**

In conclusion, The Netherlands appears to be on track to reach HCV elimination by 2030, though many challenges remain. This study demonstrates what it takes to meet the elimination targets in time, which might guide us in developing and implementing the (public) health policies that are needed. Dutch HCV elimination still needs invested stakeholders to maintain and, where necessary, improve the existing infrastructures regarding HCV care. These study results should be used as a base with which we can compare our actions in the future.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/ 10.3390/jcm10194562/s1, File S1: Available treatments and SVR percentages in The Netherlands, File S2: COVID-19 scenario results, Table S1: Total number of annual HCV antiviral drug users in The Netherlands, Table S2: Approximation of the number of annual HCV antiviral drug users for HCV infection in The Netherlands, Table S3: Calculated genotype-dependant SVR percentages during the (pegylated) interferon era (2000–2014), Table S4: Status Quo scenario model inputs, Table S5: Gradual decline scenario model inputs, Table S6: Sensitivity analysis model inputs, Table S7: Twoyear COVID-19 Delay model inputs, Table S8: Post-COVID Recovery Gradual Decline model inputs, Table S9: Forecasted year of elimination with scenarios "Two-year COVID-19 Delay" and "Post-COVID Recovery Gradual Decline", Figure S1: Actual (continuous line) and predicted (dotted lines) number of patients treated with direct acting antivirals, Figure S2: Predicted number of HCV-viraemic individuals in The Netherlands over time, following the Two-year COVID-19 Delay and Post-recovery Gradual Decline scenarios, Figure S3: Predicted incident cases (cumulative) of (A) decompensated

cirrhosis, (B) hepatocellular carcinoma, and (C) liver-related mortality in The Netherlands over time, following the Two-year COVID-19 Delay and Post-recovery Gradual Decline scenarios.

**Author Contributions:** M.v.D., S.M.B., C.J.I., J.P.H.D. and R.J.d.K. were involved in the design of this study, the acquisitioning of the data, and the expert consensus meetings. M.v.D. performed the analyses. M.v.D., S.M.B. and C.J.I. interpreted the data. M.v.D. drafted the manuscript. S.M.B., C.J.I., W.-H.C., G.B., H.B., A.S.M.D., B.v.H., C.v.N., M.J.S., M.v.d.V., J.P.H.D. and R.J.d.K. revised the manuscript critically for important intellectual content. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was non-funded. The model has been provided by AbbVie and the Centre for Disease Analysis. AbbVie did not have any role in study design, data collection, management, analysis and/or interpretation. Data from the CELINE project has been used in this study. The CELINE project is supported with an unrestricted grant from Gilead Sciences. Gilead Sciences did not have any role in study design, data collection, management, analysis and/or interpretation.

**Institutional Review Board Statement:** As data used in the development of this model were publicly available or were already collected in other, previously approved studies, ethical approval from an institutional review board was not required for the execution of this study.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Acknowledgments:** We would like to thank Anouk T. Urbanus and Irene K. Veldhuijzen from the National Institute for Public Health and the Environment, and Daniela K. van Santen from the Municipal Health Services Amsterdam for their participation in expert consensus meetings and the acquisitioning of data. Furthermore, we thank Ivane Gamkrelidze for his help in calibrating the model, performing the analyses and critically revising the manuscript.

**Conflicts of Interest:** M.v.D. declares that the Radboudumc, on behalf of M.v.D., received honoraria due to participation in advisory boards of Abbvie and Gilead. S.M.B. and C.J.I. have no conflicts of interest. W.-H.C. is an employee of AbbVie and may own stocks and/or stock options of the company. J.P.H.D. declares that the Radboudumc, on behalf of J.P.H.D., received honoraria or research grants from Novartis, Ipsen, Otsuka, Abbvie, and Gilead. J.P.H.D. served as consultant for Gilead and Abbvie, and in the last two years has been member of advisory boards of Otsuka, Norgine Gilead, Bristol-Myers Squibb (B.-M.S.), Janssen, and Abbvie. R.d.K. declares that the Erasmus University Medical Centre, on behalf of R.d.K., received honoraria for consulting/speaking from Gilead, Janssen, B.-M.S., Abbvie, Merck Sharp & Dohme and Roche and received research grants from Abbvie, Gilead, GlaxoSmithKline and Janssen.


Preface

Chapter 6 **Thrombogenesis in Atrial Fibrillation 127** Hanan Ahmed GalalAzzam

José Joaquín Rieta and Raúl Alcaraz

Raúl Alcaraz and José Joaquín Rieta

**Coronary Artery Disease 229** Atila Bitigen and Vecih Oduncu

Chapter 9 **New Oral Anticoagulants in Atrial Fibrillation 207** Lucía Cid-Conde and José López-Castro

**of Atrial Fibrillation 181**

**Section 4 Anticoagulation Therapy 205**

Chapter 7 **Applications of Signal Analysis to Atrial Fibrillation 155**

Chapter 8 **The Contribution of Nonlinear Methods in the Understanding**

Chapter 10 **Anticoagulant Therapy in Patients with Atrial Fibrillation and**

**Section 3 Signal Analysis 153**

**VI** Contents

Atrial fibrillation is a rapidly evolving epidemic associated with increased cardiovascular morbidity and mortality, and its prevalence has increased during the past few decades. In the past few years, the recent understanding of the diverse mechanisms of this arrhythmia has led to the improvement of our therapeutic strategies. However, many clinicians have still felt the frustration in management of this commonly encountered arrhythmia.

This book contains a spectrum of different topics from bench to bedside in atrial fibrillation. We try to introduce the most recent advancement of mechanisms and treatment of AF including genetics, calcium signaling, thrombogenesis, signal analysis, upstream therapies focus on re‐ nin-angiotensin-aldosterone system inhibitors, antioxidants and n-3 polyunsaturated fatty acids, and anticoagulation issues. I strongly believe that scientists, cardiologists and electro‐ physiologists will find this book very informative and useful. The references cited in each chapter will definitely act as additional source of information for readers.

I am grateful to the all the authors who contributed to this book with their valuable experi‐ ence. I also appreciate the great help from InTech editorial office, Ms. Mirna Cvijic and Mr. Dejan Grgur, who guided me through the publication process step by step. I would also like to thank for the important contributions from the co-editors of this book – Prof. Guangping Li, my mentor, and Dr. Panagiotis Korantzopoulos, my best friend who guided me to ex‐ plore the wonderful world of arrhythmia. Finally, special thanks to my family – wife, Lijian, and son, Yujie, who provided continuous inspiration and support to my work.

#### **Tong Liu, MD, PhD**

Department of Cardiology, Tianjin Institute of Cardiology Second Hospital of Tianjin Medical University, Tianjin People's Republic of China

**Section 1**

**Pharmacological Management**

**Pharmacological Management**

**Chapter 1**

**Atrial Fibrillation and the Renin-Angiotensin-**

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately 1% of the general population and up to 8% of subjects over the age of 80 years.[1] AF is a major contributor to cardiovascular mortality and morbidity, being associated with de‐ creased quality of life, increased incidence of congestive heart failure,[2] embolic phe‐ nomena, including stroke,[2,3] and a 30 % higher risk of death.[3,4] AF-associated morbidity includes a four- to five-fold increased risk for stroke, [2,5] a two-fold in‐ creased risk for dementia,[6,7] and a tripling of risk for heart failure.[5] According to the Framingham Study, the percentage of strokes attributable to AF increases steeply from 1.5% at 50–59 years of age to 23.5% at 80–89 years of age, [2] and the presence of AF ac‐ counts for a 50–90% increased risk for overall mortality.[3] From the viewpoint of the AF-related socio-economic burden, it has been estimated that it is consuming between 0.9% and 2.4% of total National Health Service expenditure in the UK,[8] while in the USA, total costs are 8.6–22.6% higher for AF patients in all age- and sex- population strata.[9] Therefore significant clinical, human, social and economical benefits are there‐

It has to be noted that although multiple treatment options are currently available, no single modality is effective for all patients.[10] AF can occasionally affect a structurally normal heart of otherwise healthy individuals (so-called "lone AF")[11], but most typically it occurs in subjects with previous cardiovascular damage due to hypertension, coronary artery dis‐ ease and diabetes. Moreover, it can be associated with clinical conditions such as hyperthyr‐ oidism, acute infections, recent cardiothoracic or abdominal surgery, and systemic

> © 2013 Perlini et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

fore expected from any improvement in AF prevention and treatment.

**Aldosterone System**

Stefano Perlini, Fabio Belluzzi,

http://dx.doi.org/10.5772/53917

**1. Introduction**

Francesco Salinaro and Francesco Musca

Additional information is available at the end of the chapter


**2. Relationship between corrosion resistance of austenitic chromium-nickel steels AISI 304, 08Cr18Ni10, AISI 321, 08Cr18Ni10Ti (contain low amount of δ-ferrite) and paramagnetic state of austenite**

Despite numerous studies of corrosion processes of various materials [1–4], the problems that arise require a comprehensive study of the mechanisms of corrosion behavior to ensure reliable and safe operation of modern structural materials. It should be noted that even in one smelter of industrial steel δ-ferrite is distributed unevenly, for example for steel 08Cr18Ni10Ti—the width of the sheet perpendicular to the rolling the amount of δ-ferrite varied from 0.01% to 0.4%. Chromiumnickel austenitic steels contain little δ-ferrite, which due to the small contact surface cannot significantly affect the corrosion behavior of austenitic steels [5]. We can assume that corrosion is affected by the pre-formed atomic-magnetic state of the whole austenitic matrix (austenite), which is characterized by the sum of magnetic moments of atoms per unit mass (specific magnetization) and described by an external parameter—specific magnetic susceptibility χ0. In [6] it was noted that the presence of a low content of δ-phase (*P*δ < 2%) in steel 12Х18Н10Т is not detected by radiography, metallographic methods show its presence, and the phase content was determined by the magnitude of the magnetization.

To study the dependence of corrosion resistance on the paramagnetic state of the austenitic matrix (parameter χ0) and evaluate the effect of low δ-ferrite content on


*<IP_ADDRESS> Platelet-derived growth factor (PDGF)*

Platelets, monocytes, and endothelial cells are responsible for production of PDGF. They recruit various inflammatory cells at the fracture site resulting in increased cellular proliferation and collagen deposition. The potential use of PDGF has been suggested in the treatment of osteoporosis and bone healing. It is thought that recombinant PDGF-BB form assists to release the pericytes from the abluminal side to release free and activated MSCs [47, 48].


*2.3. Essential Work of Fracture (EWF) Approach*

In order to characterize the polymers fracture, the linear elastic fracture mechanics (LEFM) approach is generally adopted. However, the characterization of fracture toughness by LEFM theory is difficult when relatively ductile polymers are considered due to the formation of a large plastic zone prior to crack initiation that violates the validity of LEFM approach. The fracture event of a relatively ductile polymer, having a marked plastic deformation zone at the crack tip, can be investigated by the essential work of fracture approach (EWF) originally suggested by Broberg [59] and then developed by Cotterell, Mai and co-workers [48,60–62]. According to this methodology, the fracture process zone is divided into two regions: an inner region (where the fracture process occurs) and an outer region (where the plastic deformation occurs). The total work of fracture follows this regions division and it can be separated in two contributions: the first contribution is related to the work spent in the inner fracture zone (work of fracture) and the work spent in the plastic deformation zone (non-essential work of fracture) [48].

For the application of the EWF theory, two different kinds of specimen can be used: the single edge notched (SENT) specimen and the double edge notched (DENT) specimen. Generally, the EWF approach is applied to thin sheets having a thickness between 1 mm and 0.2 mm [63]; the thickness of the specimen used (1.5 mm), although slightly higher than the standard range, is very low and consequently an attempt of applying the EWF approach was maintained.

The SENT specimen configuration illustrated in Figure 1 was adopted.

The total work of fracture, *Wf*, is defined as:

$$\mathcal{W}\_f = \mathcal{W}\_\varepsilon + \mathcal{W}\_p \tag{9}$$

where *We* is the work spent for the formation of two new fracture surfaces and it is spent during the fracture process and corresponds to the resistance to crack initiation. For specimens having a given thickness, *We* is proportional to the ligament length, *l* (where *l* = *W* − *a*). In the Equation (9), *Wp* is a volume energy, it is proportional to *l* 2, and corresponds to the energy for activating the plastic deformation mechanism antagonists to the crack propagation. Consequently, Equation (9) can be rewritten in the following form (Equation (10)):

$$\mathcal{W}\_f = w\_\varepsilon t l + \beta w\_p t l^2 \tag{10}$$

The specific total work of fracture can be written in the following form:

$$w\_f = \left(\frac{W\_f}{tl}\right) = w\_\varepsilon + \beta w\_p l \tag{11}$$

where *we* and *wp* are the specific essential work of fracture and the specific non-essential work of fracture, respectively; *β* is the plastic zone shape factor while *t*, and *l* are related to the specimen geometry and correspond to the thickness and ligament length of the SENT specimen, respectively.

With the assumption that *we* is a material constant and *wp* and *β* are independent from the ligament length, it is possible to plot Equation (11) as a straight line in a graph *wf* vs. *l*. Consequently, *we* can be determined from the intercept of the *Y*-axis of the *wf* versus *l* plot, while *βwp* is the slope of the straight line. It must be pointed out that β depends on the specimen geometry and on the initial crack length so the straight line relationship can be obtained only if the geometric similarity is retained for all ligaments lengths.


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of converting glucose to electricity at high rate and efficiency. *Biotechnology Letters*,

**16**

*Canada*

*University of Alberta*

**Potential Applications of Green**

Ozan Nazim Ciftci, Deniz Ciftci and Ehsan Jenab

**Technologies in Olive Oil Industry**

Conventional olive oil production methods create large amounts of waste and by-products. Most production plants do not invest in purification and utilization of those by-products. Purification or conversion methods may add value to those by-products and prevent the

Global trends show that "green" products and technologies are needed. Increasing environmental concerns, government measures and population drive the search for green processes to replace the conventional ones. This search is essential to achieve sustainable processing and to reduce commercial energy use (Clark, 2011). There are several applications

This chapter reviews the potential applications of major green processes such as supercritical fluid extraction, membrane technology, bioconversions and molecular

Supercritical Fluid Technology (SFT) has received growing interest as a green technology, with extraction being the main application in the food industry. Fluids become supercritical by increasing pressure and temperature above the critical point. Supercritical fluids have liquid-like solvent power and gas-like diffusivity. These physical properties make them

Carbon dioxide (CO2) is the most widely used supercritical fluid due to a lack of toxicity and flammability, low cost, wide availability, tunable solvent properties, and moderate critical temperature and pressure (31.1°C and 7.38 MPa) (Black, 1996). Because of the relatively low viscosity, high molecular diffusivity and low surface tension of the system, mass transfer is improved in supercritical CO2 (SC-CO2) in comparison to liquid organic solvents (Oliveira & Oliveira, 2000). Moreover, separation of CO2 from the product can easily be achieved by reduction of pressure, because the products do not dissolve in CO2 at atmospheric pressure. Another unique property of supercritical fluids is their selectivity. The density of a supercritical fluid is higher than that of a gas, making them better solvents. Extraction selectivity of supercritical fluids can be changed altering density which is done by adjusting

**1. Introduction**

environmental pollution.

for green technology in the olive oil industry.

distillation in the olive oil industry.

**2. Supercritical fluid technology**

ideal clean solvents for extraction of lipids.


*5.2.2. Metastases in regional lymph nodes: N*

In a recent meta-analysis including 14 studies and 5579 gastric cancer patients, high GPS was significantly associated with presence of lymph node metastases (OR 4.60; 95% CI = 3.23–6.56) as well as with lymphatic (OR 3.04; 95% CI = 2.00–4.62) invasion [106].


**Olive Oil Composition: Volatile Compounds**

Marco D.R. Gomes da Silva1, Ana M. Costa Freitas2, Maria J. B. Cabrita2 and Raquel Garcia2

*1REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia/ Universidade Nova de Lisboa, Campus da Caparica, 2Escola de Ciências e Tecnologia, Departamento de Fitotecnia, Instituto de Ciências Agrárias e Ambientais Mediterrânicas ICAAM, Universidade de Évora, Évora, Portugal*

#### **1. Introduction**

16 Olive Oil – Constituents, Quality, Health Properties and Bioconversions

Perri, E.; Raffaelli, A. & Sindona, G. (1999). Quantitation of oleuropein in virgin olive oil by

Romano, E., Benincasa, C., Caravita, M.A., Bartoletti, D., De Rose, F., Parise, A., Parise, M.R.,

Solinas, M.; Angerosa, F. & Marsilio, V. (1988). Research on some flavour components of

Steffen, A. & Pawliszyn, J. (1996). Analysis of Flavour Volatiles Using Headspace Solid-

Phase Microextraction. *J. Agric. Food Chem*., Vol.44, pp. 2187-2193

Arcavacata di Rende (CS), 21-25 September, p. 124

Vol.7, pp. 4156-4160

368

ionspray mass spectrometry-selected reaction monitoring. *J. Agric. Food Chem*.,

Perri, E., Tucci, P. & Rizzuti, B. (2008). Effetti dei processi produttivi su oli provenienti da diverse cultivar dell'Italia meridionale. Proceeding: *"XXI Convegno Nazionale della Divisione di Chimica Analitica della Società Chimica Italiana*".

virgin olive oil in relation to olives variety. *Rivista Sost. Grasse* 1988, LXV, pp. 361-

In general olive oil is defined on the basis of its sensory characteristics. European Union (EU) regulations establish the organoleptic quality of virgin olive oil by means of a panel test, evaluating positive and negative descriptors (EU regulations). For the organoleptic assessment, several volatile compounds are considered as the main responsible for negative and positive attributes. Volatile compounds, either major or minor, are crucial to olive oil quality; even when present below their olfactory threshold, they can still be important to understand their formation and degradation pathways and provide useful quality marker information.

Volatile composition of olive oils can be influenced by a number of factors, from agronomic and climatic aspects to technological ones. Cultivar, geographic region, ripeness, harvest and processing methods can affect the volatile composition of olive oil. Storage time is also critical for quality. In order to evaluate the volatile profile of olive oil, sensitive analytical techniques as well as extraction procedures were developed. The big issues on aroma analysis are, the loss of compounds during sample preparation steps, and the knowledge that some of the so-called "compounds of interest" (with higher aroma threshold) are, probably, present only in trace amounts. Due to its nature, olive oil is a difficult matrix; for these reasons several methods have been, so far, proposed. The advantages and drawbacks of these methods will be further discussed. One dimension-Gas Chromatography (1D-GC) analysis was, until recently, the most used method to analyze volatiles in different matrices. The increased development of 2D-GC, allowing higher sensitivity and enhanced separation power, is changing the 1D-GC approach. The type of 2D and/or 3D qualitative and quantitative information, provided by 2D-GC systems, promoted the development of powerful chemometrics tools allowing a useful, and potentially easy, way for data interpretation. Fingerprint comparison can be used on a routine basis, providing important and quick information concerning differences among the olive oils produced and, probably most important, also allowing frauds detection.

Olive Oil Composition: Volatile Compounds 19

inherent disruption of cellular tissues. Consequently, the LOX pathway is initiated by the hydrolysis of triglycerides and phospholipids, mediated by acyl hydrolase (AH), leading to the release of fatty acids. Lypoxygenases, after their release, become immediately active and transform the unsaturated fatty acids, produced by the action of AH, linolenic (LnA) and linoleic (LA) acids, into their corresponding 9- and 13-hydroperoxides, as shown in figure 2. The subsequent cleavage of fatty acids 13-hydroperoxides is catalysed by specific hydroperoxide lyases (HPL) leading to the formation of C6 aldehydes (*Z*)-hex-3-enal and hexanal from linolenic and linoleic acids, respectively) and oxoacids. The unsaturated form of C6 aldehyde ((*Z*)-hex-3-enal) undergo rapid isomerisation to the more stable (*E*)-hex-2 enal. The action of alcohol dehydrogenase (ADH), catalyses the reversible reduction of aliphatic C6 aldehydes to the corresponding volatile alcohols (Benicasa et al., 2003; Angerosa et al., 1998a). Alcohol species are further transformed into esters due to the catalytic activity of alcohol acetyl transferase (AAT), producing acetates (Kalua et al., 2007) (figure 2). Several factors, such as cultivar and extraction process, including operating temperature, seem to play a relevant role on the improvement of AAT activity (Salas, 2004). When the substrate is LnA, LOX catalyses, besides the hydroperoxide formation, also its cleavage, via an alkoxy radical, increasing the formation of stabilized pent-1,3-diene radicals. These compounds can suffer dimerization leading to the production of C10 hydrocarbons (pentene dimmers) or react with a hydroxyl radical present in the medium, leading to C5 carbonyl compounds (Angerosa et al. 1998b, Pizarro et al., 2011). The most important fraction of volatile compounds, of high quality virgin olive oils, comprises C6 and C5 compounds, especially C6 linear unsaturated and saturated aldehydes. The presence of other volatile compounds, namely C7-C11 monounsaturated aldehydes, C6-C10 dienals, C5 branched aldehydes and alcohols and some C8 ketones, in relatively high concentrations, in the aroma of virgin olive oil, is associated with unpleasant notes. The presence, or lack of defects, in the aroma of olive oils is related with the

contribution of the various pathways involved on volatiles formation.

LOX pathway is predominant in oils of high quality.

**sensorial quality**

When the most active pathway is the LOX cascade the olive oil aroma will not be defective.

The International Olive Oil Council (IOOC), European Commission (EC) and Codex Alimentarius have defined the quality of olive oil based on several parameters, such as free fatty acid content, peroxide value, spectrophotometric absorvances in the UV region, halogenated solvents and sensory attributes (Boskou 2006; Kalua et al., 2007; Lopez-Feria et al., 2007). In order to evaluate olive oil quality, the Codex Alimentarius and IOOC include also the insoluble impurities, some metals and unsaponifiable matter determinations (Boskou 2006).

The nutritional value of olive oil arises from high levels of oleic acid and minor components, such as phenolic compounds. It is well recognized that the consumption of some natural antioxidant phenolic compounds produce beneficial health effects. These substances possess strong radical scavenging capacities and can play a relevant role in protecting against oxidative damages and cellular aging. Together with their bioactivity, olive oil phenols have a significant role on the flavour and the bitter taste of olive oil (Boskou 2006; Servili et al. 2002). Sensory quality plays a crucial role in the acceptability of foodstuffs and

**3. The role of volatile compounds in olive oil quality: Nutritional and**

This work will be divided in four main parts: 1) a brief summary of the composition and biosynthesis of the volatile fraction of olive oil; 2) the role of volatile compounds in olive oil quality: nutritional and sensorial quality; 3) the effect of agronomic and technological practices on olive oil aroma; 4) analytical methodologies for quantification and identification of volatiles compounds: new analytical methods.