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Intelligent systems, known as expert systems, serve to this purpose in the extent that they have signed as facilitators in this process. These are systems that are based on expert knowledge, on any subject, in order to emulate human expertise in the specific field. To obtain this knowledge, the knowledge engineers, also called software engineers, need to develop methodologies for intelligent systems. In this area there is still no unified methodology that provides effective methods, notations and tools to aid in development.

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Advances in Expert Systems

Advances in Expert Systems

*Edited by Petrică Vizureanu*


The Wonders of Diptera - Characteristics, Diversity, and Significance for the World's Ecosystems

*Edited by Farzana Khan Perveen*

Published in London, United Kingdom

### *Supporting open minds since 2005*

The Wonders of Diptera - Characteristics, Diversity, and Significance for the World's Ecosystems http://dx.doi.org/10.5772/intechopen.91609 Edited by Farzana Khan Perveen

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Darine Slama, Emna Chaker, Hamouda Babba, Manoel Uchoa, Nádia Roque, Morgana F. Wachter-Serapião, Murat Helvaci, António Souza, Eduardo Jose De Arruda, Alex Martins Machado, Taiana Gabriela Barbosa De Souza, Raphael Antônio Borges Gomes, Sevidzem Lendzele, Ovono Mélodie Audrey Prisca, Mounioko Franck, Zinga Koumba Christophe Roland, Maroundou Audrey Pamela, Acapovi-Yao Géneviève Lydie, Tamesse Joseph Lebel, Simo Gustave, M'batchi Bertrand, Mavoungou Jacques François, Karima Zerguine, Azubuike Christian Ukubuiwe, Israel Kayode Olayemi, Chinenye Catherine Ukubuiwe, Bright Ugbede Sule, Rajendra S. Fartyal, Pragya Topal, Divita Garg, Jimi N. Nakajima, Anderson S. Fernandes, Farzana Khan Perveen, Anzela Khan

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**Damage Mechanism Evaluation of Large-Scale Concrete Structures Affected by Alkali-Silica Reaction Using Acoustic Emission**

**Vafa Soltangharaei 1,\*, Rafal Anay 1, Nolan W. Hayes 2, Lateef Assi 1, Yann Le Pape 3, Zhongguo John Ma 2 and Paul Ziehl 1**

Received: 25 September 2018; Accepted: 31 October 2018; Published: 3 November 2018

**Abstract:** Alkali-silica reaction has caused damage to concrete structures, endangering structural serviceability and integrity. This is of concern in sensitive structures such as nuclear power plants. In this study, acoustic emission (AE) was employed as a structural health monitoring strategy in large-scale, reinforced concrete specimens affected by alkali-silica reaction with differing boundary conditions resembling the common conditions found in nuclear containments. An agglomerative hierarchical algorithm was utilized to classify the AE data based on energy-frequency based features. The AE signals were transferred into the frequency domain and the energies in several frequency bands were calculated and normalized to the total energy of signals. Principle component analysis was used to reduce feature redundancy. Then the selected principal components were considered as features in an input of the pattern recognition algorithm. The sensor located in the center of the confined specimen registered the largest portion of AE energy release, while in the unconfined specimen the energy is distributed more uniformly. This confirms the results of the volumetric strain, which shows that the expansion in the confined specimen is oriented along the thickness of the specimen.

**Keywords:** alkali-silica reaction; acoustic emission; pattern recognition; confinement; damage evaluation


Abstract The increase in the volume of health-related research in Africa has not everywhere been accompanied by improvements in research oversight systems related to biomedical and health services research, including the strengthening of institutional review boards (IRBs) and national regulatory oversight institutions. Critical to such oversight are not only competencies in ethics for the review of clinical trials, but also competencies in diverse research methods, statistical analyses and project implementation. In Liberia, there are recognized weaknesses in the existing infrastructure and capacity to regulate and monitor clinical research based on ethical institutional regulations and guidance for the protection of human research participants. During the height of the Ebola virus disease (EVD) surge in Liberia in 2014, there was a fragile national regulatory framework to oversee research. Some researchers took undue advantage of this gap to conduct unethical research.

Keywords Ebola Virus Disease Liberia Emergency research Retrospective approval Ethics committee Institutional review board

This case study is about an attempt to seek ethics approval after the study had already been conducted. Trying to obtain retrospective approval of research undermines the legitimacy of an Institutional Review Board (IRB) and the research review process itself. If the level of risk that a research study on EVD survivors presents is only determined after its completion, then the participants would have already been exposed to harm and their autonomy compromised. The researcher in this case used the cover of "emergency research" to avoid the review process – although emergency

J. K. Tegli (&)

PREVAIL OFFICE, 1st Floor, East Wing, JFK Medical Center, 21 Street, Sinkor, Monrovia, Liberia e-mail<EMAIL_ADDRESS>
J. K. Tegli UL-PIRE Africa Center, University of Liberia, Ground Floor, GD Bldg., Monrovia 100010, Liberia

© The Author(s) 2018 D. Schroeder et al. (eds.), Ethics Dumping, SpringerBriefs in Research and Innovation Governance, https://doi.org/10.1007/978-3-319-64731-9\_14 research regulations stipulate full disclosure of proposed research prior to implementation, and there are specified consenting processes (National Institute of Medicine (2002)).

### Area of Risk of Exploitation

An investigator breached the Declaration of Helsinki and other global ethical guidelines by ignoring an ethical review oversight process that was fully functional in Liberia. The investigator was provided with information about the country's ethical review process at meetings of the Ebola Response Incident Management System, but chose to deploy the research team into targeted communities without ethical approval, collecting data through focus group discussions, key informant interviews and in-depth interviews. The data were analysed and submitted for presentation and/or publication at national and international meetings.

The entire data collection process, involving sensitive topics centred on Ebola-affected communities, was highly distressing. The consent process was conducted at the discretion of the researcher and the study team (Pollock, 2012). Providing so-called consent processes to participants in the frenzy of an epidemic can lead to misconceptions on their part. Risk mitigation measures were not fully assessed because guidance from an ethical institution was not explored or sought prior to the conduct of the study.

The fundamental pillar of respect for persons was also ignored. This should be the principle upon which each research participant makes an informed choice about whether or not to participate in the research, and thus accepts the potential risks and burdens of participation (Jasanoff, 1993). Thorough explanation to participants about the availability of the research ethics review board to address concerns regarding their rights or wellbeing, and providing contact information, are critical elements of the consent process. Whether consent is sought verbally or in writing, reference must be made to an ethics review board that reviewed and approved the research study. Ignoring one of the major pillars of ethical research – namely, ethics review – opens up a range of risks for exploitation (Martinson et al., 2005).

### Background

Whatever the context, the need for the regulation of research is clear. In March 2014, the Ebola epidemic hit Liberia very hard. With Guinea and Sierra Leone also affected, the death toll in Liberia as of May 2016 stood at 4,810, with 10,678 infected. At the peak of the epidemic in October 2014, researchers and institutions were pouring into the country to conduct all forms of research, ranging from social science, anthropological and clinical studies.

As a result of the health emergency, the ethical research institutions were overwhelmed with questions from many investigators and institutions seeking information about the application process. The ethical boards were approached by several potential investigators in and outside of Liberia for information and guidance about the review process in the country. In spite of the availability of this platform, some researchers proceeded to conduct their research studies in November 2014 without prior review and approval by the relevant IRB. They circumvented the process under the pretext of the emergency and collected data from human participants in an unethical manner.

A particular case came to light in December 2014, when the IRB denied a researcher employed by an international UN public health agency retrospective ethical approval. Such an attempt to obtain retrospective approval of research undermines the legitimacy of the IRB and the research review process itself. If the level of risk that a research study on Ebola virus disease (EVD) survivors presents is determined only after its completion, then the participants would have already been exposed to harm and their autonomy compromised. This researcher used the cover of "emergency research" to avoid the review process – although emergency research regulations stipulate full disclosure of proposed research prior to implementation, and there are specified consenting processes.

### Details of the Case

In early December 2014, the University of Liberia-Pacific Institute for Research and Evaluation IRB received an application from a researcher working for an international UN public health agency seeking approval for medical anthropological research on survivors of EVD in Monrovia. The focus of the study was on gathering information on the economic well-being of EVD survivors in Liberia. The objective was to assess the psychosocial situation and the impact of stigma and discrimination on the lives of survivors.

The research, which took place at the height of the EVD surge from November to December 2014, involved several EVD-affected communities in urban and peri-urban Monrovia. Most were from semi-literate and illiterate populations and had already been traumatized by the surge in EVD deaths. This study therefore had the potential to inflict distress on these participants: for example, it is traumatizing for EVD survivors to recount their experiences or circumstances, because these involve very recent catastrophic events in their lives.

The IRB convened and expedited the review process, given the importance of conducting the proposed research in a timely manner during the EVD outbreak. At the time, the IRB was not aware that the research had already been completed when the application was submitted for review. The researcher had left Liberia and was not present at the meeting, but was represented by a less experienced Liberian research assistant (RA).

During the IRB meeting, the RA was asked a question about the intended timetable for commencing the study. To the board's surprise, they were told that the data for the study had already been collected and analyzed. The role and responsibilities of this junior researcher in the implementation of the study were unclear and apparently minimal. The research team was only seeking approval from the IRB in order to disseminate the research results.

The IRB chair immediately called the meeting off and told the RA that the incident undermined best practices in the ethical conduct of health research. The RA was instructed to report the findings of the IRB to the principal investigator: namely that research had been conducted unethically, research review and approval regulations had been contravened, and the autonomy of the EVD survivors who were research participants had been breached.

### Reasons for IRB Decision and Conclusion

A retrospective IRB approval of a research project – that is, after participants may already have been exposed to unnecessary harm or violation of their rights – would be unethical. Conducting a research study without IRB oversight violates both ethical principles and IRB procedures. In this context, the decision takes a stance on public policy that aims at increasing compliance with IRB requirements.

Without ethics approval, it is impossible to have the results of a study published in a reputable journal. One must assume that this is why the researcher tried to obtain retrospective approval. While the decision the IRB reached was emphatic, it was preceded by a short discussion on whether granting approval retrospectively, and thereby allowing publication of the research results, may contribute to the public good (Tansey et al., 2010). However, the IRB decided firmly in the negative, partly because the research had been undertaken on a highly vulnerable group of illiterate and uneducated Liberians who would have little knowledge of the consent process.

The Liberian IRB therefore made a clear decision to uphold the autonomy of both the IRB and the research participants by refusing to approve a study retrospectively.

### References

#### Author Biography

Jemee K. Tegli is Director of Operations for the Liberia-United States Clinical Research Program, Partnership for Research on Ebola Virus in Liberia. He previously worked for the University of Liberia-Pacific Institute for Research and Evaluation as Center Director. He serves as Coordinator of the UL-PIRE Institutional Review Board (IRB) and Member of the National Research Ethics Board (NREB) of the Ministry of Health. He is an international IRB Member of the Western Intuitional Review Board (WIRB)-Copernicus Group in Puyallup, Washington.

