\r\n\tThe fifth topic is “complications and drug side effects in the treatment of pigmentation disorders”. These include drug allergies, hyper- and hypopigmentation, persistent skin depigmentation, scars, skin burns, and the potential for skin cancer and skin lymphoma. The last topic is called “coping and support along with skin pigmentation diseases”. Increase the quality of life, psychotherapy, team therapy, and asking for understanding and support from family members.
",isbn:"978-1-80356-900-0",printIsbn:"978-1-80356-899-7",pdfIsbn:"978-1-80356-901-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"2ac6c9f424eec37ed85232c2c97ef6f6",bookSignature:"Associate Prof. Shahin Aghaei",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11698.jpg",keywords:"Melanoma, Post-inflammatory Hyperpigmentation, Albinism, Piebaldism, Vitiligo, Pityriasis Alba, Laser Therapy, Cosmetic Coverage, Drug Reactions, Skin Sensitivity, Quality of Life, Team Therapy",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 5th 2022",dateEndSecondStepPublish:"June 14th 2022",dateEndThirdStepPublish:"August 13th 2022",dateEndFourthStepPublish:"November 1st 2022",dateEndFifthStepPublish:"December 31st 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Associate Professor of Clinical Dermatology and Dermatologic Surgery, lead author or contributor to nearly 60 articles published in international dermatology journals, and editor-in-chief of the Journal of Surgical Dermatology in Singapore.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"64024",title:"Associate Prof.",name:"Shahin",middleName:null,surname:"Aghaei",slug:"shahin-aghaei",fullName:"Shahin Aghaei",profilePictureURL:"https://mts.intechopen.com/storage/users/64024/images/system/64024.jpg",biography:"Shahin Aghaei, MD, graduated from Shiraz University of Medical Sciences, Iran, in 2004. He was awarded a fellowship from the International Society of Dermatopathology (ISD) from Charles University, Czech Republic, in 2008 and a fellowship in Dermatologic Surgery from the Medical University of Graz, Austria, in 2010. He is currently editor in chief of the Journal of Surgical Dermatology in Singapore and Associate Professor of Dermatology and Dermatologic Surgery at Iran University of Medical Sciences, School of Medicine. He is also a member of the American Academy of Dermatology, European Academy of Dermatology and Venereology, American Society for Laser Medicine and Surgery, International Society of Dermatology, International Hyperhidrosis Society, and Iranian Society of Dermatology.",institutionString:"Iran University of Medical Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Iran University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"225753",firstName:"Marina",lastName:"Dusevic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/225753/images/7224_n.png",email:"marina.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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It is often said that their presence is one of the most critical factors in defining an economic or prospective shale gas play. Many investigators have presumed that open natural fractures are critical to gas production from deeper plays such as the Barnett, as they are for shallower gas shales such as the Devonian shales of the northeastern US and for coal bed methane plays. A common view on production mechanisms in shales is “because the formations are so tight gas can be produced only when extensive networks of natural fractures exist” [6]. However, there is now a growing body of evidence that any natural fractures that do exist may well be filled with calcite or other minerals and it has even been suggested that open natural fractures would in fact be detrimental to Barnett shale gas production [9].
Commercial exploitation of low mobility gas reservoirs has been improved with multi-stage hydraulic fracturing of long horizontal wells. Favorable results have been associated with large fracture surface area in contact with the shale matrix and it is here that the role of natural fractures is assumed to be critical. For largely economic reasons hydraulic fracturing for increasing production from shale gas reservoirs is often carried out using large volumes of slickwater injected at pressures/rates high enough to create and propagate extensive hydraulic fracture systems. The fracture systems are often complex, due essentially to intersection of the hydraulic fractures with the natural fracture network. After hydraulic fracturing operations the injected water is flowed back. Typically, only a small percentage (on the order of 20 to 40%) is recovered.
In this paper we investigate the role played by natural fractures in the gas production process. By applying a new model of the production process to data from many shale gas wells across a number of shale plays in North America, we can for the first time begin to sort out assertion from inference in the role that these fractures play. Specifically, we are able to estimate the magnitude of the fracture surface through which gas is actually produced. We are able to demonstrate that although it may be commensurate with the expected surface area of open natural fractures for the ultra-low permeability shallow gas shales, it is in fact commensurate with a very much smaller area for the deeper gas shales such as the Barnett. Furthermore, given a typical value of the matrix permeability, almost all the gas between the fractures would have been produced in an uncharacteristically short period of time unless the producing fractures are 100s of feet apart. The implications of these findings for completion and stimulation strategies will be discussed.
\n\t\tOne of the main premises of our investigation of the production processes in shale gas plays is that the industry’s mental picture of the process remains very much influenced by the concepts developed in the 1990s of the production processes in coal bed methane resources and in shallow shale gas plays. It is appropriate therefore that we begin our discussion of shale gas production characteristics by reviewing this early work.
\n\t\t\tCoal is a heterogeneous and anisotropic porous medium, characterized by two distinct porosity systems:
\n\t\t\t\tMicropores of diameter of the order of nanometers with almost zero permeability.
Macropores or cleats, slot-like with spacing of the order of 2 cm and width of the order of microns; permeability is stress-dependent but far in excess of the micro-pore permeability. They are often formed by shrinkage of the coal matrix due to dewatering during the coalification process.
Gas is stored essentially by adsorption in the coal matrix; very little is stored as free gas in the micropores or as free gas or dissolved gas in the connate brine in the cleats. In the subsurface the cleats are usually filled with water, some of which must be produced to the surface to facilitate gas production.
The conventional view of the production process divides it into three stages (see Figure 1):
\n\t\t\t\tCleat dewatering, lasting of the order of several years; the water production rate gradually falls as water is removed from the cleats. At the same time more and more gas is produced at increasing rates and the relative permeability to gas in the cleats increases leading to lower pressures and more gas production.
Stabilized flow: eventually, most of the water in the cleats has been removed, the cleat fluid pressure bottoms out and the relative permeability to gas levels off. Over this period the gas rate slowly peaks.
Decline: there is then no more increase in drawdown available to sustain gas production and gas production declines. If the cleat pressure was constant and the pseudo-steady-state (PSS) regime is applicable (see the later discussion for definitions of this flow regime), then gas production rate should decline exponentially.
Stages in gas and water production from coal (after [
There are three essential elements to a model of the CBM production process:
\n\t\t\t\tTransport in the coal matrix, modeled as a diffusive process using Fick’s diffusion law. In principle the gas concentration in the coal matrix satisfies a diffusion equation, but it is common to use a pseudo-steady-state (PSS) approximation similar to that proposed by Warren and Root [2] in their dual porosity formulation of production from naturally fractured reservoirs. For example, King et al [3] used the PSS simplification to reduce computing time and because after a period of time the numerical accuracy was deemed to be quite acceptable. We have estimated from King’s data that the PSS solution is valid beyond about 40 days, which is much shorter than the typical duration of the production process. We note, however, that this time scale depends on the assumed values of the diffusivity in the matrix and on the spacing of the cleats, assumed to be of the order of a few cm.
Desorption at the cleat/matrix interface as characterized by the Langmuir isotherm
Transport of water and free gas in the cleat system. To avoid difficulties in defining the configuration of the cleat system, it is common to adopt a dual porosity description in which the cleat system is treated as a continuum with system characteristics analogous to those of a porous medium. Two-phase flow in this system can for the most part be adequately described by Darcy flow. In narrower cleats it may be necessary to include capillary pressure and slippage effects especially at low pressure.
It is apparent that the cleat or natural fracture system plays a very important part in the production process. The density of the cleats plays two critical roles: first, the close spacing of the cleats reduces the time required for the gas to diffuse to the cleats and, second, it is associated with a high cleat/matrix surface area without which economical gas production would be unlikely. The width of the cleat is a primary influence on the pressure drop in the whole system and therefore on the water and gas production rates. In situ the cleats are usually water-filled and presumably kept open by the pressure of the fluid they contain. The cleats may close somewhat as the pressure falls during production, though this may be more than offset by matrix shrinkage as the gas is desorbed.
\n\t\t\tGas production from Devonian shales received a great deal of attention in the 1980s and early 1990s as a result of US DoE initiatives. This is well documented in many GRI reports and industry publications. The consensus view is that these reservoirs are highly fractured containing a substantial number of fractures with spacing of the order of 1-10 cm (see, for example, [4]). Luffel et al [5] measured the matrix permeability at less than 0.1 nd. Water content of the Devonian Shale averages 2.5 to 3% of bulk volume and appears to be at irreducible water saturation. Typical depth is a few thousand feet, pore pressure is less than about 3000 psi and about 50% of the gas in place is adsorbed; there is little or no water production.
Carlson and Mercer [6] summarized the consensus view of the production process as “because the formations are so tight gas can be produced only when extensive networks of natural fractures exist.” The extent to which this statement holds for other gas shale plays is debatable, but it has certainly been influential in developing the industry’s vision of what is happening downhole.
Gatens et al [7] used a dual-porosity model similar to that formulated by Warren and Root [2] but extended to use the unsteady-state equation instead of the pseudo-steady-state (PSS) equation for matrix flow. Analysis of hundreds of Devonian wells showed that most of the production data fell into the linear transient regime (as we discuss later in this document). Luffel et al [5] obtained a good history match with data by assuming an open fracture spacing of a few feet, while Carlson and Mercer [6] needed a fracture spacing of about 80 ft, both with matrix permeability of less than 0.1 nd. An issue that does not seem to have been addressed however, is whether these fractures, if present, are in fact open and if so how they are maintained open against closure stress. If, like coal cleats, they are initially water-filled, is water production observed? An implicit assumption seems to be that they are open and gas-filled.
Carlson and Mercer [6] proposed that molecular diffusion is the dominant transport mechanism in the matrix in these extremely tight reservoirs, in which case a matrix diffusion coefficient should be used instead of the matrix permeability. They did not evaluate the consequences of this hypothesis. It remains a possibility that the use of such a coefficient would reduce the need for a large fracture surface area and ultimately for the need to propose the existence of a large open fracture network.
Thus there are three essential elements to a model of the production process in the Devonian shales:
\n\t\t\t\tDesorption of gas in the matrix (as characterized typically by the Langmuir isotherm)
Transport in the matrix towards the fracture network, modeled as Darcy flow even though the permeability is extremely small.
Transport of free gas in the fracture system.
The Antrim Shale is a shallow, under-pressured, naturally-fractured shale reservoir with characteristically low matrix permeability, and with adsorbed gas, free gas and mobile water co-existing in the reservoir. A typical Antrim well will produce considerable quantities of water early in life, and as dewatering of the reservoir progresses, water production rates decline and a corresponding increase in gas production is normally observed (as a result of gas desorption with reduced reservoir pressures), similar to a CBM well. In fact, the Antrim shale is often considered to be a hybrid of productive dry gas shale and CBM plays. It has characteristics which are similar to these other unconventional reservoirs, but it is also different in many ways. The Antrim shale is more intensely fractured than the Devonian Shales of the Appalachian Basin, with fracture spacing as close as 1 to 2 ft. Kuuskraa et al [8] have noted that the “intensity and interconnection of the fractures govern the shale’s natural producibility.”
The typical depth of the Antrim shale is less than about 2000 feet, pore pressure is a few hundred psi and more than 70% of the gas in place is adsorbed, the remainder being stored essentially as free gas in the matrix pores. Peak gas may occur as late as 3 years into production. Production data has been history-matched using similar software to that used for CBM [8]. It was found that fracture spacing of the order of a few inches facilitated a good match with production data. It was stated that if a fracture spacing of 3-6 ft was used (which is compatible with observations from cores and logs), then production would be an order of magnitude lower than observed in existing wells. One possible resolution of this conundrum may lie, as the authors suggest, in detrital silt layers within the matrix that could provide conductive flow paths. (An alternative explanation that remained unconsidered by the authors lies in the use of the PSS approximation for matrix transport, which may be completely invalid in this context.)
This description leaves many issues unresolved, but importantly places the Antrim shale as an intermediate between CBM and the other shales, in that the natural fractures appear to be conductive and initially water-filled, but has free pore gas in addition to adsorbed gas.
\n\t\t\tMost modern commercial gas shale plays are similar in many respects to the Barnett shale, though there are of course many differences and variations in the values of the parameters that control the gas production process. In these relatively deep and high pressure reservoirs, most of the gas is stored as pore gas, but the production process is still similar to that described above for shallower shale gas plays.
The subject of open natural fractures is one of the most contentious within the community of Barnett workers. Many investigators have presumed that open natural fractures are critical to Barnett gas production, as they are for the shallower gas shales, even though there is now a growing body of evidence that any natural fractures that do exist may well be filled with calcite or other minerals (see Figure 2). There are also arguments that suggest that if there was an abundance of open natural fractures within the Barnett, there would be a much smaller gas accumulation present within the reservoir. Open natural fractures, if they existed, would have led to major expulsion and migration of gas out of the shale into overlying rocks, substantially decreasing pore pressure within the Barnett and, hence, the amount of gas in place. The Barnett would not be over-pressured (that is, over-pressured relative to the bounding strata) if copious open natural fractures existed. Note that the Barnett is not just the gas reservoir, but also the source, trap, and seal for the gas; if the seal is fractured and inefficient, then the present gas in place would be reduced because the free gas would be lost, and only the adsorbed gas would remain in the shale (a similar situation to that of the Antrim Shale of northern Michigan). The huge amount of gas in place, in an over-pressured and fully-saturated (in terms of sorption) state, is ultimately what makes the Barnett so prolific.
\n\t\t\t\tMineralized natural fractures in a Barnett shale sample (adapted from [
A common argument for the necessity for open natural fractures in shale gas plays is that a large surface area is necessary for economic gas production from these very tight rocks. Later in this paper we analyze production data to estimate the magnitude of the fracture surface through which gas is actually produced. We are able to demonstrate that although it may be commensurate with the expected surface area of open natural fractures for the ultra-low permeability shallow gas shales, it is in fact commensurate with a very much smaller area for the deeper gas shales such as the Barnett. Furthermore, given the typical permeability of the Barnett shale (some 100 times that of the shallow gas shales), almost all the gas between the fractures would have been produced in an uncharacteristically short period of time unless the fractures are 100s of feet apart. These issues and conclusions will be discussed at length later in the paper.
\n\t\t\tHaving outlined the pertinent characteristics of unconventional gas reservoirs, we now document the likely production mechanisms in the various shale plays based on our understanding of their geology and the underlying geophysics.
The matrix permeability of shale gas reservoirs is extremely small, probably on the order of one tenth of a microdarcy or 100nd. It is virtually impossible to produce gas from these reservoirs in commercial quantities unless the wells are hydraulically fractured and even then, or so it is commonly believed, production is really only possible because a network of natural fractures is opened up. (It is interesting to note that gas has been produced from the ultra-tight Devonian shale plays of the North Eastern USA from more conventionally-fractured vertical wells, which implies that multi-stage hydraulic fracturing was unnecessary for these plays. This is the first hint that the role of the natural fractures may be quite different for the Devonian plays and the deeper shale plays.)
An essential element of a mathematical model of gas production from shales is therefore the ability to describe flow in a very tight rock matrix and flow in a network of fractures. In most gas shale reservoirs most of the reservoir fluid is stored in the matrix and the primary flow path is from the matrix into the fractures and thence into the wellbore. There are essentially two methods of characterizing a multiply-fractured reservoir:
\n\t\t\tDiscrete fracture network (DFN) model, in which the fractures are defined explicitly in terms of their location in the reservoir, their connectivity to one another and to the wellbore and their production characteristics, such as permeability and conductivity.
Dual porosity/dual permeability models in which the fracture network is treated as a continuum in much the same way as a porous medium is treated as a continuum for analysis of flow characteristics.
Many commercial numerical reservoir simulators have the capability of simulating flow through a complex network consisting of pores and fractures. However, one of the greatest drawbacks and limitations of simulating a discrete fracture network model is the a priori assumption that all relevant properties of the fracture network are known. Nevertheless great insights can be obtained into the impact of the essential physical processes by examining simple fracture configurations. We note that in principle many different physical and petro-physical components can be included in numerical simulations. However, in practice it is quite common to see results presented only for the special cases:
\n\t\t\t\tReservoir fluid of small and constant compressibility.
Production under constant drawdown conditions.
No desorption.
Darcy flow in fractures and matrix.
Matrix and fracture permeability independent of pressure; it is often assumed that fracture conductivity is essentially infinite.
The simplest fracture network that has been applied to shale gas production consists of a number of planar fractures placed transversely to a horizontal wellbore as illustrated schematically in Figure 3. It is apparent from many published numerical studies that under these circumstances flow from the reservoir can be described in terms of a number of identifiable flow regimes. The following account is taken from a recent paper by Luo et al [10]. These authors used a commercial reservoir simulator to calculate the flow into a horizontal well with six infinitely-conductive transverse fractures as shown in Figure 4.
\n\t\t\t\tIdealized discrete fracture network showing multiple transverse fractures originating from a horizontal well.
Numerical solutions for flow into six infinitely-conductive transverse fractures (taken [
The flow behavior can be conveniently discussed in terms of five flow regimes as follows.
\n\t\t\t\tBilinear or linear flow: soon after the well is placed on production reservoir fluid flows normal to the fracture planes and along the fractures into the well. The streamlines are shown in yellow in Figure 4; reservoir pressure is in red and the constant bottomhole or well pressure is in blue. Note that flow into the fracture tips is negligible and each fracture behaves independently of the other fractures. This regime may also be termed the infinite-acting regime in the sense that the neighboring fractures are effectively at infinity. The duration of this regime depends, as we shall see later, on many parameters including the matrix permeability, the fluid compressibility and the fracture spacing. The illustrations in Figure 4 are for infinite conductivity fractures.
Early radial/elliptical flow: flow into the fracture tips is present, but weak; flow into the fracture surfaces is still predominantly linear, but fracture interference is just beginning to impact the flow. Note that the pressure drawdown in the matrix has almost reached the mid-line between the fractures. At this point the flow regime may be described as pseudo-steady-state or fracture-boundary-dominated.
Compound formation linear flow (CFL flow): here the fractures are fully interactive and the reservoir drainage area is dominated by the area defined by the length of the well and the length of the fractures. Flow from beyond this area grows in importance.
Pseudo-radial/elliptical flow: flow from beyond the wellbore/fracture area grows in importance and appears to be radial or elliptical.
Reservoir-boundary-dominated flow: ultimately the outer boundary of the reservoir begins to impact the flow.
It is difficult to infer from these simulations the time scales and duration of these flow regimes for parameter values other than those used in the particular simulation. Indeed, this highlights one of the severe drawbacks to the full numerical approach to modeling production flow in these reservoirs: it is difficult to make general conclusions about the characteristics of the flow and their dependence on the input data without undertaking very many numerical simulations; this is a formidable task even for a restricted input data space. However, based on the semi-analytic models that are described below, we believe that for many shale gas wells it would be unusual to expect to encounter the compound formation linear flow regime for at least 10 years after the well was placed on production.
\n\t\t\tThe conventional view of a naturally-fractured reservoir is that it is a complex system composed of irregular matrix blocks surrounded by a network of more highly permeable fractures. In reality in tight gas shales some or most of the fractures may not be open to flow or they are opened up only during the hydraulic fracturing process. Warren and Root [2] were among the first to recognize that the simple model of reservoir flow based on single values of the permeability and porosity does not apply to naturally-fractured reservoirs, though they had in mind reservoirs quite different from gas shale reservoirs. In order to handle the problems associated with lack of detailed information on the structure of the fracture network they proposed a dual-porosity model in which a primary porosity associated with inter-granular pore spaces is augmented by a secondary porosity related to that of the network of natural fractures. At each point in space there are two overlapping continua—one for the matrix and one for the fracture network. The detailed geometry of the fracture system need not be specified in this model, but can include as particular examples any of the discrete fracture models described above. In typical shale gas applications the matrix has high storage capacity but low permeability and the fractures have relatively low storage capacity and higher permeability. It is quite possible (or, indeed, likely) that in many shale gas reservoirs no gas is stored in the fractures, though they may become filled with frac fluid during the hydraulic fracturing process.
In the dual porosity formulation flow from the matrix to the fractures is described by a transfer function with Darcy flow characteristics. The original Warren-Root models incorporated the pseudo-steady-state assumption in the matrix blocks and assigned a single value to the pressure within the blocks; the mass transfer rate from the matrix to the fractures depends then on the pressure differential between the matrix and the fracture. Thus these models assumed, almost implicitly, that sufficient time had elapsed that the flow in the matrix blocks between the fractures was already fracture-boundary-dominated. Later in this paper we estimate the time scale on which inter-fracture pseudo-steady-state begins and find that it is typically of the order of several years for a fracture spacing of 100 ft or more. This is quite consistent with typical simulation results described above. If the fracture spacing was as small as 10ft, we should expect to see fracture interference or the onset of PSS flow after about 10 days. For shale gas reservoirs, more complex models (unsteady state or fully transient) are needed to resolve the flow in the matrix in more detail.
A detailed discussion of the Warren-Root model, its background and similar contemporary models can be found in the excellent monograph by van Golf-Racht [11]. We note in particular that Kazemi [12] was one of the first to extend the Warren-Root model to include transient flow in the matrix blocks. Some seventeen years after Warren and Root published their seminal work, Kucuk and Sawyer [13] adapted their model for flow in shale reservoirs by incorporating effects such as desorption from the organic matrix material and Knudsen flow in the pores and, of course, incorporating full transient effects in the matrix blocks.
In the years following the formulation of the dual porosity model for naturally fractured reservoirs, solutions of the coupled partial differential equations for the pore and fracture fluid pressures were obtained using finite difference techniques. While these simulations can provide accurate solutions, often in a complicated geometry covering the entire reservoir, the large number of computations involved made them cumbersome for analysis of large data sets. In response, an alternative, faster, method of solution was developed in the 1980s. For a simplified geometry, Laplace transform solutions were developed, in which the transformed solutions were inverted numerically, using, typically, the Stehfast algorithm.
Several authors have noted that analytic approximations can be developed for certain ranges of parameter values (referring to the Warren-Root dimensionless parameters defined below) appropriate for shale gas reservoirs. It will become apparent later in this paper that for typical shale gas reservoirs the interporosity flow coefficient (or transmissivity), \n\t\t\t\t\t\t
Recently, we have taken the idea of developing asymptotic solutions one stage further. We have developed perturbation solutions for \n\t\t\t\t\t\t
The model does not make the
The model does not make the
Identification of the end of the linear infinite-acting flow period and development of the ensuing PSS solution is made explicit.
Provision of a solution form that facilitates fast and easy production data analysis.
Identification of the reservoir and completion parameters that are the greatest (primary) determinants of productivity.
Solution scheme that permits rational extension to include other physical processes, such as desorption.
For simplicity we restrict attention in this paper to single-phase flow in the matrix and assume that gas is produced at constant bottom hole pressure; we shall also neglect the impact of gas desorption. For the purposes of the present discussion the most important part of the solution is the leading order solution for the reservoir pseudo-pressure, which satisfies a standard diffusion equation.
\n\t\t\t\tHere we have used dimensionless parameters (denoted by subscript D); full definitions are provided in the Nomenclature section later in this paper. Dimensionless distance normal to the fracture face, \n\t\t\t\t\t\t
that characterizes pressure diffusion in the matrix
The appropriate initial and boundary conditions are
\n\t\t\t\tThe leading order influx from the matrix into the fracture network is given by
\n\t\t\t\tAt downhole conditions the mass flowrate from the matrix into the fracture network is
\n\t\t\t\tThe dimensionless flowrate is defined in equation (4) and the characteristic mass flowrate is defined by
\n\t\t\t\tHere A denotes the productive fracture surface area. The total mass flow rate measured at surface conditions is
\n\t\t\t\tHere subscript
The dimensionless flowrate defined in equation (4) may be readily calculated in terms of the dimensionless pseudo-pressure, either from the full numerical solution of the diffusion equation, (equation (1)), or from the early-time infinite-acting approximation to it. Both solutions provide very useful information and insights into the variation of the production rate with time. The dimensionless cumulative production is defined by
\n\t\t\t\tThe diffusion equation (1) is readily solved using standard numerical schemes as made available in mathematical software such as MATLAB. To complement this solution we have obtained an analytic approximation valid while the change in pressure has not been impacted by neighboring boundaries or fractures—often referred to as the infinite-acting approximation. The early-time approximation to the dimensionless inflow rate is
\n\t\t\t\tAnd the early-time approximation to the dimensionless cumulative production is
\n\t\t\t\t\n\t\t\t\t\tFigure 5 compares the full and early-time solutions for the dimensionless flow rate and cumulative production against dimensionless time. For convenience we have used a log-log plot here. There are several major features of this plot that are worthy of further comment:
\n\t\t\t\tThe early-time (infinite-acting) solution provides a good approximation to the full numerical solution for dimensionless time, \n\t\t\t\t\t\t\t\t
During this time frame, the flowrate is represented by a straight line of slope – ½ and the cumulative production is represented by a straight line of slope + ½.
Boundaries (or in this case neighboring fractures) begin to influence the flow after this point in time and the solution departs from the simple linear dependence on the square-root of time. This is also evident in the numerical solutions presented by Bello and Wattenbarger [15] in their Figures 5, 7, 8 and 10 and in the field data shown in their Figure 1.
The dimensionless cumulative production approaches a final value of 1 as it should because of the way we have defined the characteristic scales in our non-dimensionalization of the equations.
The error incurred in estimating the cumulative production by extrapolating the infinite-acting solution beyond its region of validity is apparent from Figure 5.
Almost 90% of the total gas that can be produced has been produced by the time \n\t\t\t\t\t\t\t\t
\n\t\t\t\t\tFigure 6 shows the full and infinite-acting solutions for cumulative production plotted against the square-root of dimensionless time. As expected from equation (10) the early-time solution is well represented by a straight line with slope \n\t\t\t\t\t\t
In anticipation of the application of these results to analysis of production data, it is useful to provide an expression for the cumulative production in dimensional terms. Analogous to equation (6) we define cumulative production at downhole conditions by
\n\t\t\t\tThe characteristic cumulative production scale is defined as
\n\t\t\t\tThe time scale \n\t\t\t\t\t\t
Analogous to equation (9) we define cumulative production at surface conditions by
\n\t\t\t\tA comparison of the full and early- time solutions for the dimensionless flow rate and cumulative production.
A comparison of the full and early- time solutions for the dimensionless cumulative production.
In view of the wide applicability of the early-time solution, it is useful to state the form taken by equation (13) during the infinite-acting period. Using the early-time approximation given in equation (9), we see that
\n\t\t\t\tIf we now use the definition of \n\t\t\t\t\t\t
Where
\n\t\t\t\tThe coefficient \n\t\t\t\t\t\t
The analysis described above suggests that for a substantial part of a shale gas well’s production history, the cumulative production varies linearly with the square-root of time. The coefficient \n\t\t\t\t\t
We illustrate this production analysis technique by comparing production from a group of wells in the Barnett shale. Figure 7 shows a conventional plot of production rate against time for several wells that had been producing for at least 5 years in an area of the Barnett field. The data was obtained from a public data base and we have plotted the production rates at yearly intervals. For clarity of presentation we have connected the data points by smooth lines. This “conventional” plot reveals nothing about the relative decline rates of the wells or provides much insight into the flow regime(s). The same data sets have been plotted in the new format in Figure 8. It is immediately apparent that for most of these wells the data falls on straight lines as expected from our analysis. The slope of these lines is readily measured and provides an estimate for the production coefficient, \n\t\t\t\t\t
In Figure 8 we have omitted the first year’s cumulative production data. Generally, early-time production data is quite severely impacted by variable drawdown conditions and so we should not expect a good straight line fit at that time. Analysis of this regime is discussed at length elsewhere [14].
\n\t\t\tProduction data from a group of Barnett wells plotted in the conventional format
Same production data from
We have established the applicability of this new analysis technique to data from very many wells in many shale gas plays across the US and Canada, though there is neither space nor time available to discuss this in detail in the present paper. Following on from that analysis, we will now go on to discuss the results in more depth and begin to draw some tentative conclusions about the production drivers, by examining the parameters that together constitute the formula for \n\t\t\t\t\t
Nature:
\n\t\t\tMatrix permeability, \n\t\t\t\t\t\t\t
Matrix porosity, \n\t\t\t\t\t\t\t
Gas viscosity, \n\t\t\t\t\t\t\t
Gas compressibility,
Initial reservoir pressure, \n\t\t\t\t\t\t\t
Reservoir temperature,
Nurture:
\n\t\t\tBottom hole flowing pressure, \n\t\t\t\t\t\t\t
Productive fracture surface area,
In developing these results we are constrained by the requirement that \n\t\t\t\t\t
This requirement sets some bounds on the fracture network characteristics, but these are generally easily met for shale gas reservoirs. For given values of the matrix permeability and the wellbore radius, the combination of fracture spacing and fracture conductivity must be sufficiently large.
It is apparent that given these conditions production for a large part of the production history of these wells depends upon the parameters listed above. We note in particular that history matching production data over this flow period furnishes only one parameter and that is the production coefficient, \n\t\t\t\t\t
We need to elaborate at this point on the parameter
Some insight about the spacing of these productive fractures can be obtained by examining the time scale of pressure diffusion in the matrix. We demonstrated earlier that we may expect the root-time solution to be valid until neighboring fractures begin to compete with one another for production. In other words, until pressure diffusion in the matrix can no longer be considered to be independent of the fracture spacing. According to the analysis presented above we should expect the cumulative data to deviate from a straight-line in the root-time plot for t> 0.15 \n\t\t\t\t\t
If we could detect the time at which this departure occurs then, we have some information with which to estimate the productive fracture spacing. Even if the entire production history to date is in the linear flow regime, we can make an estimate of a lower bound on the fracture spacing. As we see later, the fracture spacing is surprisingly large for typical shale gas plays.
We have now analyzed many shale gas production data sets using our proposed technique and have found the square-root fit to be very good. Based on this and on the mathematical analysis that supports that technique we have concluded that the production rate declines inversely with the square root of time. As we have discussed above, this is a consequence of the dominant production process of linear flow into a network of fractures. The decline rate is therefore fully determined by the physics of the production process. We should not expect to see any significant variation from well to well, from vertical to horizontal wells or indeed form play to play. What does vary is the multiplier, the production coefficient \n\t\t\t\t\t
As we have indicated above, it is relatively straightforward to use this new technique to analyze production data whether it is on a well-by-well basis or averaged over a play or area within a play. In essence, the process consists of three steps:
\n\t\t\t\tFrom the daily (or monthly or yearly) production data calculate the cumulative production for each well at different points in time.
Plot cumulative production against the square-root of time.
Estimate the Production Coefficient form the slope of the best straight line fit to the data.
The Barnett shale is a good starting point for a more in-depth data analysis, since production data is readily available from public databases and, moreover, that data extend over many wells for long periods of time. The Barnett shale occupies several counties in North Texas. It is broadly bounded by geologic and structural features and may be divided according to estimates of maturity into a gas window and oil window. Historically the major development has been in a core area located to the north of Fort Worth (Figure 9), but more recently expansion has occurred to the south and to the west. To date many thousands of wells have been drilled and completed in the Barnett, initially vertical, but now almost entirely horizontal.
It has become common practice to sub-divide the Barnett play into three areas, described as the Core, Tier 1 and Tier 2. For convenience we may define these areas according to county as follows
\n\t\t\t\tCore region: Denton, Tarrant and Wise counties, comprising 2974 horizontal wells and 3886 vertical wells
Tier 1 region: Hood, Johnson and Parker counties, comprising 3865 horizontal wells and 251 vertical wells
Tier 2 region: all other counties, comprising 687 horizontal wells and 401 vertical wells
It is apparent form this cursory division that the fraction of wells that were completed horizontally shifts from 43% in the Core area to 94% in the Tier 1 area, which reflects the development of technology with time and the spread of drilling with time to the outer areas. At the date of these figures (2009) Tier 2 was relatively unexploited.
The result of this detailed analysis (Figure 10) allows us to quantify the production variations in the Barnett Core, Tier 1 and Tier 2 areas and to distinguish the impact of horizontal and vertical well completions on the productivity. In a sense this represents a first, somewhat crude, pass at distinguishing the impact of nature (in the sense that reservoir properties depend on location, with the core area providing more fertile ground than Tier 1 or Tier 2) and nurture (in the anticipation that horizontal well technology provides more productive fracture surface area than does vertical well technology).
\n\t\t\t\tDevelopment of the Barnett shale in North Texas
In Figure 10 we have shown the cumulative distribution of production coefficient for each of the six categories defined above. The plots should be interpreted as follows. For each category the probability that a well has a specified value of the production coefficient in excess of the value on the x-axis can be read off the y-axis. For example the probability of a horizontal well in the Core having a production coefficient in excess of 0.75 (bcf/yr^0.5) is about 8%.
It is apparent that, as is to be expected, wells in the Core have better production characteristics than wells in Tier 1 and wells in Tier 2 and that in general horizontal wells have better production characteristics then vertical wells. It is interesting in this context to examine the variation of production coefficient in the core area in more detail. Figure 11 shows the location of ten of the wells in the core area with high values of the production coefficient (in green), 10 of the wells with medium values (in blue) and 10 wells with low values (in red). It is apparent that there appear to be sweet spots even within the core area, but there are substantial outliers and there are some relatively poor wells close to better wells.
\n\t\t\t\tDistribution of values of the Production Coefficient for horizontal and vertical wells in the Core region, Tier 1 region and Tier 2 region of the Barnett shale.
Preliminary identification of sweet spots in the core area of the Barnett. Each black dot represents a well; 10 wells with high Production Coefficients are identified in green, 10 medium performers are in blue and 10 poor performers are identified in red.
One of the advantages of the semi-analytic method outlined in this paper is that it enables us to make certain deductions about the magnitude of the parameters that drive the productivity of the well. In particular we can make some inferences about the magnitude of the fracture surface area through which the gas is produced and about the likely spacing of the productive fractures.
\n\t\t\tOur analytic solution allows us to relate the Productivity Coefficient \n\t\t\t\t\t\t
In Figure 12 we show estimates of the productive fracture surface area for typical strong, medium and weak performing wells in the core area of the Barnett in terms of values of the matrix permeability. In this calculation we have made reasonable estimate of the other parameters that impact the productivity coefficient such as the gas viscosity and compressibility and the matrix porosity.
Several features of this plot merit discussion:
\n\t\t\t\tWell productivity increases with productive fracture surface area and with matrix permeability, as expected.
Wells in this group typically have matrix permeabilities in the range 100-300 nd and this implies that the productive fracture surface area is in the range 1-6 million square feet (Msqft): the higher the permeability, the less fracture surface area is needed to achieve the given productivity.
If the matrix permeability was as low as even 10 nd, the required fracture surface area would approach 100 Msqft. On the other hand, matrix permeabilities of the order of 1 μd would require less than about 1 Msqft of productive fracture surface area.
Estimate of productive fracture surface area for specified matrix permeability. The three curves were developed based on analysis of Barnett shale well data using the EGI semi-analytic production model.
To place these numbers in context we note that a fracture of height 200 ft and half length 200 ft has surface area of 0.16 Msqft. Thus, 20 of these fractures would have a fracture surface area of 3.2 Msqft, which is a perfectly plausible estimate of the hydraulic fracture surface area created with modern multi-stage fracturing techniques. (Note that 20 such fractures would be spaced about 150 ft apart in a 3000 ft lateral.)
\n\t\t\t\t\tFigure 12 was developed on the basis of production data from wells in the core area of the Barnett shale, but the results apply, at least qualitatively, to other shale or tight gas plays. For example for more conventional tight gas plays for which the permeability is of the order of 1 μd or more, we should expect respectable productivity with only one such hydraulic fracture, which reinforces our experience that a vertical well with a single bi-wing fracture may be adequate for those reservoirs, but not for shale gas plays. Conversely the productive fracture surface area for economic production from ultra-tight shale plays (such as the shallow shale plays described earlier in this paper) cannot be achieved by producing from the hydraulic fractures alone.
We have been careful so far to make no formal distinction between the natural fractures and the hydraulic fractures in so far as productivity is concerned. All we have demanded is that their conductivity is sufficiently large that \n\t\t\t\t\t\t
A crude estimate of the fracture surface area that is created by pumping large volumes of frac fluid may be made by performing a mass balance and assuming that none of the fluid has leaked off or imbibed into the formation over the time in which the fracture network is created. For a total fluid volume V and assuming a created average fracture width w during pumping, the total fracture surface area may be estimated at
\n\t\t\t\t\t\n\t\t\t\t\t\t
(using any consistent set of units of course). If, for example, 100 million gallons of frac fluid were pumped and the assumed frac width was 0.2 inches, then the total surface area would be about 100 Msq ft. Clearly, this is far in excess of our estimate of the productive fracture surface area and would suggest that less than 10% of the created fracture surface area is actually productive. Naturally, this raises all sorts of other questions concerning the efficiency of this process, which we plan to address in a future project.
A similar mass balance for the proppant placed in a typical job enables an estimate to be made of the surface area of propped fractures. If we make some estimate of the likely width (0.1 in) and porosity (0.4) of a propped fracture (after closure), it appears that a propped fracture surface area of the order of a few million square feet is quite plausible.
\n\t\t\tSome insight about the spacing of these productive fractures can be obtained by examining the time scale of pressure diffusion in the matrix. We demonstrated earlier that we may expect the root-time solution to be valid until neighboring fractures begin to compete with one another for production. In other words until, pressure diffusion into a fracture can no longer be considered to be independent of the fracture spacing. According to the analysis presented earlier we should expect the cumulative production data to deviate from a straight-line in the root-time plot for \n\t\t\t\t\t\t
It is instructive to estimate the matrix diffusion time for typical values of the fracture spacing and matrix permeability. The results are shown in Figure 13. The diffusion time increases quadratically with the fracture spacing and inversely with the matrix permeability. Typical values for the diffusion time are quite low. For example, if, as we expect, linear flow continues for at least 3 years, then we should expect to see a diffusion time of the order of 20 years. Figure 13 suggests that the productive fracture spacing is likely to be of the order of 100 ft or more.
\n\t\t\t\tThe impact of fracture spacing on the time to produce 90% of the gas in place.
In figure 13 we have identified the diffusive time scale with the matrix drainage time. As we showed above, 90% of the total gas in the pore space between the fractures has been drained by this time. A time scale of about 20 years is at least consistent with the industry estimates of the effective production lifetime of these wells. It is worth noting here the consequences of much smaller fracture spacing. For a fracture spacing of only 10 ft, we estimate that 90% of the total gas production will have occurred within the first few months of production, which is quite unrealistic. Note also that the surface area of planar fractures only 10 ft apart in a 3000 ft lateral would be of the order of 150 Msq ft, which again is unreasonably large.
\n\t\t\tA common view of production mechanisms in shales is “because the formations are so tight gas can be produced only when extensive networks of natural fractures exist” [6]. To this extent gas production from some of the shallower (Devonian) shales is similar to gas production from coal. As we have discussed earlier in this paper, we expect that the deeper gas shales differ in this respect.
Using a new semi-analytic production model, we have analyzed production data from a number of shale gas wells in several different North American shale gas plays. Interpretation of the results suggest that productivity is largely determined by a small group of parameters that may be decomposed into two sub-groups representing the nature of the reservoir (such as matrix permeability and porosity) and what we may term our (engineering) attempts at nurture (including completion and stimulation parameters). Of key importance is the productive fracture surface, which unfortunately is difficult to estimate a priori. However, our interpretation of the production data suggest the following
\n\t\t\tProductive fracture surface area ~1-6 Msqft and probably within 2-4 Msq ft.
The volume of these productive fractures is very much less than the volume of water pumped, but
Productive fracture volume scales approximately with the volume of proppant placed.
Typically, there is no indication of fracture interference during production even after several years, which suggests that the productive fracture spacing is at least 100 ft.
Time to drain 90% of the fractured region or matrix blocks: ~10-20 years
We are led to the conclusion that almost all the fracturing fluid pumped during a multi-stage horizontal well fracturing operation in the shales serves to open a vast, and possibly complex, network of natural fractures and that these fractures do not make a significant contribution to the well’s productivity. We are led inevitably to questions concerning the conductivity of these, largely unpropped, fractures and to investigate the rock and fluid mechanisms that seemingly prevent them from being productive. The role of the fracturing fluid (usually slickwater) in this process should now be investigated from this new perspectivel
\n\t\tk – permeability
\n\t\t\t\n\t\t\t\t\n\t\t\t\t
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i – initial
s – surface
w – wellbore
\n\t\tRabies, an RNA virus from the genus Lyssavirus, also known as RABV, is a lethal pathogen to several species [1]. The evolutionary history of the virus suggests that its most recent ancestor likely diverged into two descendants, one infecting bats, the other infecting dogs. Once domesticated dogs became infected in the Old World, humans became the next target. Evolutionary biology tells us that rabies likely did not exist in the New World prior to the settlement of Europeans but was common throughout Europe, Asia, and Africa well before the discovery of the Americas [2].
RABV is transmitted through the saliva of an infected individual into the bloodstream of a healthy individual, typically via a bite, but possible through other wounds or ocular route. Upon infection, there are two ways the virus may manifest: furious and paralytic. Furious rabies often presents itself with bouts of anxiety, irritability, phobias, and many other symptoms that will later be discussed. Paralytic rabies has some common symptoms with furious rabies, however, paralysis is the most notable symptom just prior to death [3].
According to the CDC in 2015, nearly 60,000 human deaths occurred on average each year. Statistically, this can be interpreted as 1 human death every nine minutes [4]. Despite its large impact globally, the virus is relatively diminutive. The rabies virus has evolutionarily reduced its single-stranded RNA genome to only five genes. These genes encode five proteins, three of which make up the ribonucleoprotein (RNP) complex; the other two form the virus’s envelope [5].
While the rabies virus has been heavily researched, lives continue to be lost. There is a great understanding of the epidemiology of the virus, however little is understood about the pathogenesis. Herein, the findings regarding the diagnosis, clinical course, treatment, and prevention of the rabies virus are summarized as well as data gaps in research and understanding of this pathogen.
Once the patient has become infected, the incubation period can be as short as 5 days or as long as 2 years. However, it is common for symptoms to occur 20–90 days after initial exposure [6]. Nevertheless, there are several techniques for diagnosing a patient during and after the incubation period.
As mentioned previously, the two ways the rabies virus may present itself is paralytic and furious symptoms. A patient with paralytic rabies will show progressive paralysis until death. If infection occurred due to a bite, the paralysis typically starts around the wounded area, spreading outwards. It is also common for patients to have a fever, vomiting, weakness in muscles, and myalgia prior to the paralysis [7].
Furious rabies often presents itself with more obvious symptoms. The infected individual commonly displays mood swings, unregulated consciousness, phobias, especially hydrophobia, as well as spasms of the respiratory system [1, 8]. Other symptoms may include a cough, psychosis, delirium, and difficulties swallowing [9].
For both furious and paralytic rabies, magnetic resonance imaging (MRI) will produce the same key diagnostic images. When symptoms first arise in the prodromal phase, progression in hypersignal T2 changes can be seen around the brachial plexus and the spinal nerve roots associated with the extremity of infection origin. The main MRI feature is increased T2 signal (seen on T2 and FLAIR sequences) in the affected parts of the brain and spinal cord, with a predilection for grey matter structures including basal ganglia, thalami, hypothalami, limbic system, and brainstem. The abnormal hypersignal T2 changes will continue to progress as the patient enters a coma. Once in the comatose phase, the contrast will enhance around the spinal cord, nerve roots located at the sine and cranial region, deep grey matter, brain stem, limbic structures, and thalamus (Figure 1) [8].
Magnetic resonance images with arrows pointing to high focal areas (A. dorsal medulla, B. pons, C. hypothalamus, and D. splenium of corpus callosum) of an infected patient with furious rabies [
Another study noted that lesions could be seen throughout different areas of the neuroaxis. They, too, found that paralytic and furious rabies present the same MRI indications, however, they are more noticeable in the paralytic form. The blood–brain barrier often shows no sign of damage until the patient reaches the comatose state. Imaging of the blood–brain barrier has greatly improved as new techniques such as diffusion-weighted and diffusion tensor imaging can capture objective and subjective data [11].
There are several techniques used to diagnose a patient with a rabies infection; including reverse transcription polymerase chain reaction (rtPCR) analysis, fluorescent antibody test (FAT), tissue culturing, and viral antibody neutralization [12, 13]. The FAT assay has long been a microbiological standard for diagnosing rabies (and other viral infections). Fluorescent antibody virus neutralisation (FAVN) test is also used to diagnose rabies [13]. The CDC recommends a direct form of FAT to detect the rabies virus in animals ante-mortem, however, the animal is usually euthanized after detection and brain tissue samples taken to solidify the diagnosis post-mortem. However, diagnosis in humans requires several different types of methods such as direct rapid immunohistochemistry testing, the use of electron microscopy, and reverse transcriptase-polymerase chain reactions on biological samples (Figure 2) [15].
These images show the comparison of a positive direct FAT result (left) and a negative direct FAT result (right) [
Another test utilizing immunohistochemistry, known as the direct rapid immunohistochemistry test (dRIT) is a specific form of histology because it employs antibodies unique to RABV. While this testing method can give a reliable result in less than an hour, retrieving brain samples is very invasive [16].
Samples can also be viewed using electron microscopy. When Negri bodies are located in samples, electron miscopy can give a clear depiction of the bullet-shaped rabies virus being produced. A colloid can be used to compare the virus size to further interpret the image, however shape and size alone are not enough to identify with confidence [17].
Saliva and skin samples can be used for identifying the presence of RABV. rtPCR can be used to confirm or oppose the results of FAT test results. Because RABV is a single-stranded RNA virus, rtPCR can help transform RNA into DNA through amplification for analysis of a complement to a rabies-specific primer. This is often achieved by inoculating suckling mice and retrieving brain or kidney samples after death [15, 18].
Given that the rabies virus significantly impacts the central nervous system, it is not uncommon for hallucinations, manic episodes, anxiety, and bouts of paranoia to be present in an infected patient [19, 20]. However, these are also common symptoms of psychiatric disorders such as schizophrenia. While it is rare, it is possible that correct RABV diagnosis may be complicated by a previous diagnosis of psychiatric disorders. Patients suffering from hypochondriasis could elicit psuedorabies [20]. In several case studies with reports of hypochondriasis, patients did not respond to therapies and often attempt suicide multiple times [20, 21]. While these situations are rare, they should be noted when diagnosing patients with certainty.
The most common entry point for RABV is through the bite of an infected individual as rabies resides in saliva [22]. However, transmission from organ transplants and aerosol droplets have also been recorded [23, 24, 25]. Upon entry, an incubation period often takes place in the myocytes, and rarely fibrocytes, where the virus attaches to the G-protein of the cells, enters through pinocytosis or fusion, and replicates in the cytoplasm of the cells [5, 24]. Virions will replicate with little to no immune response until the virus interacts with and infects a nerve cell. The rabies virus gains access to the nervous system by binding to the nicotinic acetylcholine receptors on the postsynaptic membrane at the neuromuscular junction [26]. From the point of nerve cell infection, the virus will travel via axon transport through the nervous system, eventually reaching the brainstem to give rise to either encephalitis or acute flaccid paralysis [7, 27]. The incubation periods are highly variable depending on the dosage of the virus. However, in humans, the incubation period is often >1–3 months. Canine incubation periods are most commonly less than 60 days [26, 28].
Once infection is recognized by the immune system, cytokine, IgM, and IgG antibody production increases [5]. Specific cytokines, Interleukin-1β (IL-1β) and TNFα, are thought to be the reason inflammation of the central nervous system occurs post-exposure [29]. The presence of these cytokines initiate a cascade reaction, upregulating proteins necessary for the inflammatory response such as the major histocompatibility complex and adhesion molecules. These proteins then interact with leukocytes to allow the blood brain barrier to become more permeable, thus causing an immune response leading to encephalitis [30]. As for the natural defense against rabies, RABV signals a series of molecular cascades that initiates type I interferon responses that have antiviral properties, decreasing the pathogenicity of rabies [31]. However, to artificially aid the natural response, there is heavy research on the potential to activate dendritic cells which subsequently enhance the activity of interleukin proteins and high mobility group box 1 (HMBG1) to enhance immunogenicity [32, 33].
Although the rabies disease has been documented for thousands of years, it is still largely considered incurable after the onset of symptoms [34]. This is due to the small window of time during which aggressive treatment is practical and effective. With that knowledge, most often treatment resolves to be mostly palliative with aggressive treatment proving to be essentially ineffective after RABV is established in the patient.
If a patient presents for treatment early in the process of the clinical disease, the choice may be made to apply an aggressive approach. At this point, the patient must be immediately admitted to an intensive care hospital and post-exposure prophylaxis (PEP) should be administered [26]. PEP consists of immediate washing of the wound with soap and water, a post-exposure vaccination, and injection of an anti-rabies immunoglobulin (RIG) directly into the wound [35].
Active immunization has evolved greatly since the first rabies vaccine was developed and administered in 1885 [36, 37]. Louis Pasteur is credited with this first vaccine that consisted of injecting the patient with homogenates of RABV-infected rabbit spinal cord multiple times over a period of days. The initial injection was believed to be fully inactivated after an extended desiccation period, and each subsequent inoculation was increasingly more virulent as the desiccation period was decreased. While this was found to be somewhat effective, two major issues presented themselves. First, the inactivation of the RABV was inconsistent which led to some patients becoming infected after receiving the vaccine. Second, there was an inequity in the supply of the RABV-infected rabbits and the demand of the human population. These were rectified with the introduction of RABV-infected sheep and goat brain vaccines [36, 37]. These new vaccines were inactivated via chemical agents such as phenol; this proved to be much more consistent. However, soon it was understood that vaccines produced from mature brain material contained an excess of myelin which caused sensitization and ultimately killed the patients [38]. From this discovery emerged the current methodology by which rabies vaccines are created. Chick embryos served the same role as the previous tissues, but they have markedly less myelin due to the young age [39]. The same can be said of the lines of human diploid cells infected with fixed RABV for vaccines [36, 37]. In the United States, there are two CDC-approved vaccines: the human diploid cell culture vaccine (HDCV) and the purified chick embryo cell culture vaccine (PCECV) [15].
The post-exposure vaccine is primarily an intramuscular vaccine that ought to be given on day 0, 3, 7, 14, and 30 [36]. An intradermal vaccine has recently been developed in an attempt to decrease the amount of vaccine needed per injection [40]. While the decreased cost of the vaccine is an attractive option, intradermal injections are generally considered more difficult which could decrease the effectiveness of the vaccine due to improper injections. The World Health Organization (WHO) strongly recommends purified cell culture and embryonated egg-based vaccines [41].
Although the vaccines have been proven to stimulate an appropriate immune response to RABV, this immune response is often too delayed to prevent the virus from entering the nerves [42]. With this knowledge, passive immunization is recommended for all patients that have no previous history with the disease or a pre-exposure vaccination. At this time, two types of rabies immunoglobulin are available – human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). These have been used since the 1970’s to temporarily increase the concentration of rabies virus neutralizing antibodies (RVNA) specifically at the site of exposure [43]. If the patient has multiple bites or wounds, the RIG needs to be applied at each site to be effective [44]. HRIG is to be administered at a dosage or 20 IU/kg while the recommended dosage for ERIG is 40 IU/kg [42, 44]. Due to higher odds of sensitization as well as quicker elimination of the RVNA, HRIG is generally the most preferred option for passive immunization. However, it is approximately five times more expensive than ERIG. This results in a major deficiency in many of the countries most in need of rabies treatment [44].
Because the available RIGs are generally inaccessible to developing countries, WHO encouraged researchers to pursue synthetization of a human monoclonal antibodies (mAbs) cocktail that can be used to treat rabies [45]. At this time, there are a number of rabies mAbs products in clinical trials, but none have been approved by the US Food and Drug Administration [46]. In 2018, WHO officially adjusted their recommendations for treatment of rabies to include mAbs products in place of RIG if available [46].
A protocol known as the Milwaukee Protocol was presented as a potential cure in the late 20th century, but it has since been proven to be inconsistent and generally ineffective in reverting or curing the patient of the disease [47, 48, 49]. This protocol consisted of an induced coma and one or more antivirals. The coma was soon determined to be ineffective. It is now recommended that sedation should be limited to prevent the use of ventilatory support if possible [48, 49].
Antivirals could serve an important role in the treatment of the rabies virus as they act as inhibitors of viral replication. An effective antiviral could slow the progression of the rabies virus enough for the patient’s innate immune response to develop and react appropriately. However, at this time, there are few antivirals supported for the treatment of RABV. Ribavirin is a purine analogue that acts as an RNA mutagen and has shown to be clinically effective for multiple viruses including Hepatitis C and Lassa fever virus [50, 51]. Despite its inclusion in the sporadically effective Milwaukee Protocol, it has repeatedly proven to be ineffective against the rabies virus. Interferon-α (IFN-α) is a signaling protein used to trigger an immune response which has been shown to limit RABV spreading in mice trials [50, 51]. However, additional trials in which primates were administered intramuscular and intrathecal IFN-α determined the effects of immediate inoculation to be incomplete while the effects of delayed inoculation were nonexistent [52, 53]. Six human patients have been treated with IFN-α on two different dosage schedules and despite evidence of increased IFN in serum and CSF, there was no evidence of a beneficial effect on the disease itself [54]. Another therapy previously included in the Milwaukee Protocol is ketamine [50, 51]. At low concentrations, approximately 1 μM, ketamine works as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor which causes a state of dissociative anesthesia. A study from 1991 showed that a high concentration of ketamine could induce inhibitory effects on the RABV genome transcription [55]. Since that time, multiple other trials using neuron cultures and infected mice have produced evidence that ketamine is generally ineffective against the disease [56]. With that knowledge, it is believed that ketamine should not be used for treatment of the rabies virus until further studies produce more promising results. Amantadine is the third and final antiviral that was considered in the Milwaukee Protocol [47, 51]. It is a synthetic inhibitor of viral replication by impeding the release of viral genetic material into the host cell. Although amantadine demonstrated some interference in cellular trials, it failed in animal trials [57]. Minocycline, a broad spectrum antimicrobial, was considered for RABV treatment as it has proven benefits for multiple other viruses [58]. However, when applied to rabies-infected animals, Minocycline caused a number of harmful effects causing an increase in mortality [59].
More recently, researchers have addressed the use of favipiravir in treatment of rabies [50]. Available for influenza treatment in some countries, favipiravir has shown some activity against the rabies virus in mice trials [60]. Continued studies are needed to assess the future of this and other antivirals. It ought to be noted that despite variations in the effectiveness of these antivirals, all have shown that an early start of treatment greatly improves the efficacy of these therapies.
As previously mentioned, there is a small window of effectiveness for an aggressive treatment of RABV; after that window has passed, the focus of treatment is purely one of comfort for the patient. Many patients develop phobias that will likely require seclusion in a calm, quiet room. Although there is little to no evidence of human-to-human transmission, visitors and medical professionals need to be cautious of potential contamination via the patient’s secretion [61]. Dehydration is a major concern as paralytic rabies often inhibits the patient’s ability to swallow and furious rabies can cause intense hydrophobia. Treatment for the dehydration is typically a secured intravenous line. If additional nutrients are needed, they can be administered through the same line.
Rabies typically causes a generalized inflammation that induces a fever, but it can also trigger a neurogenic (central) fever as well [62]. Many antipyretics, such as acetaminophen and ibuprofen, have been successfully used to treat the generalized fever. However, those are generally ineffective towards the central fever. There is some evidence to support the use of baclofen, bromocriptine, chlorpromazine, and morphine in the treatment of a central fever [63]. However, these have not been studied specifically for a rabies-induced central fever and so practitioners should be mindful of potential side effects. Additionally, these drugs are rarely available in the developing countries where RABV is most prevalent [61]. In this case, external, physical means of cooling the patient can be used as needed.
The majority of patients infected with furious RABV develop intense agitation and fear. A variety of sedatives and tranquilizers are used to calm these symptoms. Because benzodiazepines are included on the WHO’s list of essential medicines, they are commonly used to treat rabies-induced agitation as well as many other forms [61]. They can be administered intramuscularly, intravenously, or intrarectally as needed. However, as previously mentioned, it is important to administer any sedative slowly to ensure the patient retains consciousness and does not lose respiratory function [64].
Lastly, clinicians will likely need to address the patient’s pain level. This can be accomplished using opioids such as morphine or other highly effective analgesics. These can be delivered intravenously, intramuscularly, intrarectally, or even transdermally as needed [61]. Although many of these methods of treatment are expensive and generally unlikely to cure a patient once rabies symptoms are present, palliative care is a responsibility of caretakers and clinicians.
Due to the general ineffectiveness of post-exposure treatment, the rabies virus has a remarkably high mortality rate despite the availability of vaccines that have shown a near perfect success rate when administered prior to infection. This indicates that the main issue with prevention is the lack of accessibility in the impoverished countries of Asia and Africa. In 2015, the World Health Organization (WHO) and the World Organization for Animal Health (OIE) with the help of the Food and Agriculture Organization of the United Nations (FAO) set a goal to rid the world of dog-mediated rabies by 2030 (Zero by 30) [65]. After assessing cost and general accessibility, it was decided that the best way to eliminate dog-mediated rabies is to vaccinate dogs rather than humans. Vaccinating at least 70% of dogs should effectively break the cycle of rabies transmission.
To reach this goal, WHO, OIE, FAO and many smaller agencies collaborated to create the Stepwise Approach towards Rabies Elimination (SARE) [66, 67]. A similar stepwise approach proved successful in the elimination of fox RABV from Europe [68]. SARE consists of five stages for each country to work through. Stage 0 is simply the lack of information and data on RABV cases in a country where rabies is believed to be present. Stage 1 is an assessment phase in which data are gathered to determine the extent to which RABV pervades the country of interest. During this phase, the government assesses the current guidelines or structures in place as well as collects and analyzes all available data on previous or existing RABV cases. The beginning of an action plan is usually concocted in Stage 1. Evolution of this plan happens in Stage 2; it is important to develop an understanding of the available funding at this point as that has been the biggest limitation for developing countries in the past. Stage 3 is the implementation of the country’s rabies control strategy. During this phase, the plan will likely need to be adapted to address any challenges that arise; these may include the exposure of wildlife reservoirs of RABV such as the fox rabies previously found in Europe. When reported human cases have decreased to zero, the country will shift into Stage 4 – elimination of dog RABV. This requires the maintenance of the reduced dog-to-human rabies transmission as well as continued implementation of the action plan to continue to reduce dog rabies cases. Lastly, in Stage 5, the country must develop a post-elimination strategy to maintain the freedom from human and dog rabies.
While the SARE tool has been developed to be adaptable enough to succeed worldwide, there are likely to be some setbacks in the different landscapes. Specifically, areas of poverty will be constrained by the financial resources they can acquire. Many parts of Asia have political instability that will greatly challenge the need for nation-wide commitment to this goal. Similarly, Africa’s linguistic and cultural complexity will oppose the need for excellent communication and tracking [66]. Ultimately, it will take a dedicated and educated global population to eliminate rabies as a whole; until then, vaccinating animals and at-risk populations is the most efficient means of prevention.
This chapter served to outline the diagnosis, clinical course, treatment, and prevention of the RNA virus RABV. A swift rabies’s diagnosis is imperative to ensure the patient’s greatest chance of survival. Clinicians may utilize many techniques such as MRI, rtPCR, FAT, FAVN, dRIT, and electron microscopy to diagnose patients before physical symptoms arise. The same methods can be used to confirm a diagnosis after the patient presents with symptoms if needed. Rabies can present in patients in the furious or paralytic form. Although these cause very different physical symptoms, the pathophysiology is very similar. Generally initiated by a bite or other wound, the virus will incubate in the myocytes nearest the entry point and replicate undetected for an average of 1–3 months. Eventually, the virus will infect a nerve cell and travel through axon transport to the CNS at which point it will cause encephalitis or paralysis. Once the virus has infiltrated the CNS, it is essentially incurable. However, if detected early, patients can receive PEP - a combination of active and passive immunization most frequently in the form of a cell culture vaccine and a dose of RIG. At this time, there are no antivirals considered to be effective for treating RABV. If the virus becomes established in the patient, the treatment plan is adjusted to ensure the most comfort for the patient and their loved ones. This most often consists of a variety of sedatives, pain management, antipyretics, and fluids. Due to the great lethality of RABV in humans, multiple global organizations have banded together to attempt to eradicate the modern world of the rabies virus. The Zero by 30 movement strives to implement a stepwise method to eliminate dog-mediated rabies cases worldwide by 2030. This is believed to be possible if 70% or more of the dog population is vaccinated against rabies. In combination with the vaccination goal, Zero by 30 also encourages countries to implement educational standards on rabies, bite prevention, and responsible pet ownership.
At this time, the community of RABV researchers need to be working to improve current treatment options in order to decrease the number of RABV-related deaths. This might be done by developing a mAb alternative to the too-expensive RIG options or finding an effective antiviral either currently on the market or newly developed. The release of additional rabies vaccines for humans would also help to lower the price and improve the accessibility in a way that would benefit the highly affected countries.
The authors declare no conflict of interest.
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Stienen, Pooyan Sadr-Eshkevari, Nora Prochnow, Nora Sandu, Benham Bohluli and Bernhard Schaller",authors:[{id:"78171",title:"Prof.",name:"Bernhard",middleName:null,surname:"Schaller",slug:"bernhard-schaller",fullName:"Bernhard Schaller"},{id:"78525",title:"Mr.",name:"Amr",middleName:null,surname:"Abdulazim",slug:"amr-abdulazim",fullName:"Amr Abdulazim"},{id:"78530",title:"Dr",name:"Pooyan",middleName:null,surname:"Sadr-Eshkevari",slug:"pooyan-sadr-eshkevari",fullName:"Pooyan Sadr-Eshkevari"},{id:"126039",title:"Dr.",name:"Martin",middleName:"Nikolaus",surname:"Stienen",slug:"martin-stienen",fullName:"Martin Stienen"},{id:"126040",title:"Dr.",name:"Nora",middleName:null,surname:"Prochnow",slug:"nora-prochnow",fullName:"Nora Prochnow"},{id:"126041",title:"Dr.",name:"Benham",middleName:null,surname:"Bohluli",slug:"benham-bohluli",fullName:"Benham Bohluli"}]},{id:"26863",doi:"10.5772/26362",title:"The Bearing Surfaces in Total Hip Arthroplasty – Options, Material Characteristics and Selection",slug:"the-bearing-surfaces-in-total-hip-arthroplasty-options-material-characteristics-and-selection",totalDownloads:9530,totalCrossrefCites:10,totalDimensionsCites:21,abstract:null,book:{id:"938",slug:"recent-advances-in-arthroplasty",title:"Recent Advances in Arthroplasty",fullTitle:"Recent Advances in Arthroplasty"},signatures:"Hamid Reza Seyyed Hosseinzadeh, Alireza Eajazi and Ali Sina Shahi",authors:[{id:"66361",title:"Dr.",name:"Alireza",middleName:null,surname:"Eajazi",slug:"alireza-eajazi",fullName:"Alireza Eajazi"},{id:"74857",title:"Dr.",name:"Hamid Reza",middleName:null,surname:"Seyyed Hosseinzadeh",slug:"hamid-reza-seyyed-hosseinzadeh",fullName:"Hamid Reza Seyyed Hosseinzadeh"},{id:"173207",title:"Dr.",name:"Alisina",middleName:null,surname:"Shahi",slug:"alisina-shahi",fullName:"Alisina Shahi"}]}],mostDownloadedChaptersLast30Days:[{id:"65467",title:"Anesthesia Management for Large-Volume Liposuction",slug:"anesthesia-management-for-large-volume-liposuction",totalDownloads:6203,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The apparent easiness with which liposuction is performed favors that patients, young surgeons, and anesthesiologists without experience in this field ignore the many events that occur during this procedure. Liposuction is a procedure to improve the body contour and not a surgery to reduce weight, although recently people who have failed in their plans to lose weight look at liposuction as a means to contour their body figure. Tumescent liposuction of large volumes requires a meticulous selection of each patient; their preoperative evaluation and perioperative management are essential to obtain the expected results. The various techniques of general anesthesia are the most recommended and should be monitored in the usual way, as well as monitoring the total doses of infiltrated local anesthetics to avoid systemic toxicity. The management of intravenous fluids is controversial, but the current trend is the restricted use of hydrosaline solutions. The most feared complications are deep vein thrombosis, pulmonary thromboembolism, fat embolism, lung edema, hypothermia, infections and even death. The adherence to the management guidelines and prophylaxis of venous thrombosis/thromboembolism is mandatory.",book:{id:"6221",slug:"anesthesia-topics-for-plastic-and-reconstructive-surgery",title:"Anesthesia Topics for Plastic and Reconstructive Surgery",fullTitle:"Anesthesia Topics for Plastic and Reconstructive Surgery"},signatures:"Sergio Granados-Tinajero, Carlos Buenrostro-Vásquez, Cecilia\nCárdenas-Maytorena and Marcela Contreras-López",authors:[{id:"273532",title:"Dr.",name:"Sergio Octavio",middleName:null,surname:"Granados Tinajero",slug:"sergio-octavio-granados-tinajero",fullName:"Sergio Octavio Granados Tinajero"}]},{id:"42855",title:"Critical Care Issues After Major Hepatic Surgery",slug:"critical-care-issues-after-major-hepatic-surgery",totalDownloads:8935,totalCrossrefCites:2,totalDimensionsCites:2,abstract:null,book:{id:"3164",slug:"hepatic-surgery",title:"Hepatic Surgery",fullTitle:"Hepatic Surgery"},signatures:"Ashok Thorat and Wei-Chen Lee",authors:[{id:"52360",title:"Prof.",name:"Wei-Chen",middleName:null,surname:"Lee",slug:"wei-chen-lee",fullName:"Wei-Chen Lee"},{id:"157213",title:"Dr.",name:"Ashok",middleName:null,surname:"Thorat",slug:"ashok-thorat",fullName:"Ashok Thorat"}]},{id:"72175",title:"Fontan Operation: A Comprehensive Review",slug:"fontan-operation-a-comprehensive-review",totalDownloads:1299,totalCrossrefCites:3,totalDimensionsCites:2,abstract:"Since the first description of the Fontan operation in the early 1970s, a number of modifications have been introduced and currently staged, total cavopulmonary connection with fenestration has become the most commonly used multistage surgery in diverting the vena caval blood flow into the lungs. The existing ventricle, whether it is left or right, is utilized to supply systemic circuit. During Stage I, palliative surgery is performed, usually at presentation in the neonatal period/early infancy, on the basis of pathophysiology of the cardiac defect. During Stage II, a bidirectional Glenn procedure is undertaken in which the superior vena caval flow is diverted into the lungs at an approximate age of 6 months. During Stage IIIA, the blood flow from the inferior vena cava (IVC) is rerouted into the pulmonary arteries, typically by an extra-cardiac conduit along with a fenestration, generally around 2 years of age. During Stage IIIB, the fenestration is closed by transcatheter methodology 6–12 months after Stage IIIA. The evolution of Fontan concepts, the indications for Fontan surgery, and the results of old and current types of Fontan operation form the focus of this review.",book:{id:"9585",slug:"advances-in-complex-valvular-disease",title:"Advances in Complex Valvular Disease",fullTitle:"Advances in Complex Valvular Disease"},signatures:"P. Syamasundar Rao",authors:[{id:"68531",title:"Dr.",name:"P. Syamasundar",middleName:null,surname:"Rao",slug:"p.-syamasundar-rao",fullName:"P. Syamasundar Rao"}]},{id:"45712",title:"Serdev Sutures® in Middle Face",slug:"serdev-sutures-in-middle-face",totalDownloads:4952,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"2989",slug:"miniinvasive-face-and-body-lifts-closed-suture-lifts-or-barbed-thread-lifts",title:"Miniinvasive Face and Body Lifts",fullTitle:"Miniinvasive Face and Body Lifts - Closed Suture Lifts or Barbed Thread Lifts"},signatures:"Nikolay Serdev",authors:[{id:"32585",title:"Dr.",name:"Nikolay",middleName:null,surname:"Serdev",slug:"nikolay-serdev",fullName:"Nikolay Serdev"}]},{id:"55812",title:"Postural Restoration: A Tri-Planar Asymmetrical Framework for Understanding, Assessing, and Treating Scoliosis and Other Spinal Dysfunctions",slug:"postural-restoration-a-tri-planar-asymmetrical-framework-for-understanding-assessing-and-treating-sc",totalDownloads:7701,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Current medical practice does not recognize the influence of innate, physiological, human asymmetry on scoliosis and other postural disorders. Interventions meant to correct these conditions are commonly based on symmetrical models of appearance and do not take into account asymmetric organ weight distribution, asymmetries of respiratory mechanics, and dominant movement patterns that are reinforced in daily functional activities. A model of innate, human asymmetry derived from the theoretical framework of the Postural Restoration Institute® (PRI) explicitly describes the physiological, biomechanical, and respiratory components of human asymmetry. This model is important because it gives an accurate baseline for understanding predisposing factors for the development of postural disorders, which, without intervention, will likely progress to structural dysfunction. Clinical tests to evaluate tri-planar musculoskeletal relationships and function, developed by PRI, are based on this asymmetric model. These tests are valuable for assessing patient’s status in the context of human asymmetry and in guiding appropriate exercise prescription and progression. Balancing musculoskeletal asymmetry is the aim of PRI treatment. Restoration of relative balance decreases pain, restores improved alignment, and strengthens appropriate muscle function. It can also halt the progression of dysfunction and improve respiration, quality of life, and appearance. PRI’s extensive body of targeted exercise progressions are highly effective due to their basis in the tri-planar asymmetric human model.",book:{id:"5816",slug:"innovations-in-spinal-deformities-and-postural-disorders",title:"Innovations in Spinal Deformities and Postural Disorders",fullTitle:"Innovations in Spinal Deformities and Postural Disorders"},signatures:"Susan Henning, Lisa C. Mangino and Jean Massé",authors:[{id:"204825",title:"Dr.",name:"Susan",middleName:null,surname:"Henning",slug:"susan-henning",fullName:"Susan Henning"},{id:"206242",title:"Dr.",name:"Lisa C",middleName:null,surname:"Mangino",slug:"lisa-c-mangino",fullName:"Lisa C Mangino"},{id:"206245",title:"Dr.",name:"Jean",middleName:null,surname:"Massé",slug:"jean-masse",fullName:"Jean Massé"}]}],onlineFirstChaptersFilter:{topicId:"202",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82020",title:"Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Novel Technique and Technology with Case Series",slug:"minimally-invasive-transforaminal-lumbar-interbody-fusion-a-novel-technique-and-technology-with-case",totalDownloads:6,totalDimensionsCites:0,doi:"10.5772/intechopen.105187",abstract:"Minimally invasive spine surgery (MIS) transforaminal lumbar interbody fusion (MI-TLIF) has been utilized to treat a variety of spinal disorders. Like other minimally invasive spine surgery techniques and technology, the MI-TLIF approach has the potential to limit the morbidity associated with larger exposures required for open surgery. The MI-TLIF approach has a number of advantages over many other minimally invasive spine surgery approaches including direct decompression of neural elements, collection of morselized autograph from the surgical site to achieve high fusion rates, restoration of spinal canal diameter, foraminal diameter, disk height, and reduction of spondylolisthesis. In this chapter, we discuss a novel technique for performing MI-TLIF developed by the senior author who is a leading minimally invasive spine surgeon. The technique and technology illustrated in this chapter were developed out of a recognition of a need to reduce the learning curve for performing MI-TLIF, as well as need for a cost-effective method that provides a high fusion rate, excellent clinical outcomes, and low complication rate. The indications, surgical planning, postoperative care, complications, and patient outcomes in a large series will be reviewed using this novel MI-TLIF technique.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Mick Perez-Cruet, Ramiro Pérez de la Torre and Siddharth Ramanathan"},{id:"78335",title:"Safety and Efficiency of Cervical Disc Arthroplasty in Ambulatory Surgery Centers",slug:"safety-and-efficiency-of-cervical-disc-arthroplasty-in-ambulatory-surgery-centers",totalDownloads:5,totalDimensionsCites:0,doi:"10.5772/intechopen.99589",abstract:"Introduction Anterior cervical surgeries have been safely performed in ambulatory surgery centers since 1995 with the first cases being one level anterior cervical discectomies without fusion, then in 1996, one level anterior cervical discectomies with fusion (ACDF). When it is was certain that outpatient fusion was safe, the number of ACDF levels slowly and methodically were increased to the now standard outpatient maximum of four level ACDF. During this evolution, with the introduction of arthroplasty surgery, one level arthroplasties were considered appropriate for outpatient surgery and now two-level outpatient cervical arthroplasties are routine and some three level arthroplasties have been performed with no additional morbidity compared to one level procedures. The author first reported a series of 27 patients in 2010 who underwent cervical disc replacement at an ASC. (Wohns, R. Safety and cost-effectiveness of outpatient cervical disc arthroplasty. Surg. Neurol. Int. 1, 77, 2010). The average operative time was 40 minutes and the patients were observed over a period of three hours prior to discharge. None of the patients had major complications and there were no reports of worsening or persistent pain. The results of a Delphi study in 2018 compared the safety and efficiency of one-level and two-level arthroplasty procedures performed in an ASC and in a hospital setting. (Gornet et al. Safety and Efficiency of Cervical Disc Arthroplasty in Ambulatory Surgery Centers vs Hospital Settings. Int’l J of Spine Surgery. Vol. 12, No.5, 2018, pp. 557-564). The study analyzed outcomes of 145 ASC patients, 348 hospital outpatients and 65 hospital inpatients and the conclusion was that both one and two-level arthroplasties may be performed safely in an ASC. Surgeries in ASCs are of shorter duration and performed with less blood loss without increased AEs. At the present time, there does not appear to be any contra-indication to performing the vast majority of cervical arthroplasties in an ambulatory surgery center (ASC). Furthermore, the cost of an outpatient arthroplasty is commonly 30% to 50% of the cost of hospital-based procedures.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Richard N.W. Wohns"},{id:"82255",title:"Minimally Invasive Laminectomy for Lumbar Stenosis with Case Series of Patients with Multi-level (3 or More Levels) Stenosis",slug:"minimally-invasive-laminectomy-for-lumbar-stenosis-with-case-series-of-patients-with-multi-level-3-o",totalDownloads:28,totalDimensionsCites:0,doi:"10.5772/intechopen.105186",abstract:"Lumbar stenosis is the most common pathology seen and treated by spine surgeons. It is often seen in the elderly population who frequently have multiple medical co-morbidities. Traditional approaches remove the spinous process and detach paraspinous muscles to achieve adequate canal decompression. This approach can damage the posterior tension band leading to permanent muscle damage, scar tissue formation, iatrogenic flatback syndrome, and increase risk of adjacent segment disease requiring reoperation. Performing lumbar laminectomy in a cost-effective manner is critical in effectively treating patients with lumbar stenosis. This chapter reviews a minimally invasive muscle-sparing approach to treating lumbar stenosis. The technique is performed through a tubular retractor. Direct decompression of the spinal stenosis is achieved while preserving the paraspinous muscle attachments and spinous process. This technique has multiple advantages and can potentially reduce load stress on adjacent levels and subsequent adjacent level pathology leading to further surgical intervention. In addition, the procedure shows how facet fusion is performed using the patient’s own locally harvested drilled morselized autograph to achieve bilateral facet fusion. By fusing the facets, we have shown that restenosis at the operative level is less likely to occur. This chapter will review a case series of multilevel lumbar stenosis including clinical outcomes.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Mick Perez-Cruet, Ramiro Pérez de la Torre and Siddharth Ramanathan"},{id:"80705",title:"Cervical Arthroplasty",slug:"cervical-arthroplasty",totalDownloads:38,totalDimensionsCites:0,doi:"10.5772/intechopen.102964",abstract:"Technological advances have allowed spine surgery to follow the trend toward minimally invasive surgery in general. Specifically, we have seen a corresponding rise in the popularity of cervical arthroplasty. For the treatment of cervical disc disease, arthroplasty is a less invasive option than the gold standard of cervical discectomy and arthrodesis, which by nature is more disruptive to surrounding tissues. Arthroplasty preserves the facets, maintains motion, and reduces the rate of adjacent segment breakdown. These factors counteract the negative impacts of fusion while maintaining the benefits. Arthroplasty implants themselves have become more streamlined to implant as well with less native bone destruction, and biomechanics more compatible with the native disc. While initial implants were ball and socket devices with complex fixation and plane-specific movements, later devices incorporated such motions as translation and compression. Viscoelastic components and materials more closely resembling native tissues afford a more biocompatible implant profile. Until cell-based therapies can successfully reproduce native tissue, we will rely on artificial components that closely resemble and assimilate them.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Jason M. Highsmith"},{id:"80605",title:"Minimally Invasive Treatment of Spinal Metastasis",slug:"minimally-invasive-treatment-of-spinal-metastasis",totalDownloads:42,totalDimensionsCites:0,doi:"10.5772/intechopen.102485",abstract:"Advancements in the treatment of systemic cancer have improved life expectancy in cancer patients and consequently the incidence of spinal metastasis. Traditionally, open spinal approaches combined with cEBRT (conventional external beam radiation therapy) allowed for local tumor control as well as stabilization and decompression of the spine and neural elements, but these larger operations can be fraught with one complications and delayed healing as well as additional morbidity. Recently, minimally invasive spine techniques are becoming increasingly popular in the treatment of spinal metastasis for many reasons, including smaller incisions with less perioperative complications and potential for expedited time to radiation therapy. These techniques include kyphoplasty with radiofrequency ablation, percutaneous stabilization, laminectomy, and epidural tumor resection through tubular retractors, as well as minimally invasive corpectomy. These techniques combined with highly conformal stereotactic radiosurgery have led to the advent of separation surgery, which allows for decompression of neural elements while creating space between neural elements and the tumor so adequate radiation may be delivered, improving local tumor control. The versatility of these minimally invasive techniques has significantly improved the modern management of metastatic disease of the spine by protecting and restoring the patient’s quality of life while allowing them to quickly resume radiation and systemic treatment.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Eric R. Mong and Daniel K. Fahim"},{id:"76620",title:"Minimally Invasive Lateral Approach for Anterior Spinal Cord Decompression in Thoracic Myelopathy",slug:"minimally-invasive-lateral-approach-for-anterior-spinal-cord-decompression-in-thoracic-myelopathy",totalDownloads:146,totalDimensionsCites:0,doi:"10.5772/intechopen.97669",abstract:"Myelopathy can result from a thoracic disc herniation (TDH) compressing the anterior spinal cord. Disc calcification and difficulty in accessing the anterior spinal cord pose an operative challenge. A mini-open lateral approach to directly decompress the anterior spinal cord can be performed with or without concomitant interbody fusion depending on pre-existing or iatrogenic spinal instability. Experience using stand-alone expandable spacers to achieve interbody fusion in this setting is limited. Technical advantages, risks and limitations of this technique are discussed. We conducted a retrospective chart review of all patients with thoracic and upper lumbar myelopathy treated with a lateral mini-open lateral approach. Review of the literature identified 6 other case series using similar lateral minimally invasive approaches to treat thoracic or upper lumbar disc herniation showing efficient and safe thoracic disc decompression procedure for myelopathy. This technique can be combined with interbody arthrodesis when instability is suspected.",book:{id:"10634",title:"Minimally Invasive Spine Surgery - Advances and Innovations",coverURL:"https://cdn.intechopen.com/books/images_new/10634.jpg"},signatures:"Edna E. Gouveia, Mansour Mathkour, Erin McCormack, Jonathan Riffle, Olawale A. Sulaiman and Daniel J. Denis"}],onlineFirstChaptersTotal:12},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"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:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,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. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. 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She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. 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He 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:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{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. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). 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