Coronary artery disease (CAD) represents a widespread burden to both individual and public health, steadily rising across the globe. The current guidelines recommend non-invasive anatomical or functional testing prior to invasive procedures. Both coronary computed tomography angiography (cCTA) and stress cardiac magnetic resonance imaging (CMR) are appropriate imaging modalities, which are increasingly used in these patients. Both exhibit excellent safety profiles and high diagnostic accuracy. In the last decade, cCTA image quality has improved, radiation exposure has decreased and functional information such as CT-derived fractional flow reserve or perfusion can complement anatomic evaluation. CMR has become more robust and faster, and advances have been made in functional assessment and tissue characterization allowing for earlier and better risk stratification. This review compares both imaging modalities regarding their strengths and weaknesses in the assessment of CAD and aims to give physicians rationales to select the most appropriate modality for individual patients. Coronary artery disease (CAD) represents a widespread burden to both individual and public health, steadily rising across the globe . Thus, sBoth cCTA and vasodilator stress CMR are robust imaging modalities with reported diagnostic image quality in >97% of cases .However, to compare both in their diagnostic capabilities, comprehension of what both modalities primarily test for is indispensable. In general, cCTA is widely used for the assessment of the anatomical presence of coronary artery disease, whereas stress CMR tests for the functional presence of ischemia.cCTA has the highest sensitivity 97%) of all non-invasive imaging modalities for the detection of anatomically significant CAD, but low specificity for anatomically (78%) or functionally (53%) significant CAD 7% of all. The latter is often due to partial volume or blooming artifacts which can lead to an enlargement of calcified plaques, thus resulting in an overestimation of stenosis severity . ConsequHowever, cCTA allows for the identification of patients in the early stage of CAD having non-obstructive coronary plaques. These patients have long been underrecognized since these plaques typically do not cause reduced blood flow and consequently most non-invasive tests assessing ischemia are inconspicuous. Yet, these patients are at increased risk since the rupture of non-obstructive plaques is the main cause of myocardial infarction ,13. FurtThe identification of additional patients at risk by cCTA improves patient outcome significantly, as shown in the PROMISE, CONFIRM and SCOT-HEART trial ,17,18,19In the SCOT-HEART trial, 4,146 patients with angina and suspected CAD were randomly assigned to standard care or standard care and cCTA . In the The same was observed by a registry study on 33,552 patients with <50% coronary stenoses on a cCTA, in which a new medication with a statin after cCTA was associated with a reduction in myocardial infarctions and all-cause death, directionally proportional to the observed CAD burden . cCTA isApart from coronary stenosis assessment and plaque characterization, cCTA also allows for visualization and quantification of perivascular fat suggestive of coronary inflammation, which is shown to be a negative predictor for cardiac outcome ,25.In summary, cCTA is the diagnostic modality of choice to safely assess the presence of CAD, independently of its hemodynamic relevance, and, thus, guide further treatment such as the initiation of preventive medical therapies. cCTA can achieve non-inferior diagnostic accuracy in stable CAD patients without having the periprocedural risks of an invasive coronary angiography . Stress CMR cannot safely exclude the presence of CAD. Its strength lies in the accurate assessment of the hemodynamic relevance of coronary stenosis, i.e., the testing for ischemia. Ischemia, however, is not a bivalent marker, but rather a continuum . CAD witIn summary, CMR is the modality of choice to assess hemodynamic relevance, predict prognosis and for a thorough differential diagnosis in suspected CAD patients. Broad advances have been made in the technical capabilities of contemporary CT scanners. High-end CT detectors with ≥128 slices have become a standard in many academic and non-academic sites in developed countries .source CT when operated with two different energies). An alternative technology is the combination of a single x-ray source rapidly alternating between low and high energies (fast switching) with a single detector that registers information from both energies [While conventional CT utilized a single polychromatic X-ray beam received by a single detector, dual-energy CTs (DECT) show increasing popularity. Depending on the vendor, different techniques are used. One is a second tube and detector unit at a 90° angle  and therefore a reduction in motion artifacts, which is critical in the assessment of a moving structure such as the heart . They caRegarding unenhanced CT such as coronary calcium scoring, the application of a tin filter may decrease the radiation dose in unenhanced scans without negatively affecting subjective image quality . The tinThe most recent step in hardware advances for cCTA is the so-called photon-counting CT. It uses photon-counting detectors that separately register the energy of each photon. These offer a smaller pixel size and do not require the coating of each detection pixel by an optical reflector, which accounts for a 2- to 3-fold higher resolution than conventional CT (approximately 250 µm). In a recent clinical study photon-counting coronary CT led to significantly improved image quality (detectability indexes 2.3-fold to 2.9-fold higher) at a comparable radiation dose in 14 patients who underwent both standard energy-integrating detector dual-layer cCTA and photon-counting CT . These rApart from hardware improvements, computational advances with iterative or model-based reconstruction algorithms have improved image quality and reduced radiation dose ,49,50. Since invasive FFR is the current reference standard to assess the hemodynamic relevance of coronary stenosis, great effort has been directed into implementing a non-invasive cCTA-derived FFR value that can be interpreted similarly to its invasive equivalent ,51. Different techniques have evolved that are either applied in a core lab or on-site. Models based on fluid dynamics are computationally demanding, whereas recent advances in machine learning enabled faster on-site calculation ,52,53. TA number of studies show the discriminatory power of CT-FFR for the prediction of hemodynamic relevance to be superior to cCTA alone when compared to invasive FFR or stress CMR, improving diagnostic accuracy and especially specificity ,54,55,56Another example of cCTA exceeding the limits of pure anatomical testing for CAD is CT perfusion (CTP). The anatomical visualization of coronary arteries by cCTA is followed by vasodilator stress and repeated CT imaging to assess perfusion deficits in patients where cCTA alone was not able to exclude hemodynamically relevant stenosis . CTP mayExtensive advances have also been made in the field of CMR introducing a more robust imaging acquisition, new acquisition sequences, and vast post-processing possibilities. The relatively long acquisition times remain a modality-dependent issue but decreased considerably. For example, acquisition time of cine images was reduced by ~80% through the introduction of compressed sensing . In addiThe introduction of myocardial strain measurements boosted the assessment of myocardial function with superior predictive power than ejection fraction . MyocardImproved resolution achieved by combining undersampling and motion correction has also allowed obtaining sub-millimeter isotropic CMR images. In proof-of-concept studies, the derived coronary lumenography visualizes coronaries at a quality that is sufficient to screen for coronary anomalies and even (to some degree) stenoses ,82.In stress CMR, the introduction of quantitative rather than qualitative perfusion imaging has decreased reader dependency and enabled a faster and simpler analysis . FurtherRisks of both cCTA or stress CMR are linked to the technique itself, the application of contrast agent or necessary stress medication in the course of the exam.CMR is a non-ionizing technique working with a static magnetic field and radiofrequency pulses that may be causative for (reversible) headaches or vertigo . BesidesAcute adverse reactions can occur after both CT and CMR contrast agent application, although slightly more frequently in Iodine-based CT (0.2–0.4%) than Gadolinium-based MRI (0.1–0.18%) contrast agents ,95,96,97Apart from contrast agents, both cCTA and stress CMR usually require specific medication. For cCTA, beta blockers and glyceryl trinitrate (GTN) are used to achieve adequate heart rate control, if necessary, and to dilate coronary arteries prior to the exam . These m2A receptor [For CMR, vasodilator stress CMR with regadenoson, dipyridamole, or adenosine is the current standard for patients with suspected CAD. Of those, regadenoson is best tolerated due to its high specificity to the Areceptor . Common receptor . Patientreceptor . Althougreceptor . As an areceptor . NeverthIn summary, both cCTA and vasodilator stress CMR exhibit excellent safety profiles.Over the last decade, cCTA has evolved from an imaging modality, which was mainly used to exclude significant CAD in patients at a rather low risk, to a valuable method for risk stratification and therapeutic decision making resulting in a significant improvement in patient outcome. Image quality has improved, radiation exposure has decreased, and anatomical information can be complemented by information on the hemodynamic relevance of stenoses. Consequently, it is recommended as a first-line imaging modality in patients with stable chest pain in the current guidelines ,4,108. HHowever, several factors limit the use of cCTA and the most relevant are summarized in Second, although assessment of coronary stents has improved, assessment of in-stent stenosis and their functional assessment with CT-FFR is hampered and in some cases even not possible. In addition, the evaluation of patients with severe and extensive coronary calcifications, coronary artery occlusion  or previous coronary artery bypass graft surgery can be challenging. In CT-FFR negative stenoses, additional factors such as symptom burden, current medication and comorbidities must be considered to decide whether further testing might be necessary. Here, the cCTAs and CT-FFRs blind spot concerning the presence of the coronary microvascular disease has to be mentioned . CTP migCAD evaluation by stress CMR is an important imaging modality in the diagnosis and risk stratification and, thus, is represented in current guidelines ,3,108.Of note, the concept of inducible ischemia is not yet fully understood and is the subject of current discussions ,112. TheIn patients with myocardial scarring, the viability of ischemic regions and therefore the potential benefit of revascularization is important. In these patients, the diagnostic assessment goes beyond stenosis evaluation alone and CMR can provide information on both, ischemia and viability, in a single examination. Its ability to characterize myocardial tissue allows for differential diagnostics in patients with MINOCA as CMR can identify various etiologies such as myocarditis, tako-tsubo syndrome, and thromboembolic myocardial infarction. The visualization/quantification of arrhythmogenic substrate of scar and exact calculation of left-ventricular ejection fraction with CMR is also useful in clinical practice to decide for or against an implantable cardioverter-defibrillator in patients with ischemic and non-ischemic heart disease .Regarding the choice for the appropriate imaging modality aside from the individual patient site-specific conditions should be taken into consideration. Especially, the diagnostic quality of cCTA depends on the scanner model. On a global scale, ≤64 slice CT detectors are still widely used and the possibilities for CTP or CT-FFR are limited in most areas due to technical and reimbursement restrictions . As mentApart from hardware, local staff expertise may also be different as not all sites offer cCTA and CMR. Reimbursement is different in every country and influences waiting times, local expertise, and referral choice . The totThe strength of cCTA evidently lies in the identification of additional at-risk patients, in which preventive approaches  are beneficial. Here, the fact that >50% of all myocardial infarctions are caused by non-obstructive plaques has to be emphasized, so the initiation of preventive treatment is key in influencing patient outcome ,118. HowThe potential to detect early stages of CAD makes cCTA the diagnostic modality of choice for a large proportion of patients with suspected CAD, taking into account that 75% of patients in the SCOT-HEART trial had no obstructive CAD, despite a high prevalence of cardiovascular risk factors . Although this review focuses on CAD patients, cardiac and pulmonary comorbidities also play an important role in the selection of the appropriate modality. While heavy smokers suffering from dyspnea may benefit from a combined assessment of the coronary arteries and the lungs, younger patients with a differential diagnosis of myocarditis or cardiomyopathy may benefit from myocardial tissue characterization offered by a CMR. In general, for CAD evaluation, cCTA is favorable in patients that are younger, have few comorbidities, no known cardiac disease and are currently not taking preventive medication, whereas stress CMR is more appropriate in older patients, in those with known CAD, already taking ASA/statin and in need of regular follow-ups. Of note, both cCTA and stress CMR can be used as a downstream diagnostic testing method in patients with an inconclusive test result of the primarily chosen modality.Thus, it is important to view cCTA and stress CMR as mostly complementary diagnostic modalities, each possessing strengths and limitations but both providing valuable and accurate diagnostic information to guide physicians’ treatment decisions. Physicians should strive for an individual approach in each patient with regard to patient-related factors and patient wishes considering each modality’s strengths and limitations.


Nowadays, in Mexico, most of the installed electricity generation capacity corresponds to combined cycles, representing 37.1%. For this reason, it is important to maintain these cycles in good operating conditions, with the least environmental impacts. An exergoeconomic and environmental analysis is realized to compare the operation of the combined cycle, with and without postcombustion, with the comparison of exergoeconomic and environmental indicators. With the productive structure of the energy system, the process of formation of the final products and the residues are identified, and an allocation criterion is also used to impute the formation cost of residue to the productive components related to its formation. This criterion considers the irreversibilities generated in each productive component that participates in the formation of a residue. The compositions of pollutant gases emitted are obtained, and their environmental impact is determined. The unit exergoeconomic cost of the power output in the gas turbine is lower in the combined cycle with postcombustion, indicating greater efficiency in the process of obtaining this energy stream, and the environmental indicators of global warming, smog formation and acid rain formation are higher in the combined cycle with postcombustion, these differences being 5.22%, 5.53% and 5.30%, respectively. In addition, each component has an associated irreversibility, and as a consequence, the irreversibilities accumulate in the process of obtaining each stream in the system. In this way, the process of formation of the final product is identified and in parallel, the process of formation of the residue, and the product components are identified, which have a defined product, and the dissipative components, which are characterized by the absence of a productive purpose but its usefulness lies in the dissipation of residue into the environment and its presence is important due to the interaction they have with other components to obtain the final product of the system. To carry out the exergoeconomic analysis, based on k-th component of the combined cycle, proposition 2 [The exergoeconomics determines the cost of production of a system, considering the process of product formation. However, this process is always accompanied by residues, which are energy streams or materials that are not in balance with the environment, in other words, there are thermodynamic potentials; These residue streams are wasted resources. Currently, there is no established methodology to impute the costs of residue since its formation process impacts on the one hand the cost of production and on the other hand the cost of residue. In this work, it is being imputed by means of a proposed criterion of irreversibility, where it is assumed that the productive components contribute to the cost of residue formation, in the proportion of their irreversibility generated in relation to the total irreversibility of the system. This criterion is based on accounting for irreversibilities throughout the formation process of the residues. For the combined cycle, the formation of exhaust gases is accompanied by the generation of irreversibilities in the GT and HRSG processes, on the gas side, to produce work and heat. Whereas the heat dissipated in the condenser is the result of the irreversibilities in the steam generation processes in the HRSG and the power output in the productive components of the steam cycle. With the application of the allocation rules to the components of the combined cycle , the exesition 2  of the aWith Equation (8), and under the criterion of irreversibility, it is observed that the productive components of the steam cycle do not contribute to the process of formation of the exhaust gas residue, and for the process of formation of the residual heat dissipated in the condenser, the components of the gas turbine do not contribute. However, with Equation (9), this criterion considers the irreversibility of the gas and steam sides within the HRSG. To address this problem, the level of aggregation in the HRSG is reduced, in such a way that each of its components has two subsystems (one for gases and one for steam) that exchange heat. The coupling of the GT and the SC takes place in the HRSG. In this study, the components of the HRSG are treated as adiabatic heat exchangers, where the thermal energy of the combustion gases is used for the generation of steam. The components of the HRSG are considered as subsystems made up of two thermal energy deposits that exchange heat , this is the product of the unit exergoeconomic cost of the resource and the difference between the exergy flow rates of the resource and the product of each of the system components (irreversibility):2, that is, for every kilogram of CO there are 3 kg of CO2 equivalent; however, both have no potential for acid rain and smog formation. For each kilogram of unburned CnHm, there are 21 kg of CO2 equivalent and 0.015 kg of NOx equivalent, that is, for the potential for smog formation, the most important ozone-forming process in the atmosphere is the photo- NOx dissociation and is the reference compound to express the smog-forming potential of any smog-forming product or emission. Moreover, it is noted that only CO and NO2 have an effect on HPT. NOx has the highest potential in each type, where NO2 has a value at each potential and NO has a higher ARP. With the environmental impact and human toxicity indicators, the potential risks generated by exhaust gases from power plants are evaluated. The global warming potentials (GWP), acid rain formation (ARP), smog formation (SFP) and human toxicity (HPT) are presented in T0 = 25 °C and P0 = 1.013 bar; and on the other hand, in The dead or reference state is established at gT4−vT1, is 91.77 °C. For the postcombustion section, there is no heat transfer to the water stream (liquid-vapor), the effect of postcombustion is manifested with an increase in the temperature of the exhaust gases from g5 to g6, at 104.43 °C caused by supplying the heat released by combustion in this section, of 86,371.15 kW.g15-0-a is the exergy losses due to the waste of heat by the CC exhaust gases and represents 6.28% of exergy losses. In relation to the total heat supplied in the HRSG, for the postcombustion section, the heat of combustion represents 14.57%, and the IPSH and LPSH have the lowest heat transfers to the water stream (liquid-vapor) with 0.34% and 0.93%, respectively.In Ḟ), the product (Ṗ), the irreversibility (İ) and the residue (Ṙ), as well as the exergetic efficiency (exη) of the components of the CC with postcombustion. In the second column (Ḟ), we have that the highest exergy resource flow rate is in the CCH since it is the component where the greatest external resource of the CC enters, 15.36 kg/s of fuel, to generate the combustion gases at the temperature and pressure conditions required by the GT and the pumps present the lowest exergy flow rates of the resource, due to their supplied powers, of which the low-pressure pump has the lowest flow. The exergetic flow rate of the product (Ṗ) is presented in the third column, where the turbine of the gas turbine system is the component that generates the highest exergetic flow rate of the product in the CC, with the power supplied to the compressor and the power output from the GT. The fourth column corresponds to the irreversibility flow rate (İ) where, the CCH is the component with the greatest contribution, due to the great loss of exergy that is had due to the need to reduce the temperature of the combustion gases, for their entry into the turbine of the GT system. The exergetic flow rate associated with the residue is presented in the fifth column. For this system, only those associated with the exhaust gases that come out of the chimney and the heat dissipated by the condenser towards the environment are studied. In the sixth column, the values of the exergy destruction factor are presented, this is an indicator that evaluates the exergy losses due to the irreversibility flow of equipment, in relation to the exergy flow of its resource (İ/Ḟ), where the equipment is the smallest factor found in t, HPST and IPST, and therefore, they have the greatest use of their resource. Likewise, the seventh column shows the exergetic efficiency (exη), where the gas system turbine has the highest and the lowest exergetic efficiencies are in the LPEC, the postcombustion section and the LPSH; The HPSH1 + IPRH1 section has the highest exergetic efficiency within the HRSG, due to its lower exergy factor destroyed by internal irreversibilities (İ/Ḟ) of the heat exchange sections (combustion gases with liquid-vapor stream) in the HRSG, with 7.54%; M and m do not have exergetic efficiency because they represent stream junction points.kμ, and the heat rejected into the environment by the condenser, kβ, in the components. With the criteria used, the components of the GT do not contribute to the formation of the heat dissipated by the condenser, so their allocation factor is kβ = 0 and they do not have an allocation cost for this residue; on the other hand, the components of the SC do not intervene in the formation of the exhaust gases from the HRSG, and therefore their allocation factor is kμ = 0 and they do not have an allocation cost for this residue. Furthermore, for the exhaust gases, only the GT and HRSG components intervene in the formation of the cost of this residue; the CCH contributes with a factor μ of 0.6431 to the formation of its cost, followed by the HRSG  with a factor μ of 0.1481. In the HRSG, the postcombustion section has the highest contribution with a factor μ of 0.1418, because the allocation factors per component are directly proportional to its irreversibility; For example, CC has the highest allocation factor due to the formation of the cost of this residue, since it has the highest irreversibility flow rate. For the heat rejected to the environment, the GT equipment does not contribute to the formation of the cost of this residue, and the HRSG and LPST contribute more to the formation of this cost, with β factors of 0.7335 and 0.1521, respectively.The total exergetic costs of the residues are higher than their exergetic flow rates, due to the irreversibilities accumulated during their formation process, as presented in fc1f= c2= 6.47 USD/GJ [gc1= 0 and the cost of replacement water of vc7= 0, the exergy and exergoeconomic costs are obtained, unit exergy and exergoeconomic costs for each stream, and the exergoeconomic operating costs of each component are determined.Considering that the cost of natural gas is 7 USD/GJ , the cosIn column five, the HPEV has the highest exergoeconomic cost of the residue attributed to the formation of heat dissipated to the surroundings with a value of 53.78 USD/h, due to its higher allocation factor, due to the formation of this residue, in relation to the productive components of the HRSG (liquid-vapor side) and the SC; and the condenser has an exergoeconomic cost of its residue (heat dissipated to the surroundings) of 315.84 USD/h, which is the sum of the exergoeconomic costs of allocation of the productive components of the HRSG (liquid-vapor side) and of the SC that they intervene in the formation of this residue. Finally, the sixth and seventh columns present the unit exergoeconomic costs of the resource and of operation, respectively. The LPD and the pumps are the components that have the highest unit exergoeconomic costs of the resource with a value of 6.62 USD/h and 6.07 USD/h, respectively, which indicates that the process of obtaining their resources is the most inefficient; while, the CCH has an exergoeconomic operating cost of 1344 USD/h, which is the highest, mainly due to its higher irreversibility flow rate; and the lowest operating costs are found in LPP and IPP, due to their lower irreversibility flow rates.The CC with postcombustion generates a higher power output of 310.87 MW, which represents an increase of 13.58%; the total mass flow rate of fuel in the cycle is higher in the combined cycle with postcombustion with 17.10 kg/s (11.32%), due to the mass flow rate of fuel injected in the postcombustion section, since the mass flow rate of fuel supplied in the GT is the same. The mass flow rates of steam in the SC are higher in the combined cycle with postcombustion, and therefore its power output in the SC increases in relation to the combined cycle without postcombustion; the thermal and exergetic efficiencies are higher in the CC without postcombustion with 54.30% and 62.15%, respectively, indicating a difference of 1.73% with the other combined cycle, due to the fact that their efficiencies in the SC are also lower, while, their GT efficiencies are equal.2eqCO, 2.53 gNOxeq, 2.62 g2eqSO and 0.00067 gPbeq are generated in the CC without postcombustion, and the increments of these values in the CC with postcombustion are 19.52 g2eqCO, 0.14 gNOxeq, 0.14 g2eqSO and 0.000034 gPbeq for each kWh produced.The exergoeconomic cost of the power output in the GT is higher in the CC without postcombustion, however, the exergoeconomic costs of the power output in the SC and of residue formation (combustion gases at the outlet of the HRSG and dissipated heat by the condenser) are greater in the CC with postcombustion; the unit exergoeconomic cost of the power output in the GT is lower in the CC with postcombustion, indicating greater efficiency in the process of obtaining this energy stream, and the unit exergoeconomic costs of the power output in the SC and of the formation of the residues (combustion gases leaving the HRSG and heat dissipated by the condenser) are higher in the CC with postcombustion. The EOC of the CC with post-combustion is higher at 4374 USD/h, representing an increase of 54.53% in relation to the other cycle, mainly due to its higher irreversibility flow rate, despite the fact that the exergoeconomic operating costs of the GT are equal in both cycles combined. Furthermore, the exergoeconomic operating costs of the HRSG and SC are higher in the CC with postcombustion, since there are higher irreversibility flow rates. The environmental indicators of global warming, smog formation, acid rain formation and human toxicity are higher in the CC with postcombustion, due to its higher fuel consumption, despite the fact that more power is generated in the CC with postcombustion, that is, for each kWh produced, 373.25 gGWI-5.22%, SFI-5.53% and ARI-5.30%), its human toxicity indicator increased 5.07% and its exergoeconomic operating cost increased by 54.53%.The combined cycle with postcombustion has a power output ratio between the gas turbine and the steam cycle of 1.35/1, and the combined cycle without postcombustion has a power output ratio of 1.87:1, that is, the combined cycle with postcombustion increases the power output by 13.58%; however, its thermal and exergetic efficiencies decreased 0.94% and 1.08%, respectively, its environmental indicators increased . The composition of the fuel gas is therefore a very important variable to determine the exergoeconomic, environmental and human toxicity indicators. Then the proper operation and maintenance of the fuel gas conditioning system and the combustion chamber are important to avoid increasing irreversibility flow rates in the combustion chamber. Since the combustion chamber presents the highest irreversibility flow rate, this component has the lowest exergetic efficiency and the highest exergoeconomic operating costs.In this work, a criterion has been proposed to assign the cost of residue formation to the productive components related to its formation. This criterion is based on the irreversibilities generated in each productive component that participates in the formation of a residue. The criterion is an extension of the entropy change criterion because in addition to the entropy changes it also includes the exergy flow rates associated with the transfer of heat through the limits of the energy system. With these two criteria, all the productive components of each cycle take part in the formation of their respective residues. Then, the combined cycle generates two residues, one is the exhaust gases and the other the heat dissipated by the condenser, and with the criterion of irreversibilities generated to assign the cost of residue formation to the productive components involved in its formation, it is concluded that the cost of formation of the exhaust gases is formed in all the productive components of the gas turbine and the heat recovery steam generator, and the cost of formation of the heat dissipated by the condenser is formed in all the productive components of the cycle steam, and with postcombustion, the cost of formation of the exhaust gases increased 3.56% and the cost of formation of the heat dissipated by the condenser increased 8.38%.For the exergoeconomic analysis in the combined cycle with postcombustion, the highest exergoeconomic costs of the resource and product are of the expansion turbine, of the gas turbine unit, because its resource has a high exergy flow and there is a large amount of irreversibilities accumulated during its obtaining process; the highest exergoeconomic cost of the residue attributed to the formation of exhaust gases is found in the combustion chamber, since it has the highest irreversibility flow, and therefore, it has the highest allocation factor due to the formation of combustion gases; the component with the highest exergoeconomic cost of the residue attributed to the formation of heat dissipated to the surroundings is the high pressure evaporator, due to its higher allocation factor, due to the formation of this residue, in relation to the components of the heat recovery steam generator (liquid-vapor side) and steam cycle; the exergoeconomic cost of the condenser residue is the sum of the exergoeconomic costs of allocation of the productive components of the heat recovery steam generator (liquid-vapor side) and of the steam cycle involved in the formation of this residue; the highest unit exergoeconomic costs of the resource are presented in the domes and pumps, indicating that the process of obtaining their resources are the most inefficient; the component with the highest exergoeconomic operating cost is the combustion chamber, mainly due to its greater irreversibility flow rate; and the lowest exergoeconomic operating costs are found in low pressure and intermediate pressure pumps, due to their lower irreversibility flow rates.For the comparative analysis of combined cycles with and without postcombustion, the combined cycle without postcombustion has the highest exergoeconomic cost of the power output in the gas turbine, however, the combined cycle with postcombustion has the highest exergoeconomic costs of the power output in the cycle of steam and the formation of both residues; the unit exergoeconomic cost of the power output in the gas turbine is lower in the combined cycle with postcombustion, indicating greater efficiency in the process of obtaining this energy stream, and the unit exergoeconomic costs of the power output in the steam cycle and residue formation are higher in the combined cycle with postcombustion; the combined cycle with postcombustion has the highest exergoeconomic operating cost, mainly due to its higher irreversibility flow rate, despite the fact that the exergoeconomic operating costs of the gas turbine of both cycles is the same; the exergoeconomic operating costs of the heat recovery steam generator and steam cycle are higher in the combined cycle with postcombustion, since there are higher irreversibility flow rates; and the environmental indicators of global warming, smog formation, acid rain formation and human toxicity are higher in the combined cycle with postcombustion, due to its higher fuel consumption, despite the fact that more power output in the postcombustion cycle, these differences being 5.22%, 5.53%, 5.30% and 5.07%, respectively.According to the indicators, it is concluded that a combined cycle with postcombustion can be used when there is a greater demand for power output, however, by having a higher fuel consumption, its environmental indicators are increased , its total production costs (power output from the combined cycle) and its exergoeconomic operating costs.


Aprotinin had no effect on either pre- or postsurgical clot lysis indices. Inhibition of platelet clot retraction with cytochalasin D (FIBTEM) markedly increased the preoperative clot lysis index. High pre- and post-transplantation clot lysis indices were associated with increased mortality irrespective of the activator used  and the inhibition of fibrinolysis (APTEM). Inhibition of clot retraction (FIBTEM) abolished the association of clot lysis index with mortality in both pre- and post-transplantation samples. Conclusion: Both pre- and postoperative ROTEM™ clot lysis indices predict mortality in patients following liver transplantation. Inhibitor experiments reveal that the clot lysis index is not an indicator of fibrinolysis, but indicates platelet clot retraction. The marked increase of clot lysis index during liver transplantation is caused by a decrease in clot retraction with eventual consequences for clot stability, retraction of wound margins, and reperfusion of vessels in case of thrombosis.Background: The ROTEM™ clot lysis index, describing the decrease in firmness of a clot with time, predicts mortality in various settings. The variability of the clot lysis index in surgical procedures and the involved pathophysiological mechanisms are unknown. We therefore compared pre- and postoperative clot lysis indices in liver transplantation (LTX) procedures, determined the eventual association with mortality, and investigated the mechanisms underlying decreased clot lysis index using inhibitors of fibrinolysis and clot retraction, respectively. Methods: In this retrospective cohort study, data on pre- and post-transplant ROTEM™ findings as obtained with EXTEM (tissue factor activation), INTEM (intrinsic system activation), FIBTEM (extrinsic system activation and inhibition of clot retraction), APTEM (extrinsic system activation and fibrinolysis inhibition), conventional laboratory coagulation tests, blood loss, transfusion of blood products, and outcome were registered. Results: Pre-transplant clot lysis indices showed a broad distribution ranging from 75% to 99% independent of the activator used . During the surgical procedure, median clot lysis index values markedly increased from 92% to 97% (EXTEM) and 93% to 98% (INTEM), respectively ( Rotational thromboelastometry (ROTEM™) is widely used as a bed side assay to evaluate hemostasis in liver transplantation and other clinical settings and is used to detect fibrin polymerization disturbances ,2,3,4,5.The prognostic value of the ROTEM™ clot lysis index has been explained as a fibrinolytic system inhibition in many clinical settings including LTX, sepsis, and trauma. Accordingly, increased levels of plasminogen activator inhibitor I and thrombin activatable fibrinolysis inhibitor are thought to be the correlate of the findings achieved with viscoelastic methods ,13. TherWhile the effects of pre-transplantation ROTEM™ clot lysis index on mortality and other outcome measures has been demonstrated, it is not known whether the variable is constant in an individuum or might be affected by the transplantation procedure. Moreover, it is not known whether the post-transplantation clot lysis index predicts mortality as well. To evaluate the mechanism of the clot lysis index, we investigated whether a low clot lysis index can be explained by fibrinolysis or clot retraction using selective inhibitors.After allowance of the ethics committee of the University Hospital Essen (09-4091) for the retrospective data analysis, data from 187 complete pre- and postoperative data sets were investigated in this retrospective study. Both conventional laboratory variables  and ROTEM™ coagulation variables  were determined at the beginning of LTX as well as at the end of the procedure. Moreover, patients’ age, sex, disease necessitating LTX, model of end stage liver disease score (MELD), blood loss, and coagulation factor substitution were recorded. For the generation of preoperative Kaplan–Meier curves, further 166 preoperative data sets were used.Anesthesia was performed as recently described, and was introduced with thiopental and maintained with isoflurane and fentanyl . For facRotational thromboelastometry  and conventional laboratory values were used to determine the effect of LTX on clot lysis index. Four ROTEM™ tests were used to investigate the citrated whole blood: 1. EXTEM test (tissue factor for extrinsic system activation), 2. INTEM test (ellagic acid for intrinsic system activation), 3. APTEM test (tissue factor activation combined with aprotinin to inhibit fibrinolysis), and 4. FIBTEM test . The ROTEM™ tests at the beginning and the end of the transplantation procedure were evaluated.SPSS Statistics  was used for the evaluation of data. Figures were generated with SPSS Statistics and OriginPro . Mean and standard deviation, median and quartiles, box plots, pair plots, and Kaplan–Meier analyses were used to describe the data. For statistical analyses, Wilcoxon tests, linear regression analyses (Pearson), and 2-tailed significance analyses, as well as log-rank tests, were used, as appropriate.n = 26). The diseases leading to LTX in this study are listed in n = 16), bleeding (n = 3), transplant failure (n = 2), cardiac events (n = 1), and other reasons (n = 4). Median as well as quartiles and range (given in brackets) of blood products applied in this series were as follows: red blood cell concentrates 3 U , fibrinogen 2 g , prothrombin complex concentrates 0 U , and platelet concentrates 0 U .The present study includes 187 adult patients, 51% of which were male. Median age was 51 years and median lab-MELD-score was 23. The 30-day mortality after LTX was 13.9% (p < 0.0001). Differences of clot lysis index values obtained with the EXTEM and INTEM tests were 1.6% ± 4.0% (mean and SD), demonstrating that the clot lysis index is not influenced by the activator used (extrinsic vs. intrinsic system). Moreover, there was no significant difference in the clot lysis index between the EXTEM and APTEM tests, which amounted to −0.1% ± 3.6% (mean and SD), thus indicating that differences in the clot lysis index between patients were not due to differences in fibrinolysis. Inhibition of platelet clot retraction with cytochalasin D (FIBTEM test) shifted the distribution of the presurgical clot lysis index to higher values in the post-transplantation phase . In contrast, the pre- and post-transplantation clot lysis indices in the FIBTEM test  were not different (p = 0.623). Linear regression analysis obtained from pre- and post-transplantation clot lysis index values in the absence or presence of aprotinin (EXTEM and APTEM tests) demonstrates particularly that the low clot lysis index values increased during surgery and that the fibrinolysis inhibitor did not have any effect , activated partial thromboplastin time , antithrombin , and platelet count  were correlated with pre-transplantation clot lysis index, while fibrinogen was not correlated . Moreover, pre-transplantation clot lysis index was correlated with the MELD-score . Correlation of pre-transplantation clot lysis index with other ROTEM™ variables was low and not significant in most tests , fibrinogen-substitution , prothrombin complex concentrates , platelet concentrates , volume substitution , tranexamic acid , and duration of surgery  were correlated with the clot lysis index.Linear correlation analysis excluded that red blood cells  is the so called “fibrinolytic shutdown”, supposed to be caused through increases in plasminogen activator inhibitor I and thrombin activatable fibrinolysis inhibitor . HoweverAssociation of clot lysis index with mortality: Both pre- and postoperative clot lysis indices were associated with mortality. This finding was not dependent on extrinsic and intrinsic system activation using the EXTEM and INTEM test, respectively. Moreover, inhibition of fibrinolysis using aprotinin had no effect on the association of clot lysis index and mortality. However, inhibition of clot retraction using cytochalasin D abolished the association both pre- and postoperatively.Associations of laboratory variables with clot lysis index: The results of the present study demonstrate that the pre-transplantation clot lysis index is positively associated with the MELD-score, activated prothrombin time, and INR, and negatively correlated with antithrombin levels and platelet count. Interestingly, the clot lysis index was not associated with other ROTEM™ variables. These findings demonstrate that clot lysis index alterations are more pronounced in those patients with decreased liver function and thus might be a biomarker of disease severity.Mechanism of alterations in clot lysis index in liver disease and transplantation: Concerning the mechanism responsible for an altered clot lysis index, the effect of platelet inhibition in the FIBTEM test is remarkable and suggests an involvement of platelets. Indeed, clot retraction, which is specifically inhibited by cytochalasin D in the FIBTEM test, could represent the mechanism responsible for the differences in clot lysis indices. Accordingly, it has been hypothesized that viscoelastic methods are sensitive for clot retraction . HoweverPlatelets are not only critically involved in primary hemostasis, but are also immune cells. Platelets are affected by inflammatory mediators, can release many mediators from their granules, can induce the contraction and stabilization of clots, and are involved in wound healing ,17,18,19There are some limitations of the study. Due to the retrospective design, it is not possible to further evaluate the importance of mechanisms leading to the increase in the clot lysis index during surgery. Thus, further studies are necessary to evaluate the pathophysiological mechanisms involved.Conclusions: The present study demonstrates that the clot lysis index, an indicator of 30-day mortality, increases during liver transplantation in a platelet-dependent way independent of fibrinolysis. Clot retraction is the most probable mechanism explaining the differences in clot retraction and the association with mortality.


Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Methylphenidate improved and sulpiride decreased overall accuracy and response speed. Both drugs boosted reward versus punishment learning signals to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate gates both attention and reward learning.Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults (N = 100) were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D The mechanisms underpinning the variability in methylphenidate’s effects on cognition remain unclear. Here, the authors show that such effects reflect changes in striatal dopamine-related output gating of task-relevant cortical signals, and that these changes depend on baseline dopamine synthesis capacity. Methylphenidate, a dopamine and noradrenaline transporter blocker, is the first-line pharmacological treatment for attention deficit hyperactivity disorder (ADHD), which is characterized by cognitive deficits11. In addition, it is widely used by healthy people as a psychostimulant for its cognition-enhancing effects15. However, there is large interindividual variability in the direction of the effects17 and the mechanisms underlying these effects remain unclear. This poses a major problem for treatment strategies in psychiatry and raises questions about the use of methylphenidate as a therapeutic or a smart drug.Adaptive behavior requires flexible updating of our actions and predictions in response to the constant changes around us. Catecholamine transmission is well-accepted to be essential for such flexible behavior, as demonstrated by accumulating evidence from experimental psychopharmacology showing effects of catecholaminergic drugs on performance on cognitive tasks, including reversal learning, cognitive action gating and attention shifting18, work with human volunteers has suggested a key role for dopamine in the striatum19. A large body of evidence indicates that both the therapeutic effects21 and potential for abuse22 of methylphenidate are related to its effects on reinforcement as well as surprise26, and associated striatal dopamine signaling19.Here, we investigate the neural mechanisms of methylphenidate’s effects on reward-related reversal learning: the ability to flexibly adapt behavior based on changes in reward and punishment contingencies. While evidence from work with nonhuman animals suggests that many of methylphenidate’s cognitive enhancing effects involve direct action in the prefrontal cortex27, experimental rodents29, and patients with Parkinson’s disease31. Studies in young healthy volunteers have shown that administration of methylphenidate modulates reversal-related BOLD signal in the striatum3 and impairs reversal learning in proportion to the degree that methylphenidate increased striatal dopamine release2. Genetic variation in a common dopamine transporter polymorphism, affecting primarily striatal dopamine, predicted increased perseveration during reversal learning due to increased reliance on prior reinforcement32. This evidence generally concurs with the observation that injection of D-amphetamine in the striatum of rats potentiates behavioral control by stimuli formerly associated with reward  in a dopamine-dependent manner33. While these studies establish a causal role for striatal dopamine specifically in reward-driven compulsivity as measured with reversal learning, the corticostriatal mechanisms underlying the large interindividual variability in methylphenidate’s effects remain unclear.A causal role for striatal dopamine in reward-based reversal learning is substantiated by a large body of evidence from studies with nonhuman primates34, striatal dopamine flexibly gates task-relevant actions and representations maintained in the cortex by promoting activity in the direct (Go) versus indirect (NoGo) pathway of the basal ganglia in proportion to reward (versus punishment) prediction error. Inspired by this work, we hypothesized that methylphenidate boosts reversal learning by acting on striatal dopamine to gate attention to reward-associated cortical representations. To test this output gating hypothesis36, we index drug effects on neural signals not only in the striatum and the strongly connected prefrontal brain regions, but also in task-relevant cortical areas that are specialized for the processing of selective stimulus categories. Specifically, we measured the relative stimulus-specificity of visual association cortex responses to face and scene stimuli39 while participants learned and updated their association with reward and punishment. We predicted that methylphenidate boosts reversal signals in the striatum, reward versus punishment reversal-learning performance, and the associated reward versus punishment reversal signals in the stimulus-specific visual association cortex.According to influential neurocomputational modeling work2/3-receptor antagonist sulpiride. At low doses, sulpiride acts preferentially presynaptically to increase synaptic dopamine levels in the striatum41. Therefore, we predicted parallel effects of methylphenidate and sulpiride (preregistration: https://osf.io/ey4j7/). To further establish the dependency of the effects of methylphenidate and sulpiride on striatal dopamine, we additionally measured each participant’s striatal dopamine synthesis capacity directly, with [18F]DOPA positron emission tomography (PET). We focused on the cognitive subregion of the striatum, the caudate nucleus, previously demonstrated to be essential for reversal learning42, but additionally explored the role of dopamine in the motor and motivational subregions 44.To address the role of striatal dopamine in these effects, we compared the effects of the nonspecific catecholamine enhancer methylphenidate with those of the selective dopamine D45 (https://osf.io/ey4j7/). Prior PET studies focusing on dopamine suggested a nonlinear, inverted-U-shaped relationship between dopamine and cognitive performance45, with participants with low dopamine synthesis capacity benefiting from dopaminergic drug administration, while “high-dopamine participants” were impaired by the same dopaminergic drug46. However, previous PET studies focusing on dopamine have been conducted only in small samples47, precluding inferences about the reliability of observed between-subject variability. This study combined pharmacological functional magnetic resonance imaging (fMRI) with [18F]DOPA PET in 100 healthy volunteers, thus providing a large sample to study interindividual differences in the cognitive and neural response to methylphenidate.The PET design also enabled us to test the pervasive baseline-dependency hypothesis of dopaminergic drugs, which predicts that methylphenidate’s effects depend on baseline levels of striatal dopamine48. Across all three sessions, unexpected reward and punishment outcomes, which signaled reversals, strongly activated frontostriatal circuitry . Consistent with its established performance-enhancing effects, methylphenidate increased overall task accuracy and shortened overall RTs .Methylphenidate boosted outcome-related activity in the striatum. Specifically, it increased BOLD signal during both unexpected rewards and punishments in the bilateral ventral putamen, with additional clusters in the bilateral posterior putamen . The key role of dopamine in these effects was further substantiated by a parallel effect of sulpiride, which also boosted reversal-related caudate BOLD signal depending on caudate dopamine synthesis capacity . Neither drug effect depended on dopamine synthesis capacity in the putamen or nucleus accumbens, and there were no effects of sulpiride on BOLD signal to unexpected outcomes when dopamine synthesis capacity was not taken into account.As anticipated, there was great variability between participants, with methylphenidate boosting signals in the caudate nucleus to a greater degree in participants with lower dopamine synthesis capacity in the caudate nucleus, as indexed by ; Fig. i on RTs: B = −0.005, CI = ; sulpiride × valence × nucleus accumbens ki on RTs: B = −0.006, CI = ). Thus, the drugs induced speeding of punishment predictions compared to reward predictions to a greater degree in participants with lower striatal dopamine synthesis capacity, similar to the improvements in accuracy on update trials.The pattern of drug effects on RTs generally paralleled those on accuracy. Both methylphenidate and sulpiride decreased RTs for all reward versus punishment predictions to a greater degree in participants with higher dopamine synthesis capacity in the nucleus accumbens and putamen, but not caudate nucleus .The present pharmacological fMRI/PET study provides strong support for two pervasive hypotheses about methylphenidate. First, its effects on reversal learning reflect changes in striatal dopamine-related selective output gating of task-relevant cortical signals. Second, interindividual differences in striatal dopamine synthesis capacity explain variability in its cognitive effects, thus strongly establishing the baseline-dependency principle for methylphenidate, which is the most prescribed dopaminergic drug together with the related amphetamines  that the dopamine D2-receptor agonist bromocriptine boosted reward versus punishment reversal accuracy to a greater degree in participants with lower dopamine synthesis capacity46.The second key contribution of the present study is that it firmly establishes the baseline dopamine dependency of the effects of methylphenidate and sulpiride on reward-based reversal learning, using a direct measure of striatal dopamine. Both methylphenidate and sulpiride boosted reward relative to punishment reversal accuracy to a greater degree in participants with higher dopamine synthesis capacity. This preregistered pattern of effects resembles those seen in previous pharmacological studies with this paradigm, in which methylphenidate and sulpiride boosted reward versus punishment reversal accuracy to a greater degree in participants with higher baseline working memory capacity, commonly used as an indirect proxy of dopamine synthesis capacity3, our results demonstrate that these effects depend on striatal dopamine synthesis capacity. The striatal dopamine dependency of valence-specific modulation of learning is predicted by models of striatal dopamine’s role in reinforcement learning62 and suggests that methylphenidate acts on valence-dependent release of striatal dopamine to modulate valence-dependent signaling to the aPFC, consistent with classic animal lesion studies implicating both striatum and aPFC in reversal learning, specifically the orbitofrontal cortex (OFC)63. The specific locus of the present effect also concurs remarkably well with an extensive body of work implicating the lateral OFC, and its interactions with striatal dopamine signaling, in acquiring and reversal learning of stimulus-outcome associations71.The dopamine synthesis-dependent effect of methylphenidate on behavior was accompanied by greater increases in reward versus punishment-related reversal signals in the lateral aPFC Fig. . While t72, that dopamine D2-receptor agonists likely act postsynaptically in “low-dopamine participants” with sensitized postsynaptic D2-receptors, while acting presynaptically in participants with higher dopamine synthesis capacity and putatively sensitized autoreceptors46. The effects of the D2-receptor antagonist sulpiride observed here might also reflect paradoxical presynaptic effects, particularly in participants with high synthesis capacity, which leads to a net increase in striatal dopamine release, biasing the system towards better reward learning41. A presynaptic action of sulpiride in participants with high baseline dopamine levels is substantiated by the finding that sulpiride speeded responses for reward predictions compared with punishment predictions to a greater degree in participants with higher dopamine synthesis capacity  who also exhibited the largest increases in indices that likely reflect changes in arousal and attention, i.e., valence-nonspecific speeding and accuracy  pathway activity, and a concomitant increase in the salience of unsigned surprise signals, thus promoting attention shifting after unsigned surprise. A second question is how to reconcile the present finding that methylphenidate and sulpiride-related boosting of reward-specific learning was greater in participants with higher dopamine synthesis capacity with our previous finding (in a subset of the same participants) that drug-related boosting of effort-based value and choice was greater in participants with lower dopamine synthesis capacity9? In line with prior work and the proposal put forward above, we argue that this might reflect differential roles of phasic and tonic dopamine in learning from reward and in the expression of learned value on choice84. Third, the negative effect of interindividual differences in striatal dopamine synthesis capacity on reward versus punishment learning under placebo stands in contrast to a positive effect of striatal dopamine synthesis capacity on this same task in a previous study46. This likely reflects the use of [18F]DOPA as opposed to [18F]FMT for estimating dopamine synthesis capacity. Both ligands are substrates for aromatic amino acid decarboxylase, but [18F]DOPA is subject to additional in vivo metabolism, implying lower signal-to-noise ratio than [18F]FMT, and perhaps also to some degree reflecting dopamine turnover rather than synthesis capacity85. Strikingly, there is precedent in the literature for opposite effects of [18F]FMT and [18F]DOPA, for example, as a function of aging87, as well as D2-receptor binding potential89. While the source of these contrasting effects remains to be elucidated, one might ask whether this relates to differential contributions of [18F]DOPA and [18F]FMT to tonic dopamine levels and neuronal integrity, respectively91. A final puzzle is why we did not observe effects of sulpiride on reward-specific BOLD signal (in the aPFC or elsewhere), despite sulpiride-related changes in reward-specific reversal learning. One possibility is that sulpiride’s effects on phasic dopamine signals were not sufficiently prolonged to be detectable in terms of BOLD signal changes.This study raises a number of open questions. First, why does sulpiride boost nonspecific surprise signals in the caudate nucleus and stimulus-specific visual cortex to a greater degree in participants with lower dopamine synthesis capacity? One possibility is that this striatal BOLD signal increase reflects a tonic blockade of D73. In addition, the current design with fixed timings between drug intake and task performance, and without monitoring of drug plasma levels, did not enable us to control for interindividual differences in drug plasma concentrations during scanning. A second consideration is the fact that sulpiride also acts as an antagonist of 5-HT1A receptors. However, we consider it less plausible that the effects observed here reflect changes in serotonin receptor activity, because such effects would be more substantial only at higher doses of sulpiride, due to its low affinity for the 5-HT1A receptor92. Finally, another important issue to consider in all pharmacological fMRI studies is the degree to which BOLD signal changes reflect non-neuronal drug effects, such as changes in cerebral blood flow or cerebrovascular reactivity in the absence of changes in neural activity93. We consider this unlikely in this case because the effects were regionally selective and task-specific. Specifically, the effect of methylphenidate on striatal BOLD signal was observed during unexpected relative to expected outcomes. Moreover, it was observed only in the striatum, and did not extend to other regions activated by the unexpected outcomes  = 23.0 (5.0) years). All participants provided written informed consent and were paid 309 euro on completion of the study. The study was approved by the local ethics committee . People were recruited via an advertisement on the Radboud University electronic database for research participants, and via advertisement flyers around Nijmegen. Prerequisites for participation were an age between 18 and 45 years, Dutch as native language and right-handedness. Before admission to the study, participants were extensively screened for adverse medical and psychiatric conditions. Exclusion criteria included any current or previous psychiatric or neurological disorders, having a first-degree family member with a current or previous psychiatric disorder, clinically significant hepatic, cardiac, renal, metabolic or pulmonary disease, epilepsy, hyper or hypotension, habitual smoking or drug use, pregnancy, and MRI contraindications, such as unremovable metal parts in the body and claustrophobia (more details in ref. N = 4), personal reasons (N = 1) or technical failure of the PET scanner (N = 1). Six more failed to meet the task performance criterion (described below) on one of the sessions (N = 6). For the fMRI analyses, three additional participants were excluded from contrasts comparing methylphenidate and placebo, and six were excluded from contrasts comparing sulpiride and placebo, because of poor data quality on one of the sessions  two identical capsules on each day, one 3 h before the task and one 1.5 h before the task. One of the capsules was a placebo and the other contained the drug (or another placebo on the placebo session). The dose selection was based on previous studies which had revealed significant effects and good tolerance99. Blood pressure, heart rate, medical symptoms, and mood measures were monitored three times each session: before the start of the task battery, 20 min after intake of the second capsule, and after the task battery , respectively, thereby increasing the signal-to-noise ratio in the brain103.On the fifth day, participants underwent an DOPA into dopamine provides an estimate of dopamine synthesis capacity.The brain PET data were acquired on a state-of-the-art PET/CT scanner  at the Department of Medical Imaging of the Radboud University Medical Center. We used the well-validated radio-tracer [18F]DOPA tracer was administered (~185 MBq) via a bolus injection in the antecubital vein and the PET scan was started. Dynamic PET data  were acquired over 89 min and divided into 24 frames . Data were reconstructed with weighted attenuation correction and time-of-flight recovery, scatter corrected, and smoothed with a 3-mm FWHM kernel.The procedure started with a low-dose CT scan to use for attenuation correction of the PET images. Then, the  + [unexpected punishment − expected punishment]), valence ([unexpected reward  − unexpected punishment] + [expected reward − expected punishment]), and the expectancy × valence interaction ([unexpected reward − expected reward] − [unexpected punishment − expected punishment]). The contrasts for the drug effects were created by subtracting the contrast vectors for placebo from the contrast vectors for methylphenidate/sulpiride. The resulting contrast images of each participant were taken to the group-level analysis and submitted to a one-sample t values and beta values114. The blue-black and red-yellow colors code the beta values. The t values are displayed in terms of the opaqueness of the colored blobs. All blobs that pass the threshold for significance are fully opaque; the rest are more transparent the lower the associated t value and fully transparent below a t value of 1 (to reduce clutter). Visualizing the data in this way is more revealing than only displaying t values, which hides all effects that do not reach the cutoff score for statistical significance.For visualization, we have used a dual-coded approach displaying both the To assess drug effects on stimulus-specific activity in the relevant visual association cortex, we analyzed a stimulus-specificity index for BOLD signal in the FFA/PPA related to outcomes after faces versus scenes.https://www.nitrc.org/projects/wfu_pickatlas/).First, we created individually defined ROI masks for the FFA and PPA. For each participant, we estimated a separate GLM to model the BOLD response to the face and scene stimulus, using two regressors for the onsets of the stimuli on trials where the face or scene was highlighted, respectively. The same confound regressors as in the other GLMs were included. Based on that GLM, two contrast images were created: BOLD response to faces minus scenes, and for scenes minus faces. The FFA ROI was defined as a sphere with 3-mm radius around the peak voxel of the faces minus scenes contrast within an anatomical mask of the fusiform gyrus. The PPA ROI was a 3-mm sphere around the peak voxel of the scenes minus faces contrast within the mask of the combination of the parahippocampal and lingual gyri. The anatomical bounding masks were created using the WFU_PickAtlas toolbox for SPM12 . We then extracted the average contrast estimates in the individually defined FFA  and PPA . The final stimulus-specificity index was created by subtracting estimates in the PPA from those in the FFA , resulting in a measure with greater values indicating greater stimulus specificity of the outcome-related signal in the relevant ROI.115 in R (version 4.0.2)112.Finally, the stimulus-specificity indices were analyzed in a repeated-measures ANOVA with drug status, outcome expectancy and outcome valence as within-subject factors, and dopamine synthesis capacity in the caudate nucleus as between-subjects factor. In addition, we explored the effect of dopamine synthesis capacity in the putamen and nucleus accumbens in separate ANOVA models. The ANOVA models were run using the aov_car function from the afex package (version 0.28-0)Further information on research design is available in the Supplementary InformationPeer Review FileReporting Summary


Pharmacists have important antimicrobial stewardship (AMS) roles yet limited literature exists on pharmacists’ knowledge and beliefs about antimicrobial resistance (AMR) and antimicrobials and how these beliefs influence antimicrobial supply in different countries.A cross-sectional survey was disseminated to pharmacists around the world via the Commonwealth Pharmacists’ Association and related networks. Data were collected on demographics, antibiotic supply practices, and knowledge and beliefs about AMR.A total of 546 pharmacists responded from 59 countries, most commonly from Africa (41%) followed by Asia (26%) and Oceania (22%). Respondents supplied a mean of 46 ± 81 antibiotic prescriptions/week, 73%±35% of which were given in response to a prescription. Overall, 60.2% dispensed antibiotics at least once without a prescription. Respondents had good knowledge (mean 9.6 ± 1.3 (out of 12), and held positive beliefs about AMR [mean 3.9 ± 0.6 (out of 5)]. Knowledge about antibiotics and beliefs about AMR were positively correlated. The odds of supplying antibiotics without a prescription were 7.4 times higher among respondents from lower income countries . Conversely, more positive AMR beliefs were associated with a lower odds of supplying antibiotics without a prescription .Most pharmacists had the good knowledge about antibiotics and positive beliefs about AMR. These beliefs were influenced by knowledge, work setting, and country income. A proportion of respondents provided antibiotics without a prescription; the likelihood of this occurring was higher in those who held more negative beliefs about AMR. Importantly, pharmacists are uniquely positioned as one of the most easily accessible health professionals (particularly in the community), offering key opportunities to provide medication education to patients where other clinical infrastructure is lacking or access to reliable health information is difficult.8 This is particularly relevant when most of our antibiotic use and prescribing is in primary care and for respiratory tract infections.9 Current evidence supports the role of pharmacists in reducing unnecessary prescribing, and increasing the appropriateness of prescribing, and the integration of pharmacist-led AMS practices in the community,11 for example through pharmacist-led management of uncomplicated infections, has been shown to be effective and well-received by patients.12 The World Health Organization (WHO) recognizes the importance of fostering global AMS through multidisciplinary health providers, in order to prevent emergence of further resistance,4 with a need for countries to adopt global action plans on AMR that focus on effective AMS by all health providers.13Within the supply chain of antimicrobials, a diverse range of healthcare professionals are usually involved, from the prescribing clinician, to dispensing by pharmacists, to administration by nurses or patients who are self-medicating. Pharmacists have been increasingly recognized as key members of the antimicrobial supply process14 and predominantly health-provider education through materials or meetings.15 However, these efforts to tackle AMR have varied in effectiveness,15 with education alone often having little or limited effect in terms of generating sustainable long-term improvement in antibiotic prescribing.17 This is because passive education or information provision alone often does not lead to behaviour change; and even if it does, behaviour change is likely to be short-term ‘unless motivators and values become firmly rooted and norms that support lasting change are established within population’.18In line with this, many AMR interventions have focused on changing health provider prescribing, such as implementation of prescribing guidelines, supply restrictions on various antimicrobials,19 and simply providing information is not sufficient to change behaviour on a sustainable basis.20 To change behaviours such as inappropriate antimicrobial supply and use, interventions need to go beyond information provision to understanding and addressing the psychological and behavioural drivers of antimicrobial use for the health professional.19 For example, as antimicrobials become increasingly accessible, they may be overly used by healthcare professionals to meet shortfalls in other healthcare resources and to prevent infection outbreaks where these are of imminent concern.22 In the context of community pharmacy, motivational drivers associated with running a sustainable business may conflict with optimal antimicrobial stewarding behaviour. For example, healthcare providers may be motivated to provide antimicrobials to secure customer loyalty, in the face of increased customer demand, and to turnover stock.23This may be because sub-optimal antimicrobial use in many settings is primarily influenced by behavioural drivers,24–29 Coenen et al.30 found that patient expectations and demands were a top influencing factor in the supply of antimicrobials by clinicians, even when clinicians were aware that the supply was not appropriate. One study found that 42% of physicians stated they would prescribe an antimicrobial when unsure if the infection was viral or bacterial.31 Other literature highlights that health professionals and students often have poor knowledge of AMR,32 with one study reporting that more than half of community pharmacists and physicians had poor knowledge of AMR.33 Even though AMR awareness is recognized by most health providers as an important public health issue,33 this awareness does not consistently translate into reduced antibiotic prescribing or dispensing, or involvement in AMS initiatives.24 These behaviours are not well understood and are important to explore as these can influence an individual’s motivation and beliefs about antimicrobials, and antimicrobial use.34 Despite the key role that pharmacists play in AMS, limited literature exists on pharmacists’ knowledge and beliefs about AMR and antimicrobials, and how these beliefs are linked with actual antimicrobial supply practices. These antimicrobial supply practices are likely to vary by country due to differences in antimicrobial regulation and cultural practices, yet little has been published on how beliefs and antimicrobial supply vary between countries.Inappropriate antimicrobial supply can also occur when patients request or expect antibiotic treatment for situations where antibiotics are not indicated. Studies show that health providers often prescribe or supply antimicrobials to meet patient expectations and demands, even when they may not be necessary.The aim of this study was to explore how pharmacists across the world perceive AMR and antimicrobials, and how these beliefs influence antibiotic supply practices. Specifically, we explored how beliefs about antibiotics and AMR vary between countries, and what factors predicted differences in beliefs and supply practices.36 Respondents were invited to answer an initial set of questions on their antibiotic use behaviour and knowledge based on the WHO ‘Antibiotic resistance: multi-country public awareness survey’,37 and adapted from a survey originally developed for physicians by Teixeira Rodrigues et al.36 These measures are described below.A cross-sectional survey was developed for health professionals based on previously validated surveys on antimicrobials and medicines-related behaviours.https://datatopics.worldbank.org/world-development-indicators/the-world-by-income-and-region.html), allowing countries to be classified as high, upper-middle, low-middle or low-income. For each of these countries, prescribing regulations were checked to find out if formal legislation existed to regulate antibiotic supply, and investigate whether this would affect antibiotic supply practices.Respondents were asked to choose: the country from which they were responding; age; gender ; how long they have been working in pharmacy , and which setting they are currently working in . Based on the respondent’s self-reported country, the country’s income classification was allocated using World Bank country income data from 2017 , diarrhoea, cold and flu, fever, malaria, measles, skin or wound infection, sore throat, body aches, headaches] for which higher scores indicate greater knowledge. This questionnaire had a maximum score of 12.37 The questionnaire comprised 11 statements to which respondents could indicate their level of agreement via a 5 point scale ranging from ‘agree strongly’ to ‘disagree strongly’, with a neutral mid-point. Higher scores indicate stronger agreement that AMR is important to address. Examples of items include ‘Antibiotic resistance is an important public health problem in our setting’, and ‘The prescription of an antibiotic to a patient does not influence the possible appearance of resistance’ (reverse-scored). The maximum sum score was 55, indicating a strong belief that AMR is an important issue.Beliefs about antibiotics and of AMR  were evaluated using an online questionnaire adapted from the WHO survey and other literature.The survey was disseminated to pharmacists via the Commonwealth Pharmacists’ Association, and related personal and research networks. The survey was launched during the WHO’s World Antibiotic Awareness Week, a campaign that aims to raise the awareness of the importance of preserving antibiotics by optimizing use and thus reducing AMR.2 value was reported to provide information about the percentage of variance explained by the model. Multivariable logistic regression was used to identify determinants of dispensing of antibiotics without a prescription. The outcome variable was dichotomized using responses to the question ‘Of the antibiotics you supply, roughly what percentage are given in response to you receiving a prescription?’ into ‘never dispensed antibiotics without a prescription’ (coded as ‘0’) or ‘dispensed antibiotics at least once without a prescription’ (coded as ‘1’). Respondents who stated that they did not dispense any antibiotics were excluded from analysis.Data were analysed using SPSS version 27. The data were summarized using descriptive statistics. Groups were formed for gender of the participant , and participants’ country income . Knowledge and beliefs scores were calculated by summing the score of each item. The internal consistency of Likert items assessing beliefs of AMR was checked using Cronbach’s alpha. A multiple linear regression model was used to examine predictors of beliefs about AMR. Predictor variables used in linear regression were sex , income classification , work experience , work setting , and knowledge about antibiotics. Regression coefficients with 95% CIs were derived from the linear regression model, representing the average change in beliefs about AMR score per unit change in the respective predictor variable. The adjusted RP < 0.05 was considered statistically significant.In addition to the aforementioned predictor variables, beliefs about AMR score was included as a potential predictor of dispensing antibiotics with a prescription. Logistic regression results were reported as adjusted odds ratios with 95% CIs. Age was highly correlated with work experience; thus, age was excluded from all regression models to avoid multi-collinearity. All tests were two-tailed, and a 38 All respondents provided written consent for collection of data via the survey for research purposes and for anonymous publication of the data.According to an online review by the UK NHS Research Ethics Committee, and the University College London ethics policies, no further ethics approval was deemed necessary for this study, as the online survey did not collect any identifying data, and involved the use of non-sensitive, completely anonymous survey procedures.A total of 546 pharmacists  responded from 59 countries, with the most common region of respondents being Africa (41%) followed by Asia (26%) and Oceania (22%) . Of the conditions tested, respondents most commonly (>90%) recognized the correct treatment for headaches, body aches, measles, HIV/AIDs, cold and flu, skin/wound infections, and bladder infections; respondents most commonly answered incorrectly for malaria, sore throats and diarrhoea (Table . Of the JAC-AMR Online). The internal consistency of all items forming beliefs about AMR score was satisfactory, with Cronbach’s alpha values of 0.7.Mean beliefs about AMR scores for this cohort were 3.9 ± 0.6 (out of 5), indicating that on average, most respondents recognized AMR as important and had good knowledge about factors leading to AMR. The overwhelming majority of the participants (92%) strongly agreed with the statement ‘Antibiotic resistance is an important public health problem in our setting’, and 81% of participants strongly agreed with the statement ‘Dispensing antibiotics without a prescription should be more closely controlled’. A detailed description of the Likert items assessing beliefs about AMR and their responses is provided in Table P < 0.001], showing that the regression model was a good fit of the data. The model explained 26% of the variability in beliefs about AMR scores (adjusted R2 = 0.260). There was a positive correlation between knowledge about antibiotics and beliefs about AMR, meaning that the better knowledge respondents had, the fewer misperceptions they had relating to AMR. Beliefs about AMR scores increased by 1.11 points (95% CI 0.657–1.558) for every unit increase in antibiotic knowledge score. Compared with community pharmacists, hospital pharmacists held more positive beliefs about AMR . Conversely, respondents from low and low-middle income countries had lower scores for the beliefs about the AMR domain compared with respondents from upper-middle and high income countries  , with Nagelkerke R2 = 0.406 (i.e. the model explained 40% of the variation in beliefs). In terms of country income, the odds of supplying antibiotics without a prescription were 7.4 times higher among respondents from lower income countries compared with their counterparts from higher income countries . Conversely, higher scores on the beliefs about AMR scale (i.e. more-positive beliefs) were associated with a lower odds of supplying antibiotics without a prescription . However, antibiotic knowledge score was not associated with antibiotic supply without a prescription, nor was years of work experience or work setting.Table 39–42 Similarly, there have been several studies that have explored pharmacist knowledge and beliefs about antibiotics and AMR;44 however, few examined how pharmacist decisions relating to antibiotic supply were influenced by their personal beliefs about antibiotics and AMR. A study in Thailand conducted over 10 years ago found that a pharmacists’ intention to dispense antibiotics for upper respiratory infections was strongly influenced by attitude.45 However, in Thailand at the time of the study completion, community pharmacists were allowed to dispense antibiotics without prescription, which is not the current case in most countries, where antibiotic supply is regulated by law. As such, whether beliefs also show the same association with antibiotic supply practices in other countries now is uncertain. More recent qualitative studies with pharmacists suggest that there are certain attitudes that could lead to antibiotic dispensing without a prescription.47 A Portuguese study with 32 pharmacists identified attitudes such as complacency, precaution and external responsibility as being associated with supply of antibiotics without a prescription, for example, supplying antibiotics for certain infections where pharmacists felt they knew doctors would prescribe.46 Similarly, a study with 17 pharmacists in Mozambique identified reasons for non-prescribed antibiotic dispensing as being linked to pharmacists beliefs that patients expect antibiotics, or about physicians’ prescribing practices.47This is one of the first studies to examine pharmacist beliefs about AMR, with respondents from 59 different countries, and how this influences actual antibiotic supply practices. Previous literature have highlighted the importance of considering an individual’s beliefs and perceptions about antibiotics and AMR, as this can influence their behaviour, for example, individuals with misconceptions about antibiotics had substantially increased odds of antibiotic misuse such as self-medication with antibiotics and obtaining antibiotics without prescription.48 The review found that supply of antibiotics without a prescription was commonplace in community pharmacies, primarily driven by pharmacist perceptions about their role to support customers to obtain medical services that they need. The authors suggested that educational interventions directed towards improved patient–pharmacist interactive sessions are needed for exercising appropriate and rational use of antibiotics.Similar to these qualitative studies, we found a significant negative association between beliefs about AMR and the supply of antibiotics without a prescription, meaning those with more positive and accurate beliefs about AMR were less likely to supply antibiotics without a prescription. This association was significantly influenced by the country in which the pharmacist was practising; the odds of this occurring were over 7 times higher in pharmacists practising in low/low-middle income countries. This finding has important implications when considering the development of global health policies relating to AMR as this could have implications for public access to necessary antimicrobials even though stricter regulation could reduce unnecessary antimicrobial use. AMS initiatives should consider a pharmacist’s individual beliefs about AMR but also the country context in which pharmacists practise. Key potentially modifiable factors that can influence and modify pharmacist beliefs about AMR were identified from our study, including knowledge and work setting. Our study found that knowledge about antibiotics significantly predicted beliefs about AMR, and that hospital pharmacists held more accurate beliefs about how AMR arises and more positive beliefs about the importance of addressing AMR, potentially because hospital pharmacists have more opportunities to be exposed to in-house continuing education programmes and/or AMS campaigns, and also less financial pressure to increase sales to sustain a business. This suggests that interventions that equip pharmacists with better knowledge can potentially shape their beliefs and influence their antibiotic supply practices. This is in line with the findings from a recent 2018 scoping review of AMS initiatives in community pharmacies.49 One of the key strengths of this study was having data from several different global regions, namely Africa, Asia, and Oceania, allowing exploration of pharmacist perceptions and antibiotic practices in different settings. Our study also has a large sample size of over 500 respondents, though not all pharmacists were active suppliers of antibiotics. Additionally, whilst we found significant associations between knowledge and beliefs, there were some questions in the knowledge questionnaire that were ambiguous in terms of whether antibiotics can be used to treat the condition. For example, the low-scoring conditions of diarrhoea, malaria and sore throat may reflect the fact that antibiotics can be used to treat these conditions depending on the aetiology, even though it may not be the first-line or most common treatment of choice. Our choice to use this knowledge quiz was based on the original WHO survey, however, future studies may benefit from using a validated questionnaire or alternative method of assessing antibiotic and AMR knowledge. Additionally, our sample was limited to only respondents who were able to complete the survey in English, which may explain the low respondent numbers from Europe and South America. The survey could have benefited from being translated into other languages such as Spanish, Mandarin, Arabic, French, etc. to increase responses from countries where English is not the primary language.Our findings support those reported in previous international studies and add to the literature by providing data from 59 different countries. Similar to findings from a large study conducted across Europe, we found that knowledge of antibiotics and AMR varied widely.Overall, this study found that most pharmacists had good knowledge about antibiotics and positive beliefs about AMR, with the majority recognizing the correct situations where antibiotics would be warranted for treatment and that AMR is an important public health issue that is influenced by the inappropriate prescription of antibiotics. These beliefs were influenced by respondent’s knowledge about antibiotics, work setting, and country income. Importantly, a proportion of respondents still provided antibiotics without a prescription; the likelihood of this occurring was increased in those who scored lower on the questionnaires about beliefs about AMR. Initiatives to improve antibiotic supply by pharmacists should aim to address misplaced beliefs about AMR and improve knowledge. Strategies should be tailored to the individual’s personal beliefs and different approaches are likely needed in lower and middle-income countries compared with higher income settings.dlac062_Supplementary_DataClick here for additional data file.