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### Chapter 15 Legal and Ethical Issues of Justice: Global and Local Perspectives on Compensation for Serious Adverse Events in Clinical Trials

### Yali Cong

Abstract A 78-year-old Chinese woman joined a clinical trial sponsored by a pharmaceutical company. Unfortunately a serious adverse event (SAE) occurred. The sponsor paid for the cost of the medical care arising from the SAE, but refused the family's request for compensation. The family then sued the company and the hospital in Beijing. Although the SAE was related to a complication of lower extremity angiography and not the drug itself, it was a direct consequence of participating in the trial. According to Good Clinical Practice, a set of regulations promulgated under Chinese law, "the sponsor should provide insurance to those human subjects who participate in clinical trials, cover the cost of treatment and the corresponding economic compensation for the occurrence of the harm or death associated with the trial" (SFDA in Good clinical practice. State Food and Drug Administration,2003: art. 43). The court ordered the trial sponsor to provide a translation of the company's insurance policy, so that the court could understand the amount of compensation available to the patient under the policy, but the sponsor never surrendered either the documentation or a translation. Consensus was never reached about the amount of compensation due to the patient through negotiation with the hospital, the company and the family. The litigation ended after nine hearings and five long years. This chapter provides an ethical analysis of the case relative to at least three areas of risk of exploitation when a major, international pharmaceutical company sponsors clinical research in a country with an immature legal system and where research participants have limited resources.

Keywords Clinical trial Serious Adverse Event (SAE) China Global research Justice Insurance

© The Author(s) 2018 D. Schroeder et al. (eds.), Ethics Dumping, SpringerBriefs in Research and Innovation Governance, https://doi.org/10.1007/978-3-319-64731-9\_15

Y. Cong (&)

Medical Ethics and Health Law Program, Peking University Health Science Center, 38 Xueyuan Rd, Beijing, China e-mail<EMAIL_ADDRESS>
### Areas of Risk of Exploitation

There are at least three ways in which this case illustrates the risk of exploitation.

The principle of justice requires that the benefits and burdens of research be distributed fairly. This means that participants who are injured during the research should be compensated fairly for their injuries. The present case demonstrates the main risk of exploitation during the process of an individual research participant's litigation. Although individuals may be compensated, litigation is costly and time-consuming. Studies have found that approximately 50% of the sums recovered from tort lawsuits in high-income countries (HICs) do not reach the injured parties but instead go to attorney fee payments and other costs. Legal barriers such as the assumption of risk, contributory negligence and government immunity may discourage litigation by injured research participants or preclude recovery in whole or part (Resnik et al. 2014).

Second, this case illustrates the risk of exploitation due to the considerable variation in regulations across various countries, which results in inconsistent compensation for the victim of a serious adverse event (SAE). Regarding the payout amount for compensation, trial sponsors might approach the amount differently for human research participants who suffer the same SAEs in different countries. This suggests that the values of justice may not be fulfilled, as there should be no double standards in the compensation for SAEs. While there is no data publicly available about variations in payment for SAEs, this case raises the suspicion that equal and just compensation in global studies is not being achieved, or at least not in all cases. Exploitation occurs when different patients suffer the same harm or injury, but do not receive equal compensation (or at least compensation adjusted to amounts based on average incomes in the countries concerned).

The third risk of exploitation derives from the inequality in access to resources for litigation between individual research participants and pharma sponsors. In this case the company exploited its position of litigatory strength. It did not cooperate with the local court, in that, for example, it did not supply either the original of the insurance contract or a translation into Chinese. In addition to being a failure to comply with the court's request, this delayed the legal process.

### Background

Xarelto® (rivaroxaban) or BAY 59-7939 is an oral tablet (factor Xa inhibitor), taken once a day, intended for prophylaxis of deep vein thrombosis (DVT) and the prevention of atrial fibrillation, cardiac thromboembolism and cerebral infarction. The company's application "On the BAY 59-7939 international multi-centre phase III clinical trial" was submitted to China's State Food and Drug Administration (SFDA) in October 2005 and approved in February 2006. The institutional review board (IRB) of a hospital approved the trial based on the application. Being a global clinical trial, the hospital was invited as the leading centre. The trial sponsor signed a contract with the hospital.

### The Case

A 78-year-old woman came to hospital for knee replacement surgery. During her index hospitalization in 2006, she was invited to join this clinical trial. Her daughter was with her at the time of recruitment, and they both agreed to her participation. The knee replacement surgery was conducted on 24 October 2006. In accordance with the protocol, she took the daily tablet, intended for prophylaxis of DVT and the prevention of atrial fibrillation, cardiac thromboembolism and cerebral infarction. She was enrolled from 23 October to 6 November 2006. The research protocol required the patient to undertake double lower-limb vein angiography in order to test for thrombus formation. An SAE occurred after venous angiography. The patient suffered chest tightness, shortness of breath, palpitations, cough, sweating, a very weak pulse, blood pressure dropping to 60/40 mm HG and shock. The patient regained consciousness three hours after resuscitation. The hospital's principal investigator judged this complication to be an SAE and completed the SAE report form on 15 February 2007. The SAE was also reported to the China State Food and Drug Administration on the same day.

The total expenses of the medical treatment caused by the SAE were CNY 3296.17 (approximately USD 420 in 2006), all of which the trial sponsor paid. Considering the patient's suffering and the adverse effect on her recovery of knee function, she and her family desired compensation for the limitations the SAE had imposed on her life. The patient and her family knew that the sponsor had compensation insurance for the study. The investigator reminded the patient of this, and they found relevant information in the informed consent form.

In the section entitled "Patient Notice", the consent form read, "if a subject involved in this trial is injured during the study, the insurance company will pay correspondingly". Based on the consent form, and the study investigator's explanation, the patient knew that the trial sponsor had purchased global insurance for this multi-centre clinical trial. When the patient and her family requested compensation from the hospital and the pharmaceutical company, the company refused. Despite extensive discussions, the three parties could not reach consensus. After failure to agree on a compensation amount, the sponsor and the hospital were summoned to the Beijing Chaoyang Court by the plaintiff in 2008.

### Procedure for Compensation Claim in China

Usually in China, if a plaintiff is injured and claims compensation, the court will require the plaintiff to consult with a third party to evaluate the nature and degree of the injury. Based on this evaluation, the court can then make a judgement about the seriousness of the injury, and determine an amount of compensation. In this case, the children did not want to expose their elderly mother to the pressure of visiting the evaluation centre and having to wait a long time for a result that she might not be satisfied with anyway, so they decided to spare their elderly mother this ordeal. The family did not file a suit as a lawsuit based on infringement of rights or as a suit of tort, but filed as a "dispute of contract".

### The Source of Disagreement

The sponsor argued that there was an agreement between themselves and the hospital to carry out the trial of a new drug, and hence a contractual relationship between the company and the hospital, but there was no contractual relationship between the company and the patient plaintiff. In contrast, the plaintiff argued that the hospital had clearly informed the patient (research participant) that the hospital was only a representative of the trial sponsor, and further that the research participant had been informed that the company had entrusted/endorsed the hospital to sign the contract with trial participants. On these grounds, the plaintiff declared that a contractual relationship existed between the plaintiff and the company. The Chaoyang Court ultimately accepted the plaintiff's claim as a dispute of contract.

Having accepted the suit, the court requested the parties to provide the relevant documents. It repeatedly requested the company to provide a copy of the insurance contract, and explained this requirement to the company, but the company resisted and did not submit the insurance contract. The court also asked the hospital for the insurance contract, but the hospital responded that it had been unaware that it should request that documentation. Similarly, the hospital ethics committee had not required confirmation of an insurance contract at the time the protocol was approved. The hospital argued that it had signed a clinical trial contract with the company, which had declared that it had purchased special insurance to cover economic loss by the subjects participating in the study, including any harm caused by the drugs. The third page of the participant information sheet for the study stated: "Adverse drug reactions related to angiography include angiography reaction, such as skin reaction; some will imply allergic reaction, such as anaphylactic shock". Thus an adverse event from the double lower-limb vein angiography was included.

The plaintiff then requested the hospital ethics committee to seek help from the SFDA, but the committee were informed that the SFDA did not have this document either. In short, no one but the company had access to a clear description of the amount of compensation during the earlier stages of the case.

Later in the court process, the pharma company provided Chaoyang Court with certification of insurance purchased from a German provider, certifying that the company purchased insurance effective from January 1, 2002, which covered the study overseas and participants from all countries. Each person's maximum insurance was approximately 500,000 Euro. (Chao Min Chu Zi 2009).

The court asked the company to provide a Chinese version of the insurance contract, but the company refused. After several requests, the court, the plaintiff and her family were informed that it would take a long time to prepare such a translation and that it would be too expensive (estimated cost CNY 20,000, approximately USD 3,000 at that time).

This meant that the available documentation – namely, the consent form and insurance contract – included no clear description of the exact amount of compensation, nor how to compensate for different situations, types of injury, different countries, etc. When the plaintiff claimed EUR 150,000 compensation, the company argued that there was no reasonable basis for such a claim.

Though no specific criteria were provided about the amount of compensation, the civil judgement included a clause referring to the insurance company's view that where the company was responsible for the compensation of subjects, the insurer should provide the compensation based on the requirements of the local laws where the injury occurred (Chao Min Chu Zi 2009). The pharmaceutical company requested a non-public hearing for the appeal, which made information unavailable. The plaintiff explained that she was persisting with her appeal as she suspected that there was an unfair clause in the insurance contract and that there was an unequal description of compensation for HICs and LMICs.

After five years, the lower court's judgement was issued in February 2013. The Beijing Chaoyao Court determined that according to the Chinese Good Clinical Practice regulations, the company should compensate the plaintiff with EUR 50,000. However, the plaintiff did not accept this, and appealed to the Beijing Second Middle Level Court. That court rejected the appeal.

In summary, between 2009 and 2011, nine hearings were held. The final conclusion came out in February 2013. The entire process of litigation and appeal lasted for five years. Compensation of EUR 50,000 euros was paid directly by the company, not by the insurance company. This suggested that the process of SAE compensation was dealt with internally within the company, rather than through a formal procedure that involved the insurance company.

Due to the SAE and consequent extended hospitalization, the patient was placed on strict bed rest, even though rehabilitation from the original knee replacement surgery would have required her to move. Her dream had been to travel abroad after the surgery, but participating in the trial delayed her rehabilitation from the surgery.

### Update

It was reported from Berlin on 4 May 2015, that the company's once-daily oral anticoagulant BAY 59-7939 (rivaroxaban) had been approved by China's State Food and Drug Administration for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors (Bayer 2015). Additionally, the administration has approved BAY 59-7939 for the treatment of DVT and the reduction of the risk of recurrent DVT and pulmonary embolism following acute DVT in adults. Since 2009, BAY 59-7939 has been available in China for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery.

### Lessons Learned & Recommendations

Acknowledgements To Liao Zhijie, the son of the plaintiff in this case: he emailed me the case materials and expressed willingness to have this used as a training case.

To lawyer Gao Mei, who was once the attorney of the plaintiff: I discussed the preparation of this case study with her, and she exchanged some important points with me.

To Professor Michael Fetters,University of Michigan, who was Fulbright Distinguished Chair in the Social Sciences, Peking University Health Science Center, China, Sept 2016–Jan 2017: he provided many valuable points and pointed out some language inaccuracies.

### References

### Author Biography

Yali Cong is professor of medical ethics at Peking University's Health Science Centre. In 2010, she was involved in establishing the university's first human subject protection programme. In 2008, she set up a joint centre for medical professionalism with the University of Columbia, and serves as deputy director. She is currently vice chair of the China Medical Ethics Association.

Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

### Other Resources

These open access casebooks may be useful to the reader:

Barrett DH, Ortmann LW, Dawson A, Saenz C, Reis A, Bolan G (2016) Public health ethics: cases spanning the globe. Springer International Publishing. http:// www.springer.com/us/book/9783319238463

Cash R, Wikler D, Saxena A, Capron A (2009) Casebook on ethical issues in international research. World Health Organization, Geneva. http://www.who.int/ rpc/publications/ethics\_casebook/en

UNESCO (2011) Casebook on benefit and harm. Bioethics core curriculum. Casebook series no. 2. UNESCO, Paris. http://unesdoc.unesco.org/images/0019/ 001923/192370e.pdf

UNESCO (2011) Casebook on human dignity and human rights. Bioethics core curriculum. Casebook series no. 1. UNESCO, Paris. http://unesdoc.unesco.org/ images/0019/001923/192371e.pdf

The following high-calibre Ph.D. thesis contains a range of excellent case studies:

Ravinetto R (2016) Methodological and ethical challenges in non-commercial North-South collaborative clinical trials. Leuven University Press, Leuven

Table 1 shows how the case studies selected for this book align with the ethical issues identified by the Horizon 2020 programme of the European Commission.

Table 1 Ethics dumping cases organized according to Horizon 2020 ethical issues checklists

http://ec.europa.eu/research/participants/data/ref/h2020/grants\_manual/hi/ethics/h2020\_hi\_ethics-selfassess\_en.pdf

### Index

### A

Adverse Events (AE), 7, 62, 124 Africa, 4, 10, 16, 17, 20, 24, 26, 49, 50, 52, 85, 86, 95, 99, 115 Agriculture, 93, 108, 110 Anhui province, 71–74 Anthropological research, 10, 117 Autonomy, 28, 63, 64, 115, 117, 118

#### B

Banana, 6, 91, 93–96 Bantu, 4, 15, 16, 18, 20 Benefit, 2, 5, 10, 12, 13, 16, 21, 27, 45, 50, 52, 55, 57, 61–65, 67, 69, 71, 72, 75–78, 82, 83, 85, 100–102, 107, 109, 122 Benefit sharing, 4, 5, 28, 51 Bill and Melinda Gates Foundation, 35, 39, 93 Biomedical research, 44, 51, 82–85, 87, 88, 100 Biotechnology, 82 Blood samples, 5, 57, 71, 73, 74 Botswana, 16, 20 BUAV, 85 Bushmen, 17, 18, 20

### C

Canada, 5, 23, 28, 49, 58, 84 Candidate vaccine trial, 50 Capacity building, 28 Cartagena protocol, 111 Cell-Life, 103 Cervical cancer, 4, 34–43 Children, 10, 24, 49, 50, 52, 62, 95, 124 China, 5, 72–77, 84, 86, 122–124, 126, 127 Civil society, 52 Clinical trial, 4, 5, 7, 33, 50–53, 58, 61–65, 67–69, 109, 115, 123, 124, 127 Cluster Randomised Controlled Trial (CRCT), 36, 40

Community, 4, 9–13, 16, 19, 21, 26–29, 33, 36, 37, 39, 44, 50, 52, 53, 71, 73, 77, 78, 84, 103, 108 Community-based studies, 103 Community consent, 13, 19 Community consultation, 21 Compensation, 7, 45, 56, 64, 65, 78, 122–127 Compliance, 3, 57, 87, 118 Confidentiality, 13, 63–65, 69, 101 Conflicts of interest, 53 Consent, 5, 9, 10, 13, 16–19, 26, 28, 42, 44, 51–54, 56, 63, 67, 77, 92, 94, 100, 101, 103, 104, 116, 118, 123, 125 Contraception, 55, 62 Contract Research Organisation (CRO), 68 Control arm, 33, 35, 37–40, 42–45 Control group, 36, 40, 41, 44 Convention on the elimination of all forms of discrimination against women, 64 Council for International Organizations of Medical Sciences (CIOMS), 37, 87 CRISPR/Cas9, 6, 107 Culture, 9–11, 19, 86, 96 Cytology screening, 33, 36, 38

### D

Data, 4, 5, 9, 11–13, 16, 18, 39, 44, 45, 63, 67, 68, 75, 87, 100–104, 116–118, 122 Data protection, 63, 69, 104 Declaration of Helsinki, 37, 44, 51, 53, 55, 63, 64, 68, 116 Diagnostic laboratory, 49, 51 Diarrhoea, 10, 11, 53 Discrimination, 16, 64, 117 DNA, 16, 19, 35, 40, 74, 75 Double standards, 2, 7, 34, 43, 44, 51, 122, 127

### E

East Africa, 24, 93, 95

© The Editor(s) (if applicable) and The Author(s) 2018 D. Schroeder et al. (eds.), Ethics Dumping, SpringerBriefs in Research and Innovation Governance, https://doi.org/10.1007/978-3-319-64731-9 Ebola, 5, 50, 53–56, 58, 116, 117 Emergency research, 6, 7, 115, 117 Epidemic, 5, 25, 50, 54, 116 Epidemiology, 26 Ethical guidelines, 37, 44, 116 Ethical principles, 38, 42, 63, 118 Ethical review, 3, 11, 13, 61, 65, 76, 77, 116 Ethical standards, 7, 9, 11, 33, 34, 43, 76, 78, 81, 104 Ethics approval, 3, 6, 65, 115, 118 Ethics committee, 2, 15, 19, 20, 44, 45, 49, 51–53, 56, 57, 75, 87, 96, 124 Ethics dumping, 1, 2, 7, 33–35, 42, 43, 45, 51 Ethics Review Committee (ERC), 10, 57, 126 European Commission, 84, 108 European Commission's Scientific Committee on Health, Environmental and Emerging Risks (SCHEER), 84 European Union, 6, 81 European Union Directive 2010/63/EU, 81, 83, 84, 87 Exclusion criteria, 36, 83, 125 Experimental, 39, 43, 58, 78, 82, 87, 108 Exploitation, 1–5, 9, 10, 12, 16, 20, 21, 23, 28, 34, 50, 51, 61, 64, 67, 71, 72, 77, 78, 81, 87, 88, 91, 92, 100, 102, 104, 108, 111, 121, 122, 126 Exploitative, 1, 15–17

### F

Farmers, 73–76, 92 Female Genital Mutilation (FGM), 4, 9, 11, 12 Financial incentives, 5, 57, 58, 67, 96 Food security, 6, 91, 95 Food sovereignty, 91, 96

### G

Gender, 5, 61, 64, 65 Genetically Modified (GM), 6, 91, 93–96 Genetically Modified Organisms (GMO), 94, 110 Genetic research, 5, 75 Girl, 11, 12, 25 Golden rice, 95 Good Clinical Practice (GCP), 61, 63, 121, 125, 126 Government, 5, 12, 26, 33, 35, 36, 39, 42–44, 49, 51, 71, 72, 74, 75, 77, 102, 122 Guideline for Good Clinical Practice of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH 1996), 126

### H

Harm, 6, 12, 20, 35, 42–45, 68, 100, 108, 115, 117, 118, 122, 124, 126 Health emergency, 117 Health workers, 24, 39, 40 Healthy volunteers, 5, 50, 58, 62, 67–69, 96 Hepatitis B, 5, 62, 63 High Income Countries (HIC), 2, 6, 34, 36, 42, 44, 45, 67, 73, 76–78 HIV, 23, 26, 27, 29, 103, 109 HIV/AIDS, 4, 26, 103 Horizon 2020, 84 Humanitarian, 4, 10, 12 Human Papillomavirus (HPV), 35–37, 40–42 Human participants, 44, 59, 91, 117 Human rights, 11, 29, 35, 42, 57, 59, 64, 78 Hunger, 78, 91, 94 Hunter gatherers, 4, 15–20

### I

Illegal, 4, 9, 11, 23, 27, 44, 77 Illiterate populations, 117 Immunobiology, 26 Incentives, 57, 58, 67, 96, 102 Inclusion criteria, 36, 83, 125 India, 4, 35–44, 68 Indigenous people, 17, 18 Inequality, 73, 94, 122 Information sheets, 53, 124 Informed consent, 5, 12, 13, 15–19, 27, 28, 35, 39, 42, 44, 52–56, 59, 61, 63, 64, 67, 69, 75, 92, 94, 101, 123 Informed consent process, 15, 17, 53 Institutional Review Boards (IRBs), 19, 39, 115, 117, 118, 123 Insurance, 44, 63, 64, 121–126 International Council for Laboratory Animal Science and the Council for International Organizations of Medical Sciences (ICLAS), 87

### K

Kenya, 23–25, 27–29, 85, 86 Khoisan, 15, 17, 18

#### L

Legal framework, 6, 57, 86, 107, 108 Lesbian, Gay, Bisexual and Transgender persons (LGBT), 24 Liberia, 6, 54, 115–117 Litigation, 121, 122, 125, 127 Local community, 1, 9, 10 Local Ethics Committee (LEC), 61, 65 Low and Middle Income Countries (LMIC), 2, 34–37, 41–43, 45, 50, 54, 57, 59, 68, 76–78, 91, 96, 100

#### M

Majengo, 23–29 Majengo Observational Cohort Study (MOCS), 26, 29 Medical research, 9, 16, 44, 51, 59, 63, 64, 73, 85, 100 mHealth, 6, 99–104 Multi-country, 49 Multi-site, 49 Mumbai, 3, 33, 37, 38, 40, 44 Mxit, 103

#### N

Nairobi, 4, 23–26, 29, 30, 85 Namibia, 4, 15, 16, 20 National Ethics Committee (NEC), 49, 50, 52 Nature journal, 19 Non-compliance, 5, 61 Non-Governmental Organisations (NGO), 3, 4, 9–13, 93 Non-human primates, 6, 81–86, 88 Nutrition, 91 Nutritionism, 92–94

### O

Osmanabad, 33, 37–41, 43, 44

#### P

Pap smear, 4, 33, 35, 38, 40, 43 Patents, 76, 78 Patient, 35, 54, 63, 99–103, 121–127 Peer educator, 27, 28, 30 Pharmaceutical companies, 5, 7, 49, 50, 56, 69, 71, 75, 76, 121, 123, 125, 126 Phase I/II clinical trial (testing for safety and immunogenicity), 5, 49, 50 Phase III clinical trials probably separately, 122 Philippines, 95 Placebo, 34, 35, 37, 44, 50, 54 Pre-Exposure Prophylaxis (PrEP), 28, 29 Pregnancy, 54, 55, 62, 63

Privacy, 64, 65, 78, 100–104 Proxy consent, 54 Publication, 15–18, 21, 56, 93, 108, 116, 118 Public awareness, 77, 78

### R

Randomized double blinded trial, 49, 50, 61 Recruitment, 49, 50, 52–54, 59, 123 Regulatory approval, 4, 42, 44, 51, 57, 61, 76–78, 84, 115 Reproductive rights, 63–65 Research and Development (R&D), 73, 74, 77, 78, 91 Research ethics, 5, 18, 19, 21, 27, 42, 43, 51, 52, 71, 74, 75, 78, 116 Research participants, 2, 5, 9, 10, 27, 28, 33, 37, 43, 49–52, 55–59, 71, 73, 76, 77, 115, 116, 118, 121, 122, 124, 126, 127 Research review process, 115 Respect, 15, 19, 20, 35, 40, 57, 59, 75, 78, 84, 116 Risk mitigation measures, 116 Risks, 2, 3, 5, 9–13, 16, 26, 33, 34, 42, 50, 51, 53, 55, 64, 65, 67–69, 72, 84, 88, 91–96, 100, 101, 104, 107–111, 115–117, 121, 122, 126 Rural, 10, 16, 18, 25, 33, 35, 38, 40, 72, 95 Russia, 5, 61–63 Russian Federation, 61, 63

### S

Safety, 5, 6, 23, 44, 49, 50, 52, 56, 61, 62, 68, 75, 82, 83, 94, 100, 104, 107–111 Sample, 5, 16, 26, 37, 39, 40, 49, 56, 57, 62, 73–77 San, 4, 15–21 San Code of Research Ethics, 21 Science & Technology (S&T), 71–73, 76–78 Semi-literate populations, 117 Serious Adverse Event (SAE), 7, 62, 63, 121–123, 125, 127 Sex workers, 4, 23–30 Sex Workers Outreach Programme (SWOP), 23, 27, 28, 30 Side effects, 50, 55 Sierra Leone, 54, 116 Slum, 4, 23, 24, 30, 37, 38 Social science research, 4, 116 Socio-anthropological research, 10 South Africa, 16, 20, 21, 28, 86, 103 South African San Council, 17 South African San Institute (SASI), 17 Southern Africa, 4, 15–17

Sponsor, 3, 5, 7, 42–45, 51, 61, 62, 122–124, 126, 127 Standard of care, 4, 33, 34, 37, 38, 40, 42, 43, 45 Standard regulatory procedures, 51 Stigmatization, 4 Stigmatized, 4, 12, 23, 24 Sub-Saharan Africa, 49, 50

### T

Tradition, 84 Traditional healers, 10, 11 Training, 36, 52 Transgenic, 6, 91–93 Transparency, 45, 52, 57, 59, 93 Treatment, 3, 11, 25–27, 35, 37–42, 44, 45, 50, 53, 56, 64, 73, 86, 103, 107–109, 121, 123, 126, 127 Trial, 4–6, 34–45, 50–53, 55, 58, 61, 62, 65, 68, 92–94, 96, 122–126 Trust, 3, 5, 12, 21, 30, 49, 58, 59, 108, 109

### U

Uganda, 6, 91, 93, 95, 96 UK, 85 UNICEF, 11 United Nations, 64 Universal Declaration of Human Rights, 64 Universal Declaration on Bioethics and Human Rights (UNESCO), 64 Urban, 25, 33, 35, 50, 72, 117 US government's Office of Human Research Protections (OHRP), 39, 44 US National Institutes of Health, 35, 39, 74, 84

### V

Vaccine, 5, 26, 42, 50, 53–56, 58, 59, 61–63, 82 Vaccine trial, 5, 50, 56, 58 Vulnerability, 10, 52, 64, 92 Vulnerable, 2, 4, 10, 12, 13, 16, 23, 24, 30, 34, 35, 38, 42, 64, 67, 69, 104, 126 Vulnerable groups, 63, 67, 118

#### W

West Africa, 5, 49, 50 WHO, 26, 35, 36, 53, 95, 99 Women, 4, 5, 11, 24–27, 29, 33, 35, 37–43, 45, 52, 61–65, 92–94 Working Group of Indigenous Minorities in Southern Africa (WIMSA), 17, 19 World Bank, 92 World Trade Organization (WTO), 34

### Z

Zika, 110

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**3. Overview of** *Chlamydia* **pathogenesis**

#### **3.1 Acute infections**

*Chlamydia* species cause widespread infections in humans. *Chlamydia trachomatis* serovars A–C are the leading cause of non-congenital trachoma and are the major cause of blindness and visual impairment in developing nations [7, 8]. *C. trachomatis* serovars D–K are considered the world's most common sexually transmitted pathogen causing disease in the genital tract and in men, are the primary cause of nongonococcal urethritis [7, 9]. Following vertical transmission through an infected birth *Persistence in* Chlamydia *DOI: http://dx.doi.org/10.5772/intechopen.109299*

canal, *C. trachomatis* serovars D–K cause neonatal conjunctivitis and pneumonia. Respiratory infection with *C. pneumoniae* causes an average of 10% of communityacquired pneumonia cases and 5% of bronchitis and sinusitis cases. In addition, avian strains of *C. psittaci* have long been known to cause zoonotic respiratory illness in humans [10]. The *C. trachomatis* lymphogranuloma venereum (LGV) biovar (serovars L1–L3) causes invasive urogenital or anorectal infection [11].

#### **3.2 Persistent and chronic Chlamydial infections**

*C. trachomatis* serovars D–K are responsible for about 15–40% of ascending upper genital tract infections leading to serious complications in women, such as salpingitis, pelvic inflammatory disease, ectopic pregnancy, epididymitis in men, and infertility in women and men [8]. *C. trachomatis* originating from the genital tract is also associated with reactive arthritis, which develops in 1-3% of patients after genital Chlamydial infection [9]. *C. pneumoniae*, which can also disseminate from the site of the initial infection, is linked to several chronic diseases, including asthma, atherosclerosis, arthritis, cardiovascular disease, and even late-onset Alzheimer's disease [12]. In addition, unresolved respiratory *C. pneumoniae* infection may contribute to the pathogenesis of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease [12]. Further, *C. trachomatis* impedes human papillomavirus (HPV)-induced mechanisms that maintain cellular and genomic integrity, and it may be linked to cervical cancer [13].

Clinical conditions associated with inapparent *Chlamydial* infections include asymptomatic urethritis in male individuals and cervicitis in female individuals, and silent pelvic inflammatory disease in female individuals [3, 14]. The clinical significance of persistent infection is associated with the reactivation of infection after weeks or months in individuals treated with antibiotics, and negative culture results for individuals with strong serological titers and epidemiological associations [3].


**4.2 Fault location identification**

Referring to Fig.10, ANFIS2 and ANFIS3 are developed to identify fault location in respective X and Y coordinates. According to previous literature, most of the methods in identifying the fault location for power distribution network are in fault distance from a substation or zone. This approach considers geometrical coordinates in determining fault location in which it produces more accurate and precise fault location identification. From

Fault Diagnosis in Power Distribution Network

in a 47 buses practical system

current data at each fault point.

respectively.

**4.2.2 A procedure for identifying fault location**

system.

Using Adaptive Neuro-Fuzzy Inference System (ANFIS) 327

represented by each ANFIS module. ANFIS2 consists of 64 modules that are labeled as ANFIS2-1 up to ANFIS2-64 whereas for ANFIS3, its total module is 45 from ANFIS3-1 to ANFIS3-45. The signal input to the ANFIS2 and ANFIS3 is a three-phase RMS post-fault current while the signal output is in terms of X and Y coordinates respectively as shown in Fig.11. Table 3 shows the input and output parameters of the 47 buses practical

**ANFIS module Input Output**

ANFIS2-1 Post-fault 3-phase RMS current 1.7

ANFIS2-64 " 9.1

ANFIS3-1 " 0.3

ANFIS3-45 " 5.2

Table 3. Input and output parameters of ANFIS2 and ANFIS3 for identifying fault location

The procedure for locating fault in a power distribution network by the implementation of ANFIS2 and ANFIS3 modules is clearly shown in Fig.12. The first stage is a selection of power network for testing. Then the network layout is drawn in XY plane for locating the selected fault points along the feeder and radial lines. Fig.13 presents an example of the layout. The detail specification of the network is in the next sub-section. This network layout is embedded in fault analysis simulation software such as PSS-ADEPT to collect the fault

Next, the three-phase RMS post-fault current is collected at the main substation through a simulation of fault analysis to the selected power distribution network. The fault analysis is applied to every point of the fixed coordinates while considering 10 types of fault and several fault resistors (Rf). For example, by using three fault resistors and 163 fault points, there are 1335 simulations for single fault to ground and about 486 simulations for double fault to ground. Meanwhile, about 643 simulations are required for phase to phase and three-phase faults. Therefore, the total simulation is about 2464 for power distribution network in the 47 buses practical system. The data collected is arranged in such a way that it has three columns of input parameters and one column of target values. The target is either X or Y coordinates in which they are used to train ANFIS2 and ANFIS3

Fig.10, three-phase RMS post-fault current with (IF) and without (IU) fault are compared to investigate the fault in the power system. If current is IF higher than current IU, the current IF is recorded with the merging fault type.

Fig. 10. A procedure for identifying fault location

#### **4.2.1 ANFIS2 and ANFIS3 designs for identifying fault location**

The structure of ANFIS2 and ANFIS3 are configured according to selected fault points as shown in Fig.11. For a 47 buses practical system, there are 163 fixed fault points with 64 'X' coordinates and 45 'Y' coordinates. Thus, the total coordinate point is 109. Those points are

Fig. 11. ANFIS2 and ANFIS3 design for identifying fault location in a 47 buses practical system

Fig.10, three-phase RMS post-fault current with (IF) and without (IU) fault are compared to investigate the fault in the power system. If current is IF higher than current IU, the current IF

Start

Record the three-phase RMS post-fault current (IF) and three-phase RMS current without fault (IU)

Is IF >> IU ?

is recorded with the merging fault type.

Fig. 10. A procedure for identifying fault location

1.7

STKNA2-1

Post-fault three-phase RMS current No

Develop ANFIS2 module for identifying the fault location in term of X coordinate

**4.2.1 ANFIS2 and ANFIS3 designs for identifying fault location**

The structure of ANFIS2 and ANFIS3 are configured according to selected fault points as shown in Fig.11. For a 47 buses practical system, there are 163 fixed fault points with 64 'X' coordinates and 45 'Y' coordinates. Thus, the total coordinate point is 109. Those points are

X Y

Yes

Develop ANFIS3 module for identifying the fault location in term of Y coordinate

Fig. 11. ANFIS2 and ANFIS3 design for identifying fault location in a 47 buses practical system

64 'X' coordinates 45 'Y' coordinate

0.3

5.2

STKNA3-45

Post-fault three-phase RMS current

STKNA3-1

Post-fault three-phase RMS current

9.1

STKNA2-64

Post-fault three-phase RMS current represented by each ANFIS module. ANFIS2 consists of 64 modules that are labeled as ANFIS2-1 up to ANFIS2-64 whereas for ANFIS3, its total module is 45 from ANFIS3-1 to ANFIS3-45. The signal input to the ANFIS2 and ANFIS3 is a three-phase RMS post-fault current while the signal output is in terms of X and Y coordinates respectively as shown in Fig.11. Table 3 shows the input and output parameters of the 47 buses practical system.

Table 3. Input and output parameters of ANFIS2 and ANFIS3 for identifying fault location in a 47 buses practical system


**2. Preliminary: stability of nonlinear systems**

numerical methods for the analysis and synthesis of nonlinear polynomial systems. Applications to control problems are feedback design [7, 8], motion planning [9], modeling, and control of fuzzy systems [10] to mention a few. Applications of the SOS approach to nonpolynomial

The SOS approach has been the basis of numerