**6. Conclusion**

NPSLE remains an area of great interest focusing further on the pathogenetic mechanisms, approach to diagnosis and treatment. There have been a lot of limitations described in the previous studies including the lack of well controlled clinical trials, biomarkers and novel therapies. These are the challenges in which current and future researches revolve for the benefit of SLE patients.


**8. Conclusions**

A different view regarding the common pile capacity studies was considered in this study. To evaluate the effect of the soil setup on the pile bearing capacity over time, an intelligent equation using a GP model was proposed. To develop the prediction models, a comprehensive database obtained from some geotechnical projects carried out in Mahshahr, Iran, was used. In addition, a new section, namely optimization, has been proposed for maximizing the bearing capacity. The following conclusions and remarks can be drawn from this study:

**Author Contributions:** M.K.: conceptualization, methodology, investigation, writing—original draft preparation, writing—review and editing. D.J.A.: conceptualization, methodology, investigation, formal analysis, writing—original draft preparation, writing—review and editing, supervision. M.M.S.S.: writing—original draft preparation, writing—review and editing, supervision, funding acquisition. All authors have read and agreed to the published version of the manuscript.

**Funding:** The research is partially funded by the Ministry of Science and Higher Education of the Russian Federation under the strategic academic leadership program 'Priority 2030' (Agreement 075-15-2021-1333 dated 30 September 2021).

**Data Availability Statement:** Data is available upon request.

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


**PROTEIN KINASES**

Edited by **Gabriela Da Silva Xavier**

http://dx.doi.org/10.5772/2334 Edited by Gabriela Da Silva Xavier

#### **Contributors**

Andras Mihaly, Horacio Bach, Adriana Girardi, Luciene Carraro-Lacroix, Juan Carlos Saez, Gabriela Da Silva Xavier, Yuansheng Gao, Bruno Miguel Neves, Maria Teresa Cruz, Maria Celeste Lopes, Adam Ferguson, J. Russell Huie, Etienne Roux, Prisca Mbikou, Ales Fajmut, Yoshiki Katayama, Oleksandr Minchenko, Dmytro Minchenko, Estela Jacinto, Chang-Chih Wu, Po-Chien Chou, Zheng Fu, Anna Teti, Nadia Rucci, Barbara Peruzzi, Sojin Shikano, Yukari Okamoto, Mani Indiana Funez, Paulo Gustavo Barboni Dantas Nascimento, Fabiane Hiratsuka Veiga Souza, José Eduardo Pandossio, Shunichi Murakami, Takehiko Matsushita, Yukihito Ishizaka, Ana Ivanova Maneva, Lilia Maneva-Radicheva, Megan Chircop, Rita Tostes

#### **© The Editor(s) and the Author(s) 2012**

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#### **Notice**

Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book.

First published in Croatia, 2012 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

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**Abstract**

Airborne sound insulation in buildings, whether in fixed partition elements, like partitions or party walls, or mobile elements, like doors or screens, is always related to the performance of the weakest element involved. In situ assessment of airborne sound insulation in building elements can be carried out by pressure techniques or sound intensity techniques. Sound pressure techniques are very quick but fail to discriminate the sound insulation contribution of each building element involved. Sound intensity techniques, on the other hand, allow to determine the sound transmission of each element and also to discriminate indirect transmissions up to a certain degree. In order to find areas with high sound transmission, such as leakages or weakened regions, a large number of measurements on the building element surface have to be performed. Moreover, the sound intensity technique is very timeconsuming, because it is necessary to carry out the measurement in each grid point defined. This chapter describes the use of beamforming and SONAH techniques to detect areas with lower airborne sound insulation in a building element. These techniques unify the advantages of both, pressure and sound intensity techniques, allowing the quick visualization of leakages or weakened areas of different building elements.

**Keywords:** building, insulation, leakage, SONAH, beamforming


**3. Information systems**

An information system is specifically designed to operate on information, i.e., information is the flow variable in the system. In general, systems are designed for a purpose and have the following operational properties:

A system can be defined as a combination of hardware, software, infrastructure, and trained personnel operating to achieve specified mission objectives. This definition of system includes both the communications technology and information that is employed in addition to the way in which people interact with the technology.

Modern information systems increasingly rely on globally sourced ICT components and services. The variety and abundance in the marketplace is driven by the rapid decline in cost and the rapid increase in performance advancements. As supply is able to meet the demand for low cost and more functions, today's information systems are increasingly complex in nature.


**3.3. Flat intraepithelial neoplasia**

Especially in the stomach, intraepithelial neoplasia is flat and demonstrates endoscopically with only slight, uncharacteristic abnormalities. Frequently flat intraepithelial neoplasia arises in a background of chronic gastritis later in life (beyond the fifth decade). By convention, the intraepithelial neoplasia has to divide into either low grade or high grade.

Microscopically, the main characteristics of intraepithelial neoplasia consider cytology and architecture (like in adenoma):

Low-grade intraepithelial neoplasia preserves more or less the normal glandular differentiation, the epithelia show enlarged hyperchromatic nuclei, the nucleoli are not prominent, and cell pleomorphism and cell stratification are limited.

High-grade intraepithelial neoplasia demonstrates with crowding of glands, including budding and branching of some glands. The nucleoli are prominent and often intense eosinophilic.

#### *3.3.1. Clinical significance*

Flat low-grade intraepithelial neoplasia: re-endoscopy to exclude concurrent carcinoma is suggested. The risk of carcinoma is low (about 25%). Re-endoscopy twice a year and annual after two negative endoscopies is suggested.

Flat high-grade intraepithelial neoplasia: the risk of accompanied carcinoma is high (about 85%). An excision of the whole lesion/region is necessary [2, 11].

#### *3.3.2. Vienna classification of gastrointestinal epithelial neoplasia*

Geographic differences in interpretation of gastric epithelial tumours exist (generally between Western pathologists and Japanese pathologists). The Vienna classification of (pre-)cancerous lesions of the GI-tract tries to harmonize both interpretations (**Table 5**).

**Table 5.** Vienna classification of gastrointestinal epithelial neoplasia.


**3.2 Innate and adaptive mature B cell populations**

284 Advances in Hematopoietic Stem Cell Research

Fig. 5. Normal and leukemic B cell development. B cell stages can be divided according to

Nomenclature for each sub-stage in mice is shown in black letters while the most common nomenclature for their counterparts in humans is shown in red letters. The dashed lines separating all stages indicate checkpoints at which signaling from the preBCR and BCR is required for positive selection and progression along the B-cell maturation pathway. The proBCR, preBCR, and mature receptor are also illustrated in their respective stages. Replication and recombination processes are mutually exclusive as denoted by the circular arrows and VDJ signs inside the cell. The replication stages are also frequently compromised in pediatric B cell acute leukemia. Black lines under IL-7R and preBCR indicate the stages where these receptors are most required. The differential thickness in the IL-7R line shows the sub-stages where a higher (nanograms) or lower (picograms)

transcription factors along the B cell pathway are shown in the middle and bottom panels. Blue bars mark normal gene expression, and the most common modified forms of the transcription factors associated with B cell acute lymphoblastic leukemia are revealed.

the main processes guiding development: receptor assembly, self-recognition and activation (top panel). Receptor assembly occurs in bone marrow (light blue box) by VDJ recombination in the Pro-B and Pre-B stages, whereas self-recognition starts in bone marrow and ends in periphery, and activation takes place at peripheral level.

concentration of the IL-7 is required. Homeostatic and leukemic expression of

HSC, hematopoietic stem cell.

Following antigen binding, mature B cells activate pathways that lead to proliferation and further differentiation into antibody-producing B cells (plasma cells) or memory B cells. In the spleen, mature B cells are sub-divided into follicular (FO, AA4.1-CD21intCD23high) and marginal zone (MZ, AA4.1-CD21highCD23-) B cells according to both their location and their cell-surface phenotype. A distinct subset of mature B cells is preferentially present in the peritoneal cavity; these are known as B1 cells [B220+CD11b+CD5+ (B1a) or CD5- (B1b)]. Among them, FO B cells are responsible for adaptive antibody responses, whereas MZ and B1 mature populations respond rapidly to antigenic stimulus but do not go through germinal-center reactions and thus their response can be independent of T cell help (Martin et al., 2001). Therefore, MZ and B1 B cells are thought to be part of an innate–like response. The origin of both of these populations is not well understood. While MZ B cells share part of FO pathway, the fetal liver was thought to originate a large fraction of the adult B1 B cells (Tung et al., 2006). Recently, a novel developmental model suggests that some B1 cell progenitors can be produced in bone marrow (Esplin et al., 2009).

#### **3.3 Regulation of B lineage commitment: The critical role of preBCR tonic signaling, IL-7R and transcription factors in context**

Limitation of lineage choice during development is regulated by a combination of signaling pathways and transcription factors (TF). In mice, the main receptor controlling the ProB stage is the IL-7R, which is composed of a chain (IL-7R) and the common cytokine receptor chain (c). Deletion of IL-7R or c leads to developmental arrest at the early ProB stage (von Freeden-Jeffrey et al., 1995; Cao et al., 1995).

IL-7 activates the major signaling pathway JAK–STAT, with STAT5 being the essential mediator of IL-7 signals in early B cell development (Yao et al., 2006).

By the other hand, an important characteristic of the developmental process that distinguishes B and T lymphocytes from other cell lineages is the continuous selection of these lymphoid cells for their ability to express a competent, non-self receptor. B cells that fail to express a receptor are eliminated. Thus, BCR and BCR-like receptors must generate active permissive signals that allow differentiation through the different developmental stages. Because the preBCR lacks of the light chain and therefore of the capacity to bind polymorphic ligands, it has been proposed that this receptor is able to signal constitutively and independently on ligand, an activity also known as tonic signaling. Although there is little understanding of how tonic signals are generated, the view is supported by receptor-less B cells able to differentiate into mature B cells by expression of a chimeric construct of Ig and Ig positioned in the cell surface membrane (Bannish et al., 2001).

From HSC to B-Lymphoid Cells in Normal and Malignant Hematopoiesis 287

proliferative expansion of clones that have successfully completed the rearrangement of their receptors, whereas late development is led by mechanisms of tolerance to self-antigens. All these processes in humans are less well understood than are their counterparts in mice. Importantly, human B cells can still be generated in severe combined immunodeficiency (SCID) patients with mutations in the IL-7R gene, suggesting that IL-7 signaling is not essential for human B cell development (Puel et al., 1998) although a recent study has demonstrated that in vitro human B cell production is dependent on IL-7 (Parrish et al., 2009). The fine regulatory mechanism separating proliferation and differentiation might explain why the proliferating ProB and PreB sub-stages are the ones generally found to be compromised in human pediatric B-cell acute lymphoblastic leukemia (B-cell ALL) and why this disease is characterized by leukemic blast cells that are often unable to progress through the differentiation pathway. This tendency to be arrested in proliferative states might result in an increased rate of mutations, leading to formation of neoplastic cells. Supporting the later, mice expressing B cell mutants in the adaptor protein BLNK are arrested in the large PreB stage and often develop B cell malignancies (Flemming et al., 2003). Proliferative stages

Acute lymphoblastic leukemia (ALL) is a disorder characterized by the monoclonal and/or oligoclonal proliferation of hematopoietic precursor cells of the lymphoid series within the bone marrow. At present, ALL is the most frequent malignancy in children worldwide and a serious problem of public health, constituting 25% of all childhood cancers and 75%-85% of the cases of childhood leukemias (Perez-Saldivar et al., 2011). Near to 80% of ALL cases have precursor B-cell immunophenotype, while approximately 15% show T-cell immunophenotype. Even when a relatively high efficiency of therapeutic agents has been demonstrated (Pieters & Carroll, 2010), there has been a slight but gradual increase in the incidence of ALL in the past 25 years, and appears to be highest in Hispanic population, which also show superior rates of high risk patients (Fajardo-Gutiérrez et al., 2007; Abdullaev et al., 2000; Perez-Saldivar et al., 2011; Mejía-Aranguré et al., 2011). Factors such as drug resistance, minimal residual disease, cell lineage switch, and the rise of mixed lineages often put the success of treatment at risk and change the prognosis of the illness. The molecular mechanism involved in these phenomena and the identities of the target hematopoietic populations have not been completely defined, due in part, to the fact that neither the precise origin of the disease, nor the susceptibility of primitive leukemic cells to

Over the last two decades, cancer stem cells (CSC) have been defined as cells within a tumor that possess the capacity to self-renew and to cause heterogeneous lineages of cancer cells that comprise the tumor (Clarke et al., 2006). According to MF Greaves, who proposed the original hypothesis for leukemogenesis, multiple consecutive carcinogenic hits in hematopoietic cells may drive the malignant transformation (Greaves, 1993; Greaves & Wiernels, 2003), where the second oncogenic event on pre-leukemic clones could be indirectly promoted by delayed infections (Greaves, 2006; Mejía-Aranguré et al., 2011). Our general current view suggests the occurring of oncogenic lesions in early development or in

occur in the early ProB, PreB-I and large PreB-II fractions (Figure 5).

**4. Acute lymphoblastic leukemia**

extrinsic factors, is known.

**4.1 The origin of ALL**

Once the preBCR is expressed at the end of the proB stage, it can take over many of the functions performed by the IL-7 receptor signaling. Both receptors act individually and together to allow B cell development (Figure 5). Like IL-7R, the preBCR promotes mechanisms of positive selection, survival and proliferation (Ramadani et al., 2010; Yasuda et al., 2008). The CCND3 gene, which encodes for cyclin D3, is essential for PreB cell expansion and integrates IL-7R and preBCR signals (Cooper et al., 2006).

Downstream the IL-7 and preBCR receptors, a handful of transcription factors (TF) are critical for commitment to the B cell lineage and early development; these include E2A/TCF3 (immunoglobulin enhancer binding factors E12/E47/transcription factor 3), EBF1 (Early B cell Factor 1) and PAX5 (Paired box 5) (Figure 5). Loss of E2A and EBF1 blocks entry into the B cell lineage, while loss of PAX5 redirects B cells into other lineages (Nutt et al., 1999; O'Riordan & Grosschedl, 1999). Acting together with E2A, EBF1 and STAT5, one of the main molecular functions of PAX5 is to allow VDJ recombination (Hsu et al., 2004). Also, E2A, PAX5, IKZF1 and RUNX1, among other TF, are responsible for RAG expression (Kuo & Schlissel, 2009). Moreover, IL-7R signaling fulfills an essential role in early B cell development, with STAT5 participating in the activation of the B cell regulatory genes E2A, EBF1 and PAX5. E2A encodes two TF via alternative splicing, E12 and E47. In mice lacking the E2A gene, the B cell lineage is lost, there is no heavy chain recombination, and the expression of the B cell-restricted genes EBF1, PAX5, CD79A/B and VPREB1 (CD179A) is also affected.

Enforced expression of EBF1 and PAX5 is sufficient to overcome the developmental block in mice deficient in E2A, IL-7 or IL-7R, further illustrating the transcriptional hierarchy of the B cell-specific program triggered by IL-7 receptor signaling (Nutt & Kee, 2007). EBF1 acting together with PAX5 drives the expression of many genes critical for early B cell development and B cell function, including FOXO1, MYCN, LEF1, BLNK, CD79A (MB-1), RAG2, CD19 and CR2 (CD21) (Nutt & Kee, 2007; Smith & Sigvardsson, 2004).

Although PAX5 is a positive regulator of B-cell specific genes, also functions as a repressor of non B-lineage genes such as M-CSFR, NOTCH1 and FLT3 (Cobaleda et al., 2007) so B cell development is unidirectional and mostly irreversible in homeostatic conditions.

Also important for lymphoid development are members of the Ikaros family of TFs, mainly IKZF1 (which encodes Ikaros) and IKZF3 (which encodes Aiolos). Ikaros activates B cell genes and represses genes that are unrelated to the B lineage. Expression of IKZF1 and IKZF3 is regulated by alternative splicing, which produces long isoforms (Ik-1, Ik-2, Ik-3, Aio-1, Aio-3, Aio-4 and Aio-6) that efficiently bind to DNA, and short isoforms (Ik-4, Ik-5/7, Ik-6, Ik8, Aio-2, Aio-5) that are unable to bind DNA with high affinity and do not activate transcription (Liippo et al., 2001). Ikaros is activated in early stages of lymphopoiesis and is required for both early and late events in lymphocyte differentiation. Aiolos is not required during the early specification of the B and T lineages but is essential during further B cell maturation. They also act in concert to promote preB cell cycle exit and transition to small PreB stage (Ma et al., 2010).

#### **3.4 Human B cell development**

Selection processes operating on developing B cells are similar in all mammals. Thus, early B cell development in humans is also mainly guided by VDJ recombination and by the proliferative expansion of clones that have successfully completed the rearrangement of their receptors, whereas late development is led by mechanisms of tolerance to self-antigens. All these processes in humans are less well understood than are their counterparts in mice. Importantly, human B cells can still be generated in severe combined immunodeficiency (SCID) patients with mutations in the IL-7R gene, suggesting that IL-7 signaling is not essential for human B cell development (Puel et al., 1998) although a recent study has demonstrated that in vitro human B cell production is dependent on IL-7 (Parrish et al., 2009). The fine regulatory mechanism separating proliferation and differentiation might explain why the proliferating ProB and PreB sub-stages are the ones generally found to be compromised in human pediatric B-cell acute lymphoblastic leukemia (B-cell ALL) and why this disease is characterized by leukemic blast cells that are often unable to progress through the differentiation pathway. This tendency to be arrested in proliferative states might result in an increased rate of mutations, leading to formation of neoplastic cells. Supporting the later, mice expressing B cell mutants in the adaptor protein BLNK are arrested in the large PreB stage and often develop B cell malignancies (Flemming et al., 2003). Proliferative stages occur in the early ProB, PreB-I and large PreB-II fractions (Figure 5).


**Soybeans (***Glycine max***) and Soybean Products in Poultry and Swine Nutrition**

Leilane Rocha Barros Dourado1,2, Leonardo Augusto Fonseca Pascoal1,3, Nilva Kazue Sakomura1,4, Fernando Guilherme Perazzo Costa1,3

> and Daniel Biagiotti1,2 *1Department of Animal Science,*

*2Federal University of Piauí, 3Federal University of Paraíba and 4São Paulo State University Brazil*


*Review* **Impact of Dietary Sugars on Gut Microbiota and Metabolic Health**

#### **Karina Garcia 1,2,3,4,†, Gonçalo Ferreira 1,2,3,†, Flávio Reis 1,2,3 and Sofia Viana 1,2,3,4,\***

**Abstract:** Excessive sugar consumption is a risk factor for the development of several disorders, including metabolic, cardiovascular, neurological conditions and even some cancers, and has been linked to increased morbidity and mortality. The popularization of the typical Western diet, featured by an excessive intake of saturated fats and added sugars and a low consumption of unprocessed fruits, vegetables and fiber, may directly affect the composition and functionality of the gut microbiota, staggering the balance of the intestinal microbiome that ultimately culminates into gut dysbiosis. Although added sugars in the form of nutritive and non-nutritive sweeteners are generally considered as safe, a growing body of evidence correlate their consumption with adverse effects on gut microbial ecosystem; namely an abnormal synthesis of short-chain fatty acids, altered intestinal barrier integrity and chronic inflammation that often fuel a panoply of metabolic conditions. Accordingly, this work revisited the available preclinical evidence concerning the impact of different types of dietary sugars—nutritive and non-nutritive sweeteners—on gut microbiota and metabolic health. Future research should consider gender and species vulnerability when the impact of such substances on GM community and metabolic health is scrutinized in order to guide their adequate use at doses relevant to human use.

**Keywords:** sugars; nutritive sweeteners; non-nutritive sweeteners; gut microbiota; metabolic health

#### **1. Introduction**

Sugar consumption is increasing in a global scale with a negative impact on human health [1]. Sugars can be categorized as: (i) natural dietary sugars (e.g., glucose, fructose, sucrose), typically added as extrinsic sugars to foods and beverages during processing to sweeten and increase the flavor, being classified as nutritive sweeteners [2,3]; (ii) sugar alcohols (e.g., xylitol, sorbitol), also nutritive sweetener often used as alternatives to natural dietary sugars due to their low-caloric content [4]; and (iii) non-nutritive sweeteners (e.g., sucralose, saccharin) that, due to their noncaloric value, have gained popularity and are widely used in the scope of sugar reduction strategies [5,6].

The high consumption of dietary sugars is closely related with westernized diets, comprising highly processed foods and sugar-sweetened beverages that are strongly associated with an increased risk of poor health conditions [7–9]. For instance, sweetened foods display a key role for the development of dental caries, hyperactivity, obesity, diabetes, cardiovascular disease, hypertension, fatty liver disease, dyslipidemias and even some cancers [10–13]. Notably, a large number of abovementioned diseases display a gut dysbiotic scenario as well [14–17]. The overload of dietary sugar intake drives major changes in

**Citation:** Garcia, K.; Ferreira, G.; Reis, F.; Viana, S. Impact of Dietary Sugars on Gut Microbiota and Metabolic Health. *Diabetology* **2022**, *3*, 549–560. https://doi.org/10.3390/ diabetology3040042

Academic Editor: Medha Priyadarshini

Received: 17 September 2022 Accepted: 20 October 2022 Published: 28 October 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/).

29

microbiota composition and function, namely a decreased bacterial diversity and altered metabolism that closely modulate epithelial integrity and gut inflammation [18–21]. Interestingly, gut dysbiotic scenarios driven by excessive sugar intake are strongly implicated in the development of dysmetabolic conditions, for instance metabolic syndrome, insulin resistance, dyslipidemia and type 2 diabetes and associated microvascular complications (e.g., nephropathy, retinopathy) [22–26]. Accordingly, this work aims to shed light to the impact of dietary sugars in GM composition and function and the ensuing effects in the metabolic health of the host.

#### **2. Dietary Sugars—An Overview**

Dietary sugars include distinct sources of sugars, which can be naturally occurring or added. The distinction between different types of sugars (i.e., total, free and naturally occurring) is crucial to best appreciate the association between sugar intake and health [27]. The World Health Organization (WHO) defines "free sugars" as all monosaccharides and disaccharides added to foods/beverages by the manufacturer, cook or consumption and sugars naturally present in honey, syrups, and fruit juices, including those concentrated [28,29]. The term "total sugars" refers to the combination of naturally occurring sugars and free sugars [29,30].

A healthy, well-balanced diet contains naturally occurring sugars present in fruits, vegetables, dairy products and many grains [31]. They can be in the form of simple molecules, monosaccharides (e.g., glucose, fructose, galactose) or disaccharides (e.g., sucrose, maltose, lactose), or more complex ones (e.g., polymers or polysaccharides) [32]. However, when these types of sugars are added as ingredients in processed foods to impart a sweet taste, they often correlate with excessive sugar intakes being associated with chronic disease conditions [33]. For example, fructose in the form of added sugar is particularly implicated in metabolic syndrome, hypertension, insulin resistance, lipogenesis, diabetes and associated retinopathy, kidney disease and inflammation [22–24]. Sucrose, glucose and fructose, when used in high amounts, have also a negative influence on oral hygiene and increase the risk of dental caries in children [34]. Therefore, WHO recommends in both adults and children a reduction in free sugars intake to less than 5–10% of total energy intake [29]. Furthermore, added sugars also comprise sweeteners-chemical compounds with an intrinsic sweet taste that determines their usage as sweetening agents [35,36]. Briefly, they can be classified due to their origin (natural or synthetic agents) or nutritional value (nutritive and nonnutritive) [37–39]. The structural formula of some nutritive and non-nutritive sweeteners is presented in Figure 1.

Nutritive sweeteners (NSs) enclose abovementioned carbohydrates (e.g., glucose sucrose, fructose) that provide approximately 4 kcal/g of energy and polyols (sugar alcohols), mostly hydrogenated carbohydrates that provide an average of 2 kcal/g of energy being often used as low-caloric sugar replacers [40]. Until now, several polyols have been approved to commercialization, such as xylitol (E967), maltitol (E953), sorbitol (E420), erythritol (E968), lactitol (E953) and mannitol (E421), to name just a few [41]. Such compounds elicit low glycemic and insulinemic responses due to the incomplete absorption from the small intestine into the blood stream. Moreover, they are also associated with lipogenesis inhibition [42]. However, since they are poorly absorbed in the colon, some laxative effects have been described and are not recommended for toddlers under 1 year of age [36,43].

Non-nutritive sweeteners (NNSs) or artificial sweeteners comprise substances with a great chemical diversity and a very intense sweet taste and offer little or no energy when ingested [32,44]. They are also known as high-intensity sweeteners since they are many times sweeter than sucrose. The most used NNSs are acesulfame potassium, aspartame, advantame, cyclamates, saccharin, sucralose, neohesperidin dihydrochalcone and neotame. Yet, some NNSs used in foods may also be isolated from natural sources, steviol glycosides, glycyrrhizin and thaumatin being some examples [40]. Notably, saccharin can have 300 times the potency of sucrose in terms of sweetening and has the acceptable daily intake (ADI) of 5 mg/kg of body weight. Aspartame and neotame display ADI values of

40 mg/kg and 18 mg/kg of body weight, respectively. However, due to their phenylalanine content, they are not advised for people with phenylketonuria [35,45]. Steviol glycosides are molecules extracted from the leaves of *Stevia rebaudiana* plant with an ADI limit of 4 mg/kg of body weight [46].

**Figure 1.** Nutritive and non-nutritive sweeteners chemical structures (Taken from: https://pubchem. ncbi.nlm.nih.gov/, accessed on 23 August 2022).

Even though NSs and NNSs are approved food additives that attempt to lower the overall daily caloric intake towards weight loss, concerns have emerged given their ability to modify the GM in such a way that there is the potential for an enhanced risk of glucose intolerance, insulin resistance, diabetes and increased weight [6,47,48].

#### **3. Insights of Gut Microbiota Composition and Function**

The term "microbiome", firstly utilized by Joshua Lederberg, has been gaining increasing importance, especially since 2001 [49]. Microbiome refers to a group of microorganisms

living in a symbiotic way in our body. In a normal condition, the majority of GM is constituted by four main families: *Firmicutes* (64%), *Bacteroidetes* (23%), *Proteobacteria* (8%) and *Actinobacteria* (3%). Several studies recognize the key role of these bacteria in the extraction process of nutrients and energy from food as well as in human metabolism [50,51]. Accordingly, many researchers have depicted the deleterious impact of GM dysbiosis in the development of several host diseases [52]. For instance, the change in the GM composition in patients who have type 2 diabetes (T2D) is characterized by high levels of Streptococcus mutans, *Escherichia coli* and *Lactobacillus gasseri*, as well as by decreased levels of butyrateproducing bacteria such as *Clostridium Butyricum*, *Anaerostipes*, *Eubacterium halii*, *Roseburia* and *Faecalibacterium prauznitzii* [53]. Low *Firmicutes* abundance was also found in similar studies [54,55].

In addition, some metagenome-wide association studies support the idea that unbalanced intestinal environment can lead to the development of several diseases, affecting the integrity of the intestinal barrier, the production of short-chain fatty acids (SCFAs) and the metabolism of bile acids, among others [53]. SCFAs are metabolites produced by the microbial decomposition of nondigestible food and display chief roles for intestinal health [56]. Acetate (C2), propionate (C3) and butyrate (C4) are the most abundant SCFAs (60:20:20 ratio in the human gastrointestinal tract) [57]. Several studies have shown that an abnormal synthesis of SCFAs impact the integrity of intestinal barrier [58,59]. These microbial metabolites signal by distinct G protein-coupled receptors (GPRs), namely the GPR109a, GPR43 (FFAR2), GPR41 (FFAR3) and Olfactory receptor 78 [60]. Such receptors are expressed in several types of cells such as adipose, immune, hepatic or skeletal muscle cells [61,62]. Among all SCFAs, it has been reported that GPR41 receptor is activated by propionate, GPR43 receptor by propionate, acetate and butyrate and GPR109A receptor by butyrate [63–65]. In addition, several studies have shown that the activation of these receptors by SCFAs leads to the secretion of PYY (peptide tyrosine-tyrosine) into the colon with subsequent effects on central nervous system, namely appetite reduction [66]. Furthermore, the activation of GPR41 receptor stimulates the expression of leptin by adipocytes, resulting in the inhibition of neuropeptide Y (NPY) while the activation of GPR43 receptor leads to several positive effects, such as the suppression of glucagon from pancreatic α-cell or the release of GLP-1 (glucagon-like peptide-1) by endocrine L-cells who act in β-cell via stimulation of insulin biosynthesis and enhancement of glucose-stimulated insulin secretion [50,67].

Acetate is the most abundant SCFA in the gastrointestinal tract and several positive effects have been reported [68]. Den Besten and colleagues have shown that increased levels of acetate could improve insulin sensitivity, glucose homeostasis and reduce body weight [57,69]. However, other studies have shown contradictory evidence. For instance, a study from Perry and colleagues disclosed that high levels of acetate lead to the activation of parasympathetic nervous system, promoting an increased glucose stimulated insulin secretion and a higher production and secretion of ghrelin, resulting in weight gain [70,71].

Butyrate also displays important metabolic roles such as the activation of intestinal gluconeogenesis or macrophage M2 polarization towards anti-inflammatory effects through peroxisome proliferator-activated receptor gamma (PPARγ) up-regulation [72,73]. Furthermore, several studies have shown that the activation of this receptor also improves insulin sensitivity [74]. In addition, butyrate is also able to suppress NF-kB (nuclear factor kappa B) activation, an important transcription factor involved in the regulation of some genes encoding pro-inflammatory cytokines, growth factors, adhesion molecules, and immune receptors among others [75]. Several studies suggest that butyrate confers oxidative stress protection, regulates cell proliferation and cell differentiation, intestinal gluconeogenesis activation and maintains gut barrier permeability [76].

Remarkably, propionate supplementation was found to stimulate the release of the hormones PYY and GLP-1 in healthy adults resulting in a reduced appetite, hepatic fat, adipose tissue and a higher sensitivity to insulin [77]. Other studies also found the effects of propionate in Treg cells differentiation and production of interleukin (IL)-10 [78,79].

#### **4. Impact of Dietary Sugars on Gut Microbiota and Metabolic Health**

Several studies highlight the role of carbohydrates and sweeteners on satiety control, lipid metabolism, protein glycosylation, SCFAs production and the modulation of GM itself [80]. The ability of carbohydrates to modify the GM mostly relies on the non-digestible or digestible nature of these substrates [81]. Digestible carbohydrates such as sucrose or lactose are absorbed in the small intestine following degradation into monosaccharides (e.g., glucose, fructose) through a panoply of gastrointestinal enzymes [82]. Fructose, sugar alcohols and some non-nutritive sweeteners (e.g., sucralose) are passively, slowly or very poorly absorbed in the small intestine and overflow to the large intestine [2]. Such dynamics induce significant alterations in GM, including a reduced microbial diversity and altered relative abundance of certain bacterial phylum that correlates with metabolic health status, as highlighted in the following sections.

#### *4.1. Nutritive Sweeteners*

#### 4.1.1. Glucose, Fructose, Sucrose

Consistent evidence from studies with animal models demonstrate that dietary patterns enclosing a high intake of glucose, fructose or sucrose lead to gut dysbiosis and metabolic imbalances, as summarized in Table 1. For example, in male C57BL/6J mice, the administration of a high-glucose diet (HGD) for 12 weeks elicited hyperglycemia, glucose intolerance, dyslipidemia and increased fat mass deposition [83]. In addition, the loss of gut microbial diversity, characterized by a lower proportion of Bacteroidetes and an increased proportion of Proteobacteria, has been observed [83]. Moreover, the HGD-fed animals displayed an increased gut permeability due to alterations in tight junction proteins as well as intestinal inflammation [83]. In the same study, similar results were noticed with the administration of a high-fructose diet (HfrD). Other authors also found that the administration of fructose at a low dose (2.6 g/kg/day), moderate dose (5.3 g/kg/day) and a high dose (10.5 g/kg/day) for 20 weeks leads to an increase in the serum proinflammatory cytokines (IL-6 and TNF-α: tumor necrosis factor-alpha) and a decrease in anti-inflammatory cytokine IL-10 in male Sprague Dawley rats. Notably, the higher fructose intake was associated to an increase abundancy of *Parasutterella* and *Blantia* and decreased *Intestinimonas* [84]. Furthermore, Sun and colleagues showed that male Wistar rats fed with a high-sucrose diet for 4 weeks significantly increased the serum triglycerides and cholesterol levels. Such changes were coincident with a scenario of gut dysbiosis, featured by an altered *Bacteroidetes/Firmicutes* ratio with an increase in Bacteroidetes and Verrucomicriobia and decreased Firmicutes [85].

#### 4.1.2. Polyols

The relationship between polyols (also known as sugar alcohols) and GM composition and function has been also highlighted in distinct animal models. Xiang and colleagues reported no significant effects on pancreas, liver, brain and colon organ weights although it was observed increased levels of the GM metabolites butyrate and propionate in the intestinal mucosa and lumen of male C57BL/6 mice exposed to 2% (2.17 g/kg/day) and 5% (5.42 g/kg/day) of xylitol for 3 months. At the higher dose, xylitol elicited an increased abundance of *Bifidobacterium*, *Lactobacillus*, and *Erysipelotrichaceae* and decreased contents of *Blautia* and *Staphylococcus* [86]. Nevertheless, rodent species exhibit different susceptibilities as demonstrated by Zuo and colleagues who reported a decreased abundance of *Ruminococacaeae*/*Provotella* and increased *Bacteroides levels* in male Sprague Dawley rats but only when xylitol was administered at a higher-dose (xylitol 9.90 g/kg/day) [87].

Similarly, several studies demonstrated a disturbed GM upon sorbitol consumption. Accordingly, male Wistar rats exposed to 10% sorbitol (2.07 g/day) for 16 days showed an increase in *Lactobacillus abundance* and butyrate levels in the cecum and colon. Such changes paralleled lower levels of seric triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol concentrations [88]. The consumption of 2% of lactitol also elicited a decrease in fecal pH and an increase in IgA hypersecretion in male Wistar rats without

major differences in body weight curves [89]. Table 1 summarizes the alterations of GM composition and function upon polyols consumption.

**Table 1.** Effects of nutritive sweeteners on gut microbiota and metabolic health.

#### *4.2. Non-Nutritive Sweeteners*

Likewise, a dysbiotic scenario has been reported upon the oral consumption of distinct non-nutritive sweeteners. Diet-induced obese male C57B1/6 mice presented impaired glucose tolerance and a reduction in *Lactobacillus reuteri* and an increase in fecal *Bacteroides* genus and Clostridiales order when 0.1 mg/mL of saccharin was administered for 10 weeks [92]. Similarly, the administration of 0.3 mg/mL saccharin for 6 months in male C57BL/6J mice triggered the hepatic overexpression of TNF-α and iNOS (Inducible nitric oxide synthase) along with an increase abundance of *Turicibacter Corynebacterium* and *Roseburia* and decreased contents of *Ruminococcus* and *Anaerostipes* [93]. In another study, an increase in Lactobacillus genus along with intraluminal lactic acid concentrations were observed in landrace X large white piglets fed with a diet supplemented with SUCRAM® 0.015% (*w*/*w*) saccaharin and neohesperidin dihydrochalcone for 2 weeks [94]. According to Abou-Donia and colleagues, the administration of 1.1, 3.3, 5.5 or 11 mg/kg/day of sucralose to Sprague Dawley rats for 12 weeks resulted in an increased body weight and a fewer number of *Bacteroides*, *Bifidobacterium*, *Clostridium* and *Lactobacilli* [95]. Yet, there are conflicting reports. For instance, the chronic administration of Acesulfame K solution (15 mg/kg/day) in male C57BL/6J mice did not elicit any significant change in GM composition. [96]. Nonetheless, Bian and colleagues have shown an increase in Bacteroides in male CD-1 mice fed with 37.5 mg/kg/day of Acesulfame-K along with an expressive body weight gain. Interestingly, these results were less pronounced in the female mice group, suggesting that gender differences must be taken into account [97]. In addition, aspartame and steviol glucosides are non-nutritive sweeteners that significantly disturb GM composition and function in obese and lactating rodents as well [98,99]. Table 2 outlines recent evidence focused on the impact of non-nutritive sweeteners on GM and metabolic health.

**Table 2.** Effects of non-nutritive sweeteners on gut microbiota and metabolic health.

#### **5. Conclusions**

Reduction in the dietary intake of sugars has been strongly advised for some years now to cope with the prevention of non-communicable diseases such as diabetes, cardiovascular disease and/or obesity, among others. Accordingly, the use of alternative sweeteners, particularly those with a low-caloric content, has gained popularity. However, available preclinical evidence raises awareness on the dietary use of such substances in human health since they can also display putatively unfavorable effects on GM and metabolic health, as reviewed in this work. For instance, the decrease in SCFAs biosynthesis and intestinal barrier damage due to sweeteners-induced GM dysbiosis are well-described features of cardiovascular diseases, T2D and pancreatic damage, to name just a few [102–104].

Given the multifaceted roles of GM community in human health, future studies are warranted to provide adequate evidence regarding the impact of nutritive and non-nutritive sweeteners on metabolic status, with a major focus on gender and species vulnerability. Moreover, it would be of interest to further disclose key disease-altering properties of sweeteners and their candidate roles in nutrition therapy programs [105,106]. Such information will be paramount to guide their adequate use at doses relevant to human use.

**Author Contributions:** Conceptualization, S.V.; writing—original draft preparation, G.F. and K.G.; writing—review and editing, S.V., F.R. and K.G.; visualization, S.V. and F.R.; supervision, S.V. and F.R.; project administration, S.V. and F.R.; funding acquisition, S.V. and F.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by National and European Funds, via Portuguese Science and Technology Foundation (FCT), European Regional Development Fund (FEDER), and Programa Operacional Factores de Competitividade (COMPETE): UIDP/04539/2020 (CIBB), PTDC/SAU-NUT/31712/2017, and POCI-01-0145-FEDER-031712.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

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

#### **References**


**Appendix A. List of Symbols**

### **References**

© 2020 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 (http://creativecommons.org/licenses/by/4.0/).


A further approach is based on the hypothesis of altered gene expression and protein synthesis of chromosomally abnormal embryos. One study, using a proteomic approach, has identified the first protein secreted by human blastocysts (Lipocalin-1) that is associated with generic chromosome aneuploidy (McReynolds *et al.* 2011) promising the biggest step to

PGS has proved to be one of the most controversial areas of reproductive medicine in recent times. The entire community is united in its collective will to improve IVF success, reduce miscarriage rates and ensure that couples avoid children with developmental abnormalities. The means by which this is achieved remains the subject of intense debate. What can be clear however is that the controversy will serve to increase the interest in PGS leading to

date towards a non-invasive PGS test.

new and radical future treatments.

aCGH Array comparative genomic hybridisation

CGH Comparative genomic hybridisation

MDA Multiple displacement amplification MI First meiotic division (Meiosis 1) MII Second meiotic division (Meiosis 2)

SNP Single nucleotide polymorphism

WGA Whole genome amplification

PGS Preimplantation genetic screening (for aneuploidy) PS Premature/precocious separation of sister chromatids

(2008a) A long term analysis of the HFEA Register data (1991-2006). *HFEA Website* 1. (2008b) Preimplantation genetic testing: a Practice Committee opinion. *Fertil Steril* 90, S136-43. Alfarawati S., Fragouli E., Colls P., Stevens J., Gutierrez-Mateo C., Schoolcraft W.B., Katz-

chromosomal abnormality, and embryo gender. *Fertil Steril* 95, 520-4.

Jaffe M.G. & Wells D. (2011a) The relationship between blastocyst morphology,

FISH Fluorescence *in-situ* hybridization

**10. List of abbreviations**

AMA Advanced maternal age

DNA Deoxyribonucleic acid

ADO Allele dropout

ICM Inner cell mass IVF *In-vitro* fertilisation IVC *In-vitro* culture

PB Polar body PB1 First polar body PB2 Second polar body

TE Trophectoderm

**11. References**

**9. Conclusion**

chromosomes could be analysed with more precision. Currently, increased resolution of PGS is limited by the WGA step (Ling *et al.* 2009). Achieving the highest possible resolution is directly restricted by the phenomenon of ADO when amplifying single or very few cells. Thus it necessary to invest effort in improving WGA technology before the full benefits of genomic sequencing could be realised.

With the increasing amount of data obtained from PGS technologies comes the issue of an increasing amount of 'incidental' findings of unknown pathological significance. Careful considerations of the social, ethical and legal aspects of these findings are required to combat potential problems prior to implementing higher resolution technologies.

The ultimate goal of PGS is to provide maximum benefit (in terms of information to the parent/healthcare provider) with minimal cost to the embryo. The possibility of gaining chromosome copy number information with no cost to the embryo would enable PGS to be used routinely as an embryo selection tool for IVF. An indirect aneuploidy screening test was first explored by associations with conventional embryo morphology scoring. However, morphological embryo grading is apparently at its limits to improve IVF success rates and has only shown very limited correlation with aneuploidy (Munne 2006; Gianaroli *et al.* 2007; Alfarawati *et al.* 2011a). The implementation of time-lapse imaging to embryo culture has facilitated high resolution morphokinetic analysis of embryo development in an attempt to improve IVF success rates and eliminate potentially abnormally developing embryos. Morphokinetic analysis involves continual analysis of the morphological state and rates of change during oocyte and embryo development and provides evidence of developmental milestones that can predict embryo implantation (Meseguer *et al.* 2011). Since, cells of different genotypes are known to have slightly different cell cycle times (Varrela *et al.* 1989), it follows that algorithms involving multiple developmental time points could be used to predict embryo aneuploidy at no cost to the embryo. Embryos with an abnormal karyotype (particularly those with multiple abnormalities) may have aberrant cell cycles, detectable by morphokinetic analysis, compared with normal embryos. New studies into the morphological rates of change including such developmental markers as PB extrusion, syngamy and early mitotic divisions could find more significant correlations with chromosome mal-segregation than embryo morphology alone.

Other approaches to non-invasive assessment of embryo viability include the measurement of what is used by or what is secreted by the oocyte or embryo. All culture media contain substances that are required for embryo development. Culture media will also contain all products secreted by the oocyte or embryo. Levels of these can be measured in a variety of ways to establish embryo viability (for review see Aydiner *et al.* 2010).

Analysis of spent culture media is an area already being explored as potential for a new indirect PGS platform. A recent study analysing uptake patterns of amino acids has shown that regulation of amino acid metabolism correlates with embryo aneuploidy. The study using FISH analysis of five chromosomes (13, 18, 21, X and Y) demonstrated altered amino acid turnover in embryos with grossly abnormal karyotypes when compared to genetically normal embryos (Picton *et al.* 2010). Although promising, these early data lack specificity and further work is needed to more accurately establish how embryo metabolism may be indicative of its chromosomal complement. Precise metabolic profiling of embryos with known copy number aberrations is proposed as a specific experiment to establish more meaningful correlations.

A further approach is based on the hypothesis of altered gene expression and protein synthesis of chromosomally abnormal embryos. One study, using a proteomic approach, has identified the first protein secreted by human blastocysts (Lipocalin-1) that is associated with generic chromosome aneuploidy (McReynolds *et al.* 2011) promising the biggest step to date towards a non-invasive PGS test.

#### **9. Conclusion**

234 Aneuploidy in Health and Disease

chromosomes could be analysed with more precision. Currently, increased resolution of PGS is limited by the WGA step (Ling *et al.* 2009). Achieving the highest possible resolution is directly restricted by the phenomenon of ADO when amplifying single or very few cells. Thus it necessary to invest effort in improving WGA technology before the full benefits of

With the increasing amount of data obtained from PGS technologies comes the issue of an increasing amount of 'incidental' findings of unknown pathological significance. Careful considerations of the social, ethical and legal aspects of these findings are required to

The ultimate goal of PGS is to provide maximum benefit (in terms of information to the parent/healthcare provider) with minimal cost to the embryo. The possibility of gaining chromosome copy number information with no cost to the embryo would enable PGS to be used routinely as an embryo selection tool for IVF. An indirect aneuploidy screening test was first explored by associations with conventional embryo morphology scoring. However, morphological embryo grading is apparently at its limits to improve IVF success rates and has only shown very limited correlation with aneuploidy (Munne 2006; Gianaroli *et al.* 2007; Alfarawati *et al.* 2011a). The implementation of time-lapse imaging to embryo culture has facilitated high resolution morphokinetic analysis of embryo development in an attempt to improve IVF success rates and eliminate potentially abnormally developing embryos. Morphokinetic analysis involves continual analysis of the morphological state and rates of change during oocyte and embryo development and provides evidence of developmental milestones that can predict embryo implantation (Meseguer *et al.* 2011). Since, cells of different genotypes are known to have slightly different cell cycle times (Varrela *et al.* 1989), it follows that algorithms involving multiple developmental time points could be used to predict embryo aneuploidy at no cost to the embryo. Embryos with an abnormal karyotype (particularly those with multiple abnormalities) may have aberrant cell cycles, detectable by morphokinetic analysis, compared with normal embryos. New studies into the morphological rates of change including such developmental markers as PB extrusion, syngamy and early mitotic divisions could find more significant correlations with

Other approaches to non-invasive assessment of embryo viability include the measurement of what is used by or what is secreted by the oocyte or embryo. All culture media contain substances that are required for embryo development. Culture media will also contain all products secreted by the oocyte or embryo. Levels of these can be measured in a variety of

Analysis of spent culture media is an area already being explored as potential for a new indirect PGS platform. A recent study analysing uptake patterns of amino acids has shown that regulation of amino acid metabolism correlates with embryo aneuploidy. The study using FISH analysis of five chromosomes (13, 18, 21, X and Y) demonstrated altered amino acid turnover in embryos with grossly abnormal karyotypes when compared to genetically normal embryos (Picton *et al.* 2010). Although promising, these early data lack specificity and further work is needed to more accurately establish how embryo metabolism may be indicative of its chromosomal complement. Precise metabolic profiling of embryos with known copy number aberrations is proposed as a specific experiment to establish more

combat potential problems prior to implementing higher resolution technologies.

chromosome mal-segregation than embryo morphology alone.

meaningful correlations.

ways to establish embryo viability (for review see Aydiner *et al.* 2010).

genomic sequencing could be realised.

PGS has proved to be one of the most controversial areas of reproductive medicine in recent times. The entire community is united in its collective will to improve IVF success, reduce miscarriage rates and ensure that couples avoid children with developmental abnormalities. The means by which this is achieved remains the subject of intense debate. What can be clear however is that the controversy will serve to increase the interest in PGS leading to new and radical future treatments.

#### **10. List of abbreviations**

#### **11. References**

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### *Edited by Zuzana Storchova*

Aneuploidy means any karyotype that is not euploid, anything that stands outside the norm. Two particular characteristics make the research of aneuploidy challenging. First, it is often hard to distinguish what is a cause and what is a consequence. Secondly, aneuploidy is often associated with a persistent defect in maintenance of genome stability. Thus, working with aneuploid, unstable cells means analyzing an ever changing creature and capturing the features that persist. In the book Aneuploidy in Health and Disease we summarize the recent advances in understanding the causes and consequences of aneuploidy and its link to human pathologies.

Aneuploidy in Health and Disease

Aneuploidy in

Health and Disease

*Edited by Zuzana Storchova*

Photo by Rost-9D / iStock


2.1.3. Convertible Platforms

With the dramatic rise of primary shoulder arthroplasty over the last 15–20 years has come a rise of revision shoulder arthroplasty. Though indications for revision shoulder arthroplasty vary, it remains a technically demanding and challenging procedure regardless of indication. Revision shoulder arthroplasty is associated with increased blood loss and operative times, and frequently requires the use of special implants, augments, and bone grafting [26]. The innovative development of modular platform humeral stems, those

that can be converted from an anatomic TSA construct to a reverse TSA, has significantly reduced the complexity of revision shoulder arthroplasty. It theoretically obviates the need to explant the humeral stem that in turn reduces operative time, decreases blood loss, preserves humeral bone stock, and can reduce cost [27]. Crosby et al. found a slightly better postoperative range of motion in those who underwent conversion to RSA with a convertible platform compared to those that required entire humeral implant exchange. The prevalence of intraoperative complications was significantly lower with the convertibleplatform group (0% compared to 15%), though rates of reoperation were not different [27].

**Figure 2.** Short stem anatomic TSA. AP X-ray of anatomic TSA with short humeral stem.

It should be noted that not all convertible-platform humeral components can indeed be retained at the revision setting. The convertible platform humeral stem must be well-fixed and well-positioned to be retained. Encouragingly, multiple studies have demonstrated that a vast majority, approximately 80%, can be retained [27–29].

#### *2.2. Glenoid Component Innovations*

Augmented Glenoid Components

Excess retroversion and posterior wear of the glenoid present a dilemma for the orthopedic surgeon performing anatomic TSA. Glenoids with posterior wear and formation of a neo-glenoid (Walch B2), and those with >15◦ retroversion (Walch B3) are at high risk of developing glenoid loosening with standard implants [30]. Glenoid loosening has been the most common cause of anatomic TSA failure and indication for revision. Increased osteolysis has been demonstrated in cases in which the glenoid component is placed in excess retroversion, resulting in decreased implant survival [31].

Glenoid component retroversion beyond 15◦ leads to decreased contact area and increased contact pressures, placing the glenoid component at high risk of failure [31], and though eccentric reaming can correct small posterior deficits up to 10–15◦ [32,33], one risks removing excessive native bone when eccentrically reaming for larger deficits. Primary bone grafting has demonstrated variable results and may be associated with clinical and radiographic failure [34–37]. The other remaining option to deal with excessive posterior wear and retroversion even in the setting of an intact rotator cuff is to perform RSA, and some authors prefer this method [30].

For these reasons, there has been the introduction of augmented glenoid components that theoretically reduce bone removal and shear stresses, while retaining the benefits of anatomic TSA over RSA. Full wedge and partial wedge augments of varying degrees exist. Older designs included a keel that was angled in line with the neo-glenoid face, thus directing fixation toward the anterior neck of the glenoid. Newer implants have placed vault fixation angled with the paleo-glenoid to improve fixation [38]. Strong long-term data is lacking for augmented glenoid components. However, the short-term results are encouraging with multiple studies citing revision rates of 0%–5% at 2–3-year follow-up [38–43]. Larger-degree augments may be at higher risk of failure, as demonstrated by Priddy et al. in their retrospective study of full-wedge glenoid augmented TSA compared to nonaugmented TSA, in which all failures of the augmented glenoids requiring revision came with the 16◦ augment, with no failures of the 8◦ or 12◦ augments. There were no differences in radiographic lucencies around the pegs, postop ROM or patient reported outcome measures [38].

The senior author's preference for managing glenoid retroversion includes high-side reaming a B2 or B3 glenoid for retroversion <25◦. When retroversion is 25◦ to 35◦, the preference is to use an augmented glenoid component (Figure 3). For retroversion >35◦, the senior author will perform an RSA with bone grafting of the glenoid.

**Figure 3.** Anatomic TSA with posteriorly augmented glenoid polyethylene. Axillary X-ray of posteriorly augmented glenoid polyethylene.

#### *2.3. Inlay versus Onlay Glenoid Components*

Traditional onlay glenoid prostheses exhibit signs of loosening at relatively high rates, even when optimally placed [44–46]. Metal-backed glenoids have fallen out of favor due to the unacceptably high failure rates [47], so all-polyethylene designs are the gold standard. Though somewhat controversial, pegged onlay glenoids appear to have superior survivorship to keeled glenoids [45,48]. The "rocking-horse" phenomenon at the glenoidbone interface can result in edge loading, liftoff, and subsequent component loosening. With radiolucent lines occurring in approximately 30%–75% of TSAs with onlay glenoids by 10-year follow up, and loosening resulting in clinical failure requiring revision TSA 2%–10% of the time [49–51], there indeed is need for improvement in implant design. This has led to the development of the inlay glenoid design, in which the polyethylene component is implanted flush with the glenoid bone surface. Its theoretical advantages are those of less glenoid bone removal and improved mechanical characteristics due to less implant edge loading and lift off.

In a cadaveric study by Gagliono et al., onlay glenoid components exhibited gross loosening during fatigue testing, whereas the inlay glenoid components did not, and the onlay glenoids experienced significantly higher forces acting on them than did the native or inlay glenoids [52]. Short term results are promising, with good improvement in PROs, function, and ROM, without increased complication rates, and low reoperation rates [53]. This has been true even in the setting of posterior glenoid erosion, with no differences in short term clinical and radiographic outcomes evaluating non-spherical humeral head and inlay glenoid components in concentric (Walch A) glenoids compared to non-concentric (Walch B1 and B2) glenoids, according to the work of Egger et al. [54]. Inlay components may be of particular benefit in the younger, athletic, weight-lifting population given the theoretical decrease in mechanical loosening and resultant lack of restrictions afforded to them. Early clinical results have been excellent, and most of these patients are able to return to sports and lifting at the same or higher level [53,55].

Longer term data is required to definitively say whether inlay glenoid components are superior to onlay components, but early evidence suggests that this may turn out to be the case.

The senior author typically uses an onlay glenoid component, except when glenoid dysplasia exists, in which case the preference is to use an inlay glenoid component. See Figure 4, which depicts an X-ray appearance of an inlay glenoid component.

**Figure 4.** Inlay glenoid polyethylene in setting of glenoid dysplasia. Axillary X-ray of inlay glenoid polyethylene in setting of glenoid dysplasia.

#### *2.4. Convertible Glenoid Components in Anatomic TSA*

Cemented all-polyethylene glenoid components have represented the gold standard in anatomic TSA, given the historically unreliable results of cementless glenoid components. However, given the challenges and risks of revising a cemented glenoid component, there has been a resurgence of interest in convertible metal-backed glenoid components for anatomic TSA. The new generation of convertible metal-backed trays feature improved designs including a highly stable anchorage mechanism of the metal carrier in the glenoid vault, with larger bone-implant contact area and improved stability against shear forces [56]. Short and midterm follow-up results of the latest generation of convertible glenoid systems are encouraging, with revision rates ranging from 0%–11% [56–58]. Magosch et al. reported no glenoid loosening, an implant related revision rate of 4.2%, polyethylene dissociated in 4.2%, and no complications in cases requiring revision to RSA, in their prospective study of 48 patients at a mean follow up of 49 months [56]. In the setting of failed anatomic TSA, conversion to RSA may be facilitated by convertible glenoid systems, while maintaining improvements in pain and shoulder function [59]. Long-term follow-up data is needed, but there may indeed be a role for these convertible glenoid components moving forward.

#### **3. New Perspectives and Innovations in Reverse Shoulder Arthroplasty**

Reverse shoulder arthroplasty was approved by the FDA in the US in 2003. Since then, the prevalence has increased significantly by more than 2.5 times from 7.3 cases per 100,000 persons to 19.3 cases per 100,000 persons between 2012 to 2017 [60]. Its original indication was rotator cuff arthropathy in older patients [61], but this has since been expanded as prostheses have improved and surgeon experience has become more ubiquitous. Indications now include fracture, revision shoulder surgery, rotator cuff arthropathy in relatively younger patients, tumor, and glenoid bone loss. As these indications expand, more options have developed to assist in decreasing complications and improving complex or revision surgeries.

#### *3.1. Combined Humeral and Glenoid Component Innovations* Lateralization

Reverse shoulder arthroplasty designs have evolved over the last 15 years. One major evolution has been increased lateralization of the glenoid component. Typically, in RSA, the glenoid center of rotation (COR) is still medialized relative to the native shoulder COR. The increased lateralization is in reference to the preoperative humeral position rather than the COR. The current trend is to increase lateralization to increase soft tissue tension, particularly the rotator cuff. This lateralization can be achieved by one of three methods: lateralized glenoid baseplate, lateralized glenosphere or glenoid bone grafts (e.g., BIORSA).

Lateralization can have negative and positive effects on both the glenoid and humerus. Glenoid lateralization decreases adduction impingement thereby decreasing scapular notching and improving adduction, ER and extension motion [62–66]. It also improves rotator cuff tension and prosthetic stability [67,68]. Glenoid lateralization does, however, decrease the mechanical advantage of the deltoid, increase the shear forces across the implant interface and increase acromial strain, potentially increasing the risk of stress fracture [69–74]. Humeral lateralization on the other hand improves the deltoid mechanical advantage as well as improves the posterior cuff tension and the deltoid wrap by providing a more anatomic vector of muscle pull [67,70,75,76]. The negative effects of humeral lateralization are potentially too much soft tissue tension when combined with glenoid lateralization.

#### *3.2. Humeral Component Innovations*


**Author details**

Carlos Montalvo1 \*, Claudia A. Aguilar1 , Yunuen Canedo1 , Alejandro Ruiz1 , Brenda Zermeño2 , Ruby S. Gines3 and Rosa M. Cerón1

1 Autonomous University of Carmen, Campeche, Mexico

2 Faculty of Chemical Sciences, Autonomous University of San Luis Potosí, San Luis Potosí, Mexico

3 Technological Institute of Orizaba, Orizaba, Veracruz, Mexico

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Quantification of Heavy Metal Levels in Sediments of the "Palizada" River in a Protected… DOI: http://dx.doi.org/10.5772/intechopen.104657*


**7. Conclusions**

The pilot study revealed that a properly designed questionnaire can be used to assess the relationship between hospital and sta ff preparedness and disaster response e fficiency.

The knowledge and skills of health professionals in relation to specific events and their impact on people, as well as the appropriate treatment, are essential for the quality of healthcare services during disasters.

In order to achieve the level of preparedness and the e ffectiveness of the disaster response, it is necessary that every hospital has pre-prepared and validated procedures.

An experimental study involving a range of hospitals should be carried out, using more comprehensive assessment tools, to assess the correlation between the level of preparedness and performance of the hospital and the impact of the preparation of the hospital and its sta ff towards the survival of disaster victims.

Evaluation of the preparedness and e ffectiveness of disaster response is a means of identifying and removing possible gaps and weaknesses in the functioning and e ffective management of a hospital during mass-casualty incidents.

**Author Contributions:** Conceptualization: K.G.; data collection: K.G. and M.G.; formal Analysis: K.G. and M.G.; writing—original draft preparation: K.G. and M.G. All authors have read and agreed to the published version of the manuscript.

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

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