4.3.2. Analysis of Fuel Consumption and CO2 Emissions Reduction in Hybrid Power Source

The test bed used in this study consisted of a hybrid power source with a combined capacity of 180 kW (100 kW fuel cell, 30 kW battery, and 50 kW diesel generator). The power generation in the hybrid power source was designed such that the fuel cell was set for base-load operation and the battery and diesel generator operated in sequence. At 100 kW in Figure 7, there is a 1% difference in the fuel consumption of the commercial diesel generator and the fuel cell. At 130 kW, the difference in fuel consumption with the diesel generator increases because the fuel cell and the battery, which does not need fuel supply, are operating. At 180 kW, the fuel cell, battery, and diesel generator were operating, and it can be seen that there was a reduction in the fuel consumption and CO2 emissions of the hybrid power source compared to the commercial diesel generator. At 100 kW in Figure 8, the CO2 emissions of the fuel cell are 9% of those of the commercial diesel engine. At 130 kW, at which the fuel cell and battery were operating, the difference in CO2 emissions compared with the diesel generator increases. At 180 kW, at which the fuel cell, battery, and diesel generator were operating, the CO2 emissions of the hybrid power source were reduced by 39% compared to that of the commercial diesel generator. Table 13 shows the CO2 emission reduction rates.

**Figure 7.** Comparison of fuel consumption of the commercial diesel generator and the hybrid power source.

**Figure 8.** Comparison of CO2 emissions of the commercial diesel generator and the hybrid power source.

**Table 13.** CO2 emission reduction rates in the commercial diesel generator vs. the hybrid power source.

#### **5. Analysis of Fuel Consumption and CO2 Emission Reduction in a Fuel-Cell-Based Hybrid Power Source Using Simulations of Operating Profiles by Type of Ship**

The actual electric load analysis values that were used in this study were taken from the operating profiles of ships, including a 5500 TEU Reefer Container, a 13000 TEU Container, a 40 k DWT Bulk Carrier, 130 k DWT LNG Carrier, and 300 k DWT very large crude oil carrier (VLCC). These values were scaled down for each operation mode and suitable load scenarios for each ship type were used. To utilize scale-down methodology, the linear interpolation method is applied [48]. For example, if the original 5500 TEU Reefer Container's rated power is 4154 kW, the rated power of the test bed is 180 kW, when applying the scale down method. At part load, 1424 kW will be converted to 61 kW. All following test bed operating loads were calculated in this way. For the load scenarios in Table 14, according to the ship type operating scenarios, the following power sources were applied.

**Table 14.** Load scenario according to the ship type.

#### *5.1. 5500 TEU Reefer Container*

The 5500 TEU reefer container uses the following operating modes during operations: Normal seagoing (without reefer), normal seagoing (with reefer), port in/out (without thruster), port in/out (with thruster), and load/unload. To perform the test bed experiments, the scale of the values obtained as a result of the electric load analysis were adjusted to reflect the output of each operating mode of an actual ship. As shown in Figure 9, the hybrid power source was used in the load scenarios of this ship. Normal seagoing (without reefer) was a fuel cell operation interval. Normal seagoing (with reefer) was a fuel cell + battery + diesel generator operation interval. Port in/out (without thruster) was a fuel cell operation interval. Port in/out (with thruster) and load/unload were fuel cell + battery + diesel generator operation intervals. The scale-adjusted electric load analysis was applied to the test bed, and the output tests were carried out.

**Figure 9.** Power consumption of 5500 TEU reefer container during different operation modes.

Figure 10 compares the fuel consumption during each operating mode of this ship. The fuel consumption reached a maximum during the normal seagoing (with reefer) mode and a minimum during the normal seagoing (without reefer) mode. As the load increased, the fuel consumption increased; similarly, as the load decreased, the fuel consumption decreased. However, when observing the CO2 emission reduction rates shown in Figure 11, it can be seen that the CO2 emission reduction rate was the highest in the port in/out (without thruster) mode, during which the second least amount of fuel was consumed.

**Figure 10.** Fuel consumption in each operating mode of the 5500 TEU reefer container.

**Figure 11.** Comparison of CO2 emissions and CO2 emission reduction rate in each operating mode of the 5500 TEU reefer container.


*4.1.5 Inverse correlation between concentrated urine and CD4 cell count and HDL in HIV patients*

In this study high urine creatinine has a high inverse correlation, r = −0.71, with CD4 cell count. A study has documented an association between low CD4 cells count and underweight in HIV subjects [23]. Perhaps, this might account for the high, albeit inverse, correlation between high urine creatinine and CD4 cell count noted in our study. We also observed in our study that high urine creatinine has a high but inverse correlation, r = −0.73, with serum high-density lipoprotein cholesterol. There was dearth of studies that assessed the link between serum high-density lipoprotein cholesterol and high urine creatinine.


Clinical Diagnostics of Amyloidosis

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

Amyloidosis

The Clinical Spectrum of

Amyloidosis is a group of disorders that share a common pathobiology: in each

Amyloidosis is a group of disorders that share the common feature of deposition into tissues of any one of a number of different proteins. The uniform underlying pathobiology is the finding that in each case, the protein—termed amyloid—deposited into the target organ has undergone abnormal three-dimensional folding. The abnormal folding of the peptide results in accumulation in tissues as micro-

fibrillary structures. The deposition of amyloid protein, regardless of which specific protein forms the amyloid, results in disruption in the function of the organ in which the amyloid protein is deposited. The common histopathologic feature of all amyloidosis is the finding, by light microscopy, of amorphous protein in one or more organs, typically initially recognized upon histologic review of a biopsy, as an amorphous pink material on Hematoxylin and Eosin staining (**Figure 1**). Per the International Society of Amyloidosis 2016 nomenclature guidelines, amyloid fibrils must exhibit affinity for the histologic stain Congo red, showing green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. At least 36 different proteins can undergo abnormal folding and result in deposition of amyloid, causing clinical disease. It is conventional to describe a

case, a protein that exhibits misfolding is deposited in one or multiple organs leading to disruption in organ function. These amyloid proteins are recognized as amorphous pink material in Hematoxylin and Eosin staining, with confirmation by staining with Congo red and yellow or green birefringence under polarized light microscope. To date at least 36 different types of amyloid proteins have been identified. Worldwide, AA amyloidosis is the most common type, and this occurs secondary to chronic inflammatory disease states—such as chronic infections and rheumatological disorders. In western countries, the incidence of AA amyloidosis is decreasing, and AL is the most common type of amyloidosis, characterized by amyloid due to light chain deposition. ATTR amyloidosis, which can be either hereditary or acquired, is a unique variant of systemic amyloidosis that results from mutations in the transthyretin (TTR) gene. Our review will focus on clinical features of the most common systemic amyloidosis, with a detailed review on

evaluation and management of AA, AL and ATTR amyloidosis.

**Keywords:** AA amyloidosis, AL amyloidosis, ATTR amyloidosis

*Aswanth Reddy, Enrique Ballesteros*

*and Jonathan Scott Harrison*


**1. Introduction**

This chapter aims to bring information and consideration regarding cultural competence as part of the education of the professionals that work with Communication Sciences and Disorders in Brazil. The first important information is that this professional is called Phonoaudiologist and has habilitation both in Speech and Language and in Audiology.

Phonoaudiologist is the professional with higher education that works in the area of Communication Sciences and Disorders. In all Latin America the areas of Audiology (assessment and rehabilitation of hearing and hearing disorders) and Speech-Language Therapy (assessment and intervention with communication, voice and swallowing disorders) are the professional field of Phonoaudiology.

Another major aspect that must be brought to attention is the complexity of the country. The authors will present some information about Brazil as a country and the current issues that are most relevant to the discussion of how cultural competence is considered in the education of Phonoaudiologists and the impact of COVID-19 in this regard.

It is easy to understand that the overview about Brazil will be superficial and incomplete, as would happen with any other attempt to synthesize important aspects such as the history, geography, and economy of a country in just a few paragraphs.

#### **2. Brazil: some information about the country**

What is nowadays the country of Brazil was a Portuguese colony from the sixteenth century until the nineteenth century. The formation of its people and society was the result of the genocide of the original population, the enslavement, and forced immigration through the kidnapping of African individuals aiming to boost the colony's economic workforce based on the extractivist agriculture [1]. During the three centuries of slavery, almost 4 million persons were forcibly brought from Africa to Brazil [2]. These groups, added by the European colonizers, brought different cultural elements that are now an intrinsic part of Brazilian culture in areas such as food, religion, music, and language [3].

When slavery came to an end there was no official segregation, but structural racism still can be observed. It is clear in the small numbers of African descendants in universities, or higher positions in the workforce or political posts—when the topic is black women, the lack of possibilities is even bigger. Albeit several debates have been dedicated to the racial question in Brazil, including the famous idea of a racial democracy [4], this is still a sensitive issue generating social gaps in different and complex levels of the Brazilian society in major cities as well as in small and distant towns.

Structural racism is defined as a social, economic and politic system where institutional and public policies reinforce and maintain the segregation and inequities of social groups based on ethnicity, race or "color."

The "whitening" process that the Brazilian population went through during the nineteenth and twentieth centuries, with the arrival of different groups of immigrants, mainly from Europe, the Middle East, and Japan, was a National State Policy and helped in the deepening of racial and social inequalities. Its reflexes are seen until the present day. **Figure 1** shows the origins of the 4.3 million immigrants that arrived in Brazil during the nineteenth century.

Brazil is the 5th largest country in the world and there are also enormous geographic contrasts. The largest cities are located in the southeast, a very industrialized region that concentrates almost 55% of the country's entire gross product and 42% of the population. For example, São Paulo is the largest city, with over 12.3 million inhabitants; Rio de Janeiro has a demographic density of over 5.6 thousand inhabitants per square kilometer. The north and central regions are the most rural and preserved areas, despite the recent reduction of environmental preservation policies. In the Amazon region, the state of Roraima has the lowest demographic density in the country, with 2.33 inhabitants per square kilometer.

Immigration and migration processes are also different in different regions and at various moments, with different cultural impacts. During the last decade, the number of *Perspective Chapter: Cultural Competence and the Education of CSD Professionals in Times… DOI: http://dx.doi.org/10.5772/intechopen.104649*

**Figure 2.** *Immigrants in the last decade.*

immigrants arriving in Brazil has increased from 17,188 in 2010 to 117,037 in 2020 [2]. **Figure 2** shows the origins of the largest groups of immigrants to Brazil in the last decade.

Their distribution in the different regions of the country is shown in **Figure 3**.

Brazil has many and large cultural, social, environmental, economic, and educational differences. Portuguese is the official language, spoken by the whole population (over 213 million), but there are large differences associated with specific regions of the country, traditions, age groups, and other aspects.

The original populations are still another aspect of Brazilian diversity. Of the almost 1 million persons of indigenous origin, 60% live in protected areas designated by the federal government. The North region has the largest indigenous population and there are 305 different ethnic groups that speak 274 different languages [5].

It becomes clear that cultural differences are, historically, a relevant part of Brazilian society. Therefore, all the major universities have "Culture and Extension" offices that encourage and support initiatives directed toward the integration between the universities and the specific society where they are located. This way, different actions are carried out in different universities aiming to better reach the different groups. This includes the programs in the areas of communication sciences and disorders.

*COVID-19 Pandemic, Mental Health and Neuroscience - New Scenarios for Understanding...*

**Figure 3.** *Distribution in the different regions.*

Culture and Extension offices in the universities usually have a mission statement of bringing together the university and the environment and community where it is located. The activities are usually as diverse as developing educational experiences to children of different groups to expand sports technology, or from providing health assistance to facilitating cultural shows of developing environmental systems for pollution control.


**Characterization of Magnetic Phases in Nanostructured Ferrites by Electron Spin Resonance**

Rebeca Díaz-Pardo and Raúl Valenzuela

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61508

### **Abstract**

This chapter is dedicated to the analysis of the spin resonance response (ESR) of different magnetic phases, in nanoparticles (NPs) of magnetic oxides, or ferrites. Evidence of the correlations between resonance spectrum and magnetic structure has been published, of course, in many works; however, to our knowledge, it is somewhat scattered and not easily accessible. We have chosen to carry out this analysis mainly on ferrite NPs because these magnetic materials exhibit a wide variety of magnetic properties, and as a conse‐ quence, a large diversity of classic and novel applications in technological fields ranging from electronics to biomedics.

**Keywords:** EPR, FMR, ESR, Nanoparticles, Ferrites


*3.6. Molecular Characterization*

DAMD and ISSR primers were used for molecular characterization of in vitro propagated plants growing in the greenhouse and compared with the DNA profile of the donor plant. Five DAMD primers were selected and screened out, where all the primers generated a total of 48 bands after PCR amplification with an average of 9.6 bands per DAMD primer (Table 1). The bands were monomorphic across all in vitro propagated plants of *P. amboinicus* and 100% similar to that of donor plants. The DNA banding profiles of the *P. amboinicus* genotypes using DAMD primers HVR and 33.6 are presented in Figure 5. Similarly, all nine ISSR primers tested also produced very clear, monomorphic bands within all in vitro propagated plants with a total of 150 scorable bands. The number of bands for each ISSR primer varied from 9 to 17 with an average of 11.4 bands per primer (Table 2, Figure 6).

**Figure 5.** DAMD-PCR profiles of tissue culture and donor plants of *Plectranthus amboinicus*: (**A**) profile generated using primer HVB5 and (**B**) profile generated using primer 33.6. Lane M = Lambda DNA/EcoRI+HindIII marker; lanes T1–T5 = randomly selected regenerated plants; lane DP = donor plant.

**Figure 6.** ISSR-PCR profiles of tissue culture and donor plants of *Plectranthus amboinicus*: (**A**) profile generated using primer UBC827 and (**B**) profile generated using primer UBC855. Lane M = Lambda DNA/EcoRI+HindIII marker; lanes T1–T5 = randomly selected regenerated plants; lane DP = donor plant.

#### **4. Discussion**

The most widely used approach for multiple shoot induction and plant regeneration is in vitro axillary bud proliferation, which is also thought to be the best way to ensure that the regenerated plants will have the same genetic makeup as the donor plants. Normally, dormant axillary buds are forced to develop into multiple shoots by proper application of growth regulators. Addition of cytokinins, viz., BA, Kin, TDZ, 2iP, and m-Topolin, in the medium led to the successful formation of multiple shoots in many plant species, including *P. edulis* [37,38], *P. amboinicus* [39,40], *Ruta graveolens* [33], *Pongamia pinnata* [59], *Rumex*

*pictus* [60], *Mentha* × *piperita* [61], *Atropa acuminata* [62], *Cannabis sativa* [63], *Campomanesia xanthocarpa* [64], *Zingiber officinale* [65], *Cicer arietinum* [66,67], and *Humulus lupulus* [68].

The type of cytokinin used in the current research had a significant influence on the induction of multiple buds from nodal sections, with BA being shown to be more efficient than Kin. Apart from that, until BA concentration was optimized, both the regeneration frequency and the mean number of shoots generated per nodal sections continued to increase. Similar findings have been made for shoot organogenesis in a number of therapeutic plants in the past [69–73]. From the nodal explants of *P. amboinicus*, the concentration of BA at 5.0 μM produced the greatest number of shoots, compared to the other concentrations and PGR tested in this investigation. The current findings are comparable with those of Arumugam et al. [40] and Belete and Balcha [37], where 0.5 mg/L and 1.5 μM BA alone was proved to be more effective than kinetin for shoot induction in *P. amboinicus* and *P. edulis*, respectively. The presence of high BA in the culture medium, on the other hand, showed inhibitory effects on both shoot response and proliferation, which was consistent with the findings in *Bambusa ventricose* [74] and *Sapium sebiferum* [72].

The balance between auxin and cytokinin is critical during the whole micropropagation process, since the combination of the two regulates growth and development in a plant species. As a relatively high ratio of cytokinins is combined with a low ratio of auxins, they have a synergistic effect on cell division, resulting in a higher frequency of shoot bud induction and a greater number of shoots/explants when compared to cytokinin alone in the same experiment [75,76]. It is important to maintain a proper balance of plant growth regulators in the culture medium in combination with phytohormones produced by the plant when regenerating tissues in vitro, as this is one of the primary factors responsible for the induction, differentiation, and proliferation of shoots in the growth media. Similarly, in the present study, low auxin and high cytokinin concentrations also showed the greatest potential for inducing and multiplying shoots in *P. amboinicus*, and MS medium augmented with 5.0 μM BA in conjunction with 2.5 μM NAA was found to be the most effective treatments for direct shoot regeneration and multiplication in the microenvironment. In contrast, BA in combination with TDZ promoted a high number of shoots in *P. bourneae* [35]. The role of auxin and cytokinins in increasing axillary buds proliferation and ending apical dominance is thought to be the cause of the rise in the number of shoots observed in this investigation. The combination of auxin with cytokinin was also found to be effective for shoot multiplication and elongation in many plant species, including *P. amboinicus* [39,40], *Cassia alata* [77], *Artemisia abrotanum* [78], *Syzygium cumini* [79], *Manihot esculenta* [80], *Hildegardia populifolia* [81], *Asparagus cochinchinensis* [82], *Basella rubra* [83], and *Sapium sebiferum* [72].

The ability of microshoots to induce roots is critical because it has a direct impact on their survival in the greenhouse and their ability to adapt to their new environment. In the great majority of species, auxins are significant factors in root production because they stimulate the development of adventitious roots, which are essential for rooting [84]. The micropropagated shootlets of *P. amboinicus* were effectively rooted with IBA supplied in MS agar medium. The effects of IBA containing agar rooting media are in agreement with earlier approaches for inducing roots in *P. amboinicus* [39,40] and in several medicinal plants, including *Ruta graveolens* [33], *Hemidesmus indicus* [85], *Rauvolfia tetraphylla* [86], *Sapium sebiferum* [72], *Artemisia vulgaris* [87], and *Asystasia gangetica* [88].

Preserving the genetic consistency in tissue culture plants is critical for any micropropagation system prior to commercialization or in germplasm conservation. The PCR-based SPAR markers technique is one of the most significant approaches with increased use in the assessment of the genetic stability of tissue culture plants, since it uses only a small amount of genomic DNA, avoids the use of radioactivity and DNA blotting, and is susceptible to automation. In this study, DAMD and ISSR markers, as well flow cytometry, were used to confirm the genetic integrity of *P. amboinicus* micropropagated plants. Because micropropagation is known to induce somaclonal variation in micropropagated plants, the use of multiple markers has long been advocated for a better evaluation of genetic uniformity

of in vitro plantlets [47]. Both DMAD and ISSR analyses showed a 100% monomorphic banding pattern, indicating the absence of variability among tissue culture plantlets of *P. amboinicus*. The appraisal of genetic constancy in a variety of micropropagated medicinal plants such as *Mentha arvensis* [46], *Pittosporum eriocarpum* [47], *Bacopa monnieri* [44], *Curcuma zedoaria* [48], *Ruta chalepensis* [50], *Rauvolfia serpentina* [89], *Nepenthes khasiana* [90] and *Ficus carica* [91] has been documented.


**4. Conclusions**

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**14**

*Ghent University*

*Belgium*

**Reinforcement Learning, High-Level**

Reinforcement learning (RL) has a rich history tracing throughout the history of psychology. Already in the late 19th century Edward Thorndike proposed that if a stimulus is followed by a successful response, the stimulus-response bond will be strengthened. Consequently, the response will be emitted with greater likelihood upon later presentation of that same stimulus. This proposal already contains the two key principles of RL. The first principle concerns *associative learning*, the learning of associations between stimuli and responses. This theme was developed by John Watson. Building on the work of Ivan Pavlov, John Watson investigated the laws of classical conditioning, in particular, how a stimulus and a response become associated after repeated pairing. In the classical "Little Albert" experiment, Watson and Rayner (1920) repeatedly presented a rabbit together with a loud sound to the kid (little Albert); the rabbit initially evoked a neutral response, the loud sound initially evoked a fear response. After a while, also presentation of the rabbit alone evoked a fear response in the subject. In this same paper, the authors proposed that this principle of learning by association more generally is responsible for shaping (human) behavior. According to psychology handbooks John Watson hereby laid the foundation for behaviorism. The second principle is that *reinforcement* is key for human learning. Actions that are successful for the organism, will be strengthened and therefore repeated by the organism. This aspect was developed into a systematic research program by the second founder of behaviorism,

The importance of RL for explaining human behavior started to be debated from the late 1940s. Scientific criticism toward RL arrived from two main fronts. The first was internal, deriving from experimental findings and theoretical considerations within psychology itself. The second derived from external developments, in particular, advancements in information theory and control theory. These criticisms led to a disinterest for RL lasting several decades. However, in recent years, RL has been revived, leading to a remarkable interdiscplinary confluence between computer science, neurophysiology, and cognitive neuroscience. In the current chapter, we describe the relevant mid-20th century criticisms and developments, and how these were considered and integrated in current versions of RL. In particular we focus on how RL can be used as a model for understanding high-level

cognition. Finally, we link RL to the broader framework of neural Darwinism.

**1. Introduction**

Burrhus Skinner (e.g., Skinner, 1938).

**Cognition, and the Human Brain**

Massimo Silvetti and Tom Verguts

and amygdala in bipolar disorder. *Biological Psychiatry,* Vol.66, No.5, (September 2009), pp. 516-21,ISSN 0006-3223


**COMPOSITES FROM RENEWABLE AND SUSTAINABLE MATERIALS**

Edited by **Matheus Poletto**

#### **Composites from Renewable and Sustainable Materials**

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*Review* **The Evolution and Developing Importance of Fetal Magnetic Resonance Imaging in the Diagnosis of Congenital Cardiac Anomalies: A Systematic Review**

**Marios Mamalis 1, Ivonne Bedei 1, Bjoern Schoennagel 2, Fabian Kording 3, Justus G. Reitz 4, Aline Wolter 1, Johanna Schenk 1 and Roland Axt-Fliedner 1,\***

**Abstract:** Magnetic Resonance Imaging (MRI) is a reliable method, with a complementary role to Ultrasound (US) Echocardiography, that can be used to fully comprehend and precisely diagnose congenital cardiac malformations. Besides the anatomical study of the fetal cardiovascular system, it allows us to study the function of the fetal heart, remaining, at the same time, a safe adjunct to the classic fetal echocardiography. MRI also allows for the investigation of cardiac and placental diseases by providing information about hematocrit, oxygen saturation, and blood flow in fetal vessels. It is crucial for fetal medicine specialists and pediatric cardiologists to closely follow the advances of fetal cardiac MRI in order to provide the best possible care. In this review, we summarize the advance in techniques and their practical utility to date.

**Keywords:** fetal cardiac magnetic resonance; congenital heart abnormalities

### **1. Introduction**

Fetal cardiac abnormalities represent the subgroup of prenatally diagnosed abnormalities with the highest incidence (9:1000). Fetal echocardiography to date is the gold standard in fetal cardiology. Recently, reports on fetal cardiac MRI using different techniques have been published. Cardiac MRI is able to precisely demonstrate the cardiac anatomy and abnormal heart morphology in case of congenital heart disease (CHD). Furthermore, by applying the knowledge gained on fetal lambs, it can provide information about the impact of CHD on human fetal hemodynamic status by quantifying blood flow in fetal vessels [1–3] and provides details about fetal oxygenation [1]. In this setting, MRI has been applied to define the effect of CHD and fetal growth restriction (FGR) on brain development in fetal life [1,2] in recent studies.

In this review, the established techniques and the clinical utility of cardiac MRI in daily clinical practice will be discussed.

### **2. Fetal Cardiac MRI Techniques**

Several authors refer to the utility of single-shot balanced Steady State Free Precession (bSSFP) and Fast Spin Echo sequences (SS-FSE) for detecting fetal defects [4–11]. Their contribution in providing multislice protocols is the result of a combination of high-resolution 2D static images in short time (1.0 to 1.5 mm in-plane and ≥500 ms). Although they cannot resolve fetal cardiac motion, resulting in the blurring of dynamic structures, they contribute to identify gross anatomical defects. Although bSSFP cannot preclude blurring resulting

**Citation:** Mamalis, M.; Bedei, I.; Schoennagel, B.; Kording, F.; Reitz, J.G.; Wolter, A.; Schenk, J.; Axt-Fliedner, R. The Evolution and Developing Importance of Fetal Magnetic Resonance Imaging in the Diagnosis of Congenital Cardiac Anomalies: A Systematic Review. *J. Clin. Med.* **2022**, *11*, 7027. https:// doi.org/10.3390/jcm11237027

Academic Editor: Erich Cosmi

Received: 20 October 2022 Accepted: 24 November 2022 Published: 28 November 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

from fetal motion, it can be used for the assessment of the intracardiac anatomy as a stack of a single slice cine or 2D slices and it is capable to provide information about tissue when it is combined with SS-FE. SS-FE produces "black blood" images, useful for examining the extracardiac vasculature [11].

Furthermore, the repeated acquisition of bSSFP images in the same anatomical location over time has been used to provide a dynamic "real-time" assessment of the fetal heart including measurements of cardiac function [4,6–8,12–14].

Cine imaging requires the synchronization of use of high spatial and temporal resolution images to the patient's heart rate (cardiac gating) in order to provide assessment of both cardiac anatomy and function [15]. In order to overcome the limitation of long reconstruction times, devices are developed to monitor fetal heart rate during MRI data acquisition. The most mature device for this purpose uses an MRI-compatible Doppler ultrasound gating (DUS) probe placed over the maternal abdomen [16,17]. This device monitors the blood flow and cardiac contraction based on Doppler waveform (Figure 1). The disadvantages of this method are the equipment procurement, preparation time, and monitoring of fetal lie ensuring that it is within the detection range.

The need of acceleration of acquisition led several studies to investigate the use of compressed sensing to achieve highly accelerated fetal acquisitions using either Cartesian [18,19] or radial sequences [20–22].

In order to limit the artifacts from maternal respiration, it has been attempted to either acquire data under maternal breath hold or apply free breathing methods using motion correction. The latter allows for multislice acquisition, in contrast to the method under maternal breath hold, which limits the number of slices [21–23].

With the aid of 2D, real imaging motions are recognized and data acquired during those periods are discarded. The latest fully automated methods are implied; previously used for the fetal brain volumetric reconstruction. The outlier rejection, results in better quality images by estimating the probability of each voxel and real-time image frame, classifying them as in- or outlier, and, finally, rejecting the outlier voxels and frames from the final CINE reconstruction [23–25].

To achieve a 3D demonstration of the fetal heart and extracardiac vasculature [26], and a 4D whole-heart visualization [23], the combination of 2D images and multi-planar acquisition using volumetric reconstruction methods has been applied. For instance, a 4D flow cine MRI reconstruction was achieved by exploiting the velocity-sensitive information inherent to the phase of dynamic bSSFP acquisitions in combination with signal-to-voice ratio (SVR). Multiple non-coplanar bSSFP stacks were used to reconstruct spatially identical, temporally resolved, motion-corrected magnitudes and vector flow volumes [24]. The advantages of this method represent the robustness in motion, the capability of both in-plane and through-plane motion to be corrected, and the full coverage of the fetal heart.

In 2010, an artificial cardiac triggering, or self-gating system, was proposed to the so-called Metric Optimized Gating (MOG). It detects mis gating artifact through evaluation of image metrics while images are retrospectively analyzed. Whereas this method was first developed for time-resolved phase-contrast measurements of fetal blood flow, it has since been applied to both Cartesian and radial bSSFP acquisitions and was the first method to demonstrate dynamic CINE MRI of the human fetal cardiovascular system [27,28]. MOG, however, does not address fetal or maternal body motion.

To achieve multidimensional flow in fetuses, a golden-angle radial phase-contrast cardiovascular magnetic resonance has been applied with real-time reconstructions; first performed for retrospective motion correction and cardiac gating using MOG [29].

Another approach to fetal cardiac gating is MRI self-gating, where a periodic gating signal is extracted from the MRI data itself and it is used to sort the data retrospectively [30].

**Figure 1.** Fetal cardiac MRI using Doppler ultrasound gating at 3 Tesla: The applied rapid gradientrecalled echo (GRE) steady-state free-precession (SSFP) sequence (TR = 3.9 ms, TE = 1.9 ms, field of view = 246 × 246 mm, flip angle = 60◦, slice thickness = 6 mm, matrix size 164 × 164) is adopted from standard adult cardiac MRI protocols. SSFP sequences have short acquisition times and provide high myocardium-blood contrast (composed of both T1 and T2 contributions). Fetal cardiac gating using a Doppler ultrasound sensor enables dynamic/cine imaging by acquisition of multiple images (i.e., heart phases) over the cardiac cycle. The example illustrates an end-diastolic four-chamber SSFP image and reveals physiological situs, cardiac chambers, and left descending aorta (arrow) in a healthy late term fetus (gestational age: 35 + 0 weeks). Morphometry: LCD = 441 mm, TCD = 387 mm, LVmidtransverse = 152 mm, LVlongitudinal = 261 mm, RVmidtransverse = 158 mm, RVlongitudinal = 247 mm, mitral valve plane = 86 mm, tricuspidal valve plane = 91 mm.

### **3. Current Potential and Clinical Application of Fetal Cardiac MRI**

A cardiovascular fetal MRI was first attempted in 2005 when applying real-time sequences with the aim of estimating the ventricular volume. Small case series of investigating the normal heart anatomy and congenital heart defects (CHD) followed and although some reviews have attempted to establish protocols [31], there is no consensus on which are the indications of a cardiovascular MRI. Manganaro et al. performed fetal MRI in 32 fetuses with a mean gestational age of 30 weeks from January 2007 to March 2008 with a US-assessed CHD. All the morpho-volumetric abnormalities of the heart, cardiac axis abnormal rotation, ventricular septal defects (VSDs) as well as cases with abnormal origin and course of the great vessels (GV) could be confirmed by MRI using SSFP sequences. In Figure 2, a hypoplastic right heart and a VSD in 4CV are illustrated utilizing cine SSFP in a late-term fetus in the overdiagnosis of two VSDs, the restricted evaluation of atrial septum (AS) due to the presence of foramen ovale (FO) and its low thickness, the restricted

evaluation of the size of GV due to MRI spatial resolution and SNR, and the insufficient evaluation of valves have proven that although MRI is a useful adjunct, improvements in gating, speed of sequences, and signal-to-noise improvement were necessary at that time.

**Figure 2.** Fetal cardiac MRI using Doppler ultrasound gating for assessment of dynamic/cine steadystate free-precession (SSFP) sequences (TR = 3.3 ms, TE = 1.6 ms, field of view = 300 × 300 mm, flip angle = 60◦, slice thickness = 5 mm, matrix size 288 × 288) at 1.5 Tesla: The end-diastolic four-chamber SSFP image illustrates hypoplastic right heart (arrow) and ventricular septal defect (arrowhead) in a late term fetus (gestational age: 30 + 5 weeks). Postnatal diagnosis revealed atresia of the tricuspid valve, malposition of the great arteries, and interrupted aortic arch (not visualized in the presented four-chamber view).

Over next years, some of the improvements have been achieved and cardiac MRI is able to detect the patency of the interatrial septum that is crucial information for the delivery and treatment plan for Transposition of Great Arteries (TGA) fetuses [32,33]. In a large study of Su-Zhen Dong et al., MRI was applied as an adjunct to classic fetal US, when the latter was not able, due to common known difficulties, to make a conclusive diagnosis [34]. Over 14 years, 71 cases with confirmed CHD have been reviewed applying a multi-planar reformatting reconstruction 2D SSFP technique to reconstruct the fetal cardiovascular MR images. In 60.6% of cases, MRI put a conclusive correct diagnosis and only 4.2% of cases were correct but incomplete. However, the author considers some types of defect, such as unclosed Ductus Arteriosus (DA), at birth or secundum Septal Defect (SD) as impossible to diagnose prenatally. For complex CHD, such as Pulmonary Atresia with intact ventricular septum (PA/IVS), severe Tetralogy of Fallot (TOF), Double Outlet Right Ventricle (DORV), or Transposition of Great Arteries (TGA) a definitive diagnosis could not be made by use of MRI. Finally, mild Pulmonary Stenosis (PS) and small Ventricular Septal Defect (VSD) are missed by cardiac MRI.

CMR is a useful adjunct for the evaluation of the cardiac vascular anatomy and several attempts have been made to study the aortic arch, its branches, and its anatomical position in relation to the trachea; in particular when vascular rings are suspected. Similarly, as regards the blood supply of the lungs challenging for echocardiography cases, such as pulmonary atresia with MAPCAs or pulmonary trunk can be elucidated with the aid of MRI. The drainage of both pairs of pulmonary veins is feasible to be demonstrated by MRI as well.

Su-Zhen Dong et al., in their in 2020 review, using data from 71 cases with confirmed CHD over 14 years, concluded that the Coarctation of Aorta (CoA) prenatal diagnosis was unreliable due to both the technical difficulty of imaging this region and the obligatory patency of the arterial duct in fetal life and physiologic changes of the DA after birth [34]. Su-Zhen Dong concluded in a previous study in 2018, after having examined six fetuses of mean gestational age (26.5 weeks) with Aortic Arch (AoA) abnormality using bSSFP and SSFE techniques, that fetal cardiac MRI is a useful complementary tool to assess fetuses with right aortic arch and right ductus arteriosus. In half of the cases, the aortic arch laterality abnormality was missed in prenatal US [35]. In the same line, the same author reported that MRI was able to demonstrate the abnormal course of left brachiocephalic vein in nine fetuses in a retrospective review of 7282 fetuses from June 2006 to March 2017 [36] and a LPSVC in 49 fetuses in a retrospective review from January 2010 to October 2015 [37]. A recent study of Ryd et al. has proven, after having investigated 31 fetuses at a median age of 31 weeks, that CMR had clinical utility affecting patient management and/or parental counselling in 26 cases (84%) [38]. For assessment of univentricular vs. biventricular outcome in borderline left ventricle, unbalanced atrioventricular septal defect and pulmonary atresia with intact ventricular septum (15 fetuses) fetal CMR visualized intracardiac anatomy and ventricular function, allowing assessment of outcome in 13 cases (87%). In four fetuses with hypoplastic left heart syndrome, it helped delivery planning in three of those cases (75%). For aortic arch anatomy including signs of coarctation (20 fetuses), CMR added diagnostic information in 16 cases (80%), which is not in line with the previously mentioned study of Su-Zhen Dong et al. [34]

Loyd et al., by applying novel MRI with high-resolution motion-corrected threedimensional volumes of the fetal heart and phase-contrast flow sequences gated with metric-optimized gating on 51 fetuses with suspected CoA, concluded that MRI with the aid of a multivariate logistic regression model, including aortic flow and isthmic displacement, may have an important role in predicting severe neonatal CoA outcome and need for intervention in 93% of cases [39]. In the same line is another prospective single-center cohort study of Lyod et al. in which 85 fetuses with suspected CHD have been examined from October 2015 to June 2017 using MRI with motion-corrected slicevolume registration. The data as overlapping stacks of 2D images were processed with a bespoke open-source reconstruction algorithm to produce a super-resolution 3D volume of the fetal thorax. Vascular measurements, although showed good overall agreement with 2D echocardiography in 51 cases, fetal vascular structures have been more effectively visualized with 3D MRI and have had a higher diagnostic quality score [27]. Finally, Xu Li et al. compared the accuracy in correct diagnoses of aortic arch anomalies of both fetal US and CMR using SSFP and SSFSE in 600 pregnant women from January 2013 to 22 December 2015 of them with aortic arch anomalies. MRI revealed a 95.6% accuracy misdiagnosing only one case of right aortic arch with aberrant left subclavian artery as a double aortic arch. The same case has been misdiagnosed by US, which showed an accuracy of 60.8% [40].

Apart from cardiovascular features, the application of cardiac MRI can play an additive role on extracardiac anatomy, such as laterality disorders and lung parenchyma characterization in cases of pulmonary venous obstruction or intact interatrial septum in which lymphangiectasia is suspected [41,42]. Elisabeth Mlczoch et al. investigated fetal lung volume (TLV) in 105 fetuses with CHD and mean gestational age 26 + 6 weeks of gestation from January 2004 to December 2011 by applying fetal cardiac MRI SSFP and FSE only axial T2 sequences, concluding that fetuses with CHD had significantly smaller TLV in

comparison with non-CHD fetuses and that small pulmonary arteries correlate with small TLV. A total of 17% of fetuses had TLV below normal indicating pulmonary hypoplasia [43].

Saul et al. investigated 44 fetuses with HLHS to identify which ones developed Lymphangiectasia described as nutmeg lung in MRI; the nutmeg lung MR appearance in HLHS fetuses is associated with increased mortality/OHT (100% in the first 5 months of life compared to 35% with HLHS alone). Not all patients with restrictive lesions develop nutmeg lung, and the outcome is not as poor when restriction is present in isolation. Dedicated evaluation for nutmeg lung pattern on fetal MR studies may be useful in guiding prognostication and aiding clinicians in counselling parents of fetuses with HLHS [44]

Investigations into the circulatory physiology of fetal sheep were undertaken in the 1930s by Sir Joseph Barcroft at Cambridge University. Sir Geoffrey Dawes conducted the first detailed studies of the fetal circulation. MRI spectroscopy at high field strengths and BOLD (Blood Oxygenation Level Dependent) signal allowed for information about blood and tissue oxygenation by relating the T2 and T2\* transverse-relaxation time of blood and the oxygenation state of hemoglobin on erythrocytes. Although BOLD does not provide quantitative data about blood oxygen saturation, it is possible to estimate both hematocrit and oxygen saturation by combining T1 and T2 measurements of blood. Sun et al., by applying MOG for fetal triggering and using an accelerated version of the acquisition utilized by Wedergartner's fetal lambs, which incorporates a motion correction algorithm, were able to make reproducible measurements of T2 in the larger fetal vessels in 40 late-gestation human fetuses [45].

Moreover, the relationship of fetal hemodynamics to brain and lung development in cases of fetal growth restriction (FGR) and complex CHD could be demonstrated by several studies [2]. Successively, MRI plays a role in studying hemodynamics. In Figure 3, 2D phase-contrast MR angiography is illustrated using Doppler ultrasound gating at 1.5 Tesla in a late term fetus (gestational age: 30 + 4 weeks) for the assessment of blood flow hemodynamics. In the intrauterine peri-operational period in cases of CHD, such as HLHS, it can investigate the grade of pulmonary obstruction. Furthermore, it detects the patency of foramen ovale (FO) indirectly by estimating the higher oxygen saturation in the Left Ventricle (LV) resulting from the preferential streaming of oxygenated blood through FO.

**Figure 3.** 2-D phase-contrast MR angiography (TR = 4.9 ms, TE = 3 ms, field of view = 250 mm, flip angle = 15◦, slice thickness 5 mm, matrix size = 194 × 194 mm) using Doppler ultrasound gating at 1.5 Tesla for assessment of blood flow hemodynamics. Transversal orientation through the descending aorta (arrow in **a**) with resulting magnitude image (**a**) and phase image (**b**). Blood flow hemodynamics are assessed by placement of a region of interest (ROI; dotted circle in **b**) in the vessel lumen. Dynamic blood flow over the whole cardiac cycle is encoded by signal intensities within the ROI. (**c**) In this example of a late term fetus (gestational age: 30 + 4 weeks) resulting mean flow velocity illustrates typical arterial flow waveform over the cardiac cycle.

From 2010 to 2012, Bahiyah al Nafisi et al. investigated the fetal circulation distribution in 22 fetuses with left-sided CHD at a mean of 35 weeks of gestation using phase contrast MRI and compared them with twelve normal fetuses. Fetuses with left-sided CHD had a mean combined ventricular output (CVO) that was 19% lower than normal controls. In fetuses with left-sided CHD with pulmonary venous obstruction, pulmonary blood flow was significantly lower than in those with left-sided CHD without pulmonary venous obstruction. All 3 fetuses with pulmonary venous obstruction had pulmonary lymphangiectasia. Fetuses with small but apex-forming left ventricles with left ventricular outflow tract or aortic arch obstruction had reduced ascending aortic (AAo) and FO flow compared with normal [46]. The reference ranges of the blood flow in the GV of a fetus in the late gestation have been established with the aid of MRI [47]. Recently, Roberts et al. presented a novel method for in utero whole-heart fetal 4D cine quantitative blood flow imaging. A 4D flow cine MRI reconstruction was possible by utilizing the velocity-sensitive information inherent to the phase of dynamic bSSFP and SVR. Multiple non-coplanar bSSFP stacks were used to reconstruct spatially identical, temporally resolved, motion-corrected magnitude, and vector flow volumes [24].

### **4. Conclusions**

Fetal cardiac MRI has been studied, has evolved and has an adjunctive role to fetal US, which has remained the gold standard over the last two decades. Its place, where the US cannot overcome its known limitations, has recently become of interest to several researchers. Its evolution will establish it as a necessary tool for the correct and complete diagnosis and comprehension of the anatomy and pathophysiology of CHD, the proper prenatal counselling for the outcome, and the postnatal or even prenatal operative preparation of individuals.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**3. ASCT for acute promyelocytic leukemia**

*Acute Leukemias*

group (4% vs. 1% respectively).

observed after RIC alloHSCT.

negative upon induction chemotherapy [26].

Several historical randomized trials have reported that ASCT can significantly reduce the relapse rates compare with conventional chemotherapy alone. The study performed by the Dutch–Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON-SAKK) Cooperative Consortium compared the outcomes of ASCT with chemotherapy including 517 patients who were randomly recorded between 1995 and 2006 [1]. Rates of relapse after chemotherapy vs. after ASCT were 70% vs. 58%, respectively (*P* = .02), 5 year follow up and no significant difference in LFS of 29% vs. 38% (*P* = .065). OS did not differ between these two groups and was estimated to be 41% vs. 44%, respectively, at 5 years from randomization. TRM was higher in ASCT group than chemotherapy

A meta-analysis which included 11 studies compared survival outcomes of alloSCT from matched sibling donor (MSD) or matched unrelated donor (MUD) versus ASCT in intermediate-risk AML and demonstrated alloSCT from MSDs rather than MUDs was associated with better OS than that with ASCT [13] however recent retrospective trials reported similar survival rates for AML patients who

The treatment options are not well defined in older patients with leukemia. Higher incidence of AML secondary to previous myelodysplastic syndrome (MDS), adverse mutation pattern and karyotype and poor performance status are the reasons of poor outcomes in older AML patients [16–18]. They usually do not have MSD and available regimens are limited due to many of comorbidities especially cardiovasculary disease. ASCT may be used in patients up to age 70 years with an acceptable TRM of approximately 8%, which compares favorably to 17% as was

Several reports from EBMT and CIBMTR showed long-term leukemia free survival (LFS) rates are 45–55% in patients transplanted in CR 1 and 25–35% for those transplanted in CR2 [19–21]. The patients who are not eligible for Allo-SCT ASCT may be an acceptable post-remission therapy in CR1 [14]. Allo-SCT still remains first line treatment for poor risk patients while ASCT is getting attention for good risk and especially intermediate risk patients who have favorable prognostic factors, including MRD negativity after the imitation of induction chemotherapy, a WBC count of <20,000/μL at time of the diagnosis, an FAB classification of M1–5, and ≥ 50% MPO positivity. Decision-making might benefit from taking minimal residual disease (MRD) into account [22, 23]. Real-time quantitative PCR (qPCR) and multiparameter flow cytometry (MFC) are effective techniques for monitoring MRD before and after ASCT in patients with AML, and MRD status pre-ASCT is an independent prognostic factor for both OS and LFS after ASCT [24, 25]. Whereby MRD-negative patients may be consolidated by ASCT and MRD-positive patients may proceed to allo-SCT. ASCT is generating new interest, especially in intermediate-risk patients who became MRD

The traditional conditioning regimens before ASCT that are mostly myeloablative and based on busulfan; combination of busulfan/ cyclophosphamide (BUCY), busulfan/etoposide, cyclophosphamide/Total body irradiation (TBI), Busulfan/ high dose melphalan. Different regimens such as modifications of the BCNU, etoposide, cytarabine, melphalan (BEAM) regimen, busulfan/etoposide/ cytarabine, TBI/cytarabine/melphalan could be used in different centers. Three large retrospective studies showed that busulfan/high dose melphalan regimen has better outcomes than BUCY [27–29]. Although both oral and intravenous busulfan were used in various regimens, it has become clear that the intravenous administration of busulfan should be preferred because of fewer complications [30]. Favorable longterm LFS after auto-SCT using a high-dose cytarabine-containing regimen has been showed. The most common treatment related complication of ASCT is mucositis

underwent autoSCT and allo-SCT from MSDs and MUDs [3, 14, 15].

**212**

Acute promyelocytic leukemia (APL) accounts 10–15% of AML in adults. It is highly curable disease and remission is achieved in 90% of APL patients after anthracycline-based induction therapy plus ATRA and recently arsenic trioxide (ATO). The combination of ATRA and anthracyclines remains the gold standard for high risk patients. There is not a role for stem cell transplantation in APL in CR1, independently from any initial risk category. ELN suggested that patients who relapsed after ATRA plus chemotherapy should be treated with an ATRA plus ATO based approach as salvage therapy until achievement of MRD negativity. Despite of SCT is accepted treatment for the 10–20% patients who relapsed, the choice of ASCT vs. Allo-SCT remains controversial.

EBMT reviewed 625 APL patients transplanted ASCT or Allo-SCT, lower relapse rates and higher 5 year LFS reported in Allo-SCT group. Although TRM was higher in Allo-SCT patients, Allo-SCT was recommended in CR2 when a sibling donor was available in this study [31]. Holter et al. reported OS was better after ASCT than after chemotherapy and ATO. ASCT was the preferred therapy for patients with CR2 status, and survival outcomes were superior in patients who received ASCT compared with those who received ATO-based consolidation therapy [32]. Besides ASCT is superior than allo-SCT in relapsed APL due to low TRM and durable remission, pre-SCT bone marrow cytogenetic and molecularly evaluation is important. It was recommended allogeneic HCT if the pre-HCT marrow was cytogenetically or molecularly positive [33]. ASCT is less toxic than allo-SCT, and appears equally potent particularly when a negative *PML-RARA* status is achieved before transplantation.


Meet the editor

Dr. Hideki Nakano is a physical therapist and associate professor at the Neurorehabilitation Laboratory, Graduate School of Health Sciences, Kyoto Tachibana University, Japan. He received his Ph.D. in Health Science from Kio University, Japan, and has accepted research training experience as a JSPS Research Fellow at Neurorehabilitation Research Center, Kio University, Japan, and Queensland Brain Institute, University of Queensland, Aus-

tralia. He specializes in neuroscience, neurophysiology, and rehabilitation science and conducts research using non-invasive brain function measurement and brain stimulation methods such as electroencephalography, transcranial magnetic stimulation, and transcranial electrical stimulation. His current main research interest is developing rehabilitation evaluation and treatment methods using visualization and manipulation methods of brain functions for healthy, elderly, and diseased patients.