*3.2. Measurement Scales*

Our measurement scales are the same as [7] and are widely used by empirical papers about technology acceptance. Table 2 shows the questionnaire outlining constructs, items, and theoretical foundations of each one. The responses were done over a Likert scale from 0 to 10.

**Table 2.** Constructs, items and their theoretical foundation.

**Table 2.** *Cont.*

Source: [7].

*3.3. Quantitative Methodology*

> The research used the following sequential process:

Stage 1. Measurement model analysis.

To explore potential existence of dimensions in the scales we have run principal component analysis with Varimax rotation. Subsequently we have performed an assessment on reliability, convergent and discriminant validity of scales.

Stage 2. Test hypothesis H1–H6.

In [7] we used for this analysis a PLS regression. It implies calculating R2, Q2, path coefficients, and linked statistical significance degree. On the other hand, in this paper we use Qualitative Comparative Analysis (QCA) [24] and fuzzy set QCA (fsQCA) in [23] to evaluate such hypothesis.

There is a great deal of applications of fsQCA in management and marketing [25]. As far as similar fields to ours are concerned, fsQCA has been applied instead PLS in the assessment of new technologies acceptance [26,27] and also as a complementary method to PLS [28,29].

Any correlational method in general and PLS in particular assumes symmetrical relations between variables and measures the net effect of each variable on assessed output. On the other hand fsQCA allows discovering the combinatorial effects of variables over the output as well as taking into account that these interactions could be asymmetrical [28]. So, to test hypothesis in Section 2, PLS and fsQCA follow different ways. With PLS we find an average value (a coefficient) for the influence each factor on output variables and then we test its statistical relevance from its t-ratio. When applying fsQCA we find the logical implicates that combining the presence/absence of input variables suit better output results

by using Boolean logic. Subsequently consistency and coverage measures inform about the relevance of discovered logical implicates and compare them with initial hypothesis. Figures 3 and 4 depict a graphical comparison about how PLS and fsQCA test hypothesis under the framework exposed in Section 2.

**Figure 3.** Hypothesis tested and analytical methodology with PLS in [7]. Source: Arias-Oliva, M.; Pelegrín-Borondo, J.; Matías-Clavero, G. Variables influencing cryptocurrency use: a technology acceptance model in Spain. *Frontiers in Psychology* **2019**, 10, 475.

**Figure 4.** Hypothesis tested and analytical methodology with fsQCA.

Figure 3 represents how PLS works. Coefficients a1, a2, ... , a6 quantify the sign of average influence of factors individually. Their t-ratios allow testing their particular statistical significance. To assess goodness of whole model, R2 and Q2 must be used. Figure 4 shows how fsQCA process empirical data. After a Boolean minimization, logical implicates Z1, Z2, .., Zr, Z1, Z2, .., Zs' are found. They embed the presence/absence of at least one input variable. Consistency and coverage measures summarize the significance and empirical relevance of every logical implicate. To test hypothesis, the configuration of these implicates must be interpreted accordingly.

Therefore, two measures are of interest for a given logical implicate:

•

	- Coverage (cov) that measures the proportion of the outcome explained by each recipe.

As it is usually advised by literature [26] we analyze the influence of input variables not only on the outcome (IU) but also on its negation (~IU). In our case, a facilitating condition may consist in having a powerful PC and a good internet connection. The influence of this fact in crypto use may be great, little or negligible. On the other hand, it comes fair that the negation of such condition ensures not operating with cryptos. So, if we symbolize as "~" the negation of a variable, we evaluate:

$$\text{IU} = \text{f}(\text{PE, EE, CP, FC, PR, FL}), \tag{1}$$

$$\text{I}-\text{IU} = \text{f}(\text{PE, EE, CP, FC, PR, FL}), \tag{2}$$

where f(·) symbolizes Boolean function. The implementation of fsQCA is done by using fsqca 3.1 software [71] and follows the following steps:

Step 1. Find the factorial punctuation for of the *j*th observation (*j* = 1, 2, ... , 402 in our sample) in ith variable (IU, PE, EE, SI, FC, PR and FL). We symbolize as f*ij* those values.

Step 2. Built up the membership function for input variables PR EE, SI, FC, PR and FL and output variable IU by normalizing within [0,1] their standardized factorial punctuation in step 1. So, for a variable *i*, the membership value for the *j*th observation *Xij* is:

$$m\_{X\_{ij}} = \frac{f\_{ij} - \min\_{j} \{ f\_{ij} \}}{\max\_{j} \{ f\_{ij} \} - \min\_{j} \{ f\_{ij} \}} \tag{3}$$

The membership degree within the negated fuzzy set, ~Xi is defined then as: *m*∼*Xij* = 1 − *mXij* .

Step 3. Built up a Boolean truth table which is composed by so-called "min terms". We state for the value of the jth observation in ith variable two unique the possible values: true ( *m Xij*= 1) and false ( *m Xij*= 0). So:

$$m'\_{X\_{ij}} = \begin{cases} 1 & m\_{X\_{ij}} \ge 0.5 \\ 0 & \text{otherwise} \end{cases} \tag{4}$$

Step 4. Maintain only those min terms whose consistency to produce the output are at least a threshold ε. Ragin [71] suggests ε = 0.8.

Step 5. By applying Quine-McCluskey algorithm [72] find essential prime implicates in truth table. These implicates conform so-called Qualitative Comparative Analysis complex solution (CQA-CS). That algorithm supposes implementing the following steps:

Let us remark that essential prime implicates are Boolean products whose factors may be *Xj* or ∼ *Xi*.

Step. 6. CQA-CS is usually hard to interpret and is build up with no more assumption than data. So, fsqca 3.1 also offers a parsimonious solution (QCA-PS). It is fitted from any remainder over non observed configuration of variables in order to make solution as easy as possible regardless whether it constitute an "easy" or "difficult counterfactual" case [71].

Step 7. To continue the minimization process, [23] proposes using simplifying assumptions that should be theoretically well-founded about how a given condition is causally related to the outcome. It must be supposed for non-observed configurations, if an input variable contributes to output exclusively when it is present, absent or in both cases. This step lets us obtaining so-called intermediate solution (QCA-IS).

Step 8. Let be a possible prime implicate (configuration or recipe) *Z* that without a loss of generality we built as:

$$Z = X\_1 \* X\_2 \* \dots \* X\_r \tag{5}$$

where 1 ≤ *r* ≤ *n*, *n* is the number of output variables and "∗" stands for the Boolean product. So, we can obtain for the *j*th observation:

$$m\_{Z\_{\vec{\gamma}}} = \min \{ m\_{X\_{1,\vec{\gamma}}}; m\_{X\_{2,\vec{\gamma}}}; \dots; m\_{X\_{r,\vec{\gamma}}} \} \tag{6}$$

 So, the consistency of recipe *Z* in producing output *Y* is:

$$\text{Cons}\_{Z \to Y} = \frac{\sum\_{j} \min \left\{ m\_{Z\_j}; m\_{Y\_j} \right\}}{\sum\_{j} m\_{Z\_j}} \tag{7}$$

where *Yj* stands for the value of *j*th observation in output variable (Intention to Use in our case). Consistency may be understood similar as a statistical measure of significance [73]. It is widely accepted that to consider *Z* as sufficient condition, consistency must be above 0.8. theof*ZY*is:

Subsequently, coverage recipe to produce

$$Cov\_{Z \to Y} = \frac{\sum\_{j} \min \left\{ m\_{Z\_j}; m\_{Y\_j} \right\}}{\sum\_{j} m\_{Y\_j}} \tag{8}$$

Coverage provides a measure of empirical relevance. Its analogous statistical measure is R2. A consistency above 0.8 for a recipe (6) implies that the combination is "almost always" necessary or sufficient [23]. It can be considered that a condition is completely sufficient when cons > 0.9 y cov > 0.5 (see [74]).

Step 9. Interpret intermediate and parsimonious solutions. At this point there is no a unified rule about what solution must be interpreted. Ragin in [23] suggests using QCA-IS since it supposes a compromise between simplicity of CQA-PS and complexity of CQA-CS. As it is pointed out by Thiem in [75] empirical studies are usually done over this solution. However, also in [75] it is advised searching causal relations using exclusively QCA-PS instead intermediate solution. That paper argues that QCA-CS and QCA-IS introduces matching counterfactual data with which QCA supplements the empirical observations. These artificial data may induce inferences that violate the actual causal structure that had generated the empirical data in the first place and that QCA is meant to uncover.


**Acknowledgements**

The authors are thankful to Lovely Professional University Phagwara, Punjab Agricultural University Ludhiana and Dr. YS. Parmar University of Horticulture and Forestry Solan for providing infrastructure and financial support for the study.


**Meet the editor**

Nikolay N. Nikitenkov finished his studies at the Moscow State University and there defended his candidate and doctoral dissertations in Physics. Currently, he is a professor at Tomsk Polytechnic University. He lectures in the direction of "Modern Methods of Studying Solid Surfaces and Thin Films." He is the researcher and expert in the following directions: modern technologies

for creating thin-film systems and coatings; physics of metal-hydrogen systems; and modern research methods of the surfaces and thin films. He has published over 150 articles in these areas, including more than 50 in international journals, with high rating.


**1. Introduction**

There is no doubt that a study on scattering theory is one of the most interesting topics of the Schrödinger equation. Recently, it has been revealed that the scatterings of some fundamental stationary Schrödinger equations on the real line with not only delta potentials [1–3] but also continuous potential [4] can be recovered by discrete-time quantum walks. These induced quantum walks are given by the following setting: the non-trivial quantum coins are assigned to some vertices in a finite region on the one-dimensional lattice as the impurities and the free-quantum coins are assigned at the other vertices. The initial state is given so that a quantum walker inflows into the perturbed region at every time step. It is shown that the scattering matrix of the quantum walk on the one-dimensional lattice can be explicitly described by using a path counting in [5] and this path counting method can be described by a discrete analogue of the Feynmann path integral [4]. There are some studies for the scattering theory of quantum walks under slightly general settings and related topics [6–12].

Such a setting is the special setting of [13,14] in that the regions where a quantum walker moves freely coincide with tails in [13,14], and the perturbed region can be regarded as a finite and connected graph in [13,14]. The properties of not only the scattering on the surface of the internal graph but also the stationary state in the internal graph for the Szegedy walk are characterized by [15] with a constant inflow from the tails.

**Citation:** Higuchi, K.; Komatsu, T.; Konno, N.; Morioka, H.; Segawa, E. A Discontinuity of the Energy of Quantum Walk in Impuritie. *Symmetry* **2021**, *13*, 1134. https://doi.org/10.3390/sym13071134

Academic Editor: Motoichi Ohtsu

Received: 29 May 2021 Accepted: 21 June 2021 Published: 24 June 2021

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

**Copyright:** © 2021 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/).

By [14], this quantum walk converges to a stationary state. Therefore, let *ϕ*(·): Z → C2 be the stationary state of the quantum walk on Z. The perturbed region is Γ*M* := {0, 1, . . . , *M* − 1} and we assign the quantum coin

$$\mathbf{C} = \begin{bmatrix} a & b \\ c & d \end{bmatrix}$$

to each vertex in Γ*M*. The inflow into the perturbed region at time *n* is expressed by *ωn* (|*ω*| = 1). In this paper, we compute (1) the scattering on the surface of the perturbed region Γ*M* in the one-dimensional lattice; (2) the energy of the quantum walk. Here, the energy of quantum walk is defined by

$$\mathcal{E}\_M(\omega) = \sum\_{x=0}^{M-1} \left| \left| \vec{q}(x) \right| \right|\_{\mathbb{C}^2}^2.$$

This is the quantity that quantum walkers accumulate to the perturbed region Γ*M* in the long time limit. We obtain a necessary and sufficient condition for the perfect transmitting, and also obtain the energy. As a consequence of our result on the energy, we observe a discontinuity of the energy with respect to the frequency of the inflow. Moreover, our result implies that the condition for *θ*(*ω*) ∈ N is equivalent to the condition for the perfect transmitting. Then, we obtain that the situation of the perfect transmitting not only releases quantum walker to the opposite outside but also accumulates quantum walkers in the perturbed region. Note that since this quantum walk can be converted to a quantum walk with absorption walls, the problem is reduced to analysis on a finite matrix *EM*, which is obtained by picking up from the total unitary time evolution operator with respect to the perturbed region Γ*M*. See [16] for a precise spectral results on *EM*.

This paper is organized as follows. In Section 2, we explain the setting of this model and give some related works. In Section 3, an explicit expression for the stationary state is computed using the Chebyshev polynomials. From this expression, we obtain the transmitting and reflecting rates and a necessary and sufficient condition for the perfect transmitting. We also give the energy in the perturbed region. In Section 4, we estimate the asymptotics of the energy to see the discontinuity with respect to the incident inflow.

### **2. The Setting of our Quantum Walk**

The total Hilbert space is denoted by H := 2(Z; C2) ∼= 2(*A*). Here *A* is the set of arcs of one-dimensional lattice whose elements are labeled by {(*x*; *R*),(*x*; *L*) | *x* ∈ Z}, where (*x*; *R*) and (*x*; *L*) represents the arcs "from *x* − 1 to *x*", and "from *x* + 1 to *x*", respectively. We assign a 2 × 2 unitary matrix to each *x* ∈ Z so-called local quantum coin

$$\mathbf{C}\_{\mathfrak{X}} = \begin{bmatrix} a\_{\mathfrak{X}} & b\_{\mathfrak{X}} \\ c\_{\mathfrak{X}} & d\_{\mathfrak{X}} \end{bmatrix}.$$

Putting |*L* := [1, 0]&, |*R* := [0, 1]& and *L*| = [1, 0], *R*| = [0, 1], we define the following matrix valued weights associated with the motion from *x* to left and right by

$$P\_{\mathfrak{x}} = |L\rangle\langle L|\mathbb{C}\_{\mathfrak{x}\_{\prime}} \ \ Q\_{\mathfrak{x}} = |R\rangle\langle R|\mathbb{C}\_{\mathfrak{x}\_{\prime}}$$

respectively. Then, the time evolution operator on 2(Z; C2) is described by

$$(\mathcal{U}\psi)(\mathfrak{x}) = P\_{\mathfrak{x}+1}\psi(\mathfrak{x}+1) + Q\_{\mathfrak{x}-1}\psi(\mathfrak{x}-1)$$

for any *ψ* ∈ 2(Z; C2). Its equivalent expression on 2(*A*) is described by

$$\begin{aligned} (\mathsf{U}'\phi)(\mathsf{x};\mathsf{L}) &= a\_{\mathsf{x}+1}\phi(\mathsf{x}+1;\mathsf{L}) + b\_{\mathsf{x}+1}\phi(\mathsf{x}+1;\mathsf{R}),\\ (\mathsf{U}'\phi)(\mathsf{x};\mathsf{R}) &= c\_{\mathsf{x}-1}\phi(\mathsf{x}-1;\mathsf{L}) + d\_{\mathsf{x}-1}\phi(\mathsf{x}-1;\mathsf{R}) \end{aligned} \tag{1}$$

for any *ψ* ∈ 2(*A*). We call *ax* and *dx* the transmitting amplitudes, and *bx* and *cx* the reflection amplitudes at *x*, respectively. If we put *ax* = *dx* = 1 and *bx* = *cx* = √ −1 = *i*, then the primitive form of QW in [17] is reproduced. Remark that *U* and *U* are unitarily equivalent such that letting *η* : 2(Z; C2) → 2(*A*) be

$$(\eta\psi)(\mathfrak{x};\mathbb{R}) = \langle \mathbb{R}|\psi\rangle,\ (\eta\psi)(\mathfrak{x};L) = \langle L|\psi\rangle$$

then we have *U* = *η*−1*U η*. The free quantum walk is the quantum walk where all local quantum coins are described by the identity matrix, i.e.,

$$(\mathcal{U}\_0 \psi)(\mathbf{x}) = \begin{bmatrix} 1 & 0 \\ 0 & 0 \end{bmatrix} \psi(\mathbf{x} + \mathbf{1}) + \begin{bmatrix} 0 & 0 \\ 0 & 1 \end{bmatrix} \psi(\mathbf{x} - \mathbf{1}).$$

Then, the walker runs through one-dimensional lattices without any reflections in the free case.

In this paper, we set "impurities" on

$$
\Gamma\_M := \{0, 1, \ldots, M - 1\}
$$

in the free quantum walk on one-dimensional lattice; that is,

$$\mathbb{C}\_{\mathbf{x}} = \begin{cases} \begin{bmatrix} a & b \\ c & d \end{bmatrix} & \colon \mathbf{x} \in \Gamma\_{M\prime} \\\\ I\_2 & \colon \mathbf{x} \notin \Gamma\_M . \end{cases} \tag{2}$$

We consider the initial state Ψ0 as follows.

$$\Psi\_0(\mathbf{x}) = \begin{cases} e^{i\frac{\pi}{6}\mathbf{x}}|R\rangle & : \mathbf{x} \le 0;\\ 0 & : \text{otherwise}. \end{cases}$$

where *ξ* ∈ R/2*π* Z. Note that this initial state belongs to no longer 2 category. The region Γ*M* is obtained a time dependent inflow *e*−*iξn* from the negative outside. On the other hand, if a quantum walker goes out side of Γ*M*, it never come back again to Γ*M*. We can regard such a quantum walker as an outflow from Γ*M*. Roughly speaking, in the long time limit, the inflow and outflow are balanced and obtain the stationary state with some modification. Indeed, the following statement holds.


Mentorship in Postgraduate Medical Education

*Lena Deb, Shanaya Desai, Kaitlyn McGinley, Elisabeth Paul, Tamam Habib, Asim Ali and Stanislaw Stawicki*

## **Abstract**

Mentorship is critical to the development and professional growth of graduate medical education (GME) trainees. It is a bidirectional relationship between a mentor and a mentee. Mentorship has consistently been shown to be beneficial for both the mentor and mentee, with the mentee gaining valuable skills in education, personal growth, and professional support, and the mentor attaining higher career satisfaction and potentially greater productivity. Yet, there is a lack of research and in-depth analysis of effective mentorship and its role in postgraduate medical education. This chapter outlines different approaches toward mentorship and provides the reader with basic concepts relevant to the effective and competent practice of mentorship. The authors discuss the challenges that physician mentors and mentees face, the organizational models of mentorship, the approaches and techniques for mentorship, and the deleterious effects of mentorship malpractice. Our general discussion touches on best practices for both the mentor and mentee to allow for self-improvement and lifelong learning. The variety of applicable models makes it difficult to measure effectiveness of mentorship in GME, but there is an ongoing need for expanded research on the benefits of mentorship, as greater amount of supporting evidence will likely incentivize organizations to create mentorshipfriendly policies and support corresponding institutional changes.

**Keywords:** Mentorship, Postgraduate medical education, Graduate medical education, Professional development


2.5.1. 2hJ(O–O)

Spin–spin coupling constants 2hJ(O–O) across the O–H ... O hydrogen bond are reported in Table 3. This coupling constant has a value of 12 Hz in the isolated monomer **1** and then decreases to about 10 Hz in the complexes when the acid interacts with **1** at the C=O bond. When interaction occurs at the O–H bond, 2hJ(O–O) increases to between 13 and 15 Hz. The value of 2hJ(O–O) obviously depends on the O–O distance, so it is not surprising that 2hJ(O–O) increases to about 24 Hz in the transition structures that have the shortest O–O distances. These relationships are seen most easily in Figure 6, which is a plot of 2hJ(O–O) versus the O–O distance. The second-order trendline has a correlation coefficient of 0.992.

**Figure 6.** 2hJ(O–O) versus the O–O distance for complexes **1**:acid.


**3. Making better crops through chloroplast engineering**

with balanced dose of micronutrients. Gene revolution is the only hope for second green revolution to attain these ideal crop cultivars [2]. Since the commercialization of transgenic crops in 1994, the area under GM crops is sharply increasing and has now increased to 180 million hectares. This includes crops for improved agronomic traits (herbicide tolerance and insect resistance, salinity and drought tolerance, and efficient nutrient utilization), enhanced level of micronutrients, and for the expression of therapeutic proteins and industrially important enzymes. At the same time, emotional or obsolete arguments are there to oppose the use of GM (genetically modified) products. Opponents of GM crops have straightforwardly rejected genetically modified products and have produced questionable scientific data to ban their commercialization. Plastid biotechnology has emerged as a competent field of research having potential to address all of the questions raised by the opponents of GM crops [3]. This chapter highlights significance of plastid transgenic technology to develop valuable crop plants. Further, technological advancements have been discussed to get an update about the recent research to resolve existing bottlenecks in the development and commercialization of transplastomic plants.

Transgenic technology is the technology of the day to develop crop plants with desired traits but crucial traits need to be engineered through plastid genome instead of nuclear genome [4]. It is an amazing organelle where more than 120 genes from various sources have been integrated and expressed. This organellar genome has well been explored for a wide variety of applications including crops with elevated level of resistance against biotic (insects, bacterial, viral, and fungal diseases) and abiotic stresses (salinity, drought, and cold); phytoremediation of toxic metals, cytoplasmic male sterility [5]; and production of biopharmaceuticals, vaccine antigens, industrial enzymes, biomaterials, and biofuel [6]. Hyperexpression of recombinant protein in plant expression system is only possible through plastid transformation. The high ploidy number of the plastid genome results in higher level of protein expression, and up to 70% total soluble protein is reported to be produced in tobacco [7]. Moreover, hyperexpression of therapeutic proteins and vaccine antigens in chloroplasts (leaves), leucoplasts (roots), or chromoplasts (fruits) makes it ideal organelle for the oral delivery of vaccine antigens against tetanus, cholera, anthrax, canine parvovirus, and plague [8]. Other salient advantages include possibility of multigene engineering, absence of gene silencing, position effect, epigenetic, complete absence of pleiotropic effects due to subcellular compartmentalization, and transgene containment due to maternal inheritance of plastids in most of the crops [9].

Plastid transformation was first established in unicellular green algae (*Chlamydomonas reinhardtii*) followed by model tobacco plant. It has now been well established in economically valuable crops (rice, brassica, cotton, carrot, spinach, lettuce, etc.) and even in woody plant like popular. Small circular plastid genome (plastome) facilitates targeted engineering, which has been exploited not only for basic research but also for the applied research [10]. Most of the genes present in plastome have been characterized through functional genomics. Organellar transcription and translation have been thoroughly elucidated to understand transcriptional and translational machinery of the plastids. Even the proteins involved in cross-talk between chloroplast and nucleus have been worked out. Further, plastid transformation is the most ideal

**2. Chloroplast biotechnology—an overview**

62 Transgenic Crops - Emerging Trends and Future Perspectives

It is predicted that sharply increasing population necessitates an increase in crop yield at 30% per annum. In this scenario, chloroplast biotechnology is the most ideal approach to develop crop plants with improved photosynthetic performance, enhanced nutritional value, improved agronomic traits, and producing valuable fatty acids. Plastid transformation was first established in flowering plants almost 30 years ago. Though it has been extended to other crop plants, most of the studies have been conducted in tobacco, which is nonfood nonfeed crop. This demands further efforts by the scientific community to engineer plastid genome of valuable crop plants for desired traits, leading to increased quality and quantity of food.

Most of the efforts to increase crop productivity had been made to improve photosynthetic performance of the plants. RuBisCO (the core enzyme of photosynthesis), large subunit, is encoded by chloroplasts, whereas small subunit is encoded by nuclease, which is then imported to chloroplast. Efforts have been made to engineer RuBisCO large subunit, small subunit, or both. Lin [11] attempted to express complete RuBisCO protein in tobacco from *Synechococcus elongatus* by disrupting the host native enzyme. CO2 fixation rate and carboxylase activity of the RuBisCO were increased, especially at higher concentrations of CO2 . Hence, photosynthetic performance can be improved by introducing more competent complete photosynthetic system into a plant. Raising concentration of CO2 in plastids is another possibility strategy, to improve photosynthetic carbon fixation and crop productivity. Cyanobacterial bicarbonate transporter was expressed in tobacco plastid genome, but any considerable improvement in photosynthetic performance was not observed. Expression of fructose-1,6-sedoheptulose-1,7-bisphosphatase in lettuce and tobacco chloroplasts appeared to increase productivity of engineered plants. Likewise, chloroplast-encoded chlB gene from *Pinus thunbergii* was found to promote root growth and early chlorophyll pigment development in tobacco [12]. Hence, research is in progress to engineer C3 plants to C4 by manipulating RuBisCO large subunit and photorespiratory pathway for enhanced biomass production [13].

Insect resistant crops had successfully been grown in the field since 1994. Resistance development against Bt crops is an emerging concern, which needs to be addressed through high-dose strategy and gene pyramiding. Another possibility to develop insect-resistant transplastomic plants is the upregulation of their pathogen defense mechanisms. Expression of β-glucosidase in tobacco plastome showed not only growth of the plants but also more resistance against insect pests [14]. A novel non-Bt-type insect resistance strategy has been evaluated by expressing dsRNA, targeting an essential insect gene in transplastomic plants. Disruption of target gene by RNA interference resulted in 100% mortality in adult beetles and in the larvae within 5 days of feeding [15]. Expression of agglutinin gene (pta) in leaf chloroplasts resulted in broad spectrum resistance against lepidopteran insects, aphids, and viral and bacterial pathogens [16]. A gene stack comprising CeCPI (sporamin, taro cystatin) gene from sweet potato and chitinase from *Paecilomyces javanicus* was introduced into tobacco, and resultant plants showed resistance not only against various pests and diseases but also against salinity, osmotic stress, and oxidative stress [17]. Expression of osmoprotectant (yeast trehalose phosphate synthase) in tobacco plastids resulted in 20-fold higher trehalose accumulation; as a result, plants were tolerant to drought and osmotic stress [18]. The overexpression of *mdar* transgene in tobacco plastids and the fusion of such chloroplasts to Petunia cells were suggested to possibly protect the plants against oxidative stress. Oxidative stress tolerance was also enhanced in transplastomic tobacco plants expressing flavodoxin (fld) from cyanobacteria. Transplastomic plants overexpressing panD not only appeared to produce 30–40% higher biomass but also appeared to be more tolerant to increased heat stress. Similarly, expression of arabitol dehydrogenase (*ArDH)* in tobacco chloroplasts enabled them to survive even at 400 mM NaCl [19]. Chilling tolerance as well as growth was observed to be increased in tropical forage *Stylosanthes guianensis* expressing chloroplast protein 12 [20]. Recently, plastid transformation has been reported in a valuable vegetable *Momordica charantia* [21], marine microalga *Nannochloropsis oceanica* [22], and *Cyanidioschyzon merolae* [23]*,* a red alga having ability to survive in high sulfur acidic hot spring environments. This may open new horizons in understanding stress adaptability and role of transplastomic technology in developing stress-tolerant plants.

calcium uptake machinery is present on the membranes; so, the thylakoid membrane may be the major sequester of Ca2+ in chloroplasts [28]. It was further elucidated that activity of these transporters is regulated by light or photosynthesis, so chloroplasts take up calcium during the day and store it in the lumen or some identified sequestering sites. During the night, Ca2+ is released from the store houses for long-lasting, dark-induced Ca2+ signals; hence, sensing of photoperiod and light/dark transition seems to be regulated by Ca2+ signaling. In addition to light, Ca2+ signaling is also influenced by other abiotic stimuli (salinity, cold) and hence plays

An active Ca2+ uptake machinery is present in chloroplast, which is regulated by transporters. Much research has not been conducted on these transporters; as a result, only few are known, whereas others are still to be elucidated. Two potential membrane transporters (Ca2+-ATPase) in *Arabidopsis* are AtACA1 and AtHMA1. AtACA1 is an autoinhibited Ca2+ transporter, which is predicted to be targeted to the chloroplasts. It is specifically expressed in the root and is then localized to endoplasmic reticulum or tonoplast. AtHMA1 is a heavy metal P-type ATPase in the chloroplast envelope and plays an important role in calcium transportation [29]. Recently, another transporter AtGLR3.4 (glutamate receptor) has been explored to form Ca2+ permeable nonselective cation channels and is localized in the chloroplasts [30]. In addition, two MscS homologs, localized in the chloroplast, have also been evaluated to be essential for plastidic osmoregulation [31]. Since these transporters play a

plays a significant role in Ca2+ uptake via thylakoid proton gradient. Pea thylakoid protein (PPF1) is another candidate calcium transporter at thylakoid membrane, which has been found to enhance Ca2+ currents when tested in human cultured cells. These findings demonstrate that Ca2+-binding protein and Ca2+ transporters play a significant role in immune signal transduction pathway. Anyhow, most of the genes involved in these pathways are

Plastids are known to get evolved from primitive cyanobacteria through a process known as endosymbiosis [32]. Although plastid genomes are much smaller as compared to their cyanobacterial progenitors, similarities in gene sequence as well as genome topology are evident. Just like cyanobacterial genome, plastid genomes are tightly packed with genes as a circular molecule [33]. *In vivo* genes of plastid may be present as a linear molecule or a complex branched form, and many copies of plastid genome can be harbor in each organelle. Size of plastid genomes varies from <100 to >1000 kbp (kilobase pair). The region of small single copy (SSC) and large single copy (LSC) are separated by two inverted repeats (IRs) present in the plastid genome (**Figure 1**). The thymine and adenine residues are often rich in plastid genome; a reductive evolution is also seen in those of mitochondrial genomes and bacterial endosymbionts [34]. Noncoding DNAs are abundantly present in some plastid genomes, while the others have self-splicing introns. The genome of some dinoflagellates spreads across a sea of minicircles; recently, multiple linear chromosomes formed a hairpin structure, which

antiporter also

Technical Advances in Chloroplast Biotechnology http://dx.doi.org/10.5772/intechopen.81240 65

key role in the sequestration of calcium ions into the thylakoid lumen, Ca2+/H+

**5. Advances in plastid functional genomics**

have been found in the plastid genome of certain green algae [35].

some crucial role in stress tolerance as well.

still to be elucidated.

#### **4. Chloroplasts as trouble-rescue organelles**

Chloroplasts not only are the central hubs for photosynthesis but also have evolved as fundamental trouble-rescue organelles. Recent studies have revealed that chloroplasts play a key role in switching plants from vegetative mode to defense mode. In addition to intraorganellar functions, they also play crucial role in the regulation of extraorganellar processes such as plant stress response, apoptosis, and immunity. Both of the cellular organelles (chloroplast and mitochondria) evoke their own particular Ca2+ signals [24], have their own Ca2+ binding proteins, and Ca2+ sensors, which are expected to play a significant role in Ca2+ signaling within the plant cell [25]. As a result, they have capacity to sequester and serve as sink for Ca2+, which plays a key role in physiological and environmental responses of eukaryotic cells.

Chloroplasts are important intracellular calcium (Ca2+) stores and may accumulate up to 15 mM or even higher. Most of the plastidic Ca2+ resides within the stroma or thylakoid membranes through interaction with calcium-binding proteins [26]. The concentration of free calcium was found to be very low when determined by targeting apoaequorin to the stroma of tobacco chloroplasts [27]. Hence, stroma is not the major sequester of Ca2+ in chloroplasts. This helped to elucidate that chloroplasts have their own active transporters on the envelope membranes, which help them to accumulate high concentrations of Ca2+ within the thylakoid membranes or some other unidentified Ca2+ stores. Identification of CAS (high capacity Ca2+ binding protein) in the thylakoid membranes of *Arabidopsis thaliana* revealed out that active calcium uptake machinery is present on the membranes; so, the thylakoid membrane may be the major sequester of Ca2+ in chloroplasts [28]. It was further elucidated that activity of these transporters is regulated by light or photosynthesis, so chloroplasts take up calcium during the day and store it in the lumen or some identified sequestering sites. During the night, Ca2+ is released from the store houses for long-lasting, dark-induced Ca2+ signals; hence, sensing of photoperiod and light/dark transition seems to be regulated by Ca2+ signaling. In addition to light, Ca2+ signaling is also influenced by other abiotic stimuli (salinity, cold) and hence plays some crucial role in stress tolerance as well.

An active Ca2+ uptake machinery is present in chloroplast, which is regulated by transporters. Much research has not been conducted on these transporters; as a result, only few are known, whereas others are still to be elucidated. Two potential membrane transporters (Ca2+-ATPase) in *Arabidopsis* are AtACA1 and AtHMA1. AtACA1 is an autoinhibited Ca2+ transporter, which is predicted to be targeted to the chloroplasts. It is specifically expressed in the root and is then localized to endoplasmic reticulum or tonoplast. AtHMA1 is a heavy metal P-type ATPase in the chloroplast envelope and plays an important role in calcium transportation [29]. Recently, another transporter AtGLR3.4 (glutamate receptor) has been explored to form Ca2+ permeable nonselective cation channels and is localized in the chloroplasts [30]. In addition, two MscS homologs, localized in the chloroplast, have also been evaluated to be essential for plastidic osmoregulation [31]. Since these transporters play a key role in the sequestration of calcium ions into the thylakoid lumen, Ca2+/H+ antiporter also plays a significant role in Ca2+ uptake via thylakoid proton gradient. Pea thylakoid protein (PPF1) is another candidate calcium transporter at thylakoid membrane, which has been found to enhance Ca2+ currents when tested in human cultured cells. These findings demonstrate that Ca2+-binding protein and Ca2+ transporters play a significant role in immune signal transduction pathway. Anyhow, most of the genes involved in these pathways are still to be elucidated.


**Worker and Public Health and Safety Current Views**

Sara Lal, Thomas Penzel and Ann M. Simpson Edited by

Printed Edition of the Special Issue Published in *International Journal of Environmental Research and Public Health*

www.mdpi.com/journal/ijerph


*5.2. Some Important Bioactive Compounds and Food Properties Are Still Missing*

Another limitation is often observed worldwide and consists of missing values for some important key nutrients, e.g., lipotropic compounds (such as choline, betaine, and myo-inositol) and phytic acid, but also for other characteristics of nutrients or foods, such as soluble and insoluble fibre (with different physiological effects), resistant starch, and glycaemic index [65]. It is true that some FDBs report choline content such as the USDA Database for the Choline Content of Common Foods, Release 2 (2008) [66], or the phytic acid content such as the FAO/INFOODS/IZiNCG, Global Food Composition Database for Phytate (2018) [67], or the glycaemic index [68], but this should be completed and extrapolated to other FDBs more broadly in the future, e.g., the French CIQUAL database [16].


**3. Treatment planning for cleft lip and palate patients**

The treatment of cleft lip and palate should be started right after birth. Treatment for cleft children requires a multidisciplinary approach including: facial surgery in the first months of life, preventive and interceptive treatment in primary dentition, speech therapy, orthodontics in the mixed dentition phase, oral and maxillofacial surgery, and implant and prosthetics in adults. So the treatment to achieve a proper occlusion and function often lasts from birth until adulthood. Patients with cleft lip and palate routinely require extensive and prolonged orthodontic treatment. Close cooperation between the orthodontist, surgeon, prosthodontist, and general dentist is required. Cleft lip and palate patients should be carefully evaluated by the craniofacial team in order to detect potentially serious deformities that can be associated with cleft lip and palate. The team conception allows a systematic treatment plan to be developed and allows the team members to work together properly to identify problems. Maxillary deficiency is a common developmental problem in cleft lip and palate patients. The treatment objectives are to correct the deficient maxillary arch, the anterior and posterior cross bites, correct misaligned maxillary incisors, and also obtain satisfactory overjet and overbite. The following general and local factors must be evaluated before planning any treatment.

#### **3.1. General factors**

cleft lip and palate in patients should be started after birth and continues to adulthood. Lip closure and palatal closure are performed at 3 months and around 12 months of age, respectively, as well as secondary alveolar bone graft is done between 9 and 12 years of age [9]. However, orthodontic intervention usually begins during the mixed dentition. Orthodontic treatment in patients with cleft lip and palate are focused on maxillary arch expansion, correction of upper incisor misalignments, gross rotations of incisors, and crossbites and correction of Class III skeletal growth pattern. Patients with cleft lip and/or palate should be treated by teamwork. The team conception allows a systematic treatment plan to be developed and allows the team members to work together properly to identify problems. Orthodontic treatment plan can be divided into the following stages based on the dentition stages: (1) presurgical orthopedics, (2)

In the following sections about diagnosis, classification, and treatment options in different period of time are discussed. Therefore, the aim of this chapter is to assess a rational teamwork approach to the management of the patient with cleft lip and/or palate from birth to

Ultrasonography serves as a noninvasive diagnostic tool, now regularly recommended as a routine component of prenatal consideration. This noninvasive diagnostic tool helps to determine gestational age, confirm fetal viability, check placental location, establish the growth and their number of fetuses, and examine fetal anatomy to detect any deformities [10].

The treatment of cleft lip and palate should be started right after birth. Treatment for cleft children requires a multidisciplinary approach including: facial surgery in the first months of life, preventive and interceptive treatment in primary dentition, speech therapy, orthodontics in the mixed dentition phase, oral and maxillofacial surgery, and implant and prosthetics in adults. So the treatment to achieve a proper occlusion and function often lasts from birth until adulthood. Patients with cleft lip and palate routinely require extensive and prolonged orthodontic treatment. Close cooperation between the orthodontist, surgeon, prosthodontist, and general dentist is required. Cleft lip and palate patients should be carefully evaluated by the craniofacial team in order to detect potentially serious deformities that can be associated with cleft lip and palate. The team conception allows a systematic treatment plan to be developed and allows the team members to work together properly to identify problems. Maxillary deficiency is a common developmental problem in cleft lip and palate patients. The treatment objectives are to correct the deficient maxillary arch, the anterior and posterior cross bites, correct misaligned maxillary incisors, and also obtain satisfactory overjet and overbite. The

following general and local factors must be evaluated before planning any treatment.

primary dentition, (3) mixed dentition, and (4) permanent dentition.

**3. Treatment planning for cleft lip and palate patients**

adulthood.

**2. Diagnostic considerations**

24 Designing Strategies for Cleft Lip and Palate Care

#### **3.2. Local factors**

#### **3.3. Interceptive treatment**

Interceptive treatment is recommended because it can

#### **3.4. Cleft lip repair**

The aim of lip repair is to close the cleft to create esthetics of the face and to restore muscular anatomy of the upper lip. This procedure will serve to develop lip normally with minimal scar tissue. Closure of the lip is accomplished by the plastic or maxillofacial surgeon when the patient is approximately 3 months of age and weighs at least 10 pounds.

#### **3.5. Cleft palate repair**

The objective of cleft palate surgery is to close the palate to restore normal function to eating and drinking and to enhance the development of normal speech. The palate forms the floor of the nose and the roof of the oral cavity; thus, a cleft causes a free communication between these two cavities. Treatment of cleft lip and palatal patients is complex because of potential problems with middle ear infections, speech, feeding, occlusion, creating maxillary deficiency due to scar tissue from surgical procedure, and jaw abnormalities. Surgical procedure of the cleft palate is best performed before the child reaches 12 months of age. This procedure is called palatoplasty. Additional surgeries are often needed to achieve the best results [9].

#### **3.6. Nursing care**

The role of nursing in the care of patients and or families includes family education, case management, access to team care, assistance with infant feeding, consultation, research, and primary care.

#### **3.7. Feeding problems**

An infant with a cleft may have difficulty in feeding due to lack of suction. Cleft lip patients do not usually have feeding problems. But when the palate is involved, feeding can be a crucial challenge. Normally, the palate serves as a barrier to prevent food and liquids from entering the nose. A patient with cleft palate swallows a lot of air and regurgitates food into the nose. Cleft palate patients may need a special bottle and nipple to receive milk. Patients with feeding problems should be visited regularly by a specialist to make sure that they are gaining weight well.

#### **3.8. Speech problems**

Difficulty in speech is the number one issue for cleft patients after facial and dental esthetics. They have difficulty in speaking correctly, and treatment can help them to achieve a good tongue posture. Difficulty with speech articulation is common in cleft lip and palate patients. Many patients require speech therapy after surgery. Speech therapist will repeatedly evaluate speech development and will arrange for necessitate speech therapy.

#### **3.9. Dental problems**

Dental problems have an effect on chewing, facial esthetics, speech thus these patients frequently require orthodontic treatment. Prevalence of dental anomalies such as variations in tooth number, dislocation, missing, supernumerary, tooth shape, and reduced tooth dimensions has always been found to be higher in cleft lip and or palate patients when compared with general population [11]. Akcam et al. [12] reported that a significant amount (96.7%) of children with cleft had at least one dental irregularity. Shapira et al. [13] found that in the cleft area, most developmental dental anomalies are related to the maxillary lateral incisor, both in the primary and in the permanent dentitions. Shape anomalies, such as enamel hypoplasia and peg shaped, have also been frequently seen in cleft lip and/or palate patients [14]. Tooth agenesis, known as hypodontia or congenital absence of teeth, is the most commonly detected developmental abnormality of the human dentition. All types of clefts are often associated with congenitally missing teeth [15]. Jiroutova and Mullerova [16] studied the frequency of hypodontia in cleft lip and or palate patients and found that the maxillary dentition was affected more often in cleft lip and palate, the mandible was involved more frequently in isolated cleft palate. The dental bud of the upper lateral incisor was affected most commonly in cleft lip and in cleft lip and palate, whereas the second lower premolar was most frequently absent in an isolated cleft palate. Paranaiba et al. studied prevalence of dental abnormalities in patients with nonsyndromic cleft lip and/or palate in Brazilian population and found that agenesis of the premolars and maxillary lateral incisors were significantly more frequent in patients with unilateral complete cleft lip and palate [17]. In various studies, lateral incisors were reported to be the most commonly missing teeth followed by second premolars [12, 18, 19]. While, in a another study Laatikainen and Ranta [20] found that the maxillary second premolar was the most frequently absent tooth, followed in order of frequency by the upper lateral incisor and the mandibular second premolar.

Polder et al. [21] did a meta-analysis of the prevalence of dental agenesis of permanent teeth of Caucasian populations in North America, Australia, and Europe and found that mandibular second premolar was the most affected tooth, followed by the upper lateral incisor and the upper second premolar. Shapira et al. [22] found a total of 47 missing second premolars in the upper arch and 23 missing in the mandible. In literature, Ranta [23] reported that the incidence of hypodontia rises strongly with the severity of cleft. Paranaiba et al. [17] also found that patients with unilateral cleft lip and palate were affected more significantly by dental anomalies than those with bilateral cleft lip and palate. It should be considered that ethnicity also plays an important role in prevalence of cleft and associated anomalies. Polder et al. reported that prevalence of dental agenesis in Europe and Australia was higher than in North America. In addition, they reported that the prevalence of dental agenesis in females is 1.37 times higher than in males for all three continents. Defects of enamel such as hypoplasia and opacities are common in the teeth adjacent to the cleft site. Decay is higher in these patients compared with the non-cleft populations. Therefore there is a higher incidence of caries in teeth with enamel defects, the issues of prevention and brushing are of great importance in cleft children [24].

#### **3.10. Role of psychologist in cleft lip and palate patients**

**3.6. Nursing care**

26 Designing Strategies for Cleft Lip and Palate Care

primary care.

**3.7. Feeding problems**

gaining weight well.

**3.8. Speech problems**

**3.9. Dental problems**

The role of nursing in the care of patients and or families includes family education, case management, access to team care, assistance with infant feeding, consultation, research, and

An infant with a cleft may have difficulty in feeding due to lack of suction. Cleft lip patients do not usually have feeding problems. But when the palate is involved, feeding can be a crucial challenge. Normally, the palate serves as a barrier to prevent food and liquids from entering the nose. A patient with cleft palate swallows a lot of air and regurgitates food into the nose. Cleft palate patients may need a special bottle and nipple to receive milk. Patients with feeding problems should be visited regularly by a specialist to make sure that they are

Difficulty in speech is the number one issue for cleft patients after facial and dental esthetics. They have difficulty in speaking correctly, and treatment can help them to achieve a good tongue posture. Difficulty with speech articulation is common in cleft lip and palate patients. Many patients require speech therapy after surgery. Speech therapist will repeatedly evaluate

Dental problems have an effect on chewing, facial esthetics, speech thus these patients frequently require orthodontic treatment. Prevalence of dental anomalies such as variations in tooth number, dislocation, missing, supernumerary, tooth shape, and reduced tooth dimensions has always been found to be higher in cleft lip and or palate patients when compared with general population [11]. Akcam et al. [12] reported that a significant amount (96.7%) of children with cleft had at least one dental irregularity. Shapira et al. [13] found that in the cleft area, most developmental dental anomalies are related to the maxillary lateral incisor, both in the primary and in the permanent dentitions. Shape anomalies, such as enamel hypoplasia and peg shaped, have also been frequently seen in cleft lip and/or palate patients [14]. Tooth agenesis, known as hypodontia or congenital absence of teeth, is the most commonly detected developmental abnormality of the human dentition. All types of clefts are often associated with congenitally missing teeth [15]. Jiroutova and Mullerova [16] studied the frequency of hypodontia in cleft lip and or palate patients and found that the maxillary dentition was affected more often in cleft lip and palate, the mandible was involved more frequently in isolated cleft palate. The dental bud of the upper lateral incisor was affected most commonly in cleft lip and in cleft lip and palate, whereas the second lower premolar was most frequently absent in an isolated cleft palate.

speech development and will arrange for necessitate speech therapy.

It is clear that attractive children are seen by others as happier, having more positive social behavior. Children with cleft may have a less attractive appearance and speech problems make it worst. Babies may face bullying and teasing because of their appearance. Parents may be more tolerant of misbehavior in their child and are more likely to spoil their child by being overprotective. Moreover, peer interaction also has an important role in maintaining psychosocial problems. Cleft lip and palate patients are at high risk for developing psychosocial problems especially those relating to self-concept, peer relationships, and appearance. Psychological problems affect development of children with cleft lip and palate. Therefore, these patients are treated by the interdisciplinary team to maximize positive outcome of treatment. Missing teeth, feeding difficulties, the infant's appearance, presence of misaligned teeth, and severe malocclusion can lead to social isolation. Moreover, frequent visits to the doctor and surgeries can be quite stressful. The psychologist provides treatment plan for developmental, emotional, learning, and adjustment abnormalities. They focused on the appearance, speech, patient's self-esteem, psychosocial problems, self-confidence, interpersonal relationships, and emotional handicapped problems [25].

#### **3.11. Role of otolaryngologist in cleft lip and palate patients**

Patients with cleft lip and palate have a higher incidence of hearing problems. They have more frequent problems with fluid, ear infections, and otitis media, which can be very painful. It is crucial that to have the infant's hearing tested during the first few months and it is also very important that cleft lip and palate patients have regular hearing tests to screen middle ear problems. This could adjust the development of normal hearing as well as speech. As the child gets older, the rate of ear infections seems to reduce. Any abnormality of the upper airway can affect the function of the Eustachian tube and enhance the possibility of persistent fluid in the middle ear, which is a major cause of repeated ear infections. Hearing loss can be a consequence of repeat ear infections and persistent middle ear fluid. Tubes can be inserted in the ear by an otolaryngologist to relieve fluid build-up and repair hearing. Cleft lip and palate patients are suffering from mouth breathing, feeding, hearing, speech problems, and jaw deformities. There are some areas of overlap with plastic surgery, oral and maxillofacial surgery, otolaryngology, and speech-language pathology. Oral and maxillofacial surgeon evaluates the skeletal discrepancies related to cleft and craniofacial abnormalities such as maxillary deficiency and other skeletal malocclusions. Surgeons work with other members of the group to ensure appropriate and harmonious facial form and dental arch.

#### **3.12. Role of pedodontist in cleft lip and palate patients**

The role of pediatric dentistry in treatment of cleft lip and palate cleft patients is the comprehensive preventative and therapeutic oral health care of children, counseling and caries control. These treatments include following steps:

#### **3.13. Role of orthodontist in cleft lip and palate patients**

In the management of cleft lip and palate patients the orthodontist has an important role in the cleft and craniofacial team. They are involved with diagnosis of facial morphology, guidance of the growth and development of the face, occlusion, dentition, and jaw discrepancy of the patients with cleft or craniofacial syndromes. They provide orthodontic and orthopedic treatment and general expertise for consultation with all of the other members of the cleft team. Different phases of active treatment will be necessary from birth to adulthoods. Orthodontist should consider many factors in determining when to initiate orthodontic treatment. These factors include the ability of the patient to cooperate, the severity of the malocclusion, the amount of jaw discrepancy, type of dental anomalies, existence of missing, dental shape anomalies, supernumerary teeth, and the need for future orthodontic treatment in the early mixed or permanent dentitions.

Orthodontic treatment plan can be divided into following stages based on the time of treatment:

(1) Presurgical orthopedics

**3.11. Role of otolaryngologist in cleft lip and palate patients**

28 Designing Strategies for Cleft Lip and Palate Care

to ensure appropriate and harmonious facial form and dental arch.

**3.12. Role of pedodontist in cleft lip and palate patients**

control. These treatments include following steps:

(b) Caries prevention and oral hygiene guidance.

(f) Interceptive orthodontics where appropriate.

(h) Removal of primary dentition in surgical site.

**3.13. Role of orthodontist in cleft lip and palate patients**

(a) Growth and development monitoring.

(e) Preventive and interceptive dentistry.

(c) Behavior modifications.

(g) Restorative procedures.

(i) Periodontal considerations.

(d) Routine dental care.

Patients with cleft lip and palate have a higher incidence of hearing problems. They have more frequent problems with fluid, ear infections, and otitis media, which can be very painful. It is crucial that to have the infant's hearing tested during the first few months and it is also very important that cleft lip and palate patients have regular hearing tests to screen middle ear problems. This could adjust the development of normal hearing as well as speech. As the child gets older, the rate of ear infections seems to reduce. Any abnormality of the upper airway can affect the function of the Eustachian tube and enhance the possibility of persistent fluid in the middle ear, which is a major cause of repeated ear infections. Hearing loss can be a consequence of repeat ear infections and persistent middle ear fluid. Tubes can be inserted in the ear by an otolaryngologist to relieve fluid build-up and repair hearing. Cleft lip and palate patients are suffering from mouth breathing, feeding, hearing, speech problems, and jaw deformities. There are some areas of overlap with plastic surgery, oral and maxillofacial surgery, otolaryngology, and speech-language pathology. Oral and maxillofacial surgeon evaluates the skeletal discrepancies related to cleft and craniofacial abnormalities such as maxillary deficiency and other skeletal malocclusions. Surgeons work with other members of the group

The role of pediatric dentistry in treatment of cleft lip and palate cleft patients is the comprehensive preventative and therapeutic oral health care of children, counseling and caries

In the management of cleft lip and palate patients the orthodontist has an important role in the cleft and craniofacial team. They are involved with diagnosis of facial morphology, guidance of the growth and development of the face, occlusion, dentition, and jaw discrepancy of the patients with cleft or craniofacial syndromes. They provide orthodontic and ortho-

#### *3.13.1. Presurgical orthopedics*

Presurgical infant orthopedics is sometimes used to relocate the segments of the cleft in maxilla prior to lip repair. A custom-fitted orthodontic appliance is applied to bring the parts of the lips, upper jaw, and nose closer together. This is called Nasoalveolar Molding (NAM). These appliances can make lip closure easier.

Advantages of presurgical orthopedics:

Although the evidence does not support the neonatal maxillary orthopedics as an essential or desirable routine procedure; Nonetheless, the molding of the segments achieved by these appliances does make definitive lip repair easier for the surgeon, especially for patients with a severely protruding premaxilla caused by a bilateral cleft lip [26].

#### *3.13.2. During primary dentition*

Midfacial deficiency is a common feature of cleft lip and palate patients due to scar tissue of the lip and palate closure [25]. During deciduous dentition, no orthodontic and orthopedic treatments are given because it has limited advantage. Orthodontic and orthopedic intervention starts in the mixed dentition.

#### *3.13.3. During mixed dentition*

Early orthopedic treatment in cleft palate children is essential because the maxillary bones and their component parts may be moved and altered in young children with relative ease and thereby creates a more functional dental arch. Orthodontic interventions in patients with cleft palate are focused at correction of Class III skeletal growth pattern, maxillary arch expansion, correction of upper incisor misalignments, gross rotations of incisors, and cross bite of buccal segments. Maxillary deficiency may be a reflection of the underlying skeletal abnormality for which growth modification and redirection may be indicated with a protraction headgear. Treatment approach to improve the midface deficiency was achieved by using the face mask [2, 27], tongue appliance [6], tongue plate [27], protraction head gear [3, 28], suborbital protraction appliances [4], ankylosed teeth [29], endosseous implants [30], and surgically assisted orthopedic protraction and distraction osteogenesis [8]. Jamilian et al. [6] evaluated the effectiveness of tongue appliance on deficient maxilla in growing cleft lip and palate patients. They showed that tongue appliance improved the deficient maxilla.

Tongue appliance has Adams clasp in first maxillary molars and C clasps in the upper incisors and deciduous teeth in order to increase the retention. A screw is mounted in midpalatal area to correct bilateral posterior crossbite. It was activated twice a week by the patient. Four separate tongue cribs were incorporated in the palatal area, behind the upper incisors. These cribs are long enough to cage the tongue and are adjusted in the clinic to avoid traumatizing the floor of the mouth. Tongue appliance is seen in **Figure 1**. **Figure 2** shows the profile of the patient before application of the tongue appliance and **Figure 3** shows the profile of the same patient after using the appliance. Extraoral appliances are not used suitably by the patients, whereas they prefer to apply small-sized and more convenient appliances. Besides to their large size of extraoral appliances, they need high compliance and many clinicians observe lack of cooperation by patients treated by big extraoral appliances. The philosophy of tongue appliance [31–33] is provided in the following two ways:

The more anterior the tongue, the greater pressure will be. The more posterior the crib, the greater pressure will be. Jamilian et al. [6] reported that the anterior part of maxillary plane moved superiorly (anteinclination) and posterior part of it relocated inferiorly. In other words, the maxillary posterior segment is extruded slightly and that is why the lower jaw rotated in a clockwise direction. These changes led to correction of the overjet and reducing of SNB and increasing of mandibular plane angle. Click wise rotation of the mandible is not favorable in long face patients.

**Figure 1.** Tongue appliance with expansion screw.

treatments are given because it has limited advantage. Orthodontic and orthopedic interven-

Early orthopedic treatment in cleft palate children is essential because the maxillary bones and their component parts may be moved and altered in young children with relative ease and thereby creates a more functional dental arch. Orthodontic interventions in patients with cleft palate are focused at correction of Class III skeletal growth pattern, maxillary arch expansion, correction of upper incisor misalignments, gross rotations of incisors, and cross bite of buccal segments. Maxillary deficiency may be a reflection of the underlying skeletal abnormality for which growth modification and redirection may be indicated with a protraction headgear. Treatment approach to improve the midface deficiency was achieved by using the face mask [2, 27], tongue appliance [6], tongue plate [27], protraction head gear [3, 28], suborbital protraction appliances [4], ankylosed teeth [29], endosseous implants [30], and surgically assisted orthopedic protraction and distraction osteogenesis [8]. Jamilian et al. [6] evaluated the effectiveness of tongue appliance on deficient maxilla in growing cleft lip and palate patients. They

Tongue appliance has Adams clasp in first maxillary molars and C clasps in the upper incisors and deciduous teeth in order to increase the retention. A screw is mounted in midpalatal area to correct bilateral posterior crossbite. It was activated twice a week by the patient. Four separate tongue cribs were incorporated in the palatal area, behind the upper incisors. These cribs are long enough to cage the tongue and are adjusted in the clinic to avoid traumatizing the floor of the mouth. Tongue appliance is seen in **Figure 1**. **Figure 2** shows the profile of the patient before application of the tongue appliance and **Figure 3** shows the profile of the same patient after using the appliance. Extraoral appliances are not used suitably by the patients, whereas they prefer to apply small-sized and more convenient appliances. Besides to their large size of extraoral appliances, they need high compliance and many clinicians observe lack of cooperation by patients treated by big extraoral appliances. The philosophy of tongue

(1) The force of the tongue during each swallowing might be 5 pounds. Each patient might have 500–1200 times swallowing in 24 hours. The pressure from the tongue is transferred

(2) There is substantial continuous pressure of tongue. Because tongue is caged behind the cribs that is why this force is continuous in the rest position and centric occlusion. This force pushes the nasomaxillary complex into a forward position. In other words, functional activity and physiological position of tongue create these considerable forces that are conducted by tongue through the palatal cribs and finally transmitted to the deficient

The more anterior the tongue, the greater pressure will be. The more posterior the crib, the greater pressure will be. Jamilian et al. [6] reported that the anterior part of maxillary plane moved superiorly (anteinclination) and posterior part of it relocated inferiorly. In other words, the maxillary posterior segment is extruded slightly and that is why the lower jaw

showed that tongue appliance improved the deficient maxilla.

appliance [31–33] is provided in the following two ways:

maxilla and nasomaxillary complex.

through the tongue appliance to the deficient maxilla.

tion starts in the mixed dentition.

30 Designing Strategies for Cleft Lip and Palate Care

*3.13.3. During mixed dentition*

**Figure 2.** Profile view before treatment.

**Figure 3.** Profile view after treatment.

Tongue plate has been used for correction of maxillary deficiency [27]. Mechanism of tongue plate [7] is very similar to the tongue appliance. The pressure of tongue during rest position and swallowing is transmitted through the tongue plate to the deficient maxilla. The significant pressure of the tongue that is caged behind the acrylic plate transfers the nasomaxillary complex in a forward position. Some patients had some extent of irritation on the tongue from tongue appliance that is why tongue appliance was replaced by tongue plate. This has a smoothed area and these softened edges create it undamaging for the patient. Moreover, it is adjusted in a way to avoid traumatizing the floor of the mouth. Elimination of the cribs in tongue plate might offer a better psychological sense to the patients. Extra oral appliances such as facemask and reverse chin cup [5, 34] improve the deficient nasomaxillary complex but they have an unfavorable effect on the normal mandible. Extra oral appliances rotate the mandible in clockwise rotation and it is unfavorable in normal growth pattern and long face patients. Besides, the cup of facemask can create abrasion particularly in warm climates. Tongue appliance is an intraoral appliance and it is very comfortable and simple. It is constructed easily and it is not expensive. Tongue appliance and tongue plate will be accepted better than extraoral appliances due to less conspicuous of them. Children with cleft lip and palate have suffered from birth; tongue plate and tongue appliance are more comfortable as they create the least stress to patients in comparison with other big extraoral appliances. In spite of many advantages of them, tongue appliance and tongue plate have one disadvantage. Incisor mandibular angle is reduced due to removal of the pressure of tongue to the lower incisors and acting force of orbicularis oris to them. Tongue appliance and tongue plate have a screw to correct bilateral posterior crossbite. Expansion will lose all maxillary sutures like zygomaxillary, pterygomaxillary, thus, maxilla will transfer more easily in forward direction [35, 36]. On the other hand, upper jaw may be expanded in order to improve dental function, reliving crowding, align upper incisors, eliminate functional shifts, provide access for impacted teeth in the cleft site, provide restorative treatment to carious teeth, improve maxillary deficiency, and nasal airway in mixed dentition [6, 31]. Maxillary skeletal asymmetry in unilateral lip and palate patients may be reflected in a unilateral posterior cross bite, which may be corrected with a removable appliance with a screw or a quad helix type of appliance in the mixed dentition. A bonded or non-bonded hyrax expander are recommended along with extra oral traction, such as facial mask to stimulate maxillary protraction or chin cup to control mandibular growth (**Figures 4** and **5**). Patients with maxillary cleft do not have a midpalatal suture, which requires orthopedic forces to open. Instead there is a midpalatal cleft covered with scarred and repaired palatal tissues limiting the rate and amount of expansion. The slower rate of expansion and the lower force magnitude provided by a quad helix appliance allows the soft tissue of the palate to the increasing maxillary width, avoiding a breakdown of the scar tissue that can result in an oronasal fistula. As the permanent incisors erupt adjacent to the cleft site, maxillary incisors typically are rotated, misplaced, malformed, or hypo plastic. Removable appliance is used to correct upper incisor misalignment. Moreover, incisors may be absent or peg shaped and there may be one or some supernumerary teeth. Maxillary expansion appliances can be anchored on the permanent first molars and extended anteriorly to improve maxillary arch while correcting the cross bite. Usually expansion is followed by maxillary protraction using a traditional Delaire or other protraction appliances. After the expansion and protraction phase, full fixed appliances along with Class III elastics and sometimes extractions, if necessary, are usually needed to correct the malocclusion [33]. **Figures 6** and **7** show the intraoral photograph of a patient before and after orthodontic treatment, respectively. **Figures 8** and **9** show the frontal view of the same patient in pre- and postorthodontic treatment, respectively.

**Figure 4.** Upper arch before expansion.

Tongue plate has been used for correction of maxillary deficiency [27]. Mechanism of tongue plate [7] is very similar to the tongue appliance. The pressure of tongue during rest position and swallowing is transmitted through the tongue plate to the deficient maxilla. The significant pressure of the tongue that is caged behind the acrylic plate transfers the nasomaxillary complex in a forward position. Some patients had some extent of irritation on the tongue from tongue appliance that is why tongue appliance was replaced by tongue plate. This has a smoothed area and these softened edges create it undamaging for the patient. Moreover, it is adjusted in a way to avoid traumatizing the floor of the mouth. Elimination of the cribs in tongue plate might offer a better psychological sense to the patients. Extra oral appliances such as facemask and reverse chin cup [5, 34] improve the deficient nasomaxillary complex but they have an unfavorable effect on the normal mandible. Extra oral appliances rotate the mandible in clockwise rotation and it is unfavorable in normal growth pattern and long face patients. Besides, the cup of facemask can create abrasion particularly in warm climates. Tongue appliance is an intraoral appliance and it is very comfortable and simple. It is constructed easily and it is not expensive. Tongue appliance and tongue plate will be accepted better than extraoral appliances due to less conspicuous of them. Children with cleft lip and palate have suffered from birth; tongue plate and tongue appliance are more comfortable as they create the least stress to patients in comparison with other big extraoral appliances. In spite of many advantages of them, tongue appliance and tongue plate have one disadvantage.

**Figure 3.** Profile view after treatment.

32 Designing Strategies for Cleft Lip and Palate Care

**Figure 5.** Upper arch during expansion with bonded hyrax.

**Figure 6.** Intraoral view before orthodontic treatment.

**Figure 7.** Intraoral view after orthodontic treatment.

**Figure 8.** Frontal view before treatment.

**Figure 5.** Upper arch during expansion with bonded hyrax.

34 Designing Strategies for Cleft Lip and Palate Care

**Figure 6.** Intraoral view before orthodontic treatment.

**Figure 7.** Intraoral view after orthodontic treatment.

**Figure 9.** Frontal view after treatment.

#### *3.13.4. Permanent dentition*

Comprehensive fixed appliance therapy usually occurs in the permanent dentition with the aim of preparing for alveolar bone graft that can be done by an oral surgeon. This phase usually involves aligning of malposed maxillary incisors. Reverse pull headgear or face mask therapy, expansion of maxillary arch may be continued during this time period. Final alignment of teeth is carried over with or without extraction. Orthodontic management is limited after eruption of permanent dentition. The established malocclusion and discrepancy between the upper and lower arch often require orthognathic surgery.

#### **3.14. Role of oromaxillofacial surgeon in cleft lip and palate patients**

Orthognathic procedure may be designated if a malocclusion develops due to abnormal growth of the maxilla. Treatment for adults may involve surgical in severe or camouflage in mild to moderate patients. Orthognathic surgery is performed to patients with deformities of the jaws to improve facial esthetics as well as to correct dental occlusion. Presurgical orthodontics are usually necessary to align the teeth, correct any compensations, decrowding, eliminate any dental midline discrepancy, coordinate arches, and localize space for prosthetic or implant replacement of the teeth. Ideally, the patient is referred to the surgeon after presurgical orthodontics. The postsurgical phase of orthodontics is required for creating perfect occlusion and better interdigitation after surgery.

#### *3.14.1. Pharyngeal flap*

Failure to achieve a seal between the posterior pharyngeal wall and soft palate lets leakage of air through the nose and causes cleft palate speech. This has proved not to be a problem in patients with a normal velopharyngeal mechanism. If a patient has speech problems a surgical procedure to create a pharyngeal flap probably will be required. To correct hyper nasality, this procedure contains raising a flap of tissue from the posterior pharyngeal wall and incorporating it into the soft palate. Pharyngeal flap is used when the muscles do not function appropriately or the repaired palate is too short. For adults with speech problems, pharyngeal flap, combined with an intensive schedule of speech therapy, can produce noticeable improvements.

#### *3.14.2. Distraction osteogenesis*

Distraction osteogenesis has become a new method for correction of maxillary deficiency [8, 37]. Distraction osteogenesis for maxillary advancement started in 1993 and is now broadly used in cases with skeletal Class III deformity due to maxillary deficiency [38]. Figueroa and Polley [39] reported that distraction osteogenesis was successfully used to advance the maxilla in children with cleft lip and palate. According to them the main advantages of distraction osteogenesis compared with conventional methods of craniofacial reconstruction were reduced time of surgery and cost and the ability to generate new bone. Many advantages and disadvantages of distraction devices have been detailed. For a large advancement in a patient with a cleft lip or palate, distraction osteogenesis may be advantageous. Figueroa and Polley [39] assessed the cephalometric landmarks on 14 patients with cleft palate who were treated with a rigid external distraction technique. Distraction osteogenesis provides less physical and psychological invasion in comparison to conventional LeFort osteotomy: that is, reduced operating time, less blood loss, less postoperative pain, and shorter hospitalization. Also, when intra-arch distraction is applied to lengthen the mandible or maxilla, orthodontic alignment of upper and lower arches are not necessary before the procedure [40]. Intraoral distraction osteogenesis devices are divided into two types namely bone borne or tooth borne. Advantages of these are their smaller size and better patient acceptance; however, the bone attached one has the disadvantage of the need for second intervention to remove the device [41].

Hyrax screw incorporated in an acrylic plate has been applied for treatment of maxillary deficient in cleft lip and palate patients. After creating horizontal cuts similar to LeFort 1 and vertical cuts between the premolars on both sides, a bonded hyrax screw was mounted on an acrylic plate for the slow sagittal expansion of upper arch. The distraction procedure can be initiated after 5 days of latency period.

The expansion is performed by activating the hyrax screw 0.8 mm per day after the latency period (**Figure 10**). Expansion was discontinued after achieving satisfactory overjet and occlusion (**Figure 11**). If open bite occurs during expansion period vertical elastics will be used to correct open bite. Consolidation period lasts 8 weeks and after this period hyrax screw is removed. One of the advantages of anterior maxillary distraction is that velopharyngeal area will be intact. Anterior distraction is used for skeletal deformity and fixed appliance is applied for correction of dental problems [8].

Some researchers suggested that distraction orthogenesis does not seem to have any advantages over surgery. Additionally, the occlusion at the end of distraction is much less defined than what is seen with conventional orthognathic surgery [42].

**Figure 10.** Hyrax screw incorporated in an acrylic plate.

*3.13.4. Permanent dentition*

36 Designing Strategies for Cleft Lip and Palate Care

Comprehensive fixed appliance therapy usually occurs in the permanent dentition with the aim of preparing for alveolar bone graft that can be done by an oral surgeon. This phase usually involves aligning of malposed maxillary incisors. Reverse pull headgear or face mask therapy, expansion of maxillary arch may be continued during this time period. Final alignment of teeth is carried over with or without extraction. Orthodontic management is limited after eruption of permanent dentition. The established malocclusion and discrepancy

Orthognathic procedure may be designated if a malocclusion develops due to abnormal growth of the maxilla. Treatment for adults may involve surgical in severe or camouflage in mild to moderate patients. Orthognathic surgery is performed to patients with deformities of the jaws to improve facial esthetics as well as to correct dental occlusion. Presurgical orthodontics are usually necessary to align the teeth, correct any compensations, decrowding, eliminate any dental midline discrepancy, coordinate arches, and localize space for prosthetic or implant replacement of the teeth. Ideally, the patient is referred to the surgeon after presurgical orthodontics. The postsurgical phase of orthodontics is required for creating perfect

Failure to achieve a seal between the posterior pharyngeal wall and soft palate lets leakage of air through the nose and causes cleft palate speech. This has proved not to be a problem in patients with a normal velopharyngeal mechanism. If a patient has speech problems a surgical procedure to create a pharyngeal flap probably will be required. To correct hyper nasality, this procedure contains raising a flap of tissue from the posterior pharyngeal wall and incorporating it into the soft palate. Pharyngeal flap is used when the muscles do not function appropriately or the repaired palate is too short. For adults with speech problems, pharyngeal flap, combined

Distraction osteogenesis has become a new method for correction of maxillary deficiency [8, 37]. Distraction osteogenesis for maxillary advancement started in 1993 and is now broadly used in cases with skeletal Class III deformity due to maxillary deficiency [38]. Figueroa and Polley [39] reported that distraction osteogenesis was successfully used to advance the maxilla in children with cleft lip and palate. According to them the main advantages of distraction osteogenesis compared with conventional methods of craniofacial reconstruction were reduced time of surgery and cost and the ability to generate new bone. Many advantages and disadvantages of distraction devices have been detailed. For a large advancement in a patient with a cleft lip or palate, distraction osteogenesis may be advantageous. Figueroa and Polley [39] assessed the cephalometric landmarks on 14 patients with cleft palate who

with an intensive schedule of speech therapy, can produce noticeable improvements.

between the upper and lower arch often require orthognathic surgery.

**3.14. Role of oromaxillofacial surgeon in cleft lip and palate patients**

occlusion and better interdigitation after surgery.

*3.14.1. Pharyngeal flap*

*3.14.2. Distraction osteogenesis*

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Figure 11. Hyrax screw after activation.
```


**Author details**

Joaquin Quiralte1 \*, María del Robledo Ávila1 , Stefan Cimbollek1 and Joaquin Quiralte-Castillo2

1 Allergy Unit-Hospital Universitario Virgen del Rocio, Seville, Spain

2 Department of Pediatrics, Hospital Juan Ramón Jiménez, Huelva, Spain

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 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.