Inlet conditions for the flat plate test cases.
\r\n\tThis field has grown exponentially over the past decade resulting in less postoperative pain, risk of complications, and recovery times. Arthroscopy has evolved from a diagnostic tool to a therapeutic tool capable of treating a wide range of injuries and disorders in most of the joints. Many injuries, particularly those that at one time would have been career-ending for athletes, can now be addressed with arthroscopy allowing a quicker return to a competitive level. While arthroscopy has resulted in an overall decrease in morbidity compared with open techniques, it is still an invasive procedure and inherently involves risks.
\r\n\r\n\tWith this book, we attempt to summarize the most common arthroscopic procedures, diagnosis, risks, and complications.
\r\n\tAll of the above aspects are addressed in this book, which describes the current applications of arthroscopy, explaining the mechanisms of injury for each condition, and describing the role of arthroscopy in diagnosis and treatment.
\r\n\t
Industrial design aerodynamics heavily depends on development of new CFD methods that can be only as good as their experimental database. All these industrial design CFD codes, as they may be called, are constantly in search of better physical modeling starting with appropriate transition and turbulence modeling. To this end, although numerical representation of turbulence has reached the acceptable levels of accuracy for computational aerodynamics, transition modeling has yet to reach the level of turbulence modeling capability for routine calculations. Therefore, transition modeling as part of turbulence has always been standing as the crux of the matter with regard to turbulence modeling. Today, state of the art Reynolds Averaged Navier-Stokes (RANS) solvers are widely available for numerically predicting fully turbulent part of flow fields by frequent use of, for instance, one- or two-equation turbulence closure models. However, none of these models are adequate to handle flows with significant transition effects due to the lack of practical transition modeling. Menter et al. [1] state that some of the main requirements for pragmatic transition modeling are the following: calibrated prediction of the onset and length of transition, allow inclusion of different mechanisms, allow local formulation, and allow a robust integration with background turbulence models.
\nNevertheless, transition modeling as applied to CFD methods has followed certain line of evolution covering a range of methods starting from simple linear stability methods such as the eN method [2, 3] to almost or fully predictive methods such as LES and DNS that are very costly for engineering applications [1]. The eN method is the lowest level transition model based on linear stability theory. This method has found quite wide application in numerical boundary layer methods [4], but translating this into RANS methods has proven quite demanding as it requires a high-resolution boundary layer code that must work hand in hand with the RANS method. Also, this method is also dependent on the empirical factor-n that is not universal and depends on the type of flow.
\nFollowing the eN method, a better level of complexity that is compatible with the CFD methods is the low Reynolds number turbulence models [5]. Yet, they do not reflect real flow physics and lack the true predictive capability. These methods take advantage of the fortuitous ability of the wall damping terms mimicking some of the effects of transition. Next in the line of increasing complexity comes the class of the so-called correlation-based transition models [1]. These models are based on the fundamental approach of blending the laminar and the turbulent regions of the flow field by introducing intermittency equations to the turbulence equations. In this line, based on the boundary layer methods, there are three similar examples of intermittency equation approach that was introduced by Dhawan and Narasimha [6], Steelant and Dick [7], and Cho and Chung [8]. First, Dhawan and Narasimha [6] used a generalized form of intermittency distribution function in order to combine the laminar and the turbulent flow regions. Second, Steelant and Dick [7] proposed an intermittency equation that behaves like an experimental correlation. Third, Cho and Chung [8] introduced the k-ε-γ model which was formulated by an additional transport equation-γ to the well-known k-ε turbulence model. Finally, Suzen and Huang [9] significantly improved intermittency equation approach for flow transition prediction by combining the last two methods with a model that simulates transition in both streamwise and cross-stream directions. However, these models all rely on nonlocal flow data, and it was difficult to embed these models into practical CFD codes. These models require calculating the momentum thickness Reynolds number-Reθ, which is an integral parameter, and comparing it with a critical momentum thickness Reynolds number. For this reason, these early models are “nonlocal” methods that require exhausting search algorithms for flows with complex geometries.
\nAfter the success of the “nonlocal” transition models that use intermittency transport equations including experimental correlations, a range of new methods [10, 11] has been developed, called as the local correlation-based transition models (LCTM) by Menter et al. [1] that are compatible with the modern CFD codes. This compatibility has been achieved by the experimental observation that a locally calculated parameter called as the vorticity Reynolds number (Rev) is proportional to the momentum thickness Reynolds number (Reθ) in a Blasius boundary layer. This observation is also shown to be quite effective for a wide class of flow types with moderate pressure gradients. This is due to the fact that the relative error between the two parameters is less than 10% for such flows [1]. Therefore, the vorticity Reynolds number-Rev would be used in order to avoid all the troublesome work that existed in the nonlocal models.
\nFollowing the success of the γ-Reθ two-equation transition model of Menter et al. [1], some other two-, or three-equation models are proposed, such as the near/freestream intermittency model by Lodefier et al. [12], variations of the k-kL-ω models of Walters and Leylek [13] and Walters and Cokljat [14], and the k-ω-γ model of Fu and Wang [15] with super/hypersonic flow applications. In addition, some researchers proposed extensions to local correlation-based transition models (LCTM) in order to take more physical phenomena into account. To this end, cross-flow instability effects by Seyfert and Krumbein [16], surface roughness effects by Dassler et al. [17], and compressibility effects by Kaynak [18] were included. Meanwhile, Bas et al. [19] proposed a very pragmatic approach by introducing an algebraic or a zero-equation model called later as the Bas-Cakmakcioglu (B-C) model [20]. Herein, it was shown that an equivalent level of prediction compared with the two- and three-equation models could be achieved with less equations provided that physics was correctly modeled. In parallel, Kubacki et al. [21] proposed yet another algebraic transition model with a good level of success vindicating this line of approach. Similarly, Menter et al. [22] proposed a new one-equation γ-model which is the simplification of their earlier two-equation γ-Reθ model [11] without the Reθ-equation that produced equal level of results as in the original model. Following this logical trend for reducing the total number of equations, the Wray-Agarwal (WA) wall-distance-free one-equation turbulence model [23] was complemented with the Menter et al. [22] one-equation intermittency transport-γ model to obtain the so-called two-equation Nagapetyan-Agarwal WA-γ transition model [24]. In the following, a brief review of the transition modeling is made that covers the practical applications of a range of models that are currently used in the industrial design aerodynamics. Based on the present authors’ recent experiences, the Bas-Cakmakcioglu model [20] will be covered in some detail to display the viability of the algebraic intermittency equation approach vis-a-vis the one- and two-equation local correlation-based transition models (LCTM).
\nThe well-known eN method is based on the linear stability theory [25], and it is developed by assuming that the flow is two-dimensional and steady, the boundary layer is thin and the level of disturbances in the flow region is initially very low. In this method, the Orr-Sommerfeld eigenvalue equations are solved by using the previously obtained velocity profiles over a surface in order to calculate the local instability amplification rates of the most unstable waves for each profile. By taking the integral of those rates after a certain point where the flow first becomes unstable along each streamline, an amplification factor is calculated. Transition is said to occur when the value of the amplification factor exceeds a threshold N value. Typical values of N vary between 7 and 9.
\nIn the low Reynolds number turbulence models, the wall damping functions are modified in order to capture the transition effects [5]. To be able to predict the transition onset, these models depend on the diffusion of the turbulence from freestream into the boundary layer and its interaction with the source terms of the turbulence models. For this reason, these models are more suitable for bypass transition flows. Nonetheless, due to the similarities between a developing laminar boundary layer and a viscous sublayer, their success is thought to be coincidental, and thus these modes are mostly unreliable. These models also lack sensitivity to adverse pressure gradients and convergence problems arise for separation-induced transition cases.
\nIt has been known from experiment that turbulence has an intermittent character with large fluctuations in flow variables like velocity, pressure, etc. Based on this observation, transition to turbulence has been tried to be modeled using the so-called intermittency function. One-, two- or three-equation partial differential equations have been derived to include the intermittency equation as one of the equations of the complete equation set including relevant experimental calibrations that mimic the actual physical behavior. To this end, “nonlocal” [7, 8, 9] and “local” [1, 10, 11] correlation transition models have been proposed. In the following, a systematic line of progress is presented that reveals the evolution of such models.
\nDhawan and Narasimha [6] proposed a scalar intermittency function-γ that would provide some sort of a measure of progression toward a fully turbulent boundary layer. Based on the experimentally measured streamwise intermittency distributions on flat plate boundary layers, for instance, Dhawan and Narasimha [6] introduced the following function for streamwise intermittency profile:
\nIn the above function, xt is the known transition onset location, n is the turbulence spot formation rate per unit time per unit distance in the spanwise direction, σ is a turbulence spot propagation parameter, and U is the freestream velocity.
\nCho and Chung [8] developed the k-ε-γ turbulence model that is not designed for prediction of transitional flows but for free shear flows. In this model, the intermittency effect is incorporated into the conventional k-ε turbulence model with the addition of an intermittency transport equation for the intermittency factor γ. In this model, the turbulent viscosity is defined in terms of k, ε, and γ. The intermittency transport equation is given as:
\nwhere Dγ is the diffusion term and Sγ is the source term. This model is tested for a plane jet, a round jet, a plane far-wake, and a mixing layer case. As mentioned before, although the model was not designed for transition prediction, the γ intermittency profile for the turbulent-free shear layer flows was quite realistic.
\nSteelant and Dick [7] developed an intermittency transport model that can be used with the so-called conditioned Navier-Stokes equations. In this model, the intermittency function of Dhawan and Narasimha [6] is first differentiated along the streamline direction, s, and the following intermittency transport equation is obtained:
\nIn the above equation, β(s) is a turbulent spot formation and propagation term, which is seen in the exponential function part of the Dhawan and Narasimha model. Steelant and Dick tested their model for zero, adverse and favorable pressure gradient flows by using two sets of the so-called conditioned averaged Navier-Stokes equations. Although their model reproduces the intermittency distribution of Dhawan and Narasimha for the streamwise direction, a uniform intermittency distribution in the cross-stream direction is assumed. Yet, this is inconsistent with the experimental observations of, for instance, Klebanoff [26] where a variation of the intermittency in the normal direction by means of an error function formula.
\nSuzen and Huang [9] proposed an intermittency transport equation model by mixing the production terms of the Cho and Chung [8] and Steelant and Dick [7] models by means of a new blending function. An extra diffusion-related production term due to Cho and Chung is also added to the resultant equation. This model successfully reproduces experimentally observed streamwise intermittency profiles and demonstrates a realistic profile for the cross-stream direction in the transition region. This model is coupled with the Menter’s k-ω SST turbulence model [27] in which the intermittency factor calculated by the Suzen and Huang model is used to scale the eddy viscosity field computed by the turbulence model. This model is successfully tested against several flat plate and low-pressure turbine experiments. However, as mentioned before, this model is not a fully local formulation, and thus it cannot be implemented in straightforward fashion in the modern CFD codes.
\nLangtry and Menter’s formulation of the two-equation γ-Reθ model [11] is one of the most widely used transition models as far as general CFD applications in aeronautics are concerned. This model is formulated in such a way that allows calibrated prediction of transition onset and length that are valid for both the 2-D and 3-D flows. It uses the so-called local variables and thus applicable to any type of grids generated around complex geometries with robust convergence characteristics. As mentioned in the introduction part, this model is based on an important experimental observation that a locally calculated parameter called as the vorticity Reynolds number (Rev) and the momentum thickness Reynolds number (Reθ) where
\nare proportional in a Blasius boundary layer. For most of the flow types, the relative error between the scaled vorticity Reynolds number and momentum thickness Reynolds number is reported [1] to be around 10%.
\nThe model solves for two additional equations besides the underlying two-equation k-ω SST turbulence model, an intermittency equation (γ) that is used to trigger the turbulence production term of the k-ω SST turbulence model and a momentum thickness Reynolds number transport equation (Reθ) that includes experimental correlations that relates important flow parameters such as turbulence intensity, freestream velocity, pressure gradients etc. and supplies it to the intermittency equation. The details of the model are available in the literature [1, 11].
\nWalters and Cokljat’s three-equation k-kL-ω model [14] is proposed by the introduction of a transport equation for the laminar kinetic energy (kL) into the conventional k-ω turbulence model and is used for natural and bypass transitional flows. This model is based on the understanding that the freestream turbulence is the cause of the high amplitude streamwise fluctuations in the pretransitional boundary layer, and these fluctuations are quite distinctive from the classic turbulence fluctuations. Also, growth of the laminar kinetic energy correlates with low frequency wall-normal fluctuations of the freestream turbulence. In this model, the total kinetic energy is assumed to be the sum of the large-scale energy which contributes to laminar kinetic energy and the small-scale energy which contributes to turbulence production. Thus, the transport equation for laminar kinetic energy (kL) is solved in conjunction with the turbulent kinetic energy (kT). Since the k-kL-ω model uses a fully local formulation, it is suitable for the modern CFD codes and appears to be the first local model to specifically address pretransitional growth mechanism that is responsible for bypass transition [14].
\nMenter’s one-equation γ transition model [22] is a simplified version of the two-equation γ-Reθ transition model [10, 11]. In the new model, the Reθ equation is avoided, and the experimental correlations for transition onset is embedded into the γ equation in a simplified fashion. In effect, the simplified one-equation γ model still possesses the same level of predictive capabilities as the original model. Menter et al. [22] summarize the advantages and the key changes to the model as follows: the new model is still fully local with new correlations valid for nearly all types of transition mechanisms, solves for one less equation, which is computationally cheaper; it is Galilean invariant; it has less coefficients that makes the model easier to fine-tune for specific application areas; and the new model would be coupled to any turbulence model that has viscous sublayer formulation. Menter et al. tested their model against most of the test cases which they previously used for the two-equation model. The results show that the new one-equation model is quite successful, and it would be a viable replacement for the original model.
\nFollowing the trend for reducing the number of transition equations, a novel method was developed by integrating the recent Wray-Agarwal (WA) wall-distance-free one-equation turbulence model [23] based on the k-ω closure, with the one-equation intermittency transport γ-equation of Menter et al. [22] to construct the so-called two-equation Nagapetyan-Agarwal transition model WA-γ [24]. An important difference between the one-equation turbulence model derived earlier from k-ω models and the baseline turbulence model is the addition of a new cross diffusion term and a blending function between two destruction terms [23]. It was reported that the presence of destruction terms enables the Wray-Agarwal (WA) model to switch between a one-equation k-ω or one equation k-ε model. The new two-equation model was quite successfully validated for computing a number of two-dimensional benchmark experiments such as the transitional flows past flat plates in zero and slowly varying pressure gradients, flows past airfoils such as the S809, Aerospatiale-A, and NLR-7301 two-element airfoils.
\nBas and Cakmakcioglu (B-C) model [20] is an algebraic or zero-equation model that solves for an intermittency function rather than an intermittency transport (differential) equation. The main approach behind the B-C model follows the pragmatic idea of further reducing the total number of equations. Rather than deriving extra equations for intermittency convection and diffusion, already present convection and diffusion terms of the underlying turbulence model could be used. From a philosophical point of view, the transition, as such, is just a phase of a general turbulent flow. Addition of, in a sense, artificially manufactured transition equations appear to be rather redundant. Yet, for most of industrial flow types, the experimentally evidenced close relation between the scaled vorticity Reynolds number and the momentum thickness Reynolds number stood out as the primary reason for the success of so many intermittency transport equation models following the Langtry and Menter’s original two-equation γ-Reθ model [11].
\nIn the application, the production term of the underlying turbulence model is damped until a considerable amount of turbulent viscosity is generated, and the damping effect of the transition model would be disabled after this point. The Spalart-Allmaras (S-A) turbulence model [28] is used as the baseline turbulence model, and rather than using an intermittency equation, just an intermittency function is proposed to control its production term. To this end, the B-C model is also a local correlation transition model that can be easily implemented for both 2-D and 3-D flows with reduced number of equations. For instance, for a 3-D problem, the B-C model solves for six equations (1 continuity + 3 momentum + 1 energy + 1 turbulence), whereas the two-equation γ-Reθ model solves for nine equations (1 continuity + 3 momentum + 1 energy + 2 turbulence + 2 transition). In addition, in the B-C model formulation, the freestream turbulence intensity parameter is only present in the critical momentum thickness Reynolds number function that makes the calibration of the model quite easy for different problems. The details of the B-C model formulation are presented in the following.
\nThe S-A one-equation turbulence model is used as the underlying turbulence model for the B-C model. The S-A model solves for a transport equation for a new working variable νT, which is related to the eddy viscosity. The B-C model’s transition effects are included into the turbulence model is provided by multiplying the intermittency distribution function (γBC) with the production term of the S-A equation given as:
\nThe γBC function works in such a way that the turbulence production is damped (γBC = 0) until some transition onset criteria is fulfilled. After a point at which the onset criteria is ensured, the damping effect of the intermittency function γBC is checked, and the remaining part of the flow is taken to be fully turbulent (γBC = 1). For this purpose, an exponential function of the form (1-e−x) is proposed for the γBC as follows:
\nwhere Term1 and Term2 are defined as:
\nand,
\nIn the above, ρ is the density, μ is the molecular viscosity, dw is the distance from the nearest wall, νBC is a proposed turbulent viscosity-like nondimensional term where νt is the turbulent viscosity, U is the local velocity magnitude, dw is the distance from the nearest wall, and χ1 and χ2 are calibration constants. Reθc is defined as the critical momentum thickness Reynolds number, which is a correlation that is based on a range of transition experiments. In effect, Term1 checks for the transition onset point by comparing the locally calculated Reθ with the experimentally obtained critical momentum thickness Reynolds number Reθc. As soon as the vorticity Reynolds number Rev exceeds a critical value, Term1 becomes greater than zero and the intermittency function γBC begins to increase. However, the vorticity Reynolds number Rev relation above is a function of the square of the wall distance dw; therefore, it takes a very low value inside the boundary layer where the wall distance is quite low. Because of this, Term1 alone is not enough for intermittency generation inside the boundary layer. To remedy this, Term2 is introduced. Inspecting the Term2 equation with the νBC relation shows that the regions close to wall is inversely related and the damping effect of the transition model would be disabled inside the boundary layer. In effect, Term2 checks for the viscosity levels inside the boundary layer, and the turbulence production is activated wherever νBC exceeds a critical value χ2. In order to determine the calibration constants’ χ1 and χ2 values, the well-known zero pressure gradient flat plate test case of Schubauer and Klebanoff [29] is used. This test case represents a natural transition process due to the wind tunnel used in the experiment generates a freestream Tu around 0.2%. The model calibration is done by numerical experimentation; setting χ1 and χ2 such that the transition occurs at the same location as in the experiment. As a result, the χ1 and χ2 values are set to be 0.002 and 5.0, respectively.
\nAny experimental Reθc correlation could be used in the model. However, it should be noted that, since the S-A turbulence model does not solve for the local turbulent kinetic energy, local turbulence intensity values cannot be calculated. Due to this reason, the turbulence intensity Tu is assumed, for now, to be constant in the entire flow domain as Suluksna et al. [30] and Medida [31] have also suggested. For this lack of ability for calculating the local Tu values, the B-C model has some deficiency in this respect that it cannot handle some physical effects compared with the models that can dynamically calculate the local Tu levels. Whereas this deficiency makes the B-C model rather limited, there are quite a few aerodynamic flows for which the model is still viable. The transition onset correlation that was also used in the original two-equation γ-Reθ model [1] is given by:
\nAs mentioned before, any transition onset correlation would be incorporated into the B-C model. For instance, a class of potential transition onset correlations along with the one preferred in the present B-C model is shown in Figure 1.
\nTransition onset correlations compared with experiments.
Currently, the B-C model is available in the SU2 (Stanford University Unstructured) v6.0, an open-source CFD solver by the ADL of Stanford University [32]. The SU2 can solve two- and three-dimensional incompressible/compressible Euler/RANS equations using linear system solver methods.
\nSome outstanding test cases that make a good platform for measuring novel transition model performances are simulated by the foregoing transition models. These cases cover a wide range of flows from low speed two-dimensional flat plate and airfoil test cases to three-dimensional wind turbine blade and aircraft wing test cases from low to high speeds.
\nWell-known benchmark experiments such as the Schubauer and Klebanoff natural transition flat plate experiment [29] and the ERCOFTAC T3 series flat plate experiments by Savill [33] are used. The T3 series flat plate experiments consist of three zero pressure flat plate cases (T3A, T3B, and T3A-) and five variable pressure flat plate cases (T3C1, T3C2, T3C3, T3C4, and T3C5), in which the pressure gradients are generated using an adjustable upper tunnel wall. In all ERCOFTAC T3 test cases, the free stream turbulence intensities vary between 0.1 and 6%. Table 1 summarizes the upstream conditions of the Schubauer and Klebanoff and the ERCOFTAC T3 flat plate experiments.
\nCase | \nUin | \nRe∞ | \n|
---|---|---|---|
S&K | \n50.1 | \n3.4E+6 | \n0.18 | \n
T3A | \n5.4 | \n3.6E+5 | \n3.00 | \n
T3B | \n9.4 | \n6.3E+5 | \n6.00 | \n
T3A- | \n19.8 | \n1.4E+6 | \n0.90 | \n
T3C1 | \n5.9 | \n3.9E+5 | \n6.60 | \n
T3C2 | \n5.0 | \n3.3E+5 | \n3.00 | \n
T3C3 | \n3.7 | \n2.5E+5 | \n3.00 | \n
T3C4 | \n1.2 | \n8.0E+4 | \n3.00 | \n
T3C5 | \n8.4 | \n5.6E+5 | \n3.00 | \n
Inlet conditions for the flat plate test cases.
Figure 2 shows the numerical and experimental skin friction coefficients of the zero pressure gradient test cases of S&K, T3A, T3B and T3A-, respectively. The figures include numerical predictions of several researchers, including for instance Suzen and Huang [9], Langtry and Menter [11], Walters and Cokljat [14], Menter et al. [22], Nagapetyan and Agarwal [24], and Medida [31]. In the S&K calibration case, the B-C model displays a good agreement with the experiment for the transition onset point similar to other methods. For the T3A and T3B cases, the B-C model shows rather late transition onset, whereas the other models predict some early or late onset points. Specifically, Nagapetyan and Agarwal [24] show a very good agreement with the experiment as to the transition onset and rapid skin-friction rise characteristic. Finally, for the T3A- case, the B-C [20], Menter et al. [22], Walters and Cokljat [14], and Nagapetyan and Agarwal [24] display early transition onset points with rather rapid rise in skin-friction, whereas two-equation Langtry and Menter [11] and Medida [31] models show quite good onset point and a gradual rise in the skin friction.
\nComparison of skin friction coefficients for the zero pressure gradient flat plate test cases.
Figure 3 depicts numerical and experimental skin friction coefficients for the T3C series variable pressure flat plate test cases. The T3C series flat plate test cases represent actual turbine characteristics by changing the pressure gradient by changing the upper wall profile of the wind tunnel over the flat plate. For the T3C1 case, which represents the highest turbulence intensity test case among the T3C series test cases, the B-C model results are quite in agreement with the experimental data as the transition onset location is predicted with decent accuracy. For the T3C2 case, it is observed that although the B-C model predicted a good transition onset point, the turbulent stress abruptly rises after the onset. All other models predicted the transition onset location rather late in general.
\nComparison of skin friction coefficients for the variable pressure gradient flat plate test cases.
For the T3C3 case, it is observed that the γ-Reθ model [11], k-kL-ω model [14], and WA-γ model [24] outperform the other models as the B-C model prediction shows an early transition onset, whereas the one-equation γ model [22] predicts a rather late transition onset. For the T3C4 case, which represents the lowest Reynolds number case, all the models except for the B-C and WA-γ models show flow separation as their skin friction coefficients are below zero. Here, the B-C model obtained a quite good transition onset point that agreed with the experimental data although the laminar region was rather inaccurate. Finally, for the T3C5 case, solution of the zero-equation B-C model [20], Menter et al. one-equation γ model [22], and WA-γ model [24] well agree with the experiment in the laminar region, the onset of transition is also fairly good with some delay, and again quite good agreement in the subsequent variable pressure gradient region is obtained.
\nThe S809 airfoil is a 21% thick profile, which specifically designed for horizontal-axis wind turbine applications. The S809 airfoil was tested in a low-turbulence wind tunnel (Tu = 0.2%) by Somers [34] at Re number of 2 million (based on chord length) and a Mach number of 0.15. Comparison of the numerical results by Langtry and Menter [11] γ-Reθ, Walters and Cokljat [14] k-kL-ω, and Medida [31] SA-γ-Reθ and B-C models [20] with the experimental data is given in Figures 4–6. In general, all transition models agree well with the experimental data until the stall angle. Although the lift and drag coefficients (Figure 4) are rather inaccurate after the stall angle, it is observed that the experimental measurements of the transition locations are quite successfully predicted by all models (Figure 5). Also, comparing the experimental and numerical pressure coefficient distributions on the S809 airfoil at 1̊ angle of attack, it is observed that the separation bubble is predicted quite well by all the models (Figure 6).
\nS809 airfoil (a) lift coefficients and (b) drag coefficients at M = 0.15 and Re = 2 M.
S809 airfoil transition location comparison.
Pressure coefficient distribution comparison for the S809 airfoil at 1̊.
T106 turbine cascade experiment was designed to investigate the interaction of a convected wake and a separation bubble on the suction surface of a highly loaded low-pressure turbine blade. In these experiments by Stieger et al. [35], five-blade cascade of T106 profile was placed downstream of a moving bar wake generator in order to simulate an unsteady wake passing environment of a turbomachine. In the experiment, the flow conditions correspond to a Reynolds number of nearly 91,000 based on the chord length of the T106 profile and the inlet velocity. The experimental turbulence intensity is specified to be 0.1%. Geometric details of the experimental cascade setup are given in Table 2. Comparison of the experimental and numerical pressure coefficient distributions for T106 cascade for the steady case is depicted in Figure 7. Looking at Figure 7, it is observed that the separation bubble on the blade predicted by the B-C model and the two-equation γ-Reθ model is slightly smaller in size than the experimentally measured bubble.
\nBlade chord | \n198 mm | \n
Blade stagger | \n59.3° | \n
Cascade pitch | \n158 mm | \n
Inlet flow angle | \n37.7° | \n
Design exit flow angle | \n63.2° | \n
Bar diameter | \n2.05 mm | \n
Axial distance from bars to leading edge | \n70 mm | \n
Geometric details of the T106 cascade experimental setup.
Comparison of numerical and experimental pressure coefficient distributions on the T106 blade for Re = 91,000.
Two twisted and tapered 10-meter diameter turbine blades that use the S809 airfoil profile are tested in the NASA Ames Research Center wind tunnels [36, 37]. In the experiments, the NREL wind turbine rotation speed was set to 72 RPM for all cases, whereas the wind speeds varied from 7 to 25 m/s.
\nFigure 8 compares the pressure coefficient distributions over various spanwise locations on the turbine blades at the freestream velocity of 7 m/s. It is observed that both fully turbulent and the transitional solutions differ very slightly and both agree well with the experimental data. The skin friction contours and the surface streamlines obtained by Medida [31], Potsdam et al. [38], and Aranake et al. [39] for the same freestream velocity are compared to the B-C model and the S-A model solutions in Figure 9.
\nComparison of pressure coefficient distributions for the NREL phase IV blade for U = 7 m/s freestream velocity.
Comparison of numerical skin friction contours obtained by several researchers.
DLR-F5 wing tested by Sobieczky [40] is a 0.65 m span wing with 20° sweep angle and an average chord length of 150 mm. The wing is mounted to the tunnel wall with a smooth blending region, and the angle of attack is set to be 2°. The square cross-section wind tunnel has dimensions of 1 × 1 × 4 meters. The experimental inlet Mach number and the turbulence intensity are specified as M = 0.82 and Tu <0.35%, respectively. The corresponding Re number based on the average chord is 1.5 million. In the experiment, the transition locations are determined by the sublimation technique, whereas measurements of pressure coefficients at different spanwise stations are available. In 1987, a workshop with several researchers were took place in Gottingen [41], where the results were compared against the experimental data.
\nFigure 10 shows the pressure coefficient distributions at different span locations. It is observed that the fully turbulent and the transitional solutions are very similar to each other. Figure 11 compares the skin friction contours of different numerical models with the experiment [40]. As seen, the B-C model predicts a somewhat similar transition and separation region with the experiment obtained by the sublimation and pressure measurement techniques.
\nPressure coefficient distributions for the DLR-F5 wing at M = 0.82 and Re = 1.5 M.
Skin-friction coefficient comparisons for the DLR-F5 wing.
Finally, in order to emphasize the difference between the fully turbulent and the transitional solutions, comparison of the skin friction coefficients at 80% span on the DLR-F5 wing is depicted in Figure 12. It can be clearly observed that the B-C model predicts marked extent of laminar regions for both the suction and pressure sides of the wing, which is in agreement with the contours shown in Figure 11.
\nComparison of the skin friction coefficients predicted by the S-A turbulence model and the B-C transition model at 80% span on the DLR-F5 wing.
Local correlation-based transition models in the sense of empirical correlations incorporated into Reynolds-averaged Navier-Stokes methods have been discussed. A logical path for the development of such models is highlighted such that a variety of combinations of turbulence and transition equations lead to different modeling alternatives. For instance, the pioneering work by Menter et al. [1] two-equation γ-Reθ transition model sums up to a total of four-equation model by the incorporation of the two-equation k-ω SST turbulence model of Menter et al. [27]. In the same line of development but in a leaner approach, Walters and Cokljat [14] developed a three-equation k-kL-ω model. Similarly, Medida [31] developed a three-equation S-A-γ-Reθ transition model that is a sum of the Menter et al. [1] two-equation γ-Reθ transition model and the one-equation S-A turbulence model [28].
\nIn fact, in a recent work, Menter [22] reached to the conclusion that the Reθ equation was rather redundant. Without any loss of accuracy, Menter produced a leaner three-equation k-ω SST-γ transition model by incorporating a novel one-equation intermittency transport γ-model [22] with the two-equation k-ω SST turbulence model of Menter et al. [27]. In the same line of thought, Nagapetyan-Agarwal constructed the so-called two-equation transition model of WA-γ [24] by incorporating the Wray-Agarwal (WA) wall-distance-free one-equation turbulence model [23] based on the k-ω closure with the one-equation intermittency transport γ-equation of Menter et al. [22]. These two models paved the way for developing yet another leaner transition model by Bas et al. [19] with the introduction of the algebraic Bas-Cakmakcioglu (B-C) model by incorporating an algebraic γ-function with the one-equation S-A turbulence model [28].
\nThe Bas-Cakmakcioglu (B-C) [19] model qualifies as a zero-equation model that solves for an intermittency function rather than an intermittency transport (differential) equation. The main approach behind the B-C model follows again the pragmatic idea of further reducing the total number of equations. Thus, rather than deriving extra equations for intermittency convection and diffusion, already present convection and diffusion terms of the underlying turbulence model could have been used. From a philosophical point of view, the transition, as such, is just a phase of a general turbulent flow. In a sense, addition of artificially manufactured transition equations may appear to be rather redundant. Yet, for most of industrial flow types, there is experimental evidence that a close relation between the scaled vorticity Reynolds number and the momentum thickness Reynolds number exists. This fact stands out as the primary reason for the success of the class of so many intermittency transport equation models following the Menter’s pioneering two-equation γ-Reθ model [1]. Using the present B-C model, a number of two-dimensional test cases including flat plates, airfoils, turbomachinery blades, and three-dimensional low speed wind turbine and high-speed transport plane wing were simulated with quite successful results. These results may be regarded to vindicate this leaner approach of using even lesser equations for industrial design aerodynamics problems.
\nThyroxine (T4) and 3,5,3′-triiodothyronine (T3) are the two thyroid hormones, each of them containing two iodine atoms on their inner (tyrosine) ring. The difference between them is that T3 has only one iodine atom on its outer (phenyl) ring, whereas T4 has two. Synthesis of reasonable quantities of thyroid hormones requires adequate iodine intake to allow sufficient thyroidal uptake. The World Health Organization (WHO) recommendation for daily intake of iodine is 90 μg for infants and children up to 5 years, 120 μg for children 6–12 years, 150 μg for children ≥12 years and adults, and 250 μg for pregnant and lactating women [1]. The worldwide variability of the dietary intake of iodine depends on the iodine content of the soil, water, and the dietary practice. After Iodine Global Network data [2], the iodine uptake in Romania in 2004 was considered adequate, the median urinary iodine content (MUIC, normal value ≥100 μg/L) being 102 μg/L in school-aged children, but in some geographic regions, such as mountainous villages of Mureș County, a mild iodine deficiency was detected [3]. The MUIC value (68 μg/L) in pregnant women confirmed that iodine intake in this population of Romania is insufficient [2]. Administration of supplemental iodine to subjects with iodine deficiency goiter can result in iodine-induced hyperthyroidism in nonpregnant persons [4], but iodine supplementation in mild and moderate iodine-deficient pregnant women lowers thyroid hormone level [5].
\nThyroid hormone secretion is regulated by two mechanisms: a central hypothalamic-pituitary and a local autoregulatory mechanism depending on the iodine content of the gland. The autoregulatory mechanism reduces the fluctuation of thyroid hormone secretion in the event of sudden changes in iodine supply. Iodine excess inhibits iodide accumulation, organogenesis, tyrosine binding, and thyroid hormone release. However, this inhibitory effect (Wolff-Chaikoff effect) lasts only 10–14 days, followed by the so-called escape phenomenon [6].
\nIodine is a micronutrient that is present in foods (e.g., seaweed, seafood, dairy- and grain products, eggs), added to processed foods as iodized salt, and available as a dietary supplement, but the iodine concentration of water and foods is highly variable. Studies of iodine balance, based on the assumption that a healthy subject on an adequate diet maintains equilibrium between iodine intake and losses, have provided highly variable results, thus, cannot be used for setting daily reference values [7]. When iodine losses exceed intake (negative balance), deposits are progressively depleted resulting in biological signs and in clinical symptoms of deficiency. The physiological response to iodine deficiency is the preferential synthesis of T3 instead of T4. Long-term follow-up suggests that chronic iodine deficiency may lead to insufficient thyroid function (hypothyroidism) associated with a compensatory thyroid hypertrophy/hyperplasia with goiter (enlarged thyroid gland). Myxedema, observed with severe iodine deficiency, also results from hormone deficiency and is associated with reduced metabolic rate, weight gain, swollen face, edemas, hypothermia, and mental slowness. In euthyroid subjects, the plasma concentration of iodine (inorganic and organic iodine) ranged from 40 to 80 μg/L. Concentrations between 80 and 250 μg/L are associated with hyperthyroidism, whereas concentrations above 250 μg/L usually result from iodine overload with iodinated drugs [8, 9]. The thyroid gland, being highly flexible, is able to concentrate iodine up to 80-fold, and in most healthy adults, no clinical signs will appear at an iodine intake of up to 2 g/day [10]. However, if the adaptation to high iodine intake fails, various diseases occur. Chronic excessive iodine supply can also lead to goiter [11] and may accelerate the development of subclinical thyroid disorders to overt hypothyroidism or hyperthyroidism, increase the incidence of autoimmune thyroiditis, and increase the risk of thyroid cancer [10, 12, 13]. Recently, high iodine intake (exceeding 160 μg daily) was suggested as a risk factor for type 2 diabetes [14].
\nIodine-induced hyperthyroidism (thyrotoxicosis) or Jod-Basedow effect is most frequently observed following iodine supplementation in individuals who had previously experienced severe iodine deficiency [15, 16]. A plausible explanation of this phenomenon can be the thyroid stimulating hormone (TSH) hyperstimulation of the thyroid gland, which may occur as an adaptive response to the iodine-deficient conditions and results in autonomous growth and function of thyrocyte clusters. When iodine intake increases, these nodules may synthesize an excessive amount of thyroid hormones [10]. The mechanism consists of escape phenomenon when high doses of iodine are used for thyroid hormone synthesis, which can lead to severe thyrotoxicosis. The high iodine containing amiodarone and its metabolite N-desethylamiodarone (DEA) affects T cell function by increasing the number of both helper and cytotoxic T lymphocytes and induces destructive thyroiditis, resulting in transient thyrotoxicosis, as suggested by clinical, histological, and in vitro studies [17, 18, 19].
\nHigh levels of organic iodide (thyroid hormones) also reduce the accumulation of iodide ions in the thyroid gland inhibiting the TSH secretion.
\nThe effects of iodine administration differ in patients with pre-existing thyroid pathology from those in healthy subjects and depend upon the underlying disease process.
\nThe assessment of iodine deficiency can be accomplished by assessing the prevalence and severity of goiter, by testing the excretion of iodine in urine, and by determining hormonal levels (e.g., TSH, FT4). When used alone, neither of these are sufficiently sensitive and specific to measure iodine deficiency of a population, but urinary iodine remains the index of choice in the monitoring of iodine supplementation programmes. The most successful method of intervention for iodine deficiency control is salt iodization, iodine being added to salt as potassium iodide (KI), potassium iodate (KIO3), or sodium iodide (NaI). Due to the high prevalence of hypertension and cardiovascular diseases, many countries proposed to promote the reduction of salt intake to 5 g/day (<2 g of sodium), so complementary measures are needed in order to tackle iodine deficiency [20]. But iodine also binds to fatty acids, so iodine oil can also be given orally or intravenously to severely iodine-deficient patients in the short term. Nascent iodine is like the precursor form of iodine, which converts into thyroid hormones. The human body can recognize and assimilate this form more easily than potassium salt. Lugol’s solution is a widely used commercial iodine source, which contains elemental iodine and potassium iodide also. If someone consumes high quantities of iodine-rich foods (e.g., marine food, kelp), the use of iodized salt or iodinated water may increase iodine levels above the safe upper level as recommended by WHO. Individuals, who consume large amounts of seaweed regularly, are also exposed to the risk of iodine-induced hyperthyroidism [21, 22]. Several reports are available describing diet-induced thyrotoxicosis in patients consuming seaweed-containing foods or beverages [23]. Risk factors for iodineinduced hyperthyroidism include nontoxic or diffuse nodular goiter, latent Graves’ disease, and long-standing iodine deficiency [24].
\nMost dietary supplements, as well as food and water, contains iodine as salts: sodium iodide, sodium iodate, potassium iodide, and potassium iodate. Different solid dosage forms of potassium iodide are available, but around 20% is assimilated from inorganic forms of iodine into the body [25]. Iodine is also present in most multivitamin/mineral supplements. Some case reports described that previously euthyroid patients taking nutritional supplements developed iodine-induced hyperthyroidism [26, 27, 28]. The iodine content of dietary supplements shows high variability; some supplements may contain up to 160-fold of the recommended daily intake (\nTable 1\n). Short-term increase of basal and poststimulation TSH was described even in euthyroid patients administering dietary supplements with kelp [29, 30].
\nNutritional supplement | \nIodine content per serving (μg) | \n% RDA iodine per serving (%) | \n
---|---|---|
Natural Living Iodine Plus-2®\n | \n12500 | \n8333 | \n
Terry Naturally® (Europharma) Tri-Iodine®\n | \n25000, 12500, 6250, 3000 | \n16667, 8333, 4167, 2000 | \n
Oradix StemDetox™ | \n5000 | \n3333 | \n
Survival shield X-2, Detoxadine® (nascent iodine) | \n1950 | \n1300 | \n
Dr. Mercola Iodine | \n1500, 500 | \n1000, 333 | \n
Life Extension® sea iodine | \n1000 | \n667 | \n
Commercially available nutritional supplements with iodine content exceeding the daily intake recommended by WHO (RDA—recommended daily allowances).
Iodinated contrast media (ICM) is given for computed tomography (CT), angiography, myelography, and arthrogram. The route of administration could be systemic as i.v, i.a., oral, rectal, and local. The pharmacokinetics of all currently available ICMs is similar. The half-life of ICM in normal renal function subjects is approximately 2 hours. Thus, approximately 20 hours are required for the total excretion of the administered ICM [31]. Referring to their iodine content and osmolarity, the contrast media are divided into ionic ICM with high osmolarity (1500–2000 mOsm/kg) or nonionic ICM with low and iso-osmolarity (600–1000 mOsm/kg). A list of iodinated contrast agents available in Romania and their molecular properties can be found in \nTable 2\n.
\nNonionic ICM | \nIodine content, mg/mL | \nOsmolarity | \n
---|---|---|
\n | \n||
Iobitridol | \n300, 350 | \nLow | \n
Iodixanol | \n270, 320 | \nLow | \n
Iohexol | \n240, 300, 350 | \nLow | \n
Iomeprol | \n300, 350, 400 | \nLow | \n
Iopamidol | \n300, 370 | \nLow | \n
Iopromide | \n300, 370 | \nLow | \n
Ioversol | \n240, 300, 320, 350 | \nLow | \n
\n | \n||
Ethiodized oil | \n480 | \n\n |
The iodine content of nonionic iodinated contrast media (ICM) and their molecular properties.
The safety profile of the systemic administered nonionic low- or iso-osmolar contrast currently in use is 5- to 10-fold better than the ionic high-osmolar agents [32, 33]. The ratio of iodine atoms to the number of contrast particles in low-osmolar solution is higher than compared with high osmolar ICM and hence have a greater concentration of iodine than the high osmolar [32]. In both low and high osmolar ICM, the iodine content is far greater than the recommended daily allowance. Patients generally are given 50 and 100 mL of contrast per CT scan; however, it is essential to know that not all CT scans require contrast media administration (see \nTable 3\n) [31, 33, 34, 35].
\nCT type | \nContrast indicated | \nContrast not indicated | \n
---|---|---|
Head | \nNeoplasm, meningitis, encephalitis, focal neurologic deficits, skull base disorders, orbital and vision disorders, pituitary imaging, complicated sinonasal disease, seizures, cerebral angiography | \nHead trauma, acute stroke, intracranial hemorrhage | \n
Cervical | \nCervical mass or lymphadenopathy, suspected tumor or infection, abnormalities of cranial nerves X, XI, and XII, brachial plexopathy | \nTrauma unless arterial injury is a possibility or the mechanism of injury is penetrating | \n
Cardiothoracic | \nHeart and thoracic vessels, trauma, staging primary thoracic neoplasms | \nCoronary calcium scoring, pulmonary parenchymal evaluation lymph node evaluation | \n
Abdominopelvic | \nVirtually all other gastrointestinal, hepatopancreaticobiliary, genitourinary, gynecologic indications | \nColonography, renal stone evaluation, extraparenchymal lymphoma | \n
Musculoskeletal | \nEvaluation of soft tissue masses and suspected septic arthritis or infected prostheses | \nExtremities and spine | \n
CT angiography | \nEvaluating the lumen of an artery, vein, or a pseudoaneurysm and to assess for end-organ ischemia outside the brain or lung to detect active bleeding | \nMonitoring a known aneurysm for growth or for detection of a hematoma | \n
Indications of contrast enhancement in CT imaging.
Higher doses of ICM may be required for invasive procedures such as cardiac catheterization. Typical doses for CT scans provide 2500–5000 μg of bioavailable free iodine and 15–37 g of total iodine [36]. Nonbioavailable iodine may be liberated to free iodide, particularly with increased half-times in the body (i.e., impaired kidney function) [35, 36]. After ICM administration, iodine deposits remain elevated for up to 4–8 weeks in patients with healthy thyroid. The urinary iodine excretion increased by 300–400% from baseline to peak levels after 1.1 week and normalized by 5.2 weeks following ICM administration [37].
\nAfter exposure to the iodine-containing contrast agent, the most rapid (hours to days) effect of pharmacologic doses of iodine is the Wolff-Chaikoff effect. The mechanism for this acute effect is partially explained by the generation of iodolactones, iodoaldehydes, and/or iodolipids, which inhibit thyroid peroxidase activity, necessary for thyroid hormone synthesis [37]. The decrease of thyroglobulin proteolysis resulting in reduced thyroid hormone secretion also may be contributing to the ICM-induced Wolff-Chaikoff effect. The diminished serum T4 and T3 concentrations temporarily increased the serum concentrations of TSH, in some cases above the normal range. The phenomenon is transient in euthyroid adult patients and does not typically determine permanent hypothyroidism [38].
\nICM use could lead to thyroid dysfunction, namely to hypo- and hyperthyroidism. Iodine excess-induced hypothyroidism appears when the thyroid fails to escape from the acute Wolff-Chaikoff effect. It occurs in patients with a wide variety of underlying thyroid abnormalities, including Hashimoto’s thyroiditis, previously treated Graves’ disease, history of thyroid lobectomy, postpartum lymphocytic thyroiditis, interferon therapy, or type 2 amiodarone-induced thyrotoxicosis [12, 39, 40]. Not only the previous thyroid disorder but also the age of the patients is a contributing factor in hypothyroidism development. A systematic review evidenced that hospitalized neonates, especially premature infants exposed to iodinated contrast media, are at increased risk for development of hypothyroidism [41]. It could be hypothesized that hypothyroidism in this case to be partially secondary to an immature thyroid gland and an exaggerated Wolff-Chaikoff effect. Older age patients are also at high risk of developing hypothyroidism after ICM exposure, as reported in a study including the Asian population [42].
\nPatients with one exposure to ICM showed the highest risk of thyroid dysfunction compared with non-ICM exposure and a correlation was still found between the frequency of ICM exposure and the risk of hypothyroidism [42]. Conflicting data appear regarding to the time of onset of hypothyroidism after ICM administration: Rhee et al. [43] showed that the median time interval until the occurrence of hypothyroidism was 1 year, but Kornelius et al. [42] reported that hypothyroidism may develop 2.1 years after ICM exposure.
\nICM-induced hyperthyroidism rarely occurs in individuals without prior thyroid dysfunction. Previously existent thyroid diseases, such as nodular goiter, Graves’ disease, and long-standing iodine deficiency followed by thyroid autonomy, were reported to be associated with a higher risk of hyperthyroidism after ICM exposure [4, 13, 24, 36, 42]. The mechanism of ICM-induced hyperthyroidism involves impairment of the acute Wolff-Chaikoff effect due to rapid iodine excess and influx into the thyroid gland. Excess iodine intake will result in transient or permanent hyperthyroidism [13, 24, 42]. Kornelius et al. [42] found in their study a 22% increased risk of hyperthyroidism after ICM administration. Older patients (between 20 and 60 years) presented a more than twofold increased risk of hyperthyroidism compared with younger patients (less than 20 years old). The number of ICM exposures did not increase the risk of hyperthyroidism. It could be hypothesized that the “stunning effect” plays a certain role in hyperthyroidism, involving a diminished absorption of excess iodine in patients with repeated iodine exposure.
\nAmiodarone is a class III antiarrhythmic agent, having short- and long-term actions on multiple molecular levels [44]. Its molecular structure resembles T3. However, amiodarone can alter thyroid function (inducing both hypo- and hyperthyroidism), which is due to amiodarone’s high iodine content and its direct toxic effect on the thyroid follicle cells. Amiodarone is a benzofuran derivative with great lipophilicity, which is extensively distributed in adipose tissue, cardiac and skeletal muscle, liver, lung, and the thyroid. During its liver metabolization, approximately 6 mg of inorganic iodine per 200 mg of amiodarone ingested is released into the systemic circulation [45]. The average iodine content in Romanian diet is approximately 50–75 μg/day [3, 46, 47]. Thus, 6 mg of iodine markedly increases the daily iodine load. Amiodarone elimination from the body occurs with a half-life of approximately 55–100 days. The long half-life of both amiodarone and his active metabolite, DEA, contributes to his toxicity. For a therapeutic effect, a plasma concentration between 0.5 and 2.5 μg/mL is required; however, serum levels do not correlate well with efficacy or with adverse effects [45, 48, 49, 50].
\nThe effects of amiodarone on thyroid function can be divided into those effects that are due to iodine and those effects that are intrinsic properties of the drug.
\nAfter chronic amiodarone administration, the thyroid dysfunctions may occur in 5–22% of the patients. Risk factors for the development of thyroid disease include not only treatment duration and cumulative amiodarone dose but also age, gender, pre-existing thyroid pathology, and associated nonthyroid conditions [51, 52, 53]. The normal autoregulation process of thyroid prevents normal individuals from becoming hyperthyroid after exposure to the high iodine content substances. When intrathyroidal iodine concentrations reach a critically high level, iodine transport and thyroid hormone synthesis are transiently inhibited until intrathyroidal iodine stores return to physiological levels (see the Wolff-Chaikoff effect). Patients with underlying thyroid pathology, however, have defects in autoregulation of iodine: for example, in autoimmune thyroid disease exists a “fail to escape” from the Wolff-Chaikoff effect. The result is the development of goiter and hypothyroidism in Hashimoto’s disease. Patients with areas of autonomous function within a nodular goiter do not autoregulate iodine and the addition of more substrate may result in excessive thyroid hormone synthesis and thyrotoxicosis (see Iod-Basedow) [13, 54, 55].
\nAmiodarone inhibits peripheral deiodinase (outer ring 5′-monodeiodination of T4), thus decreasing T3 production and increasing T4 level; reverse T3 (rT3) accumulates since it is not metabolized to T2 [4, 56, 57]; amiodarone and, particularly, the metabolite DEA block T3-receptor binding to nuclear receptors [58] and decrease the expression of some thyroid hormone-related genes [59]; amiodarone may have a direct cytotoxic effect on thyroid follicular structures, which results in a destructive thyroiditis [60]. Martino et al. described marked distortion of thyroid follicle architecture, necrosis, apoptosis, inclusion bodies, lipofuscinogenesis, markedly dilated endoplasmic reticulum, and macrophage infiltration after amiodarone [19]. The role of the pre-existing autoimmune process is widely debated, due to the conflicting results of the retrospective study data [17, 18, 55]. Even if amiodarone does not induce de novo autoimmune thyroid disease, by the direct cytotoxic effect, it may cause the release of pre-existing autoantibodies and thus worsen destructive thyroiditis. In a study [61], it was described that in women the prolonged amiodarone treatment (for over 2 years) increased the antithyroid peroxidase titer.
\nPredisposing factors for amiodarone-induced thyrotoxicosis include environmental factors such as dietary iodine (deficiency), as well as intrinsic factors such as pre-existing thyroid pathology. Depending on these factors, a great variability exists regarding the incidence of amiodarone-induced thyroid dysfunction ranges (5–22%) [51, 52, 62, 63].
\nDietary iodine intake affects an individual’s risk of amiodarone-induced thyroid dysfunction: in iodine-deficient areas, amiodarone-induced thyrotoxicosis (AIT) appears to be more common than hypothyroidism [64], whereas in iodine-sufficient areas, amiodarone-induced hypothyroidism is more common than hyperthyroidism [19]. The incidence of reported AIT in different studies varies but remains within the range of 5–10% in most studies [51, 52, 63]. As was reported in a previous study from the UK, AIT appears more frequently in men than in women [65], but the time of onset of AIT is unpredictable. It can occur at almost any time throughout the course of amiodarone treatment and last for as long as 6–9 months after treatment withdrawal, almost certainly because of the drug’s long half-life and associated iodine load [66]. One study illustrates the importance of the underlying thyroid status near the dietary iodine intake in relation to the risk of developing amiodarone-induced thyroid dysfunction. In Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of autoimmune thyroid disease, amiodarone was associated with a 2% rate of hyperthyroidism. In contrast, in Pisa, Italy, an area of borderline iodine intake and a high prevalence of nodular goiter, amiodarone was associated with 9.6% rate of hyperthyroidism [67].
\nThe clinical effects of amiodarone on thyroid function in any individual are dependent upon the underlying status of that individual’s thyroid gland. In euthyroid individuals receiving amiodarone, acute changes in thyroid function tests include [68, 69]:
Serum total T4 and free T4 concentrations rise by 20–40% during the first month of therapy.
Serum T3 concentrations decrease by up to 30% within the first few weeks of therapy.
Serum rT3 concentrations increase by 20% soon after the initiation of therapy.
Serum TSH concentration usually rises slightly after the initiation of treatment and may exceed the upper limit of normal.
After 3–6 months of therapy, a steady state is reached in most patients who were euthyroid at baseline:
Serum TSH concentration normalizes.
Serum total T4, free T4, and rT3 concentrations remain slightly elevated or in the upper normal range.
Serum T3 concentrations remain in the low normal range.
Amiodarone may also cause destructive thyroiditis with transient thyrotoxicosis followed by hypothyroidism in patients without underlying thyroid disease [60].
\nAbnormal thyroid process: in patients with underlying multinodular goiter or latent Graves’ disease, hyperthyroidism (increased synthesis of T4 and T3) may occur. The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone production.
\nThree types of AIT can be distinguished. In type 1 AIT, thyroid hormone synthesis is increased, whereas in type 2 there is an excess release of T4 and T3 from the preformed thyroid hormones, due to destructive thyroiditis. Type 3 AIT is a mixed form, existing an overlapping condition between type 1 and type 2 AIT. These types differ in their pathogenesis, clinical or paraclinical signs, and management [63].
\nThe risk of either type increases with higher cumulative doses or reintroduction of amiodarone [53, 70].
\nThe distribution of AIT by type (1 or 2) varies by geographical region. This is thought to be primarily due to differences in dietary iodine intake. In iodine-deficient regions, as some geographical zones were in Romania before universal salt iodization [3], AIT occurs in approximately 10–12% of patients with type 1 AIT usually predominating [64, 67]. However, the distribution of cases by type may be changing, as illustrated in a report of 215 consecutive patients with AIT seen at a single institution in Italy over 26 years [71]. In 1980 compared with 2006, 2 of 6 (40%) versus 12 of 14 (86%) of new AIT cases were type 2. Possible explanations for this observation include improved dietary iodine intake in the region and the avoidance of amiodarone use in case of previously diagnosed thyroid disease. Our unpublished data from a study conducted in a single institute (Endocrinology Clinic, Târgu Mureș, Romania) in two different periods, which included 5 years, similarly show a moderate increase of type 2 AIT after the introduction of universal salt iodization (governmental decision no. 586/5 June 2002; see \nTable 4\n).
\nStudy period | \nType 1 AIT/total patients | \nType 2 AIT/total patients | \nType 3 AIT/total patients | \n
---|---|---|---|
1994–1998 | \n4/7 (57%) | \n1/7 (14%) | \n2/7 (29%) | \n
2001–2005 | \n17/38 (45%) | \n9/38(24%) | \n12/38 (31%) | \n
Distribution of AIT types in patients of the Endocrinology Clinic, Târgu Mureș, Romania, in two study periods (1994–1998 and 2001–2005).
Clinical signs of AIT are classical thyrotoxicosis symptoms such as unexplained weight loss, proximal myopathy, restlessness, heat intolerance, low-grade fever, or exacerbation of tachyarrhythmia, heart failure, or angina pectoris; however, the adrenergic manifestations of amiodarone-induced hyperthyroidism are often masked because its distinct antiadrenergic properties and impairment of conversion of T4 to T3 [68, 72]. Patients with amiodarone-induced hyperthyroidism have a threefold higher rate of major adverse cardiovascular events (mostly ventricular arrhythmias) compared with euthyroid controls [73]. The presence of severe left ventricular dysfunction, especially in older patients with AIT, may be associated with increased mortality [74].
\nDifferentiating the two types of AIT is critical since therapy differs. However, the distinction may be difficult using clinical criteria, partly because some patients may have a mixture of both mechanisms, presenting the type 3 (type 1 + type 2) AIT. Thyroid function tests (TSH, T4 and T3 plasma levels) do not help to distinguish type 1 AIT (hyperthyroidism) from type 2 AIT (transient thyrotoxicosis).
\nType 1 AIT appears usually early after amiodarone introduction (3–20 months after exposure) [19, 66, 71]. It is characterized by hyperfunctional thyroid tissue with elevated blood flow on color Doppler [75, 76]. Furthermore, the enlarged or nodular thyroid tissue fixes either on 24-hour 123I-scan or on 99 mTc-SestaMIBI radio isotope scan despite the daily ingestion of 6 mg or more bioavailable iodine [77, 78].
\nType 2 AIT is a destructive thyroiditis which onset time is after 20–30 months of amiodarone introduction. It appears in patients with apparently normal thyroid morphology and is due to the massive release of thyroid hormones. The mechanism is similar to that of subacute thyroiditis, but the thyrotoxicosis is usually less severe and could spontaneously resolve in some cases [79]. The features of the two types of AIT are presented in \nTable 5\n.
\n\n | Type 1 AIT | \nType 2 AIT | \n
---|---|---|
Pre-existing thyroid disease | \nYes | \nNo | \n
Pathophysiology | \nIodine overload | \nDestruction/inflammation | \n
Ultrasound findings | \nGoiter/nodule(s) | \nNormal | \n
Color flow Doppler | \nIncreased or vascularity | \nReduced or absent vascularity | \n
Radio iodine uptake (I123-Scan)/SestaMIBI-Scan | \nNormal or increased | \nAbsent | \n
Characteristics of type 1 and type 2 amiodarone-induced thyrotoxicosis (AIT—amiodarone-induced thyrotoxicosis).
However, interpretations of color flow Doppler sonogram in amiodarone-associated hyperthyroidism require an experienced sonographer, and other markers for differential diagnosis were also sought. In two studies, serum interleukin-6 concentrations were higher in patients with type 2 AIT [80, 81]. In a third study, interleukin-6 concentrations were not useful for distinguishing type 1 from type 2 AIT [76].
\nPreventing therapy for iodine-induced hyperthyroidism is not generally recommended. However, older patients with known multinodular goiter and/or subclinical hyperthyroidism should be told of the risk for iodine-induced hyperthyroidism, and alternatives to contrast-enhanced CT scanning should be considered when appropriate (e.g., noncontrast CT, magnetic resonance imaging). Iodine-induced hyperthyroidism is particularly important in geriatric patients for several reasons: (1) the prevalence of thyroid nodular disease is higher in older patients than in younger patients, (2) the hyperthyroidism may be more difficult to detect clinically, (3) apathetic hyperthyroidism often being present, and (4) older adults more often have underlying heart disease [21]. In high-risk patients (older, history of multinodular goiter with autonomy), treatment with a thioamide or perchlorate prior to the administration of an iodine load may blunt or prevent the induction of hyperthyroidism [82, 83]. However, there are insufficient randomized trial data to support the use of thioamides or perchlorate. Routine measurement of thyroid function tests (TSH, and if low, free T4 and T3) in older patients after exposure to iodinated radiographic contrast agents is favored by some experts, particularly since the symptoms of hyperthyroidism in older adults may be atypical [84, 85, 86].
\nIodine-induced hyperthyroidism (iodine content supplements and dietary nutrients, ICM, type 1 AIT) is usually self-limited (lasting 1–18 months) if the source of iodine is discontinued. The American Thyroid Association (ATA) [87] and European Thyroid Association (ETA) recommendations [40] as initial therapy for patients with iodine-induced hyperthyroidism are discontinuation of iodine (except for amiodarone, which could be continued in type 2 AIT), avoidance of further exposure, and administration of a beta-adrenergic antagonist drug (assuming there are no contraindications to its use) to minimize the manifestations of the overactive thyroid. Thyroid tests (TSH, free T4, total T3) should be measured initially at 4- to 6-week interval and then less frequently (TSH and free T4 every 3 months) depending upon the results of prior testing. Beta blockers can be tapered and discontinued after thyroid tests return to normal.
\nDue to the lack of sufficient evidence, there is no consensus regarding the decision to continue or stop amiodarone in patients with type 1 AIT. The decision should be individualized taking into account the risks of patients and taken jointly by cardiologists and endocrinologist [40]. Amiodarone should be continued in critically ill patients with life-threatening cardiac disorders [88]. When deciding whether to discontinue amiodarone, the following should be considered: amiodarone may be necessary to control a life-threatening arrhythmia; since the half-life of elimination from the body is prolonged, there is no immediate benefit to stopping amiodarone; amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta-adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs.
\nIn case of amiodarone withdrawal, after the restoration of euthyroidism and normalization of urinary iodine excretion (generally 6–12 months), radioactive iodine (RAI) therapy can be performed. Recombinant human TSH (rhTSH) administration increases the sensibility of the thyroid gland to RAI therapy. If RAI administration is contraindicated, total thyroidectomy should be considered for definitive treatment of the underlying thyroid disease [40]. In the absence of the thyroid gland, amiodarone reintroduction, when necessary, could be safe. In the case of the thyroid gland is conserved, the recurrence rate of type 1 AIT after amiodarone reintroduction is 9% [89]. As ETA suggested, emergency thyroidectomy in severe cardiac patients may be required not only in type 1 but also in all types of AIT. Prior to thyroid surgery, plasmapheresis is able to remove the excess of thyroid hormones [40]. It was reported in a study, including seven patients with AIT, that iopanoic acid short-course administration prior surgery permitted a safe and uneventful thyroidectomy [90].
\nThioamides (thiamazole, carbimazole, propylthiouracil) are effective in older patients with underlying heart disease having severe and prolonged (>1 month) hyperthyroid symptoms, except the emergency situations. All thioamides are blocking thyroid hormones synthesis, propylthiouracil having an additional inhibiting effect on T4–T3 transformation. ATA recommended, the starting dose of thiamazole, to be 10–20 mg once daily because of its long duration of action, allowing for once-daily dosing, more rapid efficacy, and lower incidence of side effects [87]. ETA recommended very high daily doses of the drug (40–60 mg/day of thiamazole) for a more extended time, considering that in type 1 AIT the iodine-enriched thyroid gland of patients is less responsive to thioamides [40]. Carbimazole, the prodrug of thiamazole, is an alternative choice of treatment, available in some European countries, but not in Romania. Due to the teratogenicity of thiamazole, propylthiouracil (not currently available in Romania) can be used in the first trimester of pregnancy [68]. To increase the sensitivity and response of the thyroid gland to thioamides, potassium or sodium perchlorate (not available in Romania) has been used. Perchlorate reduces thyroid iodine uptake by sodium/iodide symporter inhibiting action and discharge iodine from the thyroid, but toxic effects are limiting its use. To minimize the nephro- and medullotoxicity of the drug, doses not exceeding 4 × 250 mg/day and a shorter period than 4–6 weeks were used [40, 87, 91]. Thyroid function should be assessed after 4 weeks by measurement of serum TSH, free T4, and T3. The dose of thiamazole is then tapered with the goal of maintaining a euthyroid state. Thereafter, thyroid function tests (TSH, free T4) should be measured every 3 months. Many patients with underlying autonomous nodular thyroid disease are able to taper and discontinue thiamazole within 6–12 months. In case of thioamide allergy, lithium is used to control the hyperthyroidism temporarily [91, 92], but it has a narrow therapeutic range, produces nephrotoxicity, and its efficacy is not well documented. Therefore, it is not recommended by ETA for the type 1 AIT treatment [40]. However, it was reported that lithium-associated rhTSH administration increases RAI sensibility of the thyroid follicles in AIT [93].
\nAfter resolution of the acute episode of iodine-induced hyperthyroidism, treatment of the underlying thyroid disease should be addressed. For patients with underlying Graves’ disease, treatment options include continuing thiamazole, radioiodine ablation, or surgery. Patients with underlying autonomous adenoma or multinodular goiter who return to euthyroidism after discontinuation of iodine do not necessarily require definitive treatment. However, these patients are at risk for recurrent hyperthyroidism if given iodine again.
\nType 2 AIT generally is self-limited and amiodarone is not necessary to discontinue. When the efficacy of non-thioamide type antithyroid drugs to restore euthyroid state was compared, the best results were obtained with 30 mg oral prednisone therapy. The rate of achievement of euthyroid state was 100% when glucocorticoids were used versus 71% obtained after perchlorate administration [94]. ETA recommendation, for this reason, is oral glucocorticoids as the first-line treatment for type 2 AIT. In patients in whom a mixed form of AIT is suspected, thioamides together with glucocorticoids should be given initially, or glucocorticoids should be added after a period of 4–6 weeks of inadequate response [40]. In addition, it must be noted that i.v. administration of glucocorticoids (hydrocortisone, dexamethasone) has crucial benefits (inhibiting T4 transformation to T3) in thyroid storm and preoperative management of any type of thyrotoxicosis [91]. It was reported that glucocorticoid therapy (oral prednisone) restored the normal thyroid function and shrink goiter, preventing surgery, in a patient diagnosed with iodine containing supplement-induced hyperthyroidism [95].
\nIodine, as an essential microelement of the human body, plays a very important role in thyroid physiology. Adequate intake is necessary to keep thyroid hormone synthesis at normal rate. Dietary intake and urinary excretion should be equivalent, but a remarkable adaptive capacity of the thyroid gland can compensate for excess intake on short term. However, existing thyroid disease (subclinical or overt) or specific risk factors may impair the patient’s response to high iodine exposure, which can result in hypothyroidism or hyperthyroidism. On the other hand, iodine excess may also be hardly recognizable because various sources (e.g. seafood, kelp, dairy products, iodized salt, iodized water, nutritional supplements, iodine containing contrast media, and drugs) can all contribute to iodine intake. Of these, iodine containing contrast media and drugs are administered only under controlled conditions but represent the most frequent cause of iodine-induced thyrotoxicosis. In general, preventive actions are not recommended, but screening for risk factors, such as elderly patients, persons with multinodular goiter, subclinical hyperthyroidism, or manifest hyperthyroidism should take place prior to iodine administration. Consequently, high-risk patients should benefit preventive treatment with thioamide or perchlorate. Amiodarone-induced thyrotoxicosis has remained a difficult task requiring a close collaboration between cardiology and endocrinology to overcome complications, but individualization of the therapy should be undertaken. Based on the specific features of thyrotoxicosis, thioamides, perchlorate, or high-dose glucocorticoids may be considered for an optimal therapeutic intervention. If contraindicated, radioiodine therapy may also be useful to treat amiodarone-induced thyrotoxicosis.
\nThe authors declare no conflict of interest.
AIT | amiodarone-induced thyrotoxicosis |
ATA | American Thyroid Association |
CT | computed tomography |
DEA | N-desethylamiodarone |
ETA | European Thyroid Association |
ICM | iodinated contrast media |
MUIC | median urinary iodine content |
RAI | radioactive iodine |
RDA | recommended daily allowances |
rhTSH | recombinant human thyroid stimulating hormone |
rT3 | reverse 3,3′,5′-triiodothyronine |
T3 | 3,5,3′-triiodothyronine |
T4 | thyroxine |
TSH | thyroid stimulating hormone |
WHO | World Health Organization |
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\\n\\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nOAI-PMH
\\n\\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\\n\\nLicense
\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\\n\\nPeer Review Policies
\\n\\nAll scientific works are Peer Reviewed prior to publishing. Read more
\\n\\nOA Publishing Fees
\\n\\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. 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