**6. Prospect**

178 Macro to Nano Spectroscopy

acrylate, poly-casein or other thin films. The main body of the artificial lens can be made of polymethacrylate. The researchers have attached increasingly great importance to the qualitative analysis of polymer materials for this kind of medical equipments. As explicitly specified in YY0477-2004 "Orthokeratology Using Gas Permeable Rigid Contact Lens", infrared spectrum analysis is adopted to determine the components of the lens materials. The following drawing is the infrared spectrum analysis of this material: point 2961cm-1 is the methyl characteristic peak of methyl acrylate; points 1104 cm-1 and 1046 cm-1 are characteristic absorption peaks of siloxane, points 1730 cm-1,1227 cm-1 and 1199 cm-1 are ester peaks of methyl acrylate; points 893 cm-1 and 7556 cm-1 are the structure characteristic peaks of polymethacrylate; also it is worth knowing that carbonyl peak on point 1769 cm-1

5.5 The innovation of instrument performance and the development of computer application technology provide possibility for combined use of the previous stand-alone analysis instruments. The combined use of various types of instruments has greatly improved the accuracy and reliability of the analysis and testing results. With combination use of thermogravimetric analysis and IR spectrum and other analytical methods in recent years, thermogravimetric analysis is increasingly playing an important role in study of thermal behavior in chemical materials. In comparison with traditional thermogravimetric analysis method, TGA-IR spectrum combined analysis can directly and accurately determine the various physical-chemical change during the heating proves and identify the chemical composition of decomposition or degradation products during the during the weight loss process. Thus, it has been a key experimental method in studying thermostability and thermal decomposition (degradation) process of various inorganic, organic and polymer materials and proves a promising prospect in respect of thermal performance analysis of the materials. As Fourier transform infrared spectrometer is of high noise-signal ration and high precision, it may detect the slight intensity change and frequency shift of the infrared bands in the sample before and after the heat treatment. Thus to provide structural differences of polymer film for three different thermal stages of high molecular polymer, from high-elastic state slow cooling, high-elastic state quenching to heat treatment below temperature Tg. The

is the characteristic peak of fluoro-alkylated methyl acrylate.

Fig. 6. Infrared spectrogram of PVC

FTIR is becoming widely used in the field of medical polymer materials, especially for quantitative analysis of the material properties. At present, the study on application of infrared spectroscopic technology or combined application of IR spectrum with other technologies in polymer material, to be still growing. With rapid development of scientific technology, the research in IR spectrum is further deepened. IR spectrum is not only widely used in polymer materials but is also widely used in pharmaceuticals, foods and environmental science. The gradually improved infrared detection method may be used on vivo analysis of pathological tissue and greatly contribute to the rapid and accurate diagnosis of the diseases. Meanwhile, the disease mechanism and progression maybe clarified through analysis of infrared spectrogram of tissues or cells.


**7. Indications and strategies of intraoperative IVC interruption**

With regard to dealing with the IVC intraoperatively is one of the difficulties of IVC thrombectomy. There necessity of reconstruction after IVC resection is still controversial.

Indications for vena caval interruption include invasion of the venous walls, severe adhesion of the tumor to the vascular endothelium, complete occlusion of the vena cava, and the presence of distal thrombus [21, 39, 40]. In addition, the texture of the cancer thrombus is one of the influencing factors. With regard to preoperative imaging, the IVC in line with the indications of interruption and accompanied by sufficient collateral circulation, meanwhile, without serious cardiac, hepatic, and renal insufficiencies can be completely cut off. IVC venography and intraoperative ultrasound can help determine the disjointed lumina, which enables protection of the established collateral circulation trunk. IVC interruptions include complete and partial vena caval resections with reconstruction. Based on our experience, for right tumors, the height of the tumor thrombus, which is below the secondary hepatic portal, linear cutters are used to successively cut off the proximal, distal, and left renal veins of the tumor thrombus (**Figure 1I**). With regard to right tumor thrombus above the secondary hepatic portal, or left tumor thrombus above the level of the right renal vein and combined with distal thrombus, the vena cava can be resected partially. Methods for right thrombectomy include cutting off the lumina of the IVC below the secondary hepatic portal and reconstructing the lumina of the IVC above the secondary hepatic portal. The left thrombectomy procedure is resecting the lumina of the IVC below the level of the right renal vein and reconstructing the lumina of the IVC above the level of the renal vein.

Meanwhile, IVC interruption is safe and feasible during vena caval thrombectomy [39, 40], and the establishment of collateral circulation can avoid severe hemodynamic disorders. Different strategies of interruption ought to be generated preoperatively based on the height of tumor thrombus, tumor side, degree of vena caval obstruction and invasion, and establishment of collateral circulation.


Meet the editor

Henry Soo-Min Park, MD, MPH, is a board-certified radiation oncologist who currently serves as Assistant Professor of Therapeutic Radiology and Chief of Thoracic Radiotherapy at the Yale School of Medicine. He also serves as the department's Director of Continuing Medical Education, the Medical Student Clerkship, and the Yale Radiation Oncology Consortium e(focusing on comparative effectiveness and health services research), as

well as associate director of the residency program. Dr. Park received his undergraduate degree from Yale College, master's degree from Harvard School of Public Health, and MD from Yale School of Medicine. He completed his internal medicine internship at Harvard Medical School's Beth Israel Deaconess Medical Center and returned to Yale New Haven Hospital for his residency and chief residency in radiation oncology.

Contents

**Section 1**

**Section 2**

**Section 3**

The Value of Multiple Perspectives

*by Güntuğ Batihan and Kenan Can Ceylan*

*by Andrew X. Li and Justin D. Blasberg*

Radiotherapy: An Alternative to Surgery

Current Status and Future Perspectives *by Hiroshi Doi and Kozo Kuribayashi*

Image-Guided Ablative Therapies for Lung Tumors *by Joyce W.Y. Chan, Rainbow W.H. Lau and Calvin S.H. Ng*

Robotic Surgery for Non-Small Cell Lung Cancer

*by Henry Soo-Min Park*

**Preface XI**

Introduction **1**

**Chapter 1 3**

Surgical Advances **9**

**Chapter 2 11**

**Chapter 3 27**

Radiotherapeutic and Ablative Technology **41**

**Chapter 4 43**

**Chapter 5 63** Definitive Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer:

**Chapter 6 81**

*by Paul Van Houtte, Charlier Florian, Luigi Moretti and Dirk Van Gestel*

The Role of Minimally Invasive Surgery in the Treatment of Lung Cancer

Introductory Chapter: Recent Progress in Lung Cancer Treatment -

## Contents

Preface

Lung cancer management has undergone revolutionary changes in recent years. This book introduces the reader to some of the most relevant and exciting advances in the field. The book begins with a discussion of minimally invasive surgical techniques followed by a review of the progress in nonoperative therapies like radiotherapy and ablation. Next, the book examines systemic therapy that has moved well beyond standard cytotoxic chemotherapy and that can often be combined with local therapies even for metastatic disease. Finally, the book presents several newer diagnostic and therapeutic tools that have not yet become

This book is dedicated to patients with lung cancer who have contributed to the acquisition and consolidation of knowledge by consenting to data collection through clinical trials or registries. By comprehensively reviewing the most impactful innovations of the modern era, we hope to inspire you to imagine what

**Henry S. Park, MD, MPH**

Yale School of Medicine, New Haven, CT, USA

Department of Therapeutic Radiology,

mainstream.

might be possible in the near future.


*2.1. Search Strategy*

In developing our search criteria we decided to exclude research on self-harm due to wide international variations in definitions based on degree of suicidal intent [13], although acknowledging that self-harm is a key risk factor for suicide in men in high-income countries [14]. We chose the age range 15–29 to cover WHO definitions of youth (aged 15–24 years), teenagers (aged 15–19 years), and young adults (aged 20–24 years) [1], as well as the upper limit of under 30 used in the Greenlandic suicide prevention strategy [9]. We registered our review protocol on PROSPERO register of systematic reviews, and used the PRISMA checklist to guide the design and reporting of our study [15].

We searched the online database, PubMed, using the MeSH terms "Suicide" and "Greenland" and the equivalent keywords Suicid\* and Greenland, to give the final search criteria (("Suicide" [Mesh]) OR Suicid\*) AND ("Greenland" [Mesh] OR Greenland). We used no date restrictions on publication period. The search was repeated on Embase, and with slight variation on PyscINFO as the MeSH term "Greenland" was not available. No restrictions were applied to age-range or gender, as the predicted relatively limited number of articles on this topic made it feasible to apply age and gender exclusions post-search. We conducted the search on 11 October 2017 and screened titles and abstracts for eligibility, followed by full text review. We conducted secondary searching of the reference lists of identified articles, and of the publications lists of identified authors, and emailed international experts in the field to identify additional references. We repeated the search in PubMed on 15 August 2018 to check for any recent studies.

### *2.2. Inclusion and Exclusion Criteria*

We included articles:

We excluded articles:


**Author details**

Rameshwar Prasad Department of Neonatology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 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.

**135**

*Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists*

diaphragmatic hernia: a populationbased study of 32 million births in the United States. J Matern Neonatal Med 2014;27:1438-1444. https://doi.org/10.31

Langmark F, Knutrud O. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg 1978;13:227-

09/14767058.2013.858691.

[8] Harrison MR, Bjordal RI,

230. https://doi.org/10.1016/ s0022-3468(78)80391-1.

[9] Snoek KG, Greenough A, van Rosmalen J, Capolupo I, Schaible T, Ali K, et al. Congenital Diaphragmatic Hernia: 10-Year Evaluation of Survival, Extracorporeal Membrane Oxygenation,

and Foetoscopic Endotracheal

[10] Morini F, Lally KP, Lally PA, Crisafulli RM, Capolupo I, Bagolan P. Treatment Strategies for Congenital Diaphragmatic Hernia: Change Sometimes Comes Bearing Gifts. Front Pediatr 2017;5:195. https://doi. org/10.3389/fped.2017.00195.

[11] Antonoff MB, Hustead VA, Groth SS, Schmeling DJ. Protocolized

[12] Yang W, Carmichael SL, Harris JA, Shaw GM. Epidemiologic characteristics of congenital diaphragmatic hernia among 2.5 million california births, 1989-1997. Birth Defects Res Part A Clin Mol Teratol 2006;76:170-174. https://doi.

[13] Mcateer JP, Hecht A, De Roos AJ, Goldin AB. Maternal medical and behavioral risk factors for congenital diaphragmatic hernia. J Pediatr Surg

management of infants with congenital diaphragmatic hernia: Effect on survival. J Pediatr Surg 2011;46:39-46. https://doi.org/10.1016/j.

jpedsurg.2010.09.060.

org/10.1002/bdra.20230.

org/10.1159/000480451.

Occlusion in Four High-Volume Centres. Neonatology 2018;113:63-68. https://doi.

*DOI: http://dx.doi.org/10.5772/intechopen.94839*

Tibboel D, Post M. Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia. Am J Pathol 2000;156:1299-1306. https://doi. org/10.1016/S0002-9440(10)65000-6.

Rasmussen SA. Population-based study of congenital diaphragmatic hernia: Risk factors and survival in metropolitan Atlanta, 1968-1999. Birth Defects Res Part A Clin Mol Teratol 2003;67:261-267. https://doi.org/10.1002/bdra.10039.

[3] Wright JCE, Budd JLS, Field DJ, Draper ES. Epidemiology and outcome of congenital diaphragmatic hernia: a 9-year experience. Paediatr Perinat Epidemiol 2011;25:144-149. https://doi. org/10.1111/j.1365-3016.2010.01172.x.

[4] Levison J, Halliday R, Holland AJA, Walker K, Williams G, Shi E, et al. A population-based study of congenital diaphragmatic hernia outcome in New South Wales and the Australian Capital Territory, Australia, 1992-2001. J Pediatr Surg 2006;41:1049-1053. https:// doi.org/10.1016/j.jpedsurg.2006.01.073.

[5] Burgos CM, Ehrén H, Conner P, Frenckner B. Maternal Risk Factors and Perinatal Characteristics in Congenital Diaphragmatic Hernia: A Nationwide Population-Based Study. Fetal Diagn Ther 2019;46:385-391. https://doi.

[6] McGivern MR, Best KE, Rankin J, Wellesley D, Greenlees R, Addor MC, et al. Epidemiology of congenital diaphragmatic hernia in Europe: A register-based study. Arch Dis Child Fetal Neonatal Ed 2015;100:F137– F144. https://doi.org/10.1136/ archdischild-2014-306174.

[7] Balayla J, Abenhaim HA. Incidence, predictors and outcomes of congenital

org/10.1159/000497619.

[1] Keijzer R, Liu J, Deimling J,

**References**

[2] Dott MM, Wong L-YC,

*Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists DOI: http://dx.doi.org/10.5772/intechopen.94839*


**3. Other applications of gamma radiation to wood**

One of the interesting areas of application of gamma rays and X-rays is in non-destructive analysis of density and water content and their distribution in solid wood, and the woodbased materials, i.e. wood panels (Davis *et al.* 1993, Lu and Lam, 1999). Karsulovič *et al.* (2002) used gamma irradiation in their studies for non-destructive detection of decay and other defects in logs. In this way, the quality of the timber can be to some extent predicted prior to mechanical processing. Because of extremely high energy of gamma radiation, it penetrates through the entire cross section of wood. Consequently, gamma rays can be used as a catalyst for polymerization of monomers in monomer-impregnated wood as well as for chemical modification of wood to create wood-plastic composites – WPC (Chawla, 1985; Sheikh and Afshar Taromi, 1993; Bakraji *et al.* 2001; Bakraji *et al.*, 2002). Struszczyk *et al.* (2004) mentioned three possible uses of gamma radiation:

According to Kunstadt (1998), insects do not withstand doses between 0.7 and 1.3 kGy, while elimination of fungi requires significantly higher doses. Unger *et al.* (2001) mentioned doses between 0.25 and 3 kGy to be adequate for extermination of wood-destroying insects, depending on species and developmental stage. Extermination of wood decay fungi in wood usually requires higher doses, ranging from 2 to 18 kGy depending on the fungus species. Mycelium of the fungus *Serpula lacrymans* can be killed off with 2 – 3 kGy, but it can be reduced to 0.5 kGy if the temperature rises to 50 °C. Unger *et al.* (2001) also stated that the bacteria elimination requires doses of 3 – 15 kGy. Lester *et al.* (2000) sterilised New Zealand soft woods including radiata pine (*Pinus radiata*) against Huhu beetle larvae (*Prionoplus reticularis*) and concluded that doses between 2.5 and 3.7 kGy are enough to control wood destroying insects and that moisture content of wood during irradiation has an important role in radiation dose determination. Magaudda *et al.* (2001) stated that the dose of 10 kGy is sufficient for practical disinfestations of Whatman paper-destroying insects. Freitag and Morrell (1998) reported on gamma radiation doses around 15 kGy to be adequate to combat pests in wood (predominantly insects). They have also stated that the doses for extermination of *Xylophagous* microorganisms in wood are much higher than for sterilisation of other materials. Csupor *et al.* (2000) irradiated wood decayed by *Xylophagous* fungi in the range from 2 to 1400 kGy, and they concluded that 12 kGy is sufficient for safe sterilisation of wood against fungi. The European Standard EN 113 (CEN, 1996) requires doses between

The treatment time depends on the power of the irradiation source, and there is no significant difference if the wood was irradiated with a weaker source for a longer time or with a stronger source for a shorter time (Unger *et al.*, 2001; Hasan, 2006 mentioned Ražem, 2005). The important quantity is the absorbed dose (the amount of absorbed energy per mass unit) which irradiated substance receives (Fairand and Ražem, 2010). On the contrary Curling and Winandy (2008) reported that dose rate and total dose of gamma radiation differently affect both, bending strength and some chemical components in tested wood.

One of the interesting areas of application of gamma rays and X-rays is in non-destructive analysis of density and water content and their distribution in solid wood, and the woodbased materials, i.e. wood panels (Davis *et al.* 1993, Lu and Lam, 1999). Karsulovič *et al.* (2002) used gamma irradiation in their studies for non-destructive detection of decay and other defects in logs. In this way, the quality of the timber can be to some extent predicted prior to mechanical processing. Because of extremely high energy of gamma radiation, it penetrates through the entire cross section of wood. Consequently, gamma rays can be used as a catalyst for polymerization of monomers in monomer-impregnated wood as well as for chemical modification of wood to create wood-plastic composites – WPC (Chawla, 1985; Sheikh and Afshar Taromi, 1993; Bakraji *et al.* 2001; Bakraji *et al.*, 2002). Struszczyk *et al.*

b. as the initiator of the catalytic polymerization of monomers in the cellulose chain and c. as pre-treatment for further chemical processing of cellulose in order to improve its

**2.1 Doses of gamma radiation necessary for wood sterilisation**

25 and 50 kGy for wood sterilisation in lab testing procedures.

**3. Other applications of gamma radiation to wood**

(2004) mentioned three possible uses of gamma radiation:

solubility.

a. as pre-treatment in the chemical modification of cellulose;

Klimentov and Bysotskaia (1979); Chawla (1985) and Šimkovic *et al.* (1991) reported that gamma irradiation as a pre-treatment for the "softening" of wood prior to chemical processing, can significantly reduce the use of chemicals. Oldham *et al.* (1990) used gamma radiographic technique for analysing wood destruction by fire. They determined the efficiency of fire retardants by measuring the difference in absorbed gamma radiation energy in wood protected by these retardants before and after burning the wood. Bogner (1993) and Bogner *et al.* (1997) used different surface activators in order to achieve greater adhesion of adhesives to wood. Among other used activators, gamma radiation at different doses was also used. The results show that after treatment of wood by gamma radiation in doses range of 0 and 100 kGy, glue improves adhesion to wood and thus increases the strength of glued bonds. The first investigations of the influence of gamma radiation on lignocellulose materials, in terms of increasing the solubility of insoluble high-polymerized sugars such as cellulose, were performed by Klimentov and Bysotskaia (1979) and Klimentov *et al.* (1981).


**7. Conclusions and future prospect**

The surface of TiO2 can be modified by oxocomplexes of the first transition metals (MOCs/ TiO2) with the loading amount precisely controlled by using the CCC technique. Among the MOCs/TiO2, Fe2O3-, Co2O3- and NiO-surface-modified TiO2 possess unique physicochemical properties such as strong visible-light absorption and the excellent reduction ability of O2. Spectroscopic experiments and first-principles DFT simulation have revealed that the surface modification with the MOCs raises the VB maximum of TiO2 due to the formation of plural metal–O–Ti interfacial bonds. Surface-to-bulk and/or bulk-to-surface interfacial electron transfer induced by visible-light absorption enhances charge separation. This novel coupling system consisting of MOCs and TiO2 would be promising as the "solar environmental catalyst."

The standard potentials of multiple-electron ORRs (*E*0 (O2/H2O2) = +0.695 V and *E*0 (O2/H2O) = +1.229 V versus SHE) are much more positive than that of one-electron ORR. Therefore, the hybridization of appropriate electrocatalysts for the multiple-electron ORR can impart visiblelight activity to many metal oxide semiconductors with *E*g < 3 eV. The effectiveness of this approach has recently been verified in the Pt NP-WO3 (Eg = 2.7 eV) [43] and Cu(acac)2-BiVO4 (Eg = 2.4 eV) hybrid systems [44], where Pt NP and O2-bridged Cu complex work as excellent electrocatalysts for multiple ORRs, respectively.

As a future subject, we further suggest the importance of the effective use of the infrared ray occupying 52% of the solar energy for the catalytic reactions (Figure 1). For example, Co2O3/ TiO2 exhibits high levels of photocatalytic and thermocatalytic activities [29], whereas Mn2O3/ TiO2 exhibits a high thermocatalytic activity for the oxidation of organic compounds [45]. Further, MOCs/TiO2 with the VB maximum level (or the oxidizing ability of the VB holes) finetuned by the loading amount may open up the application of MOCs/TiO2 to "green" and selective chemical transformations [46–48].


**7. Conclusions**

Aerosolizing catheters convert liquids into particles at the point of expulsion. Typically, an aerosolizing catheter is first passed into the trachea and then the vector is instilled. The Microsprayer® (PennCentury) and the AeroProbe® catheter (Trudell Medical International) are examples of delivery systems for this application. According to the manufacturer, it is possible to generate particles with aerodynamic diameters of 4–8 μm. The Trudell AeroProbe was previously used to aerosolize helper-dependent adenovirus vectors to rabbit airways [136, 137] and to deliver Sendai virus vectors to sheep [138]. Since Sendai virus and lentiviruses are both enveloped, it is likely that this approach is feasible with lentiviral vectors. In addition,

aerosolized VSVG-LVs have been successfully delivered to the airways of mice [139].

segments.

338 Cystic Fibrosis in the Light of New Research

lulose.

**6.2. Insertional mutagenesis**

the least economic delivery strategy for LVs.

Successful vector aerosolization has been reported in mice [140], rabbits,[136, 137], pig [141] and sheep airways [142, 143]. By 2–3 weeks of age, wild type pigs are large enough to be sedated and have a pediatric bronchoscope passed into the trachea. The AeroProbe® catheter can be passed to the carina via the bronchoscope suction channel with the animal breathing sponta‐ neously. In this way, an integrating vector can be aerosolized and targeted to specific bronchial

In the case of nebulizers, the liquid is first converted into mist and then passively inhaled. Using this strategy, a plasmid-based vector was delivered to the airways of CF patients in a phase IIB gene therapy trial [144]. This approach could potentially be used to deliver DNA transposon or hybrid vectors. However, this strategy may not be feasible with enveloped viral vectors because this class of vectors may not be stable enough to withstand nebulization. In addition, nebulization requires a large volume of concentrated material; therefore, would be

Atomizers are a subclass of aerosolizing catheters that deliver larger sized particles. An atomizer, such as the MADgicTM (LMA) atomizer, delivers large droplets (~30–90 μm in diameter), which may vary in size depending on the force applied to the syringe plunger. This type of device is often used to topically deliver medications to the airways [145]. Our group has observed that this type of atomizer is an effective delivery device for multiple viral vectors including FIV, particularly when formulated with a viscoelastic material such as methylcel‐

Since persistent gene expression from lentiviral vectors requires genomic integration, they show promise for treating life-long genetic diseases; however, there is inherent risk when introducing a transgene with integrating vectors. Insertional mutagenesis may disrupt normal cell functions by inactivating an essential host gene or inappropriately causing expression of an undesirable gene. The risk will vary depending on the vector used, the transgene cassette, and the cell type targeted. In many cases, enhancer effects pose the greatest danger. So far, malignant cell transformation after vector-mediated insertional mutagenesis has only been observed in three clinical entities (X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease (CGD), and Wiskott–Aldrich syndrome (WAS)), all of which occurred in conjunction with the use of first-generation gamma-retroviral vectors harboring LTRs with strong enhancer/promoter sequences [146-150]. These studies were conducted in

Within a year of the discovery of CFTR, investigators validated the concept that gene replacement could reverse the ion transport defect *in vitro*, suggesting that gene therapy may be possible [164, 165]. We and others have demonstrated that CFTR delivery by integrating vectors can correct the CF anion defect *in vitro* and *in vivo*, and although further pre-clinical trials are warranted, there is great potential for translating this strategy to the clinic. As discussed, estimates of the percent of CF epithelia requiring correction vary and there is debate about which cell types must be corrected to achieve phenotypic correc‐ tion; however, interest in CF gene therapy remains strong as barriers to gene transfer are identified, outcome measures are established, CF animal models with lung disease are developed, and better delivery systems are engineered. Demonstration of corrective gene transfer to pristine newborn lungs in CF animal models is a vital first step before looking ahead to correcting more diseased lungs. Newborn screening for CF is now established in all 50 states, allowing early disease detection. This offers an opportunity to introduce an integrating therapeutic gene transfer vector to the airway epithelium prior to the onset of chronic infection and inflammation. This strategy is a potentially life-long curative therapy regardless of the disease-causing mutation.


**1. Introduction**

Temperature can adversely affect the normal functioning of plant metabolism [1,2]. In the last few decades, climate change-induced rising temperatures have beome a major challenge for modern crop production, especially in southern Mediterranean regions [3]. Thus, efforts to achieve maximum crop yields to ensure food security for an ever-increasing human population remain challenging. Global food security could be jeopardized if mitigation efforts are not implemented aggressively [4]. Any fluctuation in an environmental cue such as temperature can directly affect the production of temperature-sensitive crops, and hence food security, causing considerable losses to growers and other stakeholders. According to the Inter-Governmental Panel on Climate Change, global temperatures increased by 0.74 ◦C within a century (1906–2005), which was ascribed to ongoing anthropogenic activities and their resultant greenhouse gases [5]. The terrestrial surface temperature is expected to increase by a further 1–6 ◦C by 2050, with arable areas projected to see the greatest increases [6]. There is little doubt that the ongoing climate change will affect all societies inhabiting the globe [7,8], decreasing crop production, and threatening food security. Therefore, strategies are needed to ameliorate its effects on modern agriculture.

Heat stress is a condition of unfavorable temperature causing irreversible damage to plants [9]. High-temperature stress adversely affects plant physio-biochemical and molecular characteristics, resulting in poor plant growth and development [10]. At the physiological level, heat stress negatively influences photosynthesis by adversely affecting

**Citation:** Zulfiqar, F.; Ashraf, M.; Siddique, K.H.M. Role of Glycine Betaine in the Thermotolerance of Plants. *Agronomy* **2022**, *12*, 276. https://doi.org/10.3390/ agronomy12020276

Academic Editors: Channapatna S. Prakash, Ali Raza, Xiling Zou and Daojie Wang

Received: 18 November 2021 Accepted: 20 January 2022 Published: 21 January 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/).

the oxygen evolving complex, photosystem II, RuBisCo, and energy-(ATP) producing processes [11,12]. Furthermore, heat stress-induced disturbance of the electron transport chain leads to excessive reactive oxygen species (ROS) production in different cell organelles, such as mitochondria and chloroplasts, causing severe damage to DNA and cell membranes by inducing lipid peroxidation and ultimately causing cell death 13]. Increasing the capacity of heat stress-induced excessive ROS scavenging is considered an efficient defense strategy for ameliorating heat stress in plants [13]. A plant's thermotolerance ability is attributed to enhanced plasma membrane thermostability and reduced toxic ROS levels [14]. Plants have naturally adapted various defense mechanisms to counteract harsh environmental conditions such as heat stress. These defense mechanisms include an antioxidant machinery, osmolyte accumulation, maintenance of membrane integrity, and increased biosynthesis of heat-shock proteins (HSPs) by upregulating their associated genes' expression [15,16]. These defense mechanisms are involved in cellular defense against heat stress. Osmolyte accumulation has a significant role in mediating stress tolerance in plants (reviewed in Zulfiqar et al. [17]). Various studies have reported enhanced GB accumulation in plants under heat stress, revealing the positive role of this osmolyte in heat stress tolerance [18–22]. Sorwong and Sakhonwasee [23] stated that exogenous GB application alleviated the heat stress-induced reduction in leaf gas exchange traits.

There are no critical reviews on the role of GB in heat stress tolerance. Here, we summarize the fundamental impact of GB in inducing heat stress tolerance in economically important crops.

#### **2. GB Structure and Biosynthesis in Plants**

Glycinebetaine is an *N*,*N*,*N*-trimethylglycine quaternary ammonium compound that is naturally produced in numerous living organisms, including plants [24]. At physiological pH, GB is electrically a neutral molecule, but dipolar in nature. There are two pathways related to GB biosynthesis in plants [25]. The initiating metabolites for these pathways are choline and glycine [26]. GB biosynthesis in plants occurs via N methylation of glycine or the oxidation of choline [27]. GB biosynthesis, particularly in higher plants, is a two-step pathway beginning with choline, which is catalyzed by a ferredoxin-dependent Riesketype protein, namely, choline monooxygenase (CMO), and by a soluble NAD+-dependent enzyme [28,29]. Betaine aldehyde is oxidized by NAD+-dependent betaine aldehyde dehydrogenase (*BADH*) to produce GB. Both *BADH* and CMO generally exist in chloroplast stroma [24,30] (Figure 1).

**Figure 1.** Biosynthesis of GB in plant cells (Figure adapted from Sakamoto and Murata [24]; Ashraf and Foolad [31]).

#### **3. Glycine Betaine-Accumulating and -Non-Accumulating Plants**

Glycine betaine is a vital compatible osmolyte that plays multifarious roles in plant growth and metabolism. However, plant species differ in naturally accumulating GB. It is now evident that GB synthesis occurs in both chloroplasts and cytosol [32,33], but chloroplastic GB has been positively related to stress tolerance, whereas cytosolic GB has not shown such a relationship [32]. Thus, the presence of high amounts of GB in a plant may not necessarily account for its enhanced stress tolerance. Metabolic restriction of GB synthesis in plants has been ascribed to the availability of the substrate (choline) [33]. Since choline occurs in the cytosol [34], its transport to chloroplasts through appropriate transporters is essential for GB synthesis [34,35]. GB-non-accumulating plants have either limited amounts of intrinsic choline or poor activity of choline transporters in the chloroplast envelope [35]. Thus, genetic engineers need this information to generate transgenic lines with high GB-accumulating ability.

Plants accumulate various amounts of GB; naturally accumulating plants under normal and stress conditions are categorized as GB accumulators, while non-accumulating plants do not increase GB level under stress [36]. Table 1 lists GB accumulators and non-accumulators. Natural GB accumulators accrue a certain amount of GB solely under stressful cues [18,21]. For example, Alhaithloul et al. [22] studied the responses of *Catharanthus roseus* and *Mentha piperita* under HS and drought stress, individually and in combination. They reported that the level of GB increased by 46% and 58% for *C. roseous* and *M. piperita*, respectively, in response to HS, and more so under combined heat and drought stress. This evolutionary adaptation enables plants to survive under a varied range of climatic conditions. Screening plants for their ability to accumulate osmolytes, particularly GB, offers a way to target such plants for acquiring GB biosynthesis-related genes to develop GB-producing plants.

**Table 1.** Glycine betaine accumulating crops.


**2.2 Comb polymers**

In general, comb polymers contain pendant polymer chain and they are structurally related to grafting copolymers. The comb–branched system containing of low molecular weight of polyether chain is grafted to a polymer backbone. Thus, it lowers the glass transition temperature (ܶ) and then helps to optimize the ionic conductivity by improving the flexibility of polymer chain into the system. The elastic poly[ethylene oxide–co–2–(2– methoxyethoxy)ethyl glycidyl ether] [P(EO/MEEGE)]–based polyether comb polymer electrolytes were synthesized by Nishimoto and co–workers. The degree of crystallinity was decreased with increasing the composition of MEEGE in copolymers, which in accordance with higher ionic conductivity. The introduction of the side chain of MEEGE in the copolymers enhances the flexibility of polymer matrix and hence improves the ion mobility. The highest ionic conductivity of 10-4 Scm-1 was achieved at room temperature (Nishimoto et al., 1998). Until today, this technique is still being employed in this area. Recently, many researchers have keen of interest on polyvinylidene–co–hexafluorophosphate (PVdF–co– HFP) copolymer. Composite polymer electrolytes prepared by adding SiO2 nanowires into (PVdF–co–HFP) are described by Zhang et al. The ionic conductivity of this composite polymer electrolyte is up to 1.08×10−3 Scm−1 with the electrochemical window of 4.8 V (Zhang et al., 2011).


**Analytical Methods for Toxics Determination**

Printed Edition of the Special Issue Published in *Molecules* Clinio Locatelli, Marcello Locatelli and Dora Melucci Edited by

www.mdpi.com/journal/molecules


**2. Arc cutting torch**

The high energy density cutting torch used in this numerical study consisted of a cathode centered above an orifice in a converging-straight copper nozzle. The cathode was made of copper (7 mm in diameter) with a hafnium tip (1.5 mm in diameter) inserted at the cathode center. A flow of oxygen gas cooled the cathode and the nozzle and was also employed as the plasma gas. The gas passed through a swirl ring to provide arc stability. The nozzle consisted in a converging-straight bore (with a converging length of 1 mm, and a bore 1 mm in diameter, 4.5 mm length) in a copper holder surrounding the cathode (with a separation of 0.5 mm between the holder and the cathode surface). To avoid plasma contamination by metal vapors from the anode (usually the work piece to be cut), a rotating steel disk with 200 mm in diameter and 15 mm thickness was used as the anode (Freton et al., 2002). In this study, the disk upper surface was located at 6 mm from the nozzle exit. The arc was transferred to the edge of the disk, and the rotating frequency of the disk was equal to 24 Hz. At this velocity, a wellstabilized arc column was obtained, and the lateral surface of the anode disc was completely not melted. Thus, practically no metal vapors from the anode were present in the arc. A scheme of the torch indicating several geometric dimensions is presented in Fig. 1.

By performing a small orifice (1 mm in diameter) on the lateral of the cathode surface the pressure in the plenum chamber (*pch*) was measured by connecting a pressure meter at the upper head of the cathode. The gas mass flow (*dm/dt*) injected in the torch was also registered. In this experiment, the arc current, the plenum pressure and the gas mass flow, were fixed to values of 30 A for the arc current, *pch* = 0.7 MPa and *dm/dt* = 0.71 g s-1, respectively.

**Figure 1.** Schematic of the Cutting torch.


**Abstract**

Caesarean section (CS) refers to delivery of a foetus through surgical incisions made through abdominal and uterine walls. It's a life-saving procedure when complications arise during pregnancy. It may be an emergency or a planned procedure. Although desirable, CS may be medically unnecessary. CS is a major procedure associated with immediate and long-term maternal and perinatal risks and may have implications for future pregnancies. Since 1985, international healthcare community considers ideal rate for CS to be 10–15%. However, in the last decade, there has been concern about the rising rates of CS from as low as 2% in Africa to as high as 50–60% in Dominican Republic and Latin America. To this effect, there have been attempts to regulate the rates, and the Ten Group Classification System under the Robson criteria is such an attempt. CS rates are on the increase due to varying reasons ranging from patient, institutional, care provider and societal factors. There have been modifications in the CS technique and the drugs used postoperatively from Pitocin to addition of Misoprostol. Need has developed from Reproductive Health Specialists to review indications, rates and terminologies used and evaluate practices in low-, middle- and high-income countries regarding CS.

**Keywords:** caesarean section, rates, LMICs

## **1. Definition**

Caesarean delivery commonly referred to as caesarean section and occasionally caesarean birth is defined as the delivery of a foetus(es) through surgical incisions made through the anterior abdominal wall (technically referred to as laparotomy) and the anterior uterine wall (technically denoted to as hysterotomy) [1, 2]. This definition considers only the intrauterine location of the foetus and not whether the foetus is delivered alive or dead [3]. Since the words "caesarean" and "section" are both derived from verbs that mean to cut, some authors [1] urge that the phrase "caesarean section" is a tautology. Consequently, the terms "caesarean delivery" and "caesarean birth" are preferable.

Although infrequent, there are reports of foetal survival from advanced abdominal pregnancies resulting into live birth [4]. The procedure for delivery of such foetus(es) is not caesarean section but rather laparotomy. It is technically challenging to assign the type of procedure carried when simultaneous abdominal and intrauterine pregnancy is encountered [5]. Considering the definitions above, it would be urged that the procedure is caesarean section for the intrauterine foetus and laparotomy for the abdominal pregnancy. However, laparotomy alone would suffice. Confusion also arises among medical students when a foetus before the age of viability has to be delivered through abdominal surgery. Most obstetricians and gynaecologists refer to this procedure as hysterotomy rather than caesarean section.


*Communication* **Study of Coarse Particle Types, Structure and Crystallographic Orientation Relationships with Matrix in Cu-Cr-Zr-Ni-Si Alloy**

**Chengdong Xia 1, Chengyuan Ni 1, Yong Pang 1,\*, Yanlin Jia 2, Shaohui Deng 1 and Wenhui Zheng 1**

1 College of Mechanical Engineering, Quzhou University, Quzhou 324000, China<EMAIL_ADDRESS>(C.X.)

2 School of Materials Science and Engineering, Central South University, Changsha 410083, China

**\*** Correspondence<EMAIL_ADDRESS>
**Abstract:** Coarse particles in Cu-0.39Cr-0.24Zr-0.12Ni-0.027Si alloy were studied with scanning electron microscopy and transmission electron microscopy. Three types of coarse particles were determined: a needle-like Cu5Zr intermetallic phase, a nearly spherical Cr9.1Si0.9 intermetallic phase and (Cu, Cr, Zr, Ni, Si)-rich lath complex particles. The crystallographic orientation relationships of the needle-like and nearly spherical coarse particles were also determined. The reasons for formation and the role of the coarse phases in Cu-Cr-Zr alloys are discussed, and some suggestions are proposed to control the coarse phases in the alloys.

**Keywords:** Cu-Cr-Zr alloy; coarse particle; crystal structure; orientation relationship


**3. The gender difference in tinnitus**

*An Overview and Management of Multiple Chronic Conditions*

tia was related to hearing loss [8].

**2. The gender difference in presbycusis**

effect of estrogen on the auditory system.

Therefore, many authors focus on the association between defects in central auditory processing and neurodegenerative diseases [4]. Alzheimer's disease (AD) is the commonest neurodegenerative dementia that occurs in population after 40 years. With the increase of age, the incidence of AD is increased rapidly among the population. Epidemiological surveys show that the prevalence of AD between the ages of 40 and 65 is 1 in 5000 [5]. However, the overall prevalence of dementia increased to 8.5% after 65 years old. By the 85 years old, the prevalence is >20% and creates a devastating burden between family and society [6]. In addition to age, gender, education level, and disease states, such as cardiovascular disease, hyperlipidemia, etc., are all considered as the critical factors of AD [7]. Hearing loss is reported as the independent risk factor for the development of dementia, and 46.4% of demen-

Presbycusis can contribute to the emergence of tinnitus. In an epidemiological cohort study, participants were 17% more likely to have tinnitus with every 5-dB increase in pure tone audiometry (PTA) [9]. Tinnitus is charactered as the conscious perception of an abnormal sound in the ears or head either unilaterally or bilaterally, without any external acoustic stimulus [10]. The prevalence of tinnitus increases with increasing age and hearing loss [11, 12]. The etiology of tinnitus remains mostly elusive. Presbycusis-related tinnitus increases cognitive load, including mental balance, attention, concentration, and immediate recall [13]. However, the evidence between tinnitus and cognitive impairment has not been found yet. As lifespans lengthen, the prevalence of elderly populations with presbycusis, dementia, and tinnitus increases rapidly. This review aims to figure out the characters and gender differences of elderly populations with presbycusis-related tinnitus and cognitive impairment and investigate possible mechanisms and treatments.

Apart from age, gender seems to be one of the reasons accounting for hearing loss. Numerous epidemiological evidence have suggested that women have better auditory function than men. However, the sexual dimorphism of the function of auditory is tended to converge with aging [14]. Men demonstrate a higher prevalence of presbycusis compared to women. In the 20–69 years old age group, more American men suffer bilateral hearing loss than women [15]. Above 70 years old, men also show independently associated with a higher prevalence of hearing impairment in the United States [16]. For Asian people, similarly, men show higher associated with high frequency hearing loss in the Korean. However, after the age of 60, the level of hearing decline between men and women is similar to age [17]. Pearson et al. found the evidence that the hearing sensitivity decreases with age in both men and women, more rapidly in men than women in young ages or frequencies, in which the decrease begins between age 30 in men and later in women. Though women maintain better auditory function at a young age, they tend to decline fast after menopause. By age 80, the rates of hearing loss are similar between men and women. Sexual dimorphism may be due to the loss of estrogen and progesterone protection [18]. Sexual hormones help women to have benefits in high frequencies. Compared to women at the same age (after menopause), a large cohort study of the healthy population showed that older men had a 10–25 dB worse hearing threshold in the high frequencies [19]. While women have shorter latencies in auditory brainstem response [20], the difference from sex and age cannot be simply explained by the effects of anatomical abnormalities or occupational noise, but it may be related to the decrease of endogenous estrogen that lost the protective

**44**

Elderly Women suffered a lower prevalence of hearing loss and tinnitus loudness than men did, but tinnitus annoyance was stronger in older women than men [21]. However, the underlying mechanism of the difference between men and women is still mysteries. Nondahl et al. reported that an epidemiological cohort study containing 3267 participants from 21 to 84 years old demonstrated that the prevalence of tinnitus was higher for men than for women (11.9 vs. 9.4%, p = 0.02), and higher for older (age from 55 to 84 years old) than younger participants (14.4 vs. 9.0%, p < 0.001). However, adjusted for factors related to tinnitus, it showed no association between sex and tinnitus [9]. An epidemiological study of 6333 population in China showed no significant difference in prevalence between men and women age >60 years [22]. For the loudness of tinnitus, some found a low correlation of gender [23], while others reported significantly higher loudness in men compared to women. However, older women tend to report a higher level of an emotional reaction than men with tinnitus [20] and frequently more severe, accompanied by vertigo [24].

### **4. The gender difference in cognitive impairment**

The majority of epidemiological research indicated that women with aging are sensitive to dementia even after controlling for increased life span and education level, which show a rapid decline in a cognitive deterioration compared with agematched men [25]. The animal experiment indicated that follicular depletion might initiate age-related impairments for cognitive flexibility [26]. The postmenopausal women have a two-fold higher lifetime risk of developing AD than men and demonstrate a faster cognition decline [27, 28]. However, some clinical evidence show that older women performed better on the global function test while men at the same age on the executive function test, respectively [29], and found more significant risk for men [30]. Other studies suggested that gender does not play a role in the prevalence of AD [31, 32].

### **5. The association between presbycusis and tinnitus**

Several researches suggest that hearing loss contributes to the higher prevalence of tinnitus [33]. At present, the following two reasons are mostly considered. One reason is the sensory deprivation of the auditory system. The decrease in auditory stimulation leads to the unbalance between excitation and inhibition in the auditory nervous system [34]. The auditory nervous system has both suppression and excitation response region. Once a sound is inputted, excitation action will be activated and lateral inhibition appears consequently. Hearing loss reduces the activity of cochlear and downregulates inhibitory neurons processes, thereby activating the central auditory structures, increasing the spontaneous firing rate of neurons, resulting in the awareness of tinnitus. Sound stimulation at different frequencies can inhibit the formation of tinnitus. Studies have shown that high frequency sounds have a stronger suppression of tinnitus, and the decline of high frequency is a common and typical symptom in the ARHL [35]. The activation of neural plasticity in the central auditory system plays a vital role in maintaining the sensory of tinnitus [36]. Because when the auditory nerve was removed, the tinnitus persists [37]. Neural plasticity can change the processing of sounds, reroute auditory signals in the central nervous system, increase neural synchrony, and promote coherent

firings of activity in many neurons [38]. Another reason is that hearing loss and tinnitus share the same common risks, including age, cardiovascular disorders, and noise exposure [39].

## **6. The association between presbycusis and cognitive decline**

Clinically, patients with presbycusis usually perform worse than others in function of speech and communication, resulting in negative psychosocial endings such as social isolation and social frailty [40]; depression, poor cognitive performance and even induce cognitive decline [33, 41]; and low physical performance and physical frailty [42, 43]. A meta-analysis of 36 epidemiological studies and 20,264 participants showed that the decline of cognitive domains are significantly associated with ARHL [44]. Hearing loss is considered as the independent risk factor for the development of dementia, and 46.4% of patients with dementia were accompanying hearing loss [8]. There may be a bidirectional connection between presbycusis and dementia. On the one hand, it is more likely for the elderly with hearing impairment to suffer dementia than the healthy elderly [45], and on the other hand, the hearing threshold of the elderly with dementia is significantly lower than the healthy elderly [45–47]. A large cross-sectional study in the UK shows the association between hearing aid use with better cognitive function [48]. The hearing intervention significantly improves the auditory and cognitive function in the elderly [49].

Presbycusis and dementia may share some common pathophysiological mechanisms [50, 51] once degradation on one pathway may accelerate the degradation on each other disease. The hypothetical mechanistic pathways are still uncertain. However, some authors may agree that hearing loss can impair speech perception and distort peripheral encoding of sound by the cochlea. Besides, peripheral hearing loss has a negative influence on the measurements or process of central auditory; finally, it increases cognitive load, depletes cognitive reserve, alters brain structure and function, and affects global cognition [52, 53]. Hearing loss will cause social isolation and loneliness associated with chronic stress and depression. The psychosocial outcomes contribute to hippocampal atrophy and cognitive decline through the hypothalamic-pituitary-adrenal (HPA) axis [8, 54]. The dysfunction of HPA axis results in the atrophy of pyramidal cell dendrites, thereby reducing the ability of hippocampal structural plasticity and synapse generation.

### **7. The association between cognitive decline and tinnitus**

Little research focuses on the association between presbycusis co-occurring with tinnitus and dementia. However, central nervous degenerative diseases such as dementia will affect central auditory systems (i.e., temporal and adjacent frontal lobes) and cause central auditory disorders, which is an essential physiological pathway of the diseases. Not only the central auditory structure but also the nonauditory brain areas (i.e., frontal cortex or the limbic system) play a vital role in sound perception, understanding, and emotional awareness [55]. Inflammation and ischemia will cause disturbances to the central nervous system [56]. When the neural substrates of tinnitus (i.e., medial temporal lobe, primary auditory, and frontal cortices) are involved, tinnitus and hearing allergies occur [57]. Meanwhile, inflammation and ischemia can develop neurodegeneration disease of AD in frontoparietotemporal [58]. AD shares the same pathological basis with

**47**

**9. Conclusion**

central auditory function.

**Acknowledgements**

*Presbycusis-Related Tinnitus and Cognitive Impairment: Gender Differences and Common…*

tinnitus, although targets in different areas. On the other hand, chronic tinnitus is significantly associated with anxiety and depression. The limbic system was proved to contribute to the emotional burden. Presbycusis co-occurring with tinnitus may accompany vestibular/balance difficulties, similar to anxiety and depression; it will

**8. The treatments in the coexistence of presbycusis-related tinnitus and**

Presbycusis-related tinnitus and cognitive impairment are complex diseases without any effective treatment by far. However, compared to age-matched men, women before menopause seem to have a better auditory and cognitive function, while the different fades away with age. Sex hormones may play an important role. The association among the diseases indicates the feasibility of intervening in the hearing loss to ameliorate the tinnitus and cognitive impairment. A comprehensive assessment is a prerequisite for treatment. Hearing aid and cochlear implantation

Emerging studies suggest that the use of hearing aid or cochlear implants can not only focus on auditory rehabilitation but also improve the symptom of cognitive function and tinnitus [59–62]. However, the prevalence of hearing aid use is low [63]. Only 14.2% of Americans 50 years old with hearing loss wear hearing aids, not to mention the populations in developing countries [64]. Many patients with hearing loss tend to ignore the hearing loss as normal aging until the accelerated deterioration of the auditory function. Furthermore, the expensive cost of hearing

In turn, advanced technology and equipment (i.e., virtually reality) can be designed to improve cognitive function and central auditory disorder through reasonable and repeated cognitive and behavioral treatment for functions such as

Presbycusis-related tinnitus and dementia are a common disturbance to the elderly but always be unnoticed at an early stage. Age is the most important factor for the diseases. Apart from age, most epidemiological evidence suggest that women have a better auditory and cognitive function and less prevalence of tinnitus than men; however, the advantages disappear with age. The three diseases interact and promote each other with decreased peripheral hearing perception and central nervous system dysfunction. The elderly should pay attention to auditory function carefully. Maintaining normal peripheral and central auditory function can reduce cognitive decline and tinnitus. Conversely, the elderly with cognitive decline or tinnitus should actively participate in cognitive and behavioral treatment to enhance

This work was supported by the Medical Science and Technology Support Project of Shanghai Science and Technology Commission<PHONE_NUMBER>0), Shanghai Center for Clinical Medicine and Key Discipline Construction (2017ZZ02010).

aid and cochlear implantation hold back the eager of intervention.

sensation, cognition, emotion, and motor control [65, 66].

reduce social activity and finally leads to late-life cognitive decline [53].

*DOI: http://dx.doi.org/10.5772/intechopen.90956*

**cognitive impairment**

are the most important treatment of hearing loss.

*Presbycusis-Related Tinnitus and Cognitive Impairment: Gender Differences and Common… DOI: http://dx.doi.org/10.5772/intechopen.90956*

tinnitus, although targets in different areas. On the other hand, chronic tinnitus is significantly associated with anxiety and depression. The limbic system was proved to contribute to the emotional burden. Presbycusis co-occurring with tinnitus may accompany vestibular/balance difficulties, similar to anxiety and depression; it will reduce social activity and finally leads to late-life cognitive decline [53].

## **8. The treatments in the coexistence of presbycusis-related tinnitus and cognitive impairment**

Presbycusis-related tinnitus and cognitive impairment are complex diseases without any effective treatment by far. However, compared to age-matched men, women before menopause seem to have a better auditory and cognitive function, while the different fades away with age. Sex hormones may play an important role. The association among the diseases indicates the feasibility of intervening in the hearing loss to ameliorate the tinnitus and cognitive impairment. A comprehensive assessment is a prerequisite for treatment. Hearing aid and cochlear implantation are the most important treatment of hearing loss.

Emerging studies suggest that the use of hearing aid or cochlear implants can not only focus on auditory rehabilitation but also improve the symptom of cognitive function and tinnitus [59–62]. However, the prevalence of hearing aid use is low [63]. Only 14.2% of Americans 50 years old with hearing loss wear hearing aids, not to mention the populations in developing countries [64]. Many patients with hearing loss tend to ignore the hearing loss as normal aging until the accelerated deterioration of the auditory function. Furthermore, the expensive cost of hearing aid and cochlear implantation hold back the eager of intervention.

In turn, advanced technology and equipment (i.e., virtually reality) can be designed to improve cognitive function and central auditory disorder through reasonable and repeated cognitive and behavioral treatment for functions such as sensation, cognition, emotion, and motor control [65, 66].

### **9. Conclusion**

*An Overview and Management of Multiple Chronic Conditions*

noise exposure [39].

the elderly [49].

firings of activity in many neurons [38]. Another reason is that hearing loss and tinnitus share the same common risks, including age, cardiovascular disorders, and

Clinically, patients with presbycusis usually perform worse than others in function of speech and communication, resulting in negative psychosocial endings such as social isolation and social frailty [40]; depression, poor cognitive performance and even induce cognitive decline [33, 41]; and low physical performance and physical frailty [42, 43]. A meta-analysis of 36 epidemiological studies and 20,264 participants showed that the decline of cognitive domains are significantly associated with ARHL [44]. Hearing loss is considered as the independent risk factor for the development of dementia, and 46.4% of patients with dementia were accompanying hearing loss [8]. There may be a bidirectional connection between presbycusis and dementia. On the one hand, it is more likely for the elderly with hearing impairment to suffer dementia than the healthy elderly [45], and on the other hand, the hearing threshold of the elderly with dementia is significantly lower than the healthy elderly [45–47]. A large cross-sectional study in the UK shows the association between hearing aid use with better cognitive function [48]. The hearing intervention significantly improves the auditory and cognitive function in

Presbycusis and dementia may share some common pathophysiological mechanisms [50, 51] once degradation on one pathway may accelerate the degradation on each other disease. The hypothetical mechanistic pathways are still uncertain. However, some authors may agree that hearing loss can impair speech perception and distort peripheral encoding of sound by the cochlea. Besides, peripheral hearing loss has a negative influence on the measurements or process of central auditory; finally, it increases cognitive load, depletes cognitive reserve, alters brain structure and function, and affects global cognition [52, 53]. Hearing loss will cause social isolation and loneliness associated with chronic stress and depression. The psychosocial outcomes contribute to hippocampal atrophy and cognitive decline through the hypothalamic-pituitary-adrenal (HPA) axis [8, 54]. The dysfunction of HPA axis results in the atrophy of pyramidal cell dendrites, thereby reducing the

ability of hippocampal structural plasticity and synapse generation.

**7. The association between cognitive decline and tinnitus**

Little research focuses on the association between presbycusis co-occurring with tinnitus and dementia. However, central nervous degenerative diseases such as dementia will affect central auditory systems (i.e., temporal and adjacent frontal lobes) and cause central auditory disorders, which is an essential physiological pathway of the diseases. Not only the central auditory structure but also the nonauditory brain areas (i.e., frontal cortex or the limbic system) play a vital role in sound perception, understanding, and emotional awareness [55]. Inflammation and ischemia will cause disturbances to the central nervous system [56]. When the neural substrates of tinnitus (i.e., medial temporal lobe, primary auditory, and frontal cortices) are involved, tinnitus and hearing allergies occur [57]. Meanwhile, inflammation and ischemia can develop neurodegeneration disease of AD in frontoparietotemporal [58]. AD shares the same pathological basis with

**6. The association between presbycusis and cognitive decline**

**46**

Presbycusis-related tinnitus and dementia are a common disturbance to the elderly but always be unnoticed at an early stage. Age is the most important factor for the diseases. Apart from age, most epidemiological evidence suggest that women have a better auditory and cognitive function and less prevalence of tinnitus than men; however, the advantages disappear with age. The three diseases interact and promote each other with decreased peripheral hearing perception and central nervous system dysfunction. The elderly should pay attention to auditory function carefully. Maintaining normal peripheral and central auditory function can reduce cognitive decline and tinnitus. Conversely, the elderly with cognitive decline or tinnitus should actively participate in cognitive and behavioral treatment to enhance central auditory function.

### **Acknowledgements**

This work was supported by the Medical Science and Technology Support Project of Shanghai Science and Technology Commission<PHONE_NUMBER>0), Shanghai Center for Clinical Medicine and Key Discipline Construction (2017ZZ02010).

*An Overview and Management of Multiple Chronic Conditions*


**Author details**

Ewelina Widelska\*, Barbara Sowińska-Świerkosz and Wojciech Walczak University of Life Science in Lublin, Poland

\*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.


*Article* **The Effect of Nonthermal Pretreatment on the Drying Kinetics and Quality of Black Garlic**

**Klaudia Masztalerz 1 , Tomasz Drózd˙ z˙ 2 , Paulina Nowicka 3 , Aneta Wojdyło 3 , Paweł Kiełbasa 2 and Krzysztof Lech 1,\***

**Abstract:** Black garlic is obtained from regular garlic (*Allium sativum* L.) through the aging process and consequently gains many health-promoting properties, including antidiabetic and antioxidant. However, the material is still prone to microbiological deterioration and requires a long time to dry due to its properties. Therefore, this study aimed to investigate the effect of various drying methods on the quality of black garlic as well as determine the influence of selected nonthermal pretreatments on the drying kinetics and quality of black garlic, which is especially important in the case of the materials that are difficult to dry. The Weibull model was chosen to describe drying kinetics. Additionally, color, water activity together with antioxidant activity, phenolic compounds, and antidiabetic potential were determined. This study found that the application of a pulsed electric field (PEF), a constant electric field (CEF) as well as a magnetic field (MF) significantly reduced the time of drying (by 32, 40, and 24 min for a PEF, a CEF, and a MF, respectively, compared to combined drying without the pretreatment), and resulted in high antidiabetic potential. However, the highest content of phenolic compounds (1123.54 and 1125.36 mg/100 g dm for VMD125 and CD3h-VMD, respectively) and antioxidant capacity (ABTS = 6.05 and 5.06 mmol Trolox/100 g dm for VMD500 and CD6h-VMD, respectively) were reported for black garlic treated by vacuum-microwave drying and combined convective pre-drying followed by vacuum-microwave drying. Overall, the nonthermal pretreatment decreased the time of drying and showed very good efficiency in maintaining the antidiabetic potential of black garlic, especially in the case of the materials pretreated by a constant electric field (IC50 = 99 and 56 mg/mL, for α-amylase and α-glucosidase, respectively).

**Keywords:** antidiabetic potential; antioxidant capacity; constant electric field; drying; magnetic field; pretreatment; pulsed electric field; total phenolic content