*5.1. Comparison to Other Algorithms*

We compare CODB with other three competing algorithms (i.e., Brushfire, Dynamic Brushfire, and algorithms proposed by Boris Lau et al. [23] (we abbreviate it as BL below)) which are discussed in Section 2 in four typical scenarios as shown in Figure 9.

**Figure 9.** The grid maps used to compare performance of different algorithms. (**a**) Full reconstruction; (**b**) 75% changed; (**c**) 50% changed; (**d**) 25% changed. Within these figures, the obstacles marked in black and blue are static, while the obstacles marked in yellow randomly change their positions or shapes.

We set aside four grid maps (from Figure 9a to Figure 9d) which have the same size (100 × 100) while allowing different proportions of the obstacles (i.e., fully reconstruction, 75%, 50%, and 25% respectively) to randomly change their positions or shapes. After each set of changes, we use the above mentioned four algorithms to construct or reconstruct the DMs. We run each algorithm on each scenario 100 times, and the comparisons of the performances among these algorithms are shown in Table 7 and Figure 10 (i.e., the average computation time scaled in milliseconds and its variance) and Table 8 and Figure 11 (i.e., the maximal size of the priority queue *OPEN* during construction and its variance).

\* Dynamic algorithms that only repair the affected portions.

**Table 8.** Comparison of themaximal size of the priority queue*OPEN*(Onlydynamic algorithms are compared).

**Figure 10.** The average computation time provided by the four algorithms for updating DMs. The algorithms prefixed with "\*" are dynamic algorithms and only update the affected areas.

**Figure 11.** The average cell visits provided by the three dynamic algorithms.

For the first scenario in which full reconstructions are inevitable since all the obstacles are moved or reshaped, the extra operations that enable local repairs make Dynamic Brushfire (8.61 ms) and BL (7.22 ms) slower than their static counterpart, Brushfire (6.34 ms). However, due to the integration of Canonical Ordering strategy, CODB can substantially prune the search space; thus, it still maintains an obvious advantage over the other three algorithms in time efficiency (4.26 ms), even in the case of full reconstructions. As for the other three scenarios, as the proportion of the dynamic obstacles decreases, dynamic algorithms gradually manifest their superiority in speed. Among the three dynamic algorithms, CODB is also faster than the others due to fewer cell visits, reducing the computation time by at least 50%.


**2.4 Osteoporosis**

Another feature of RA is secondary osteoporosis. RA patients have greater incidence of osteoporosis and osteoporotic fractures than matched non-RA controls (e.g. Frank & Gottwalt, 2009; Huusko et al., 2001; Sinigaglia et al., 2006); with this increase attributed to the disease itself (systemic inflammation), treatment with high dose oral glucocorticoids, and sedentary lifestyle (Cantley et al., 2009; Frank & Gottwalt, 2009; Huusko et al., 2001; Sinigaglia et al., 2006; ). Interestingly, after high-dose steroid therapy, the reduced bone mineral density (BMD) in RA patients has been found to be most strongly associated with low strength (quadriceps and handgrip) and poor physical function (Huusko et al., 2001; Madsen et al., 1998, 2001).


*Statistical Analysis*

Descriptive statistics were used for baseline patient and tumor characteristics. The change in renal function (eGFR) from baseline versus post-treatment at the latest available time point in follow-up was evaluated using the paired sampled *t*-test. Local, regional, distant disease control and overall survival (OS) were estimated using the Kaplan-Meier method. OS was calculated as the time between the first fraction of MRgRT and the date of the last follow-up. LC was calculated as the time between the first fraction of MRgRT and the date of last imaging. Statistical analysis used for plan comparisons was performed using the Wilcoxon Signed-Rank test. A *p*-value of < 0.05 was considered to be statistically significant. Decision tree analysis (CHAID, Chi-square automatic interaction detection) was used to explore predictive pretreatment characteristics and most significant cut-off values to identify patients for

whom daily re-optimization was needed. Baseline volumetric, geometric, and dosimetric parameters, i.e., GTV size (cc), laterality (left, right), location (interpolar, upper or lower pole), V33Gy, V30Gy, V25Gy, and V20Gy for each OAR structure separately or combined in one structure were used as input variables. The qualitative re-optimization benefit variable ("redundant" or "needed") was selected as the target variable for decision tree analysis. The significance level for node splitting was set at *p* < 0.05. Stopping parameters to prevent over-fitting were applied by setting the minimum number of records in a leaf to be at least 10% of the data set. The Statistical Package for the Social Sciences (SPSS) version 26 (IBM® SPSS Statistics, Armonk, NY, USA) was used to perform all statistical analyses.


Scope of the Series

Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the expression, structure, and function of molecular and cellular components. While a daunting task, learning is facilitated by our identification of common, effective signaling pathways employed by nature to sustain life. As a main example, the cellular interplay between intracellular Ca2 increases and changes in plasma membrane potential is integral to coordinating blood flow, governing the exocytosis of neurotransmitters and modulating genetic expression. Further, in this manner, understanding the systemic interplay between the cardiovascular and nervous systems has now become more important than ever as human populations age and mechanisms of cellular oxidative signaling are utilized for sustaining life. Altogether, physiological research enables our identification of clear and precise points of transition from health to development of multi-morbidity during the inevitable aging process (e.g., diabetes, hypertension, chronic kidney disease, heart failure, age-related macular degeneration; cancer). With consideration of all organ systems (e.g., brain, heart, lung, liver; gut, kidney, eye) and the interactions thereof, this Physiology Series will address aims of resolve (1) Aging physiology and progress of chronic diseases (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling & (3) how changes in plasma membrane produced by lipid peroxidation products affects aging physiology.

Contents

**Section 1**

of Antioxidants

of Kawasaki Disease

**Section 2**

*by Tae Gyu Choi and Sung Soo Kim*

**Preface XI**

Redox Biology and Medicine **1**

**Chapter 1 3**

**Chapter 2 11**

**Chapter 3 35**

**Chapter 4 53**

Antioxidants **71**

**Chapter 5 73**

**Chapter 6 95**

Introductory Chapter: Free Radical Biology in Metal Toxicities—Role

*by Swastika Das, Shrilaxmi Bagali, Sayandeep K. Das, Aravind V. Patil,*

Physiological Functions of Mitochondrial Reactive Oxygen Species

*Ishwar B. Bagoji, Kusal K. Das and Mallanagouda S. Biradar*

Role of Oxidative Stress in the Cardiovascular Complications

Radiation-Generated ROS Induce Apoptosis via Mitochondrial

Effects of Oxidative Stress on Spermatozoa and Male Infertility

Nonenzymatic Exogenous and Endogenous Antioxidants *by Ziad Moussa, Zaher M.A. Judeh and Saleh A. Ahmed*

*by Rosa Vona, Donatella Pietraforte, Lucrezia Gambardella, Alessandra Marchesi, Isabella Tarissi de Jacobis, Alberto Villani,*

*Domenico Del Principe and Elisabetta Straface*

*by Sandra Claro, Alice Teixeira Ferreira and Maria Etsuko Miyamoto Oshiro*

*by Yi Fang and Rongzhen Zhong*


**3. Food safety systems**

Effective food control systems are needed to improve the applicability and control of food safety [77]. Currently, the HACCP, ISO 22000 and PAS 220 are the most commonly used internationally approved food safety systems.

#### **3.1. Hazard analysis and critical control points (HACCP)**

HACCP was first used in the 1960s by the American Pillsbury company for the purpose of producing "zero defect" products for the US Army and NASA. Later, starting in the 1970s, it began to be used as a reference by the Food and Drug Administration (FDA) in official supervisions. It was adopted by the Codex Alimentarius Commission in 1992 and published as the HACCP international standard for the first time. Since then, the food industry and official authorities have been using it to protect against and control the risks of potential dangers that could threaten food safety [78].

Initially, HAACCP had three principles:

The HACCP, as it is applied today, has five starting steps and is governed by seven principles. The starting steps were created by Codex, and they should be completed prior to implementing the seven HACCP principles. The starting steps help to ensure that the HACCP system is implemented and managed in the most effective way possible [79].

The HAACP system is applicable for any company operating within the food chain, regardless of their size. In the implementation stage, the HACCP system should be supported by certain preliminary condition programs. A company interested in implementing this system should already be following the requirements of this preliminary condition program. Preliminary condition programs include national regulations, codes of practice or other food safety prerequisites. In general, preliminary condition programs involve factories and equipment, staff training, cleaning and sanitation, maintenance chemical control, waste management, storage and transportation [78].

**Table 3.** HACCP Implementation in 12 Steps

HACCP is an internationally accepted system and in most countries, it is required that companies within the food industry implement this system.

#### **3.2. ISO 22000**

In 2005, The International Organization for Standardization (ISO) published a standard for the Food Safety Management System known as ISO 22000. The ISO 22000 system is a combination of preliminary condition programs, HACCP principles and implementation steps defined by the Codex Alimentarius Commission and ISO 9001:2000 standard components. After it was defined, it began to be used in more than 50 countries within 2 years [80].

The basic approach of the ISO 22000 standard is to implement a preventive system that serves to protect consumers from foodborne diseases. This standard controls all the processes in the food chain, including infrastructure, staff and equipment. In business establishments, the Food Safety Management System implementations include production control, product control, equipment control, maintenance, general hygiene practices, staff and visitor hygiene, trans‐ portation, storage, product information, training, the selection and evaluation of suppliers, communication and other similar issues [81].

The main goal of this standard is to have a system in place that determines the unacceptable risks that may result from process errors and to secure product safety and consumer health. Food safety supervision over product, design, production and quality control determines and eliminates the potential dangers. The fundamental role of ISO 22000 is not only to provide food safety but also to improve the sensory and nutritional quality of food, and it also plays a primary role in the quality assurance of service practices in industrial production. Lastly, this standard helps to reduce operational losses by instituting a more effective use of resources to increase productivity, and thereby, directs the establishment to a system of total quality [80].

#### **3.3. PAS 220 (publicly available specification)**

This standard was created by the major global food producers in cooperation with the Confederation of Food and Drink Industries (CIAA) with the purpose of eliminating the weaknesses of the ISO 22000 food safety system standard. Nestle, Unilever, Danone and Kraft, the sector leaders generally known as "G4", collectively published the PAS 220 standard, which refines the preliminary conditions programs. The PAS 220 standard is applicable for all types of companies and was made available in 2008. It was intended that the PAS 220 standard be used together with the internationally accepted ISO 22000 standard [82].

The content and topics of PAS 220 elaborate on the 10 sub-titles in the ISO 22000 standard and adds 5 of its own, resulting in the following 15 items [82]: