Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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In this new context of variability and climatic changes, these ecosystems undergo notable modifications amplified by domestic uses of which it was subjected to. Indeed the ecosystems render diverse services to humanity from their composition and structure but the tolerable levels are unknown. The preservation of these ecosystemic services needs a clear understanding of their complexity. The role of research is not only to characterise the ecosystems but also to clearly define the tolerable usage levels. Their characterisation proves to be important not only for the local populations that use it but also for the conservation of biodiversity. Hence, the measurement, management and protection of ecosystems need innovative and diverse methods. For all these reasons, the aim of this book is to bring out a general view on the function of ecosystems, modelling, sampling strategies, invading species, the response of organisms to modifications, the carbon dynamics, the mathematical models and theories that can be applied in diverse conditions.",isbn:null,printIsbn:"978-953-51-0572-5",pdfIsbn:"978-953-51-5289-7",doi:"10.5772/2276",price:139,priceEur:155,priceUsd:179,slug:"diversity-of-ecosystems",numberOfPages:498,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"ee698d03ccce547bc8cdb4f13ebb2822",bookSignature:"Mahamane Ali",publishedDate:"April 27th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/1850.jpg",numberOfDownloads:46825,numberOfWosCitations:74,numberOfCrossrefCitations:22,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:86,numberOfDimensionsCitationsByBook:2,hasAltmetrics:0,numberOfTotalCitations:182,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 10th 2011",dateEndSecondStepPublish:"June 7th 2011",dateEndThirdStepPublish:"October 12th 2011",dateEndFourthStepPublish:"November 11th 2011",dateEndFifthStepPublish:"March 10th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"103960",title:"Prof.",name:"Mahamane",middleName:null,surname:"Ali",slug:"mahamane-ali",fullName:"Mahamane Ali",profilePictureURL:"https://mts.intechopen.com/storage/users/103960/images/system/103960.jpg",biography:"Prof. Ali Mahamane is a Lecturer at Abdou Moumouni University (Niger). He was born in 1964 at Kendadji, Tillabéri, Niger. He got his first degree in Agricultural Sciences from the Abdou Moumouni University and later specialised in Arid Regions Forestry (ENGREF, Montpellier, France). He pursued his studies at the University of Ouagadougou, Burkina Faso where he obtained his M. Phil in 1997. In 2000, he got a tenure appointment at the Faculty of Sciences at Abdou Moumouni University. He registered for his Ph. D thesis at the Université Libre de Bruxelles, Belgium in April 2005. He published more than 38 Scientifics articles both in national and international journals. He is National Coordinator of UNDESERT Project (Understanding and combating desertification to mitigate its impact on ecosystem services). \nPresently Ali Mahamane is Deputy Vice Chancellor and Dean of Faculty of Sciences and Technics at the University of Maradi (Niger).",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Abdou Moumouni University",institutionURL:null,country:{name:"Niger"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"841",title:"Biodiversity",slug:"environmental-sciences-ecology-biodiversity"}],chapters:[{id:"36220",title:"Macrofaunistic Diversity in Vallisneria americana Michx. in a Tropical Wetland, Southern Gulf of Mexico",doi:"10.5772/35331",slug:"macrofaunistic-diversity-in-vallisneria-americana-michx-in-a-tropical-wetland-southern-gulf-of-mex",totalDownloads:2486,totalCrossrefCites:0,totalDimensionsCites:3,hasAltmetrics:0,abstract:null,signatures:"Alberto J. 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1. Introduction
High‐frequency electromagnetic fields are used now in telecommunications and radar systems, astrophysics, plasma heating and diagnostics, biology, medicine, technology and many other applications. Special electromagnetic systems excite and guide these fields with given time and space distribution. A designer or a researcher of such systems ought to know in detail their electromagnetic field characteristics. This goal can be achieved or by experimental study, often too long in time and expensive, or by computer simulation. The last choice becomes more and more preferable with fast progress of computational electrodynamics and computer efficiency.
All macroscopic electromagnetic phenomena are governed by Maxwell\'s equations. Unfortunately, these remarkable equations have so many solutions, that choice of the one satisfying given initial and boundary conditions (BC) often becomes very difficult problem. A number of commercial computer codes based on numerical solution of Maxwell\'s equations are available at this time. These codes make possible high‐frequency electromagnetic field simulation.
Researches have not yet created a universal code, efficiently simulating electromagnetic field excited by an arbitrary technical or nature source in an arbitrary medium. Some codes are more suitable for solving one kind of problems and other codes—another kind. Hence, developing new, more universal and efficient computer codes is an actual task. On the other side, a designer of electromagnetic devices and systems has to choose most efficient computer code for solving his/her particular problem. He/she can do right choice only if he/she understands the basics of a numerical method used in the given code.
The goal of the presented chapter is to formulate electromagnetic problems and to describe in short prevailing numerical methods of its solving. As an example, the chapter also gives more detailed description of the radio frequency simulator (RFS) computer code, developed in collaboration of Saint‐Petersburg State Electrotechnical University and LG Russian R&D Centre. Some results obtained by means of this code demonstrate its accuracy and efficiency.
The author hopes that this chapter would be useful for researchers and designers of modern telecommunication devices and systems.
2. Basic equations
Maxwell\'s equations are the basic ones, describing macroscopic electromagnetic fields in an arbitrary medium. In modern notation, these equations have the form
∇×H=∂D∂t+JE1
∇×E=−∂B∂tE2
∇⋅D=ρE3
∇⋅B=0E4
In these formulas, J,ρ are the electric current and electric charge densities (field sources), E,H are the electric and magnetic field intensities (or simply electric and magnetic fields), D,B are the electric and magnetic flux densities, ∇ is Hamilton\'s differential operator and × is the sign of vector and scalar products.
The constitutive relations couple flux densities and field intensities:
D=εE=ε0εrEE5
B=μH=μ0μrHE6
Here, ε,μ are the absolute permittivity and permeability, ε0=107/(4πc2),μ0=4π⋅10−7 are the dielectric and magnetic constants (we use the SI units in this chapter) and εr,μr are the relative permittivity and permeability, which can be scalars or tensors, depending on medium properties. Equations (1), (2), (5) and (6) form a system of 12 scalar differential equations of the first order with 12 unknowns—components of E,H,D,B vectors, which are functions of space coordinates and time. To solve this system, one needs to define initial and boundary conditions. These conditions together with the equations form an electrodynamics problem (EMP).
Initial conditions define electric and magnetic field intensities in the computational region at the initial moment of time.
The most frequently used boundary conditions (BC) are as follows:
On the surface separating two dielectrics:
n×(E2−E1)=0;n×(H2−H1)=JsE7
where n is the unit normal to the surface directed from the first medium to the second and Js is the surface electric current density.
On the surface of perfect electric conductor (PEC):
n×E=0E8
Similarly, on the surface of perfect magnetic conductor (PMC)
n×H=0E9
Approximate Leontovich boundary condition holds on the impedance surface:
en×(en×Ė)−jZsk0η0μren×(∇×Ė)=0E10
where Zs is the surface impedance. For metals, Zs=(1+j)ωμ/(2σ).
We define radiation (adsorption) condition on the surface throw where radiation propagates without reflections. Higdon [1] proposed general absorption boundary conditions (ABCs) theory of arbitrary order of approximation. For a wave, propagating under arbitrary angle ϕ to the border x=Const, the first‐order Higton\'s ABC are
(∂∂x+cosϕu∂∂t+ξ)Eτ=0E11
where ξ is constant, providing solution stability and u is the phase velocity of the wave. Higher order ABC can be constructed by multiplying several first‐order operators (11).
Another expression for ABC can be derived from the wave equation. For the wave propagating along the normal en to the border, we get
(∇×Ė)τ+jk0εrμren××Ė=0E12
There are two types of EMPs: an inner problem, when the solution is defined in a closed space region with certain boundary conditions on its border, and an outer problem presuming existence of the solution in the unbounded space excluding some regions with prescribed conditions on their boundaries. We ought also to define field sources in the computational region and initial conditions—electrical and magnetic fields at some moment of time. The proper initial and boundary conditions guarantee existence and uniqueness of the solution [2, 3].
Equations (1)–(4) presume arbitrary time dependence of sources and fields. But very often field dependence on time expresses by the harmonic law: a=amcos(ωt+ϕ), where a is any component of the field, ω=2πf is the angular frequency, f is frequency and ϕ is the initial angle. In this case, we can simplify Maxwell\'s equations, using notation
E(r,t)=Re[Ė(r)ejωt],E13
where Ė(r)=Exejϕxex+Eyejϕyey+Ezejϕzez is the complex electric field amplitude (phasor). Magnetic field H is presented similarly. Using these notations, we can write Maxwell\'s equations for phasors:
∇×H˙=jωε˙Ė+J˙E14
∇×Ė=−jωμ˙H˙E15
∇⋅(ε˙Ė)=ρ˙E16
∇⋅(μ˙H˙)=0E17
Here, ε˙=ε0ε˙r,μ˙=μ0μ˙r are the complex absolute permittivity and permeability and ε˙r=(ε′r+jε″r), μ˙r=(μ′r+jμ″r) are the relative complex permittivity and permeability. The equation systems (14)–(17) are simpler than the original one because it does not contain time as independent variable and has only six unknown functions.
3. Basis stages of electromagnetic problem solution
Solution of a given electromagnetic problem can be divided on several subsequent steps (stages):
Problem formulation—defining the goal of the computation, necessary input and output data, admissible inaccuracy of the results.
Analytical treatment—formulating of equations, initial and boundary conditions, geometrical description of the computational region and filling medium properties. The choice of the numerical solution method, transforming equations to the form, most suitable for the chosen method, a‐priory analysis of equations and their solutions properties.
Problem discretization—transfer from continuous functions to discrete ones and from functional equations to the system of linear algebraic equations (SLAE), in the certain sense approaching the initial problem.
Algebraic solution—choosing the most efficient numerical method and solving the SLAE with the prescribed accuracy.
Post‐processing—calculation of fields, characteristics and parameters of the electromagnetic system and visualization of the results.
Each stage of the solution adds its own contribution to the total solution error. The first step adds the so‐called inherent error arising due to inaccuracy of input data. This error cannot be eliminated on the next stages of solution. The second stage adds mathematical model error caused by imperfect adequateness of the model to the real physical process. Problem discretization adds the so‐called numerical method error, the value of which depends on the quality of the discretization process. At last, computational error arises on stages 4 and 5 due to finite accuracy of numbers presentation in a computer and finite number of operations. With progress in the computational mathematics and computer, the main error sources move from the uncontrolled first stages to the fourth and fifth stages, where we can often predict the error value a‐priory.
4. Numerical methods classification
The solution of real‐life electromagnetic problem is a very complicated task. There are no universal methods, capable to solve efficiently an arbitrary problem. Hence, a number of numerical methods were elaborated, each of them is the most efficient for its particular range of problems. The numerical methods divide on two large groups.
The first group solves problems involving Maxwell\'s equation (1)–(4), containing time as an independent variable. This group makes possible to find the solution in time domain (TD) with arbitrary time dependence of fields. This group of methods is the most suitable for solving non‐linear problems. If the problem is linear, Fourier transform can be used to find frequency spectrum of the solution.
The most popular method of this group is the Finite Difference Time Domain (FDTD) method, proposed by Yee [4, 5]. Another method, successfully used in time domain, is the Finite Integration Technique (FIT), firstly proposed by Weiland [6]. The Transmission Line Matrix (TLM) method, proposed by Johns and Beurle [7], also works efficiently in time domain. Its detailed description can be found in [8]. These methods were implemented in a number of computer codes, such as SPEAG SEMCAD™ (FDTD), CST Studio Suite™ (FIT, TLM) and many others.
The second group deals with Eqs. (14)–(17) for field phasors, supposing harmonic time dependence of fields. This group provides solution in Frequency (or Spectral) Domain (FD). The finite element method (FEM) is one of the most efficient representatives of this group. The first application of this method to the solution of mechanical problems refers to the year 1943 [9]. The book [10] contains detailed description of the method, which is rather universal and accurate. The Method of Moments (MoMs) and its varieties are also frequently used in FD. In contrast with FEM, MoM uses integral form of basic equations, where electric current density distribution on conducting surfaces excited by external sources is unknown. The book [11] reflects modern state of the MoM. Mentioned methods were implemented in codes ANSIS HFSS™ (FEM), Altair FEKO™ (MoM, FEM) and other commercial computer codes. Of course, there exist many other numerical methods and various implementations.
Most of modern methods allow implementation both in TD and in FD.
Because it is impossible to give detailed representation of all numerical methods in a limited space, we give here more detailed information about the FEM method, which was implemented in the computer code radio frequency simulator (RFS) [12].
5. Finite element method for electromagnetics
5.1. Main features of the method
The finite element method belongs to the variational methods of solving partial differential equation (PDE). It presumes formulating a functional, which is stationary (has minimum or maximum value) on the equation solution. In order to find functional extremum, the computational region is partitioned on a number of subregions (finite elements). After that, we approximate an unknown function in each finite element (FE) by superposition of basis functions. Basis functions have to be simple and form a linearly independent system. Applying Ritz method or Galerkin algorithm, we fulfil discretization of the problem, that is, transition from the partial difference equation to the system of linear algebraic equations (SLAE). Numerical solution of the SLAE gives unknown coefficients of basic functions, which are used to restore electromagnetic field. At last, needed components of electromagnetic field and system parameters are calculated.
5.2. Mesh generation
Partitioning of the computational region (mesh generation) is the first stage of problem solution by FEM. It supposes dividing the computation region on a set of subregions—finite elements. FEs must densely fill the region and be nearly conformal to its border. In contrast to FDTD or FIT methods, a FEM mesh can be irregular and contain FEs of different forms. Tetrahedron FEs are used most commonly, because they allow dense packing and quite correctly approximate curvilinear borders. However, mesh generation for regions with complex forms filled with different materials is a very complex task.
Delaunay tessellation is a common way of mesh building. It includes several stages. Firstly, a surface triangle mesh is generated. Then, a volume mesh based on the surface mesh and covering the whole computational region is being built. The method can build a rather good mesh without self‐intersections. Some commercial codes, such as SYMMETRIX MeshSym™, can be used to generate mesh by this procedure.
Unfortunately, this method cannot be applied to tessellation of complex geometrical models consisting of hundreds of parts made from various materials. Usually, an electromagnetic simulation code imports such models from various CAD systems (see, e.g. Figure 1). As a rule, imported models contain a number of errors caused by insufficient attention of a designer or arising in the process of graphic formats transforms. As a result, mesh generator fails to build the mesh.
Figure 1.
A part of the handset CAD model.
On the other side, CAD models are often excessively detailed. They contain peculiarities, not influenced on electromagnetic field. Figure 2 shows an example of such extra detailed CAD model. The application of standard mesh generator to such a model can result in excess mesh size. Correction and simplification of the model manually needs several working days of the qualified engineer.
Figure 2.
A part of the CAD model with excessive details.
An advanced method of mesh generation was developed and implemented in the RFS simulation code. The algorithm begins from assigning materials and attributes to the model parts. Most important objects, such as ports, printed circuit board (PCB) and antennas, are labelled as ‘electrically important\'. This is the only stage of the algorithm, which is made manually. This stage can be omitted for simple models. Then the code builds surface meshes for each detail of the system. The third stage presumes elimination of individual meshes interceptions and building united surface mesh. Electrically important, metal parts and parts with higher permittivity have priority in this process. At last, a global volume mesh is generated [13]. The user can control mesh quality (maximum to minimum ratio of tetrahedron\'s dimensions and other mesh parameters).
We proved this algorithm on more than 190 models of mobile handsets and showed its 100% reliability. Generated meshes contained more than 1.5 billion tetrahedrons. Figure 3 shows a CAD model of the handset (a), surface mesh (b) and volume mesh (c), built by the described algorithm.
Figure 3.
CAD model of the handset (a), united surface mesh (b) and volume mesh (c).
5.3. Basic equation
Consider a region V, delimited by a surface S, where electromagnetic field has to be calculated. We suppose that the region V is filled by linear medium. Applying curl operator to Eq. (15) and substituting into result Eq. (14), we get PDE of the second order
∇×(μ˙r−1∇×Ė)+jση0kĖ−ε˙rk2Ė=−jkη0J˙imp,E18
where J˙imp is the imposed current density, k=ω/c is wave number, c=(ε0μ0)−1/2 is the light velocity in free space, σ is medium conductivity and η0=μ0/ε0=120π ohm is the intrinsic impedance of free space. After solving this equation, we can find magnetic field by means of Eq. (15):
H˙=jkη0μ˙r∇×Ė.E19
To solve Eq. (16), we divide the computation region on finite elements and approximate the field in each FE by superposition of basis functions. It is natural to approximate vector unknown function in Eq. (16) by a set of vector basis functions. We name such variant of FEM as vector finite element method (VFEM).
Nedelec [14] proposed a set of vector basis functions for triangle and tetrahedral FE. These functions are associated with tetrahedron edges and have the form
wm=ζm1∇ζm2−ζm2∇ζm1,E20
where ζmn is the barycentric function of the vertex (node) node n of the edge m (m=1,…,6,n=1,2). The barycentric functions are polynomials of the first order. For a given Descartes coordinate system
ζp=ap+bpx+cpy+dpz,E21
where p is vertex number. As a tetrahedron has six edges, Nedelec\'s basis consists of six functions. Figure 4 shows the numbering scheme for nodes and edges, needed for the correct use of Nedelec\'s functions.
Figure 4.
Numbering order of a tetrahedron\'s vertices and edges.
Coefficients in Eq. (17) can be found from the equation
where xp,yp,zp,p=1…4 are the coordinates of the p‐th tetrahedron\'s node.
Nedelec\'s basis functions have the following properties:
Dimension of these functions is L−1.
They have zero divergence and their curl is constant inside the FE. This property provides the absence of spurious solutions of the problem.
Projection of the function wm on the edge m is constant, and its projection on the other edges is equal to zero. Hence, these functions provide continuity of tangential electric field on the border between neighbouring tetrahedrons.
Circulation of function wm along its edge is equal to unity.
Full first‐order polynomial set for electric field approximation contains 12 functions (3 E‐vector projections, each needs four functions). However, Nedelec\'s set contains only six basis functions. Hence, it does not form full first‐order polynomial system. The order of approximation by these functions is lower than one. Finite elements with these functions are called FE of order 1/2 or CT/LN (constant tangential/linear normal) according to the behaviour of these functions along edges and in normal direction to them.
Striving for increasing approximation accuracy led to creating another set of basis functions with higher order of approximation. A set of 20 functions (12 associated with edges and eight with faces) forms FE of order 1.5 or LN/QN (linear tangential/quadratic normal) [15, 16]. There exist basis functions of order 2.5 and higher, but they are rarely used.
With the aim of simplicity, we consider further only Nedelec\'s basis functions. So, electric field intensity in q‐th tetrahedron is approximated as
Ėq(r)=∑n=16x˙nqwnq(r),q=1,…,Nq,E23
where Nq is the total number of tetrahedrons.
Coefficients x˙mq have the sense of voltage on edge (with reverse sign). Really, taking integral along an edge
Vmq=−∫LqĖq⋅dlm=−∑n=16x˙nqwnqdlm=−x˙mq,E24
due to the fourth property of basis functions.
Let us consider q‐th tetrahedron. According to Galerkin\'s method, we multiply Eq. (16) by basis function wmq, belonging to this tetrahedron and integrate the product over the tetrahedron volume Vq. As a result, we obtain the so‐called week form of Eq. (16):
Transformation of the first term of this equation and subsequent substitution into result approximation (19) gives a system of linear algebraic equations:
where Nq is the total number of FE in the computation region.
The system of Eq. (25) can be written in matrix form:
Q¯qXq≡(T¯q+jkU¯q−k2R¯q)X¯q=−S¯q−jkB¯q,E26
where Qq,T¯q,U¯q,R¯q are square matrices having dimension 6 × 6, S¯q,B¯q are column vectors having six components, dependent on the given boundary conditions and implicit current density in the q‐th finite element. Depending on BC, Sq can sometimes be a square 6 × 6 matrix.
Equation (26) is called the local matrix equation, and matrix Qq is the local matrix of q‐th FE. Such matrices should be built for every FE in the computational region.
Components of matrices T¯q,U¯q,R¯q and vectors S¯q,B¯q are defined by the expressions
tmn=μ˙r−1∫V(∇×wm)⋅(∇×wn)dV;E27
umn=η0σ∫Vwm⋅wndV;E28
rmn=ε˙r∫Vwn⋅wmdV;E29
sm=μ˙r−1∮S[(∇×Ė)×wm]dS;E30
bm=η0∫VJ˙imp⋅wmdV.E31
Medium in these expressions is supposed to be homogeneous inside the FE. Index ‘q\' denoted FE number is omitted. We can see that in order to calculate elements (27)–(31), it is sufficient to calculate two integrals:
fmn=∫V(∇×wn)⋅(∇×wm)dV and hmn=∫V(wn⋅wm)dV.E32
We use the next algorithm for the calculation of matrices and vectors elements:
For each tetrahedron
Coefficients of the barycentric functions are calculated by means of Eq. (22).
In these expressions, V is the volume of the tetrahedron.
Construction of the global matrix (assembling) for all tetrahedrons is a rather complex task, because many nodes, edges and faces are common for neighbour FEs (see Figure 5, which shows two neighbour tetrahedrons, separated for reader\'s convenience). They have three common vertices and three common edges. Hence, the united matrix for two FEs has only 9 dimensions instead of 12.
Figure 5.
Two neighbour tetrahedrons. Edges e11 and e22, e31 and e32, e51 and e62 and vertices v11 and v12, v21 and v32, v41 and v42 are common for both FEs.
The code RFS uses the next algorithm for building the global matrix:
Calculate a local matrix for the tetrahedron number one (q = 1). Give its edges global numbers from 1 to Nc=6.
Choose the tetrahedron with q = 2
Choose the edge of this tetrahedron with m = 1. Check whether this edge coincides with any edge of the previous tetrahedron. If it does, calculate its matrix elements and add them to corresponding matrix elements of the previous tetrahedron. In the other case, give the edge global number Nc+1 and fill a corresponding element of the global matrix. Set Nc=Nc+1.
Do this procedure for all edges of the tetrahedron.
Repeat point 2 for every tetrahedron in the region testing whether a given edge of the tetrahedron coincides with any edge, previously included in analysis.
Similar assembling procedure is valid for basis functions of higher order.
As a result, we get a global matrix of the problem, a global vector of the right side of Eq. (26) and a global vector of unknowns. Dimension of the global matrix is equal to the total number of coefficients (degrees of freedom) in formulas (23).
5.4. Numerical approximation of boundary conditions
Border between two dielectrics. A finite element mesh is built so that every tetrahedron lies inside one of the media. Hence, the common face of two neighbour tetrahedrons lies on the separation surface or approximate it in the case of curvilinear border. Due to basis function properties, tangential electric field of both tetrahedrons is equal on the face edges, consequently electric fields are equal on the whole face area. As a result, BCs (7) for electric field are satisfied automatically. As for magnetic field intensity, its continuity on the border between media with different permeabilities is not guaranteed.
Electrical wall. According to Eq. (8), tangential electric field on PEC surface is equal to zero. Hence, three coefficients of Eq. (25) belonging to edges, lying on the surface, are equal to zero. Corresponding rows and columns of local matrix of the given tetrahedron have to be eliminated.
Magnetic wall. According to Eq. (9), surface tangential magnetic field on the PMC is equal to zero. We can see from Eqs. (27)–(31) that only term sm has to be changed:
sm=jk0η0∫S(H×wm)en=0.E39
This expression is equal to zero as the mixed product under the integral has two vectors (H,en) with the same direction. Therefore, PMC BC does not change local matrix.
Absorption boundary conditions. Formula for matrix elements smn can be derived from Eq. (11):
smn=jk0μr/εr∫S(en×wm)⋅(en×wn)dS.E40
Expressions for the higher order ABC can be found in [10].
Impedance surface. Impedance surface has finite surface conductivity σs. Such surface is a good approximation of the metal surface in microwave frequency band. Using Leontovich BC (10), we can derive expression
smn=−jk0η0σs∫Swm⋅wndS.E41
These values must be added to the corresponding elements of the local matrix. Of course, they are nonzero only for functions associated with edges lying on the impedance surface.
Excitation sources. Electromagnetic field in the system excites by electric current or by electric or magnetic fields, defined on a part of the system border. In the first case, we use Eq. (26) to calculate right‐hand vector elements. In the second case, we define the so‐called ports—surfaces on which nonzero excitation field exists. Frequently, we define port as cross section of the regular transmission line (TL). Such ports are called wave ports. If TL cross section has simple form (rectangular, circular, etc.), we can define field on the port analytically. Otherwise, we have to solve two‐dimensional (2D) boundary problem.
Together with wave ports, lumped ports (LPs) are often used. These ports are defined by current I and intrinsic admittance Zi. LPs are used when excitation source dimensions are very low compared to the whole‐system dimensions or wavelength. Geometrical model of LP is a segment of a straight line (linear LP) or a rectangle (planar LP). Linear and planar LPs are implemented in the RFS code. Arbitrary number of tetrahedron\'s edges or (and) faces can cover such LPs. We suppose that surface current density and electric field distributions on the PL are homogeneous. Values of right‐hand vector for a planar LP are calculated by Eq. (31), where J˙imp=I/w, I is port current and w is port width. Implemented model of the LP excludes limitations imposed on the mesh generator by other models.
Lumped elements. Embedding of lumped elements (LEs) into 3D field model enlarges the capability of the code, as an LE excludes the necessity of generating very fine mesh inside such parts as resistors, capacitors and inductors. In the RFS code, linear and planar LEs are implemented [17].
The presence of LEs modifies the global matrix by adding to diagonal matrix elements terms
q′mm=−jk0η0Yl,E42
where Y is the admittance of the LE, l is its length. The RFS code implements models of a resistor, capacitor and inductor, and their parallel connection. The number of LEs in the model is unlimited.
5.5. Fast‐frequency sweep
The finite element method in frequency domain solves the problem at one specific frequency. Calculation of the system frequency response (e.g. S‐matrix) needs solving the problem many times (often several hundreds or even thousands). This procedure takes much computation time.
Considerable economy of computational resources can be achieved by implementing the so‐called fast‐frequency sweep (FFS). The algorithm of FFS is based on model‐order reduction (MOR) technique. According to the MOR, we seek solution in one frequency point and then expand left and right sides of Eq. (21) in frequency power series. Terms with the same power are equated and full solution as a function of frequency is restored. The RFS code implements one of such algorithms—well conditioned asymptotic wave form evaluation (WCAWE) [18]. This method was adapted to the RFS procedures, particularly for LE models, and showed high efficiency, making possible to calculate system fields and parameters in three‐octave frequency band using full solution only in one frequency point. Hence, computation time for wideband systems decreases by tens and hundreds times without losing accuracy.
6. The RFS code description
The RFS code is designated to solve complex 3D electromagnetic problems, especially mobile handsets modelling. It contains graphic user interface for creating and editing geometric objects or for import CAD models. Geometric primitives, besides boxes, cylinders, spheres, pyramids and cones, include coaxial and strip lines and wizards for creating human head and hand models (phantoms), spiral antennas and other objects. All Boolean operations, such as extrusion, skinning and others, are also implemented. The code includes a rich material library.
Two types of meshing are available: exact automatic meshing based on Delaunay tessellation and hand meshing with automatic geometry corrections. We recommend the last one for meshing complex models, imported from CAD codes, for example, for full models of a handset. Two types of basis functions can be used: low order (CT/LN) and high order (LT/QN). The last is used as default, but for complex models with many small details, we recommend low‐order basis.
The code solves several types of problems: driven solution in one frequency point, driven solution in frequency band with given frequency step (solution in each point or FFS), eigenmode, EMS and EMI problems. The code can perform parametric solution when one or several geometric or (and) material parameters changes in a given order. The results can be represented as functions of these parameters.
Post‐processing includes the calculation of S‐, Y‐ and Z‐parameters, field distribution in a volume, on a surface or along a line, the calculation of cavities intrinsic impedance, specific absorption rate (SAR) and EMC/EMI parameters. Results are represented in one‐dimensional (1D), 2D and 3D graphs, tables and can be exported in a file.
7. Computation results
Firstly, we validated the code by solving problems having analytical solution. One of such problems is an eigenvalue problem for cylindrical cavity. A cylindrical cavity has curvilinear surface, so calculation can demonstrate the quality of surface approximation by a tetrahedron mesh. The analysed cavity had radius 10 mm and height 15 mm. Cavity walls were supposed to be perfectly conducting. Eight eigen frequencies and eigen fields were calculated using high‐order basis functions (LT/QN).
Computation results together with analytical data are shown in Table 1. The table also contains relative calculation error δ. Azimuthal inhomogeneous modes are twice degenerated. Numerical errors remove this degeneration, so two eigen frequencies for each mode are given. Degenerated modes differ by their field, turned by 90° in azimuth direction and computation results confirm this phenomenon. Difference between degenerated eigen frequencies is no more than hundreds of per cent.
Mode
Analytical eigen frequency (EF), GHz
Mesh size
6768
15,026
26,580
EF, GHz
δ, %
EF, GHz
δ, %
EF, GHz
δ, %
TM010
11.474
11.502
0.235
11.4905
0.135
11.4848
0.085
TE111
13.302
13.317 13.319
0.11 0.135
13.3132 13.3139
0.084 0.089
13.3104 13.311
0.063 0.067
TM011
15.216
15.232
0.098
15.2287
0.077
15.2241
0.052
TE211
17.670
17.696 17.705
0.147 0.198
17.6853 17.6877
0.086 0.102
17.6802 17.6811
0.058 0.063
TM110
18.284
18.3246 18.3287
0.222 0.244
18.3081 18.3102
0.131 0.143
18.299 18.291
0.082 0.083
Table 1.
Comparison of analytical and computational eigen frequencies for a cylindrical cavity.
The table demonstrates that eigen frequency calculation error decreases with mesh refinement and not exceeds 0.1% on the last mesh.
Another example, an electric dipole, consisted of two perfectly conducting cylinders, connected to the linear‐lumped source (Figure 6). To solve this outer problem, we ought to constrain computational region by the so‐called air box with ABC on its surface. The code automatically determines air box size so that the minimal distance between the dipole and the air box is not less than λ/4, where λ is wavelength in free space.
Figure 6.
A dipole model: a, dipole structure; b, mesh; c, 3D directivity chart; d, 2D directivity chart in the plane ϕ=0.
Cylinders have diameter 0.5 mm and length 9.5 mm. Together with a lumped port of 1‐mm length, the total dipole length is 20 mm. Excitation frequency was chosen to be 1.5 GHz, so the ratio l/λ=0.1. Such a dipole can be considered as elemental (Figure 6a). Its directivity is described by the formula D(θ,ϕ)=1.5sin2θ.
Figure 6b shows mesh used in simulation. The sphere inside cylinder contains refined local mesh, surrounding the dipole. The total number of tetrahedrons is 64553. The 3D directivity chart is shown in Figure 6c, and 2D directivity chart in plain ϕ=0 in Figure 6d. Calculated dipole directivity is 1.506 with relative error of 0.4 %. This error can be caused by the finite diameter of cylinders.
Figure 7a shows handset together with human head and hand phantoms. The handset has PIFA‐type antenna. Reflection coefficient of this antenna in the presence of the phantoms was calculated by RFS code and code SEMCAD [19], based on FDTD method.
Figure 7.
A handset with human head and hand phantoms: a, model; b, reflection coefficient chart.
Finite element mesh built by the RFS code in the phantom contains only 200,000 tetrahedrons. The total mesh size was about 450,000 tetrahedrons. Efficient algorithm of SAR calculation, implemented in the RFS code, provides using such comparatively small mesh size without the loss of accuracy. SEMCAD hexagonal mesh had about 1.5 billion of cells.
Figure 7b shows the module of reflection coefficient versus frequency for FRS and SEMCAD. As can be seen, both codes give similar results, especially for resonant frequencies.
We also calculated maximum SAR level in a brain tissue, averaged on 1 g of the tissue. The results are shown in Table 2. As can be seen, both codes give similar results, but SEMCAD solution time was nearly five times greater than RFS.
Frequency, MHz
SAR, W/kg
RFS
SEMCAD
900
1.08
1.06
2000
1.18
0.99
Table 2.
SAR, averaged over 1 g of brain tissue
8. Conclusion
The problem of high‐frequency electromagnetic field simulation is formulated. A short survey of numerical methods for solving high‐frequency electromagnetic problems is presented. It was shown that one of the most efficient methods for solving inner EMP and outer EMP with moderate electrical size is the vector finite element method in frequency domain. The algorithm of this method, including mesh generation, building of the global matrix, boundary conditions approximation, SLAE solving and FFS technique was described. Some peculiarities of lumped ports and elements implementation into the RFS computer code were also depicted. Simulation results for a simple systems having analytical solution, as well as for complex problems, such as handset antenna analysis near human head show high accuracy and efficiency of the code. The code can be used for the solution of antenna problems, waveguide problems, PCB analysis and microwave resonator problems.
Acknowledgments
The author expresses his deep gratitude for valuable help provided by R.V. Salimov and R.I. Tikhonov from the Russian R&D Centre LG Electronics Inc.
\n',keywords:"electromagnetics, numerical methods, computer simulation, microwaves, cellular phones",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/54292.pdf",chapterXML:"https://mts.intechopen.com/source/xml/54292.xml",downloadPdfUrl:"/chapter/pdf-download/54292",previewPdfUrl:"/chapter/pdf-preview/54292",totalDownloads:1631,totalViews:393,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:50,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"August 30th 2016",dateReviewed:"January 17th 2017",datePrePublished:null,datePublished:"June 7th 2017",dateFinished:"March 2nd 2017",readingETA:"0",abstract:"High‐frequency and microwave electromagnetic fields are used in billions of various devices and systems. Design of these systems is impossible without detailed analysis of their electromagnetic field. Most of microwave systems are very complex, so analytical solution of the field equations for them is impossible. Therefore, it is necessary to use numerical methods of field simulation. Unfortunately, such complex devices as, for example, modern smartphones cannot be accurately analysed by existing commercial codes. The chapter contains a short review of modern numerical methods for Maxwell's equations solution. Among them, a vector finite element method is the most suitable for simulation of complex devices with hundreds of details of various forms and materials, but electrically not too large. The method is implemented in the computer code radio frequency simulator (RFS). The code has friendly user interface, an advanced mesh generator, efficient solver and post‐processor. It solves eigenmode problems, driven waveguide problems, antenna problems, electromagnetic‐compatibility problems and others in frequency domain.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/54292",risUrl:"/chapter/ris/54292",book:{id:"5707",slug:"computer-simulation"},signatures:"Andrey D. Grigoriev",authors:[{id:"195247",title:"Prof.",name:"Andrey",middleName:null,surname:"Grigoriev",fullName:"Andrey Grigoriev",slug:"andrey-grigoriev",email:"adgrigoriev@mail.ru",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195247/images/4789_n.jpg",institution:{name:"Saint Petersburg State Electrotechnical University",institutionURL:null,country:{name:"Russia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Basic equations",level:"1"},{id:"sec_3",title:"3. Basis stages of electromagnetic problem solution",level:"1"},{id:"sec_4",title:"4. Numerical methods classification",level:"1"},{id:"sec_5",title:"5. Finite element method for electromagnetics",level:"1"},{id:"sec_5_2",title:"5.1. Main features of the method",level:"2"},{id:"sec_6_2",title:"5.2. Mesh generation",level:"2"},{id:"sec_7_2",title:"5.3. Basic equation",level:"2"},{id:"sec_8_2",title:"5.4. Numerical approximation of boundary conditions",level:"2"},{id:"sec_9_2",title:"5.5. Fast‐frequency sweep",level:"2"},{id:"sec_11",title:"6. The RFS code description",level:"1"},{id:"sec_12",title:"7. Computation results",level:"1"},{id:"sec_13",title:"8. Conclusion",level:"1"},{id:"sec_14",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Higdon R.L. Numerical absorbing boundary conditions for wave equation. Math. Comp. 1987;49:65–90.'},{id:"B2",body:'Stratton J.A. Electromagnetic Theory. 1st ed. New York and London: McGraw‐Hill Book Company; 1941. 648 p.'},{id:"B3",body:'Jackson J.D. Classical Electrodynamics. 3rd ed. New York: John Wiley & Sons, Inc.; 1999. 815 p.'},{id:"B4",body:'Yee K.S. Numerical solution of initial boundary value problems involving Maxwell\'s equations in isotropic media. IEEE Trans. Antennas Propag. 1966;14(5):302–307.'},{id:"B5",body:'Taflov A., Hagness S.C. Computational Electrodynamics: The Finite‐Difference Time‐Domain Method. 3rd ed. New York: Artech House; 2006. 1006 p.'},{id:"B6",body:'Weiland T. A discretization method for the solution of Maxwell\'s equations for sis‐component fields. Electron. Commun. 1977;31(3):401–410.'},{id:"B7",body:'Johns P.B., Beurle R.L. Numerical solution of 2‐dimensional scattering problems using a transmission‐line matrix. Proc. IIE. 1971;118(9):1203–1208.'},{id:"B8",body:'Christpoulos C. The Transmission‐Line modelling Method. Oxford: Morgan and Claypool; 2006. 124 p.'},{id:"B9",body:'Courant R.L. Variational methods for solution of problems of equilibrium and vibration. Bull. Am. Math. Soc. 1943;5(1):1–23.'},{id:"B10",body:'Jin J. The Finite Element Method in Electromagnetic. 2nd ed. New York: John Wiley & Sons, Inc.; 2002. 752 p.'},{id:"B11",body:'Gibson W.C. The Method of Moments in Electromagnetics. Boca Raton, FL: Taylor & Francis Group; 2008. 272 p.'},{id:"B12",body:'Grigoriev A.D., Salimov R.V., Tikhonov R.I. Cellular handsets antenna modelling by finite element method. J. Commun. Technol. Electron. 2012;53(3):261–270.'},{id:"B13",body:'Grigoryev A.D., Salimov R.V., Tikhonov R.I. Efficient Analysis of Full Mobile Hanset CAD Models with Automatic Correction Geometric Errors. In: 26th Annual Review of Progress in Applied Computational Electromagnetics; April 26–29; Tampere, Finland. Tampere: Tampere University of Technology; 2010. pp. 416–420.'},{id:"B14",body:'Nedelec J.C. Mixed finite elements in R3. Numer. Meth. 1980;35:315–341. doi:10.1007/BF01396415.'},{id:"B15",body:'Webb J.P. Hierarchical vector basis functions of arbitrary order for triangular and tetrahedral finite elements. IEEE Trans. Antennas Propag. 1999;47(8):1244–1253.'},{id:"B16",body:'Andersen L.S., Volakis J.L. Hierarchical tangential vector finite elements for tetrahedra. IEEE Microw. Guided Wave Lett. 1998;8(3):127–129.'},{id:"B17",body:'Grigoryev A.D., Salimov R.V., Tikhonov R.I. Multiple‐cell lumped element and port models foe the vector finite element method. Electromagnetics. 2008;25(6):18–26.'},{id:"B18",body:'Slone R.D., Lee R., Lee J.‐F. Well‐conditioned asymptotic wave form evaluation for finite elements. IEEE Trans. Antennas Propag. 2003; 51(9):2442–2447.'},{id:"B19",body:'SPEAG. SEMCAD X, intuitive, powerful, DC to light [Internet]. 2014. Retrieved from http://www.speag.com/'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Andrey D. Grigoriev",address:"adgrigoriev@eltech.ru",affiliation:'
Saint‐Petersburg State Electrotechnical University ‘LETI’, Saint‐Petersburg, Russia
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1. Introduction
Since the end of 2019, when the first cases were documented in Wuhan (China), the corona virus disease 2019 (COVID-19), a zoonotic infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly and rampantly, raising major concerns regarding public health, while applying an unprecedented, continuous strain, on the global medical infrastructure. COVID-19 was officially declared a pandemic by the World Health Organization on 11 March 2020 [1], and since then it has affected over 400 million people worldwide, with a cumulative mortality rate of under 2% [2] and recent alleviation of clinical outcomes due to the development and widespread implementation of efficient vaccination. Taking into account the extreme polymorphism of clinical presentations, ranging from asymptomatic to severe systemic effects, mainly involving the respiratory and cardiovascular systems, and fatal, rapidly progressing, acute respiratory distress syndrome (ARDS), the containment of transmission, at least in the pre-vaccination era, and the therapeutic management of COVID-19 and its systemic complications, has proven to be quite a challenge for clinicians, especially in the case of high-risk patients [3].
A novel member of the β-coronavirus genus, group 2, the enveloped, positive-sense RNA single-stranded SARS-CoV-2, has established itself as the third emerging, highly pathogenic coronavirus, to infect humans and cause a large-scale outbreak since the early 2000s, after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) [4]. Even though mortality rates are lower for SARS-CoV2 than for previous related coronavirus outbreaks (>35% for MERS-CoV and > 10% for SARS-CoV), contagiousness is much higher (MERS-CoV and SARS-CoV had only 10000 cumulative cases between them), as transmission is mainly airborne (via respiratory droplets), with multiple alternative mechanisms being reported (aerosols, direct contact with contaminated surfaces, and fecal-oral transmission [4]).
From a genomic viewpoint, SARS-CoV-2 shares ~80% sequence identity with SARS-CoV and ~ 50% with MERS-CoV, encoding 16 nonstructural proteins (that make up the replicase complex), 9 accessory proteins, and 4 structural proteins – spike (S), envelope (E), membrane (M), and nucleocapsid (N). The SARS-CoV-2 life cycle revolves around the envelope S protein. Direct contact between the Spike receptor-binding domain and the innate cellular receptor (angiotensin-converting enzyme 2 – ACE2), if provided adequate cleavage of the viral Spike S1/S2 polybasic cleavage site by host-cell proteolytic enzymes, will ensure Spike activation in endosomes and virus-cell membrane fusion (cell surface and endosomal compartments), allowing viral RNA to be released into the host-cell cytosol. Viral replication ensues, with subsequent expulsion into the intercellular space [4]. In fact, the S gene of SARS-CoV-2 represents the distinguishing genomic feature from SARS-CoV, sharing <75% nucleotide identity [4].
The main tissue tropism of SARS-CoV-2 is pulmonary, targeting high ACE2 expression cells (airway/alveolar epithelial cells, vascular endothelial cells, and alveolar macrophages) [5]. Even so, higher levels of ACE2 messenger RNA expression can be found in many extra-pulmonary tissues as well and nearly undetectable amounts of ACE2 still support viral host-cell entry. Therefore, additional, underappreciated, cell-intrinsic factors must also be involved in host-cell entry [4]. Noteworthy, a subpopulation of human type II alveolar cells has been documented, which manifest abundant ACE2 expression, and concomitant high levels of messenger RNA, specific to certain cellular proviral genes (coding elements of the, SARS-CoV-2 cell entry facilitating, and endosomal transport system) [6]. Also, ACE2 expression regulation must be considered, as, during viral infection, ACE2 gene expression in human airway epithelial cells is upregulated by type I and II interferons [5].
Considering the multitude of the medical literature written on the topic of multisystem impairment occurred during the infection with the SARS-CoV-2 virus, the purpose of our research was to summarize the opinions of experts concerning the cardiovascular alterations associated with COVID-19, and for this aim we reviewed the most significant articles published on PubMed, Medline, and Research gate on these topics and provided individualized summaries of expert opinions.
2. Effects of the SARS-CoV-2 virus on the cardiovascular system
The COVID-19 pandemic greatly challenged clinicians, both due to the sheer number of patients, but also because of the lack of therapeutic consensus and incomplete understanding of disease pathogenesis. Most fatal cases of COVID-19 relate to a severe atypical pneumonia, accompanied by a sudden systemic deterioration, despite therapeutic intervention in the hospital setting.
The infection with the SARS-CoV-2 virus primarily affects the respiratory structures, but the involvement of the cardiovascular system is also frequent. Cardiovascular complications in addition to respiratory disease may develop in all phases of COVID-19, which can start with the dramatic picture of acute heart failure (ACF), acute coronary syndrome (ACS), pulmonary venous thromboembolism (VTE), or even sudden cardiac death, as shown in Figure 1. The pathophysiological mechanisms underlying these disproportionate effects of the SARS-CoV-2 infection on patients with cardiovascular comorbidities, however, remain incompletely understood [7]. Thromboembolic events, usually accompanied by violent, pulmonary, and/or systemic complications, have been described from early on, since the beginning of the pandemic, with infectious inflammatory response patterns rapidly shifting into a typical systemic inflammatory response syndrome (SIRS) or ARDS, which could potentially induce multi-organ failure (MOF) and, subsequently, death. As we enter the third year of the pandemic, COVID-19 pathophysiology is slowly unraveling as we begin to better comprehend the complex interplay between the direct cytotoxic effects of SARS-CoV-2 on pneumocytes and endothelial cells, the emerging local and systemic inflammatory response, and the ways in which these responses interact with hemostatic homeostasis, a mechanism which has been deemed as central and, at least to this extent, unprecedented [8].
Figure 1.
Main COVID-19-associated cardiovascular complications and underlying pathophysiological mechanisms.
2.1 Cardiac tissue damage
COVID-19 was initially considered to be solely a respiratory disease, yet clinical outcomes quickly revealed that, undeniably, this infection implies multi-organ involvement. Perhaps most notably, the heart has been shown to represents a target organ for SARS-CoV-2-related pathogenesis, with a high prevalence of cardiac injury following COVID-19, often diagnosed only through biomarker evaluation. Beyond subclinical myocardial damage, SARS-CoV-2 infection may also cause more aggressive, clinically apparent modifications, such as myocarditis, accompanied by a subsequent diastolic dysfunction or severe reduction of left ventricle ejection fraction, not to mention the fact that heart failure may represent a short−/long-term consequence of COVID-19-related inflammatory cardiomyopathy, with dramatic consequences regarding prognosis [9].
Regarding myocardial damage in COVID-19, although the full pathophysiology is still incompletely understood, multiple mechanisms are most likely incriminated (see Figure 2), which, globally, can be divided into two main groups: direct, specific modifications, related to the cytopathic effects of SARS-CoV-2 infection, and indirect, general modifications, commonly seen in other severe infections, as well [10].
Figure 2.
Pathophysiology of COVID-19-related myocardial injury [15, 16].
2.1.1 Direct cytopathic myocardial injury
The aforementioned ACE2, a type I transmembrane protein, highly expressed in different organs (heart, lungs, gut, and kidneys), mediates SARS-CoV-2 entry into the host cells, with different clinical implications, depending on the targeted organ, and represents the key molecular entity involved in the direct cytopathic effects of SARS-CoV-2 infection within the cardiac tissue. After entering the host cell through the host ACE2 receptor, SARS-CoV-2 utilizes the host’s RNA-dependent RNA polymerase to replicate its own structural proteins, which are then assembled, and the newly formed virions are released from the infected cells, perpetuating the viral life cycle. Theoretically, as a consequence of this process, infected cells may become damaged/destroyed [11].
This idea is supported by a recent autopsy study, analyzing cardiac tissue from 39 consecutive patients who died as a consequence of COVID-19, which found viral genome in the myocardial tissue, yet in situ hybridization showed that the most likely localization of SARS-CoV-2 not to be in the cardiomyocytes, but rather in interstitial cells or macrophages invading the myocardial tissue [12]. Even so, in engineered heart tissue models of COVID-19 myocardial pathology, SARS-CoV-2 demonstrated the ability to directly infect cardiomyocytes through ACE2, resulting in contractile deficits, cytokine production, sarcomere disassembly, and cell death [9].
Furthermore, ACE2 must not be viewed as a mere bystander in the pathophysiology of COVID-19 myocardial injury, seeing as, besides being the host cell receptor of SARS-CoV-2, ACE2 is an enzyme involved in the renin-angiotensin-aldosterone system (RAAS). Specifically, ACE2 cleaves angiotensin II, a very potent vasoconstrictor, into angiotensin 1–7, which manifests vasodilator and anti-inflammatory effects. ACE2 also demonstrates a weak affinity for angiotensin I (or proangiotensin, formed by the action of renin on angiotensinogen), competitively limiting angiotensin II synthesis by ACE. Angiotensin I is converted by ACE2 into the nonapeptide angiotensin 1–9, which will manifest vasodilator effects through subsequent angiotensin type 2 (AT2) receptor stimulation. Therefore, ACE2 can counteract the undesirable effects of angiotensin II, demonstrating vasodilator, antioxidant, and anti-fibrotic effects [13]. In the context of SARS-CoV-2 infection, after S protein binding is complete, the virus attaches ACE2 through membrane fusion and invagination, causing a downregulation of ACE2 enzymatic activity [13]. Additionally, ACE2 also demonstrates immunomodulatory properties, both directly, via its interactions with macrophages, and indirectly, as it reduces expression of angiotensin II, which stimulates inflammation [14]. Thus, ACE2 downregulation in the context of SARS-CoV-2 infection may increase angiotensin II levels, favoring AT1 receptor activity, with a subsequent vasoconstriction, fibrotic, proliferative, and pro-inflammatory effects [10].
2.1.2 Indirect mechanisms of myocardial injury
As is the case with all severe respiratory infections, COVID-19 has a general deleterious effect on the cardiovascular system, with fever and sympathetic activation causing tachycardia and implicitly increasing myocardial oxygen consumption [9, 10], while prolonged bed rest and systemic inflammation will favor coagulation disorders, as supported by clinical findings – both venous and atypical arterial thromboembolic events have been documented in COVID-19 patients (see subchapter 3.4. Thromboembolic events and bleeding risk). Hypoxemia, another hallmark of COVID-19, will determine enhanced oxidative stress and increased production of reactive oxygen species, with subsequent intracellular acidosis, mitochondrial damage, and cell death [7, 9].
Moreover, another series of indirect mechanisms for COVID-19-related myocardial damage appears as a result of the abnormal inflammatory response which may be elicited by SARS-CoV-2 infection (i.e. a pro-inflammatory surge, the so-called “cytokine storm,” which may occur as early as 1 week after the initial exposure and infection) [15].
Indeed, individual immune response is the cardinal element behind SARS-CoV-2 infection progression. Upon viral genome expulsion into the host cytosol, SARS-CoV-2 viral replication begins, with aberrant RNA sequences, byproducts of replication, being, in turn, detected by intracellular receptors, which activate the cellular antiviral response, involving enhanced leukocyte chemotaxis and transcriptional induction of type I and III interferons (IFN-I/-III), followed by under-regulation of IFN-stimulated genes [16]. Lung cell damage incurred during replication will also activate the local immune response, resulting in monocyte/macrophage recruitment [16], while chemokines will induce specific leukocyte subset recruitment and coordination [16]. Circulating immune cell relocation in the pulmonary tissue will determine additional cytokine/chemokine production, while also creating multiple imbalances in immune cell populations – increased leukocyte count and neutrophil-lymphocyte ratio, with decreased lymphocytes (especially T cells [17]), thus setting the scene for immune response dysregulation [3].
In fact, the relationship between SARS-CoV-2 infection and extensive activation of inflammation signaling pathways has been well documented, representing the main immunopathological mechanism through which severe forms occur, in susceptible individuals. During the acute phase of the infection, a disproportionate response occurs between T helper cell populations (types 1 and 2), characterized by high circulating levels of interleukin (IL)-1β, IL-1RA, IL-2, IL-6, IL-7, IL-8, IL-9 IL-10, interferon gamma-induced protein-10 (CXCL10), monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein 1α (CCL3) and 1β (CCL4), granulocyte colony-stimulating factor, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF) α [16, 18, 19], which mediate widespread lung inflammation, in an attempt to eradicate the pathogen [3]. The resulting hyper-inflammatory status, as well as the individual excessive levels of certain circulating cytokine species, have been independently associated with an unfavorable evolution and increased mortality [20]. This hyper-inflammatory state seems, at least intuitively, to be pivotal in the development of cardiac injury, seeing as positive correlations have been established between the increase in inflammatory markers and myocardial damage in COVID-19 [21, 22]. Indeed, this idea is additionally supported by previous studies, in other septic conditions, evidencing that the release of pro-inflammatory cytokines such as TNFα and IL-1β, were responsible for myocardial cells depression through modulation of calcium channel activity and nitric oxide production [23].
It may also be the case that the cytokine storm following SARS-CoV-2 infection determines the AHF, recurrently seen in severe COVID-19, as the inflammatory activation and oxidative stress background are similarly expressed generally in heart failure, predisposing to a more severe clinical course [24].
Lastly, the aforementioned marked inflammatory changes will also take place in the endothelium, as shown in postmortem histological studies, evidencing lymphocytic endotheliitis with apoptotic bodies and viral inclusion in multiple organs [7, 25]. Endotheliitis can lead to disseminated intravascular coagulation, with small or large vessels thrombosis and infarction, and will determine significant new vessel growth through a mechanism of intussusceptive angiogenesis [25].
2.2 Coagulation disturbances
After becoming infected, roughly 20% of COVID-19 patients will be incapable of controlling/halting viral replication through their initial immune response, which may be aberrant/insufficient or overwhelmed by a high initial viral load, or both [26]. This subgroup of patients will thus progress to a more severe disease phenotype, with aggravating symptomatology secondary to uncontrolled viral replication, leading to host pneumocyte and endothelial cell apoptosis, which in turn will activate platelets, induce procoagulant factor expression (fibrinogen, factors V, VII, VIII, X, and von Willebrand), and increase inflammatory response, as the body tries and fails to keep the infection localized to the lungs [27]. This sequence of host responses will additionally damage the pulmonary parenchyma (through further destruction of pneumocytes, microangiopathy, and inflammatory microthrombi), causing even more severe symptoms and hindering oxygenation, thus imposing the need for an additional oxygen supply. Even so, at this point, a relative balance between procoagulant and anticoagulant (but also pro-inflammatory/anti-inflammatory) factors is still maintained. In only approximately 5% of symptomatic patients, the pro-inflammatory processes involved in the immune response to SARS-CoV-2 infection will derail into the so-called “cytokine storm,” which will fuel pro-inflammatory and pro-coagulatory processes even further, resulting in systemic endotheliitis and capillary leakage, cellular dysfunction, organ dysfunction (including ARDS), and overt activation of the (systemic) coagulation cascade resulting in the need for critical organ support [28]. In fact, SARS-CoV-2 infection may trigger endothelial dysfunction not only through the direct cytopathic effect of invasion on vascular endothelial cells but also through indirect mechanisms, such as hypoxia and the induced inflammatory response [27]. Moreover, some patients have also manifested antiphospholipid antibodies [28].
Therefore, all factors of the classic Virchow triad are influenced during the course of COVID-19, and they contribute synergically to the risk of thromboembolic events: hemodynamic changes (increased blood viscosity due to elevated fibrinogen, but also venous stasis due to hospitalization and disease-related immobilization); hypercoagulability (due to an overwhelming inflammatory state, occurring early after infection); and endothelial injury/dysfunction (ACE2 receptor expression on endothelial cells allows viral entry and cytopathic effects – endotheliitis) [3].
3. Acute cardiovascular complications of COVID-19
3.1 Myocarditis/pericarditis
It is generally accepted that viral infections, and corona viruses even more, are a common cause of myocarditis, frequently associated with congestive heart failure (CHF), and an increased risk to sudden death due to ventricular arrhythmias [29]. Emerging data suggest an increased association between myocarditis and COVID-19, observed more frequently in hospitalized patients, associated with an increased risk of adverse outcome, including higher mortality rates [30].
According to Dallas criteria, acute myocarditis is defined as “inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical for the ischemic damage associated with coronary artery disease.” Proposed pathophysiological pathways are myocardial injury due to the direct action of the virus, mediated via ACE2 receptors, and an intense, prolonged inflammatory response resulting in the release of high amounts of cytokines [29, 31, 32] together with additional factors such as hypoxia, increased metabolic demands, and physiological stress. At biopsy, myocyte and interstitial cells necrosis and mononuclear cell infiltrates were detected.
The real prevalence of acute myocarditis in patients infected with the SARS-CoV-2 virus is difficult to establish. In the medical literature, in these patients, the estimated incidence of acute myocarditis ranges from 12–17% or even 22–31% in ICU patients [33]. The symptoms vary from mild, nonspecific ones: palpitations, breathlessness, chest pain, common in influenza, to the dramatic picture of AHF with dyspnea, arrhythmias, or even sudden cardiac death. On the electrocardiogram (ECG), there are nonspecific ST, PR, and T-wave abnormalities, but signs mimicking an ACS, tachyarrhythmias, and conduction disturbances associated or not with left ventricular echocardiographic alterations and elevated levels of high sensitive troponins are also frequently seen [31, 33]. Another aspect is that the main diagnostic criteria require endomyocardial biopsy and cardiac magnetic resonance imaging (MRI), which are sometimes difficult or even impossible to access in COVID-19 patients due to the increased risk of contamination [33, 34]. It has been discussed that the prevalence of myocarditis rose parallel with the evolving strains of the SARS-CoV-2 virus being higher in patients infected in 2021 than in 2020 [30].
The incidence of pericarditis in COVID-19 patients ranges from 3% to 4.8% [35, 36]. It is often associated with myocarditis in COVID-19 patients with pneumonia and elevated inflammatory markers, as demonstrated by Diaz et al. in a meta-analysis performed on 33 studies, mainly case reports. The principal mechanism seems to be an autoreactive, inflammatory response [36].
Pericarditis manifests itself with a variety of symptoms, such as chest pain, fever, and dyspnea [36]. Pericardial friction rub is seldom encountered (9.3%) [36]. The predominant characteristic of this type of pericarditis is pericardial thickening observed at transthoracic echocardiography (TTE) persisting several weeks during recovery [37]. Over 50% of patients have pericardial effusion, mostly small to moderate in size, with 34% having large pericardial effusion, and even pericardial tamponade developed in about half of this last subset of patients [36]. On the ECG, 60% of patients present the typical four-stage evolution: diffuse ST elevation with depression of the PR segment, normalization of ST elevation, diffuse T-wave inversion, and in the end, normalization of the ECG [66]. Some patients presented unspecific signs, such as diffuse ST elevation, PR depression, and focal T-wave inversion [36].
The treatment of acute pericarditis consists in high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen, Indomethacin, or Naproxen recommended until symptom relief is achieved, and in addition, colchicine is recommended to be used for 3 to 6 months. Aspirin may be an alternative to NSAIDs [36]. Although low to moderate doses of steroids could be recommended in patients with SARS-CoV-2 infection, in most cases, this therapy is started sooner because of the associated viral myocarditis [36]. Furthermore, steroids can also be added to NSAIDs and colchicine as triple therapy for patients with an incomplete response. In the case of cardiac tamponade, pericardial drainage represents the standard of care [36]. Usually, the evolution of pericarditis associated with COVID-19 is benign.
3.2 Acute coronary syndrome
An increased incidence of ACS has been reported in several viral infections such as influenza, SARS, and MERS, being associated with a 3- to 10-fold increased risk, but in COVID-19 exact data are lacking [31, 32]. As principal potential pathophysiological pathways are considered: destabilization of atherosclerotic plaques due to systemic inflammation with an increased release of pro-inflammatory cytokines, the “cytokine storm,” associated microangiopathy, activation of prothrombotic factors, as well as other specific changes of immune cell polarization toward more unstable phenotypes. Contributing factors also are myocardial oxygen supply/demand mismatch in the context of increased metabolic demands due to tachycardia/arrhythmias, fever, and hypoxia. These factors probably represent also the best explanation for the increased troponin levels observed in many patients with acute COVID-19 in the absence of typical cardiovascular manifestations (chest pain, specific ischemic electrocardiographic modification, and parietal hypokinesia at TTE) [31, 32], the more so as some other complications such as myopericarditis may have similar symptoms, and often patients with COVID-19 may not have typical angina symptoms.
Patients already suffering with coronary artery disease and heart failure may be exposed in a greater extent to ACS as a consequence of coronary plaque rupture or stent thrombosis in the context of systemic inflammation [31, 32]. For this reason, it is strongly recommended that in patients with a previous history of coronary artery disease and especially in those with coronary interventions, antiplatelet therapy should be continued, eventually even intensified, together with other plaque stabilizing agents such as statins, beta-blockers, and angiotensin-converting enzyme inhibitors [27, 30, 38, 39].
In this global health systems crisis, an adequate diagnosis and management of ACS is complicate and health care institutions worldwide have reexamined their protocols considering the increased risk of contamination of healthcare personal and the high requirements for protective equipment [34, 40, 41]. However, risk stratification is difficult due to limited bedside approach for an accurate ECG and TTE examination [31, 42]. The treatment of acute myocardial infarction (AMI) in COVID-19 patients is even more controversial. While in patients diagnosed with non-ST elevation myocardial infarction (non-STEMI), the result of a PCR testing could be expected prior to cardiac catheterization, in cases with ST elevation myocardial infarction (STEMI), the American College of Cardiology (ACC) recommends reconsidering fibrinolysis in patients with “low-risk STEMI” such as inferior without right ventricular extension, or lateral STEMI without altered hemodynamic. Thus percutaneous coronary intervention (PCI) remains the most indicated therapy, remaining the best option also in non-STEMI patients who are hemodynamically unstable [34, 42, 43].
In a large meta-analysis, DeLuca et al. concluded that COVID-19 pandemic has significantly impacted the therapy of patients with STEMI, with a 19% reduction in PCI procedures leading to increased morbidity and mortality, aspects evidenced also in other studies [34, 40, 43].
3.3 Increased risk of arrhythmias
Arrhythmias were observed precociously in COVID-19 patients worldwide, several centers reporting a large spectrum of electrocardiographic abnormalities [31, 32]. In most cases, sinus tachycardia due to multiple, concomitant causes (hypoperfusion, fever, hypoxia, and anxiety) was observed, but also atrial tachycardia and fibrillation (AF), and less frequently atrioventricular block (AVB) and polymorphic ventricular tachycardia (VT), significantly increasing the morbidity and mortality, and explaining at least in part, the increased number of cardiac arrests noticed in out-of-hospital patients [44, 45]. It was considered that underlying mechanisms are myocardial injury, inflammation, coexisting hypoxia, electrolytic (especially hypokalemia) and acid–base imbalances, and activation of the sympathetic nervous system, which is contributing the medication used to treat this disease such as hydroxychloroquine, azithromycin, and antivirals that prolong the QT interval [46, 47].
Perhaps the most comprehensive study written on this topic is the one of Coromilas et al. who analyzed data collected from over 4000 patients with COVID-19 and arrhythmias, from 4 continents and 12 countries, and concluded that the majority of them (81.8%) developed supraventricular arrhythmias including AF and atrial flutter, 21% of subjects had ventricular arrhythmias, and 22.6% developed bradyarrhythmias [47]. They also observed that arrhythmias were more frequent in patients over 60 years old, male gender prevailed, and frequently systemic hypertension and diabetes mellitus were associated comorbidities [33, 46, 47].
Treatment of arrhythmias should follow the standard guidelines for the management of arrhythmias focusing on the underlying pathophysiological mechanisms, and addressing as much as possible the reversible causes, especially electrolyte abnormalities. In the case of recurrent, uncontrolled ventricular arrhythmias not responding to antiarrhythmic therapy, implantable cardioverter defibrillators may be recommended, and for persistent high-degree AVB transvenous pacemaker insertion [48].
3.4 Thromboembolic events and bleeding risk
As the pandemic unravels, medical literature has provided robust insight into the unique mechanisms of and specific propensity for COVID-19 thrombogenicity, identified as considerably different from other severe infectious and non-infectious diseases. The relationship between SARS-CoV-2 infection and subsequent dysregulation of coagulation homeostasis is reflected in the various rates of occurrence of major venous and arterial thromboembolic/thrombotic events, which, in more extreme cases, have been documented to occur concomitantly. A recent comparative study, which retrospectively evaluated thromboembolic risk in large patient cohorts of COVID-19 and Influenza, found that COVID-19 was independently associated with a higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared to Influenza, with secondary analysis showing a similar risk for ischemic stroke and myocardial infarction, and a higher risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with COVID-19 [49].
In spite of early thromboprophylaxis, most frequently, VTE negatively impacts clinical outcomes in COVID-19 hospitalized patients, and the risk seems to be greatest in the intensive care unit (ICU) setting, among the critically ill [50]. Major arterial thrombotic events and VTE have been reported at a higher frequency, in COVID-19 ICU patients, as compared to non-ICU patients, over a 30-day period, despite a thromboprophylaxis rate of 85–90% [51]. Moreover, a recent meta-analysis of 12 studies, in which all patients were under thromboprophylaxis, with either low molecular weight or unfractionated heparin, still showed a 31% pooled prevalence of VTE for ICU admissions [52]. Very recently, an overall incidence of 17.3% for VTE among hospitalized COVID-19 has been reported (~2/3 DVT), with significant discrepancies between pooled incidences of VTE for ICU admissions as compared to general ward patients (27.9% vs. 7.1%, respectively), while including catheter-associated thromboembolism, isolated distal DVT, and isolated pulmonary emboli reached the highest incidence rates. Even so, VTE incidence was higher when assessed within a screening strategy (33.1% vs. 9.8% by clinical diagnosis), meaning that, in clinical practice, it is very likely that many COVID-19 patients with subclinical VTE remain undiagnosed [53]. Moreover, VTE prevalence in COVID-19 patients varies widely depending on the subpopulation evaluated, seemingly correlating well with disease severity and preexisting metabolic and cardiovascular comorbidities, a statement reflected by the variability of occurrence rates reported: <3% in non-ICU patient [51], >30% for ICU cases, with DVT and subsequent PE representing the most common thrombotic complication in the ICU setting [54], while autopsy findings of COVID-19 fatalities suggest it may reach nearly 60% [55].
Interestingly, amounting data suggest that the majority of so-called PE diagnoses occur without a recognizable source of venous embolism and may be better defined as primary in situ pulmonary arterial thrombosis, a direct consequence of the SARS-CoV-2 pulmonary disease, entailing thrombotic occlusion of small−/mid-sized pulmonary arteries, which will result in the infarction of afferent lung parenchyma [56]. This may explain why PE is the most prevalent thrombotic event seen in COVID-19 patients [54] and why screening yielded a higher incidence of VTE than clinical evaluation of asymptomatic patients. In a recent investigation, duplex ultrasound was performed for clinical suspicion of DVT, reporting 41.58% confirmed DVT, 6.93% superficial thrombophlebitis and, surprisingly, 23.76% PE (mostly involving distal pulmonary vessels), yet only 7.92% had PE and concomitant, associated DVT, meaning that 2/3 of PE occurred in the absence of a recognizable DVT, suggesting a causal mechanism of primary thrombosis rather than embolism [56]. Additionally, postmortem analyses of COVID-19 fatalities have frequently documented thrombosis of small- and mid-sized pulmonary arteries, a lesion capable of causing hemorrhagic necrosis, fibrosis, disruption of pulmonary circulation, acute pulmonary hypertension (PH), and ultimately death [55]. Other severe morphopathological modifications of pulmonary tissue architecture have also been frequently reported in COVID-19 autopsy reports, such as severe endothelial injury, with disruption of cell membranes, rampant vascular thrombosis, and significant angiogenesis [25], while other organs also showed microthrombotic lesions on autopsy, but at a lower rate (cardiac thrombi, epicardial coronary artery thrombi and microthrombi in myocardial capillaries, arterioles, and small muscular arteries) [55].
An aforementioned study, analyzing 184 COVID-19 ICU cases, all receiving thromboprophylaxis, demonstrated a 31% cumulative incidence of the defined vascular complication composite outcome (PE, DVT, ischemic stroke, ACS, or systemic arterial embolism). The main independent predictors of thrombotic complications identified were age, with an adjusted hazard ratio (aHR) of 1.05/per year, and coagulopathy [54]. Conversely, regarding VTE, an extensive meta-analysis (44 studies/14,866 hospitalized COVID-19 patients), on the topic acute complications and mortality, reported a much lower prevalence of 15% for VTE, than previously reported. This value may be influenced not only by cohort size but also by other factors such as heterogeneous reporting between the studies evaluated and increased risk of bias, resulting in very low-quality evidence [57].
On the other hand, as seen in the above-mentioned studies, VTE can still occur in noncritically ill COVID-19 patients; therefore, rigorous elaboration of adequate screening and risk stratification protocols for VTE, especially for mild and moderate COVID-19 phenotypes, will be essential, as these patients are much less likely to undergo tromboprophylaxis.
Regarding arterial thromboembolism (ATE), incidence rates among COVID-19 diagnosed patients have consistently been reported as being much lower than for VTE, since the early days of the pandemic (3.7%) to date [54]. Unsettlingly, large-vessel strokes in young and generally healthy people, which became infected with SARS-CoV-2, have been consistently reported [25, 55]. Early retrospective studies, seemingly corroborated these findings, claiming that acute, new-onset, cerebrovascular disease was not uncommon in COVID-19 patients – out 219 consecutive COVID-19 patients, 10 (4.6%) developed acute ischemic stroke and 1 (0.5%) had intracerebral hemorrhage [58] –,and that SARS-CoV-2 infection carried an increased risk of ACS, especially via coronary stent thromboses [59]. Nevertheless, investigations involving a much larger sample size showed that the actual incidence of ATE (thrombotic/embolic) is, in fact, much lower than initially reported in earlier studies [51, 60]. A large cohort retrospective study, evaluating 1114 COVID-19 patients with independently adjudicated thrombotic/embolic events, found stroke and ACS incidence were 0.1% (1/1114) and 1.3% (14/1114), respectively [51]. Most authors agree that thrombotic events occur early in the evolution of COVID-19, and in order to combat the hypercoagulable and prothrombotic state, administration of anticoagulants is recommended to reduce this risk [27].
Of great importance is the fact that, due to several factors such as thrombocytopenia, hyperfibrinolytic state, consumption of coagulation factors, which initiate their action later on, after 1 to 3 weeks, COVID-19 patients may also become prone to bleeding. This must be taken into account, especially in severe COVID-19 cases, where concomitant administration of anticoagulants as thromboprophylaxis is very likely to occur [61]. Additionally, critically ill COVID-19 patients have an even more increased bleeding risk, due to thrombocytopenia/platelet dysfunction or coagulation factor deficiencies, or both [62], which are frequent occurrences in this clinical population. Thus, it has become increasingly difficult to establish an adequate, integrative, anticoagulant prophylaxis strategy for COVID-19.
As opposed to the numerous investigations debating over thromboembolic events, there are much fewer articles focusing on major bleedings and just a few case reports on hematomas in COVID-19. Al-Shamkary et al. reported an overall incidence of 4.8–8% referring to bleeding events, and of 3.5% for major bleedings [62], being mostly associated with advanced age, comorbidities and apparently, more frequent in males.
All in all, thromboembolic events are a frequent morbidity encountered in COVID-19 patients, especially in those with severe forms and comorbidities. For their prophylaxis/treatment anticoagulant therapy is recommended, thus increasing the risk of bleedings. Both thromboembolic events and hemorrhagic complications aggravate the evolution of these patients, representing significant negative prognostic factors and increasing the morbidity and mortality associated with COVID-19.
4. Subacute and long-term cardiovascular sequels following the infection with the SARS-CoV-2 virus
The important contribution of COVID-19 in the pathogenesis of acute cardiovascular involvements is now well established, but because this pandemic is a new disease, long-term data on post-COVID-19 complications were not available [63, 64]. However, more and more studies revealed that the infection with the SARS-CoV-2 virus also causes chronic cardiac complications, even when the viral load is normalized [63, 64], explaining the persistence of symptoms during recovery observed in an increasing number of individuals [65]. In some patients, myocarditis, subacute pericarditis, persisting arrhythmias, pulmonary hypertension, or heart failure have been observed raising serious concerns and indicating that in symptomatic patients, a comprehensive evaluation and a regular long-term follow-up are needed for effective therapeutic regime and to prevent a worse evolution of these cardiovascular complications.
4.1 Pulmonary hypertension
It is well known that pulmonary hypertension (PH) may occur during the acute phase of the SARS-CoV-2 infection as a consequence of extensive lung injury and of altered pulmonary circulation, frequently leading to right heart failure (RHF), shearing common pathophysiological mechanisms with other complications encountered in this illness, and significantly increasing the mortality [66, 67].
In COVID-19 patients, the prevalence of PH varies wildly, depending on the studied population, ranging from 7.69% to 12–13,4% or even 22% in severe COVID-19 cases [67, 68]. While this topic was largely debated in the medical literature, information over its outcome is less available. It has been observed that some patients are predisposed to develop interstitial lung disease (ILD) frequently associated with persisting PH and explaining, at least partially, the persisting symptoms observed in patients with subacute and long COVID-19 [69, 70]. The backgrounds of this disease are complex and multifactorial, including a large variety of pathophysiological types, ranging from arterial PH (group 1), PH of group 3 – due to ILD, to chronic thromboembolism (group 4 PH) or even of group 2 PH (secondary left heart disease) [70, 71]. In their study, Suzuki et al., observed a unique hystopathological finding identified only at the autopsy of COVID-19 patients, namely thickened pulmonary vascular walls, considered an important hallmark of arterial PH [71]. This finding suggests that COVID-19, depending on the severity of the lung injury and the inflammatory responses, could favor the development of PH, and some of these patients may develop in the future signs and symptoms of PH and RHF [71].
The diagnosis of PH is difficult and implies right heart catheterization, which is limited during the pandemic considering the risk of contamination and shortness of personal and resources. In patients infected with SARS-CoV-2, TTE allows an accurate estimation of the systolic pressure in the pulmonary artery, being the most utilized method for the diagnostic and follow-up of these patients. A specific therapy for this type of PH has not been described, and future studies are needed to clarify its management.
4.2 Heart failure
AHF may appear precocious in the evolution of the SARS-CoV-2 infection, in some cases being even the first manifestations. Since COVID-19 and AHF/worsening of CHF shear similar symptoms, distinguishing these two pathologies is challenging, the more so as these two conditions may coexist. Some studies describe an increased prevalence of ACH (23% or even 33%) in patients hospitalized for COVID-19 being associated with an increased risk of mortality [63]. In many cases, it is difficult to establish if AHF is the consequence of a new myocarditis/cardiomyopathy or it represents the exacerbation of previously undiagnosed CHF. Responsible pathophysiological mechanisms of AHF in COVID-19 may include acute myocardial injury due to inflammation (myocarditis), tachyarrhythmia or ischemia, or to acute respiratory failure, acute kidney injury, and hypervolemia [9, 29, 31]. Importantly, RHF may also be present especially in patients with severe pulmonary injury and PE contributing to the increased mortality of these patients [37].
Diagnosis may be difficult, but clinical presentation, history of preexisting cardiovascular comorbidities, evidence of cardiomegaly, and/or bilateral pleural effusion on chest radiography are suggestive. Increased levels of B-type natriuretic peptide (BNP)/N-terminal B-type natriuretic peptide (NT-proBNP) could be an important clue for AHF/worsened CHF, although elevated BNP/NT-proBNP values were also found in COVID-19 patients in the absence of AHF. An important contribution offers TTE demonstrating enlarged cardiac cavities, impaired systolic performance, and other important signs [34, 49, 72].
Therapy of AHF in COVID-19 patients should be performed according to guidelines [63] based on the same recommendation as in subjects without COVID-19, with special attention to early detection and treatment of complications, especially hypoxia, thrombotic/bleeding events, and cardiac arrhythmias. It is important to consider AHF/CHF when administering intravenous fluids avoiding excessive fluid replacement and to be conscious on the cardiac adverse effects of medications used in the treatment of COVID-19 [9, 31, 64].
Referring to patients already diagnosed with CHF, it is well known that they are predisposed to develop more severe forms of COVID-19, being predisposed to a higher mortality. The SARS-CoV-2 infection may also unmask a latent CHF, particularly heart failure with preserved ejection fraction (HFpEF) which is common among elderly overweight, hypertensive patients. In addition, as a consequence of myocardial injury, cardiac fibrosis may occur, explaining the increased frequency of diastolic dysfunction identified on TTE. The risk to develop overt CHF is present both during the acute phase of COVID-19 and during the recovery from the acute illness in survivors [31, 33, 72, 73].
Another aspect is that the COVID-19 pandemic negatively impacted the outcome of patients with CHF who avoided or delayed hospital controls or admissions due to fear of contamination. They presented themselves to the hospital only when their condition was severe, which lead to an increased mortality worldwide [9, 74].
4.3 New onset or aggravation of systemic hypertension
The relationship between the infection with the SARS-CoV-2 virus and systemic hypertension is very complicated and difficult to establish. While it is generally accepted that COVID-19 patients with a history of cardiovascular diseases, especially systemic hypertension, have a worse outcome and increased mortality [29, 75], it is very difficult to establish if there is a new onset or a worsening of a chronic hypertension in the context of this illness, since a previous comprehensive evaluation is not available in the majority of cases. A meta-analysis of Lippi et al. evidenced a nearly 2.5-fold increase of severity and mortality of severe COVID-19 in patients with associated systemic hypertension, especially in those older than 60 years with other comorbidities [75].
Other large meta-analyses focused on the impact of hypertension’s severity and its control and the outcomes but failed to document significant connections [76]. It was concluded that hypertension is associated with endothelial dysfunction strongly impacted in COVID-19, and patients with more severe forms have more advanced atherosclerosis and consecutive complications, thus increasing the morbidity and mortality. As the concerns regarding therapy with ACE inhibitors were not found to be justified, treatment should be given according to guidelines to optimize blood pressure values [77].
4.4 Postural orthostatic tachycardiac syndrome
The postural tachycardia syndrome (POTS) is the result of an autonomic dysregulation which determines increased vasoconstriction when standing, resulting in blood pooling within the splanchnic vasculature and limbs, with reduced venous return to the heart. An excessive compensatory tachycardia and increased plasma noradrenaline levels contribute to symptoms, the commonest of which are fatigue, palpitations, light-headedness, headache, and nausea symptoms reported by many of patients with long-COVID (between 15% and 50% according to some studies) [78]. Although orthostatic intolerance is common among patients recovering from a COVID-19 infection, not all have POTS, some of them have only orthostatic hypotension [78].
The exact pathophysiological mechanism of POTS is not fully clarified, and there are several mechanisms involved, including hypovolemia, autonomic denervation, hyperadrenergic stimulation, and autoimmune pathology. It is not well established whether the same recognized pathophysiology of POTS is also present in patients with long COVID further studies being necessary [78].
4.5 Aggravation of preexisting cardiovascular pathologies
From the early stages of the infection with the SARS-CoV-2 virus, it became evident that underlying cardiovascular diseases, obesity, diabetes mellitus, and more advanced age are associated with a higher risk for severe COVID-19 infection [34]. Individuals already suffering from cardiovascular diseases were more likely to be infected with the virus, and the virus infection was likely to determine the deterioration of basic heart disease [79]. Apparently, among COVID-19 patients, there were almost 50% diagnosed with chronic diseases, 40% of them with cardiovascular and cerebrovascular disorders, chronic kidney failure, and chronic obstructive pulmonary disease, having an increased risk of morbidity or even death related to this infection. A large study from the USA reported that the most common comorbidities among patients with COVID-19 were systemic hypertension (56.6%), obesity (41.7%), diabetes (33.8%), coronary artery disease (11.1%), and CHF (6.9%) [33], and a retrospective cohort study in China conducted on patients with cardiovascular comorbidities evidenced a fivefold higher mortality risk (10.5%). Based on these results, hypertension and cardiovascular comorbidities can be considered as risk factors for persons with severe symptoms of the disease.
In COVID-19 cases, it is important to recognize the clinical characteristics of infected persons to identify and effectively treat the associated comorbidities and the newly developed cardiovascular complications as well to reduce patients’ morbidity and mortality. Since many antiviral drugs may determine cardiac insufficiency, arrhythmia or other cardiovascular disorders, therefore, during the therapy of this illness, especially with antiviral therapy, the risk of cardiac toxicity needs to be closely monitored [79].
Another aspect is that of the long-term outcome of patients who suffered from a SARS-CoV-2 infection. In a recent and comprehensive study realized on over 150000 individuals recovering from COVID-19 [80], Xie et al. highlighted that beyond the first month after infection, people with COVID-19 experienced at 12 months an increased morbidity risks and burdens of cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease, and other cardiac disorders [80]. These risks were obvious regardless of age, race, gender, and associated cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease, and hyperlipidemia, being evident even in individuals without history of cardiovascular pathology before the SARS-CoV-2 virus infection, raising concerns that these risks might be present even in people at low risk of cardiovascular disease [80]. These risks and associated burdens increased parallel to the severity of the acute phase of COVID-19: from non-hospitalized individuals – who were the majority – to hospitalized patients, especially to those admitted to the intensive care units [80].
4.6 Cardiovascular effects of medication used to treat COVID-19
It has been observed that many of the medications used for the treatment of COVID-19 strongly interfere with other medications used in the therapy of cardiovascular diseases, such as anticoagulants, antiplatelets, statins, antihypertensives, and especially antiarrhythmics favoring the occurrence of arrhythmias [31]. Some antibiotics (azithromycin), corticosteroids, antimalarials (chloroquine, hydroxychloroquine), newly developed therapies, still under study such as antivirals (remdesivir, ribavirin, lopinavir/ritonavir, and favipiravir), and biologics (tocilizumab) determine cardiotoxicity, interact with electrolyte metabolism, and many of them, especially Lopinavir/ritonavir, may cause QT and PR prolongation favoring the occurrence of arrhythmias or conduction disturbances, mainly in patients already treated with drugs prolonging the QT interval. Data over the mechanism of action and potential effects of main medication used in the treatment of COVID-19 is presented in Table 1 [31].
Medication
Mechanism of action
Cardiovascular effects and drug interactions
Azithromycin
Interacts with the synthesis of proteins and binds to 50s ribosome
Interferes with statins, anticoagulants, and antiarrhythmics, prolonging QT interval and favoring arrhythmias (torsades de pointes).
Chloroquine and Hydroxychloroquine
Alterations in the pH of endosomal/organelle
May induce direct myocardial toxicity worsening myocarditis and cardiomyopathy.
Alter intracardiac conduction resulting in bundle branch block, AV block.
Interact with antiarrhythmics favoring ventricular arrhythmias, torsades de pointes.
Methylprednisolone
Anti-inflammatory
Determines fluid retention, hypertension, and dyselectrolytemia.
Interacts with anticoagulants.
Remdesivir
Inhibitor of RNA polymerases
May cause hypotension and arrhythmias.
Ribavirin
Inhibits RNA and DNA virus replication
Interacts with anticoagulants.
May cause severe hemolytic anemia.
Lopinavir/Ritonavir
Lopinavir inhibits protease and Ritonavir inhibits CYP3A metabolism
Interacts with anticoagulants, antiplatelets, statins, and antiarrhythmics.
May determine prolonged QT interval, AV blocks, and torsades de pointes.
Favipiravir
Inhibits RNA-dependent RNA polymerases
Interacts with anticoagulants, statins, and antiarrhythmics.
May interfere with some medication metabolism such as statins.
May determine hypertension.
Table 1.
Interactions of medications used in the treatment of COVID-19.
4.7 Cardiovascular effects related to vaccination
After the introduction of mRNA COVID-19 vaccines a higher incidence of myocarditis in vaccine recipients. A study performed on the data basis from an Israeli national database concluded that the incidence of myocarditis after two doses of the BNT162b2 mRNA vaccine was reduced (risk ratio = 3.24), significantly lower than after COVID-19 (risk ratio = 18.28), but higher than in unvaccinated individuals. The risk of myocarditis was higher after the second dose of vaccine and in young male recipients [81].
Similar results were also reported by other researcher, with an elevated risk of myocarditis, pericarditis, and myopericarditis observed particularly among young males with 39–47 expected cases of per million second mRNA COVID-19 vaccine doses administered [82]. They reported an increased risk of myocarditis after the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine [82].
5. Conclusions
The impairment of the cardiovascular system in COVID-19 comprises a wide spectrum of dysfunctions, ranging from mild to severe, or even life-threatening forms, often having an acute onset, sometimes continuing during recovery or even resulting in chronic pathologies. Individuals are affected regardless of age, race, gender, and associated cardiovascular risk factors, but those with a history of cardiovascular pathology prior to the SARS-CoV-2 virus infection have a worse outcome. Therefore, a comprehensive cardiologic evaluation, including TTE, is justified to assess the involvement of the cardiovascular system, for initiating a proper therapy as soon as possible and to schedule a follow-up program particularly in patients at high risk.
\n',keywords:"COVID-19, inflammation, cytokine storm, myocardial injury, heart failure, thromboembolic events, arrhythmias",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81733.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81733.xml",downloadPdfUrl:"/chapter/pdf-download/81733",previewPdfUrl:"/chapter/pdf-preview/81733",totalDownloads:13,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 12th 2022",dateReviewed:"February 27th 2022",datePrePublished:"May 13th 2022",datePublished:null,dateFinished:"May 13th 2022",readingETA:"0",abstract:"Although the infection with the severe acute respiratory syndrome (SARS-CoV-2) virus affects primarily the respiratory system, it became evident from the very beginning that the coronavirus disease 2019 (COVID-19) is frequently associated with a large spectrum of cardiovascular involvements such as myocarditis/pericarditis, acute coronary syndrome, arrhythmias, or thromboembolic events, explained by a multitude of pathophysiological mechanisms. Individuals already suffering of significant cardiovascular diseases were more likely to be infected with the virus, had a worse evolution during COVID-19, with further deterioration of their basal condition and increased morbidity and mortality, but significant cardiac dysfunctions were diagnosed even in individuals without a history of heart diseases or being at low risk to develop such a pathology. Cardiovascular complications may occur anytime during the course of COVID-19, persisting even during recovery and, potentially, explaining many of the persisting symptoms included now in terms as subacute or long-COVID-19. It is now well accepted that in COVID-19, the occurrence of cardiovascular impairment represents a significant negative prognostic factor, immensely rising the burden of cardiovascular pathologies.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81733",risUrl:"/chapter/ris/81733",signatures:"Cristina Tudoran, Mariana Tudoran, Voichita Elena Lazureanu, Adelina Raluca Marinescu, Dorin Novacescu and Talida Georgiana Cut",book:{id:"11369",type:"book",title:"RNA Viruses",subtitle:null,fullTitle:"RNA Viruses",slug:null,publishedDate:null,bookSignature:"Ph.D. Yogendra Shah",coverURL:"https://cdn.intechopen.com/books/images_new/11369.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-667-3",printIsbn:"978-1-80355-666-6",pdfIsbn:"978-1-80355-668-0",isAvailableForWebshopOrdering:!0,editors:[{id:"278914",title:"Ph.D.",name:"Yogendra",middleName:null,surname:"Shah",slug:"yogendra-shah",fullName:"Yogendra Shah"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Effects of the SARS-CoV-2 virus on the cardiovascular system",level:"1"},{id:"sec_2_2",title:"2.1 Cardiac tissue damage",level:"2"},{id:"sec_2_3",title:"2.1.1 Direct cytopathic myocardial injury",level:"3"},{id:"sec_3_3",title:"2.1.2 Indirect mechanisms of myocardial injury",level:"3"},{id:"sec_5_2",title:"2.2 Coagulation disturbances",level:"2"},{id:"sec_7",title:"3. Acute cardiovascular complications of COVID-19",level:"1"},{id:"sec_7_2",title:"3.1 Myocarditis/pericarditis",level:"2"},{id:"sec_8_2",title:"3.2 Acute coronary syndrome",level:"2"},{id:"sec_9_2",title:"3.3 Increased risk of arrhythmias",level:"2"},{id:"sec_10_2",title:"3.4 Thromboembolic events and bleeding risk",level:"2"},{id:"sec_12",title:"4. Subacute and long-term cardiovascular sequels following the infection with the SARS-CoV-2 virus",level:"1"},{id:"sec_12_2",title:"4.1 Pulmonary hypertension",level:"2"},{id:"sec_13_2",title:"4.2 Heart failure",level:"2"},{id:"sec_14_2",title:"4.3 New onset or aggravation of systemic hypertension",level:"2"},{id:"sec_15_2",title:"4.4 Postural orthostatic tachycardiac syndrome",level:"2"},{id:"sec_16_2",title:"4.5 Aggravation of preexisting cardiovascular pathologies",level:"2"},{id:"sec_17_2",title:"4.6 Cardiovascular effects of medication used to treat COVID-19",level:"2"},{id:"sec_18_2",title:"4.7 Cardiovascular effects related to vaccination",level:"2"},{id:"sec_20",title:"5. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19-11 March 2020. [cited April 27, 2021]. 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Medical Hypotheses. 2021;147:110483'},{id:"B72",body:'Tudoran M, Tudoran C, Lazureanu VE, Marinescu AR, Pop GN, Pescariu AS, et al. Alterations of left ventricular function persisting during post-acute COVID-19 in subjects without previously diagnosed cardiovascular pathology. Journal of Personalized Medicine. 2021;11:225-232'},{id:"B73",body:'Baycan OF, Barman HA, Atici A, Tatlisu A, Bolen F, Ergen P, et al. Evaluation of biventricular function in patients with COVID-19 using speckle tracking echocardiography. International Journal of Cardiovascular Imaging. 2020;37(1):135-144'},{id:"B74",body:'Rey JR, Caro-Codón J, Rosillo SO, Iniesta ÁM, Castrejón-Castrejón S, Marco-Clement I, et al. Heart failure in COVID-19 patients: Prevalence, incidence and prognostic implications. European Journal of Heart Failure. 2020;22(12):2205-2215'},{id:"B75",body:'Lippi G, Wong J, Henry BM. Hypertension in patients with coronavirus disease 2019 (COVID-19): A pooled analysis. Polish Archives of Internal Medicine. 2020;130(4):304-309'},{id:"B76",body:'Sheppard JP, Nicholson BD, Lee J, McGagh D, Sherlock J, Koshiaris C, et al. Association between blood pressure control and coronavirus disease 2019 outcomes in 45 418 symptomatic patients with hypertension: An Observational Cohort Study. Hypertension. 2021;77(3):846-855'},{id:"B77",body:'World Health Organization. Guideline for the Pharmacological Treatment of Hypertension in Adults. Geneva: World Health Organization; 2021 [cited February 8, 2022]. Available from: https://apps.who.int/iris/handle/10665/344424'},{id:"B78",body:'Kavi L. Postural tachycardia syndrome and long COVID: An update. The British Journal of General Practice. 2022;72(714):8-9'},{id:"B79",body:'Naeini MB, Sahebi M, Nikbakht F, Jamshidi Z, Ahmadimanesh M, Hashemi M, et al. A meta-meta-analysis: Evaluation of meta-analyses published in the effectiveness of cardiovascular comorbidities on the severity of COVID-19. Obesity Medicine. 2021;22:100323'},{id:"B80",body:'Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nature Medicine. 2022'},{id:"B81",body:'Mevorach D, Anis E, Cedar N, Bromberg M, Haas EJ, Nadir E, et al. Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel. The New England Journal of Medicine. 2021;385(23):2140-2149'},{id:"B82",body:'Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nature Medicine. 2021'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Cristina Tudoran",address:"tudoran.mariana@umft.ro",affiliation:'
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
Wellcome Trust (Funding available only to Wellcome-funded researchers/grantees)
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From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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The model parameters deciphered here are the amplitude coefficient (k), horizontal location (x0), depth of the body (z), and shape (q). Inversion of the model parameter suggests that constraining the horizontal location and the shape factor offers the most reliable results. Investigation of convergence rate, histogram, and cross-plot examination suggest that the interpretation method developed for the self-potential anomalies is stable and the model parameters are within the estimated ambiguity. Inversion of synthetic noise-free and noise-corrupted data for single structures and multiple structures in addition to real field information exhibits the viability of the method. The model parameters estimated by the present technique were in good agreement with the real parameters. The method has been used to invert two field examples (Sulleymonkoy anomaly, Ergani, Turkey, Senneterre area of Quebec, Canada) with application of subsurface mineralized bodies. 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In fact, under some specific conditions the NCMs could be used either as effective adsorbent material or alternative source of minerals. This chapter presents an outline of a general review of factors that affect the application ability of NCMs and a descriptive analysis of NH4+ and REE adsorption behavior and extraction of rare earth elements (REE) by an ion-exchange with NH4+ ions onto NCMs. Clays and NCMs both effectively remove various contaminants from aqueous solution and serve as alternative sources of minerals, as extensively discussed in this chapter. This review compiles thorough literature of current research and highlights the key findings of adsorption (NH4+ and REE) that use different NCMs as adsorbents or alternative sources of minerals (i.e., REE). The review confirmed that NCMs excellently remove different cations pollutants and have significant potential as alternative source of REE. However, modification and further development of NCMs applications for getting the best adsorption and the best extraction of REE onto NCMs, which would enhance pollution control and leaching system is still needed.",book:{id:"7315",slug:"minerals",title:"Minerals",fullTitle:"Minerals"},signatures:"Aref Alshameri, Xinghu Wei, Hailong Wang, Yang Fuguo, Xin Chen, Hongping He, Chunjie Yan and Feng Xu",authors:[{id:"172947",title:"Prof.",name:"Xin",middleName:null,surname:"Chen",slug:"xin-chen",fullName:"Xin Chen"},{id:"250327",title:"Dr.",name:"Aref",middleName:null,surname:"Alshameri",slug:"aref-alshameri",fullName:"Aref Alshameri"},{id:"306625",title:"Dr.",name:"Aref",middleName:null,surname:"Alshameri",slug:"aref-alshameri",fullName:"Aref Alshameri"},{id:"306656",title:"Prof.",name:"Fuguo",middleName:null,surname:"Yang",slug:"fuguo-yang",fullName:"Fuguo Yang"},{id:"306658",title:"Dr.",name:"Wei",middleName:null,surname:"Xinghu",slug:"wei-xinghu",fullName:"Wei Xinghu"},{id:"306660",title:"Prof.",name:"Wang",middleName:null,surname:"Hailong",slug:"wang-hailong",fullName:"Wang Hailong"},{id:"306664",title:"Prof.",name:"Yan",middleName:null,surname:"Chunjie",slug:"yan-chunjie",fullName:"Yan Chunjie"},{id:"306665",title:"Dr.",name:"Xu",middleName:null,surname:"Feng",slug:"xu-feng",fullName:"Xu Feng"},{id:"306671",title:"Prof.",name:"He",middleName:null,surname:"Hongping",slug:"he-hongping",fullName:"He Hongping"}]}],mostDownloadedChaptersLast30Days:[{id:"71052",title:"Enhanced Humidity Sensing Response in Eu3+-Doped Iron-Rich CuFe2O4: A Detailed Study of Structural, Microstructural, Sensing, and Dielectric Properties",slug:"enhanced-humidity-sensing-response-in-eu-sup-3-sup-doped-iron-rich-cufe-sub-2-sub-o-sub-4-sub-a-deta",totalDownloads:596,totalCrossrefCites:7,totalDimensionsCites:7,abstract:"The CuFe(2−x)EuxO4 (where x = 0.00, 0.01, 0.02, 0.03) nanoparticles are synthesized by solution combustion method. The influence of Eu3+ on the structural, morphological, dielectrical, and humidity sensing study is recorded. The XRD pattern peaks of the as-prepared CuFe(2−x)EuxO4 (where x = 0.00, 0.01, 0.02, 0.03) nanoparticle confirm the polycrystalline spinel cubic structure with a small amount of CuO impurity phase at 38.87° and 48.96°. Surface morphology of the samples was studied by scanning electron microscope (SEM) images of the nanoparticles, and their respective average grain size was estimated using Image software. Chemical composition of all prepared samples was analyzed by EDS spectra. The dielectric parameters of AC conductivity, electric modulus, and impedance of the samples were measured over a range of frequencies from 0.1 KHz to 1 MHz at room temperature. Europium-doped copper ferrite samples showed good humidity sensing response, response and recover times, and stability over a %RH range of 11–91%. These types of samples are very useful for sensor application, battery applications, electronic applications, and automotive applications.",book:{id:"9247",slug:"mineralogy-significance-and-applications",title:"Mineralogy",fullTitle:"Mineralogy - Significance and Applications"},signatures:"I.C. Sathisha, K. Manjunatha, V. Jagadeesha Angadi, B. Chethan, Y.T. Ravikiran, Vinayaka K. Pattar, S.O. Manjunatha and Shidaling Matteppanavar",authors:[{id:"266255",title:"Dr.",name:"Veerabhadrappa",middleName:null,surname:"Jagadeesha Angadi",slug:"veerabhadrappa-jagadeesha-angadi",fullName:"Veerabhadrappa Jagadeesha Angadi"},{id:"321561",title:"Dr.",name:"I.C.",middleName:null,surname:"Sathisha",slug:"i.c.-sathisha",fullName:"I.C. Sathisha"},{id:"321562",title:"Dr.",name:"K.",middleName:null,surname:"Manjunatha",slug:"k.-manjunatha",fullName:"K. Manjunatha"},{id:"321564",title:"Dr.",name:"B.",middleName:null,surname:"Chethan",slug:"b.-chethan",fullName:"B. Chethan"},{id:"321565",title:"Dr.",name:"Y.T.",middleName:null,surname:"Ravikiran",slug:"y.t.-ravikiran",fullName:"Y.T. Ravikiran"},{id:"321566",title:"Dr.",name:"Vinayaka K.",middleName:null,surname:"Pattar",slug:"vinayaka-k.-pattar",fullName:"Vinayaka K. Pattar"},{id:"321567",title:"Dr.",name:"S.O.",middleName:null,surname:"Manjunatha",slug:"s.o.-manjunatha",fullName:"S.O. Manjunatha"},{id:"321568",title:"Dr.",name:"Shidaling",middleName:null,surname:"Matteppanavar",slug:"shidaling-matteppanavar",fullName:"Shidaling Matteppanavar"}]},{id:"65826",title:"Introductory Chapter: Mineral Exploration from the Point of View of Geophysicists",slug:"introductory-chapter-mineral-exploration-from-the-point-of-view-of-geophysicists",totalDownloads:1635,totalCrossrefCites:3,totalDimensionsCites:3,abstract:null,book:{id:"7315",slug:"minerals",title:"Minerals",fullTitle:"Minerals"},signatures:"Khalid S. Essa and Marc Munschy",authors:[{id:"102766",title:"Prof.",name:"Khalid S.",middleName:null,surname:"Essa",slug:"khalid-s.-essa",fullName:"Khalid S. Essa"},{id:"292929",title:"Prof.",name:"Marc",middleName:null,surname:"Munschy",slug:"marc-munschy",fullName:"Marc Munschy"}]},{id:"69811",title:"Chemical Synthesis and Characterization of Luminescent Iron Oxide Nanoparticles and Their Biomedical Applications",slug:"chemical-synthesis-and-characterization-of-luminescent-iron-oxide-nanoparticles-and-their-biomedical",totalDownloads:564,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The syntheses and characterizations of biocompatible luminescent magnetic iron oxide nanoparticles has drawn particular attention as diagnostic and drug delivery tools for treatment of cancer and many other diseases. This chapter focuses on the chemical synthetic methods, magnetic and luminescent properties, including the biomedical applications of iron oxide nanomaterials and luminescent magnetic iron oxide-based nanocomposite materials. The influences of functionalizing with short ligands such as dopamine and L-cysteine on the magnetic properties of synthesized nanoparticles are described. The chapter contains some data on necessary reagents and protocols for bioconjugation aimed at cell culture and step by step the MTT assays used to evaluate cytotoxicity are also presented. In the final section of the chapter, we focus on the biomedical applications specifically for diagnosis and treatment of breast cancer treatment. This chapter also investigates the application of various characterization techniques for analysis of the structural, optical and magnetic properties of the iron oxide nanoparticles and as their nanocomposites.",book:{id:"9247",slug:"mineralogy-significance-and-applications",title:"Mineralogy",fullTitle:"Mineralogy - Significance and Applications"},signatures:"Martin Onani, Leandre Brandt and Zuraan Paulsen",authors:[{id:"258023",title:"Dr.",name:"Martin",middleName:null,surname:"Onani",slug:"martin-onani",fullName:"Martin Onani"},{id:"302723",title:"Dr.",name:"Leandré Bianca",middleName:null,surname:"Brandt",slug:"leandre-bianca-brandt",fullName:"Leandré Bianca Brandt"},{id:"302725",title:"MSc.",name:"Zuraan",middleName:null,surname:"Paulsen",slug:"zuraan-paulsen",fullName:"Zuraan Paulsen"}]},{id:"27429",title:"An Introduction to Mineralogy",slug:"an-introduction-to-mineralogy",totalDownloads:6621,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"1600",slug:"an-introduction-to-the-study-of-mineralogy",title:"An Introduction to the Study of Mineralogy",fullTitle:"An Introduction to the Study of Mineralogy"},signatures:"Cumhur Aydinalp",authors:[{id:"98959",title:"Prof.",name:"Cumhur",middleName:"---",surname:"Aydinalp",slug:"cumhur-aydinalp",fullName:"Cumhur Aydinalp"}]},{id:"27435",title:"A Review of Pathological Biomineral Analysis Techniques and Classification Schemes",slug:"a-review-of-pathological-biomineral-analysis-techniques-and-classification-schemes",totalDownloads:4303,totalCrossrefCites:1,totalDimensionsCites:6,abstract:null,book:{id:"1600",slug:"an-introduction-to-the-study-of-mineralogy",title:"An Introduction to the Study of Mineralogy",fullTitle:"An Introduction to the Study of Mineralogy"},signatures:"Maria Luigia Giannossi and Vito Summa",authors:[{id:"101919",title:"PhD.",name:"Maria Luigia",middleName:null,surname:"Giannossi",slug:"maria-luigia-giannossi",fullName:"Maria Luigia Giannossi"},{id:"108348",title:"Dr.",name:"Vito",middleName:null,surname:"Summa",slug:"vito-summa",fullName:"Vito Summa"}]}],onlineFirstChaptersFilter:{topicId:"651",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81626",title:"Use of Natural Safiot Clay for the Removal of Chemical Substances from Aqueous Solutions by Adsorption: A Combined Experimental and Theoretical Study",slug:"use-of-natural-safiot-clay-for-the-removal-of-chemical-substances-from-aqueous-solutions-by-adsorpti",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.101605",abstract:"The main objective of this work was to investigate the potential of Natural Safiot Clay (NSC), as an adsorbent for the removal of two cationic dyes such as Basic Blue 9 (BB9) and Basic Yellow 28 (BY28) from single and binary systems in aqueous solutions. For this, the effects of three factors controlling the adsorption process, such as initial dye concentration, adsorbent dose, and initial pH on the adsorption extent, were investigated and examined. The natural safiot clay was characterized using the following technique: energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), DRX, and Fourier transform infrared (FT-IR) and pH of the point of zero charge (pHZPC). Energy-dispersive X-ray spectroscopy results indicate high percentages of Silica and Alumina. FT-IR spectrum identified kaolinite as the major mineral phase in the presence of quartz, calcite, and dolomite. The quantum theoretical study confirms the experimental results, through the study of the global and local reactivity and the electrophilicity power of the dyes. The electrophilicity power of dyes affects the removal efficiency. The theoretical study proves that BB9 (ω = 6.178) is more electrophilic than BY28 (ω = 2.480) and more interactions with surface sites. The results of the molecular dynamics simulation indicate that the dyes are adsorbed parallel to the surface of natural Safi clay (kaolinite), implying the strong interaction with the kaolinite atoms. All the results of quantum chemistry calculations and simulations of molecular dynamics are in perfect agreement with the results of the experimental study.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Aziz El Kassimi, Mohammadine El Haddad, Rachid Laamari, Mamoune El Himri, Youness Achour and Hicham Yazid"},{id:"80866",title:"Normative Mineralogy Especially for Shales, Slates, and Phyllites",slug:"normative-mineralogy-especially-for-shales-slates-and-phyllites",totalDownloads:44,totalDimensionsCites:0,doi:"10.5772/intechopen.102346",abstract:"First, an insight into normative mineralogy and the most important methods for calculating the standard or norm minerals, such as the CIPW norm, is given. This is followed by a more detailed explanation of “slatenorm” and “slatecalculation” for low and very low metamorphic rocks, such as phyllites, slates, and shales. They are particularly suitable for fine-grained rocks where the mineral content is difficult to determine. They enable the determination of a virtual mineral inventory from full chemical analysis, including the values of carbon dioxide (CO2), carbon (C), and sulfur (S). The determined norm or standard minerals include the minerals—feldspars, carbonates, micas, hydro-micas, chlorites, ore minerals, and quartz. The advantages of slatenorm and slatecalculation compared to other methods for calculating normal minerals of sedimentary rocks are discussed.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Hans Wolfgang Wagner"},{id:"80770",title:"Mg-Ilmenite from Kimberlites, Its Origin",slug:"mg-ilmenite-from-kimberlites-its-origin",totalDownloads:57,totalDimensionsCites:0,doi:"10.5772/intechopen.102676",abstract:"The main regularities of the saturation of kimberlite rocks with the accessory mineral Mg-ilmenite (Ilm), the peculiarities of the distribution of Ilm compositions in individual pipes, in different clusters of pipes, in diamondiferous kimberlite fields, are considered as the example of studies carried out within the Yakutian kimberlite province (Siberian Craton). Interpretation of different crystallization trends in MgO-Cr2O3 coordinates (conventionally named “Haggerty’s parabola”, “Steplike”, “Hockey stick”, as well as the peculiarities of heterogeneity of individual zonal and polygranular Ilm macrocrysts made it possible to propose a three-stage model of crystallization Ilm: (1) Mg-Cr poor ilmenite crystallizing from a primitive asthenospheric melt; (2) Continuing crystallization in the lithospheric contaminated melt by MgO and Cr2O3; (3) Ilmenite subsequently underwent sub-solidus recrystallization in the presence of an evolved kimberlite melt under increasing oxygen fugacity (ƒO2) conditions.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Sergey I. Kostrovitsky"},{id:"80553",title:"Investigation of Accessory Minerals from the Blatná Granodiorite Suite, Bohemian Massif, Czech Republic",slug:"investigation-of-accessory-minerals-from-the-blatn-granodiorite-suite-bohemian-massif-czech-republic",totalDownloads:48,totalDimensionsCites:0,doi:"10.5772/intechopen.102628",abstract:"The Central Bohemian magmatic complex belongs to the Central European Variscan belt. The granitic rocks of this plutonic complex are formed by several suites of granites, granodiorites, and tonalites, together with small bodies of gabbros, gabbro diorites, and diorites. The granodiorites of the Blatná suite are high-K, calc-alkaline to shoshonitic, and metaluminous to slightly peraluminous granitic rocks. Compared to the common I-type granites, granodiorites of the Blatná suite are enriched in Mg (1.0–3.4 wt.% MgO), Ba (838–2560 ppm), Sr. (257–506 ppm), and Zr (81–236 ppm). For granodiorites of the Blatná suite is assemblage of apatite, zircon, titanite, and allanite significant. Zircon contains low Hf concentrations (1.1–1.7 wt.% HfO2). The composition of titanite ranges from 83 to 92 mol.% titanite end-member. Allanite is relatively Al-poor and displays Feox. ratio 0.2–0.5.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Miloš René"},{id:"80423",title:"Minerals as Prebiotic Catalysts for Chemical Evolution towards the Origin of Life",slug:"minerals-as-prebiotic-catalysts-for-chemical-evolution-towards-the-origin-of-life",totalDownloads:106,totalDimensionsCites:0,doi:"10.5772/intechopen.102389",abstract:"A transition from geochemistry to biochemistry has been considered as a necessary step towards the emergence of primordial life. Nevertheless, how did this transition occur is still elusive. The chemistry underlying this transition is likely not a single event, but involves many levels of creation and reconstruction, finally reaching the molecular, structural, and functional buildup of complexity. Among them, one apparent question is: how the biochemical catalytic system emerged from the mineral-based geochemical system? Inspired by the metal–ligand structures in metalloenzymes, many researchers have proposed that transition metal sulfide minerals could have served as structural analogs of metalloenzymes for catalyzing prebiotic redox conversions. This assumption has been tested and verified to some extent by several studies, which focused on using Earth-abundant transition metal sulfides as catalysts for multi-electron C and N conversions. The progress in this field will be introduced, with a focus on the CO2 fixation and ammonia synthesis from nitrate/nitrite reduction and N2 reduction. Recently developed methods for screening effective mineral catalysts were also reviewed.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Yamei Li"},{id:"80338",title:"Ionic Conductivity of Strontium Fluoroapatites Co-doped with Lanthanides",slug:"ionic-conductivity-of-strontium-fluoroapatites-co-doped-with-lanthanides",totalDownloads:54,totalDimensionsCites:0,doi:"10.5772/intechopen.102410",abstract:"Britholites derivatives of apatite’s that contain lanthanium and neodymium in the serial compounds Sr8La2−xNdx(PO4)4(SiO4)2F2 with 0 ≤ x ≤ 2 were subject of the present investigation. The solid state reaction was the route of preparing these materials. Several techniques were employed for the analysis and characterization of the synthesized powders. The chemical analysis results indicated that molar ratio Sr+La+NdP+Si was of about 1.67 value of a stoichiometric powder. The X-ray diffraction data showed single-phase apatites crystallizing in hexagonal structure with P63/m space group were successively obtained. Moreover, the substitution of lanthanium by neodymium in strontium phosphosilicated fluorapatite was total. This was confirmed by the a and c lattice parameters contraction when (x) varies coherently to the sizes of the two cations. The infrared spectroscopy and the 31P NMR (MAS) exhibited the characteristic bands of phosphosilicated fluorapatite. The pressureless sintering of the material achieved a maximum of 89% relative density. The sintered specimens indicated that the Nd content as well as the heating temperature affected the ionic conduction of the materials and the maximum was 1.73 × 10−6 S cm−1 obtained at 1052 K for x = 2.",book:{id:"11137",title:"Mineralogy",coverURL:"https://cdn.intechopen.com/books/images_new/11137.jpg"},signatures:"Khouloud Kthiri, Mohammed Mehnaoui, Samira Jebahi, Khaled Boughzala and Mustapha Hidouri"}],onlineFirstChaptersTotal:10},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:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,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:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{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. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},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. 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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. 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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. 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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. 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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. 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,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},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. 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Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. 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His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. 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He received grants from Alianza del Pacifico for a stay at the University of Magallanes, Chile, in 2014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) to work in the Food and Agriculture Organization’s Animal Production and Health Division (AGA), Rome, Italy, in 2014–2015. He has collaborated with researchers from different countries and published ninety-eight journal articles. 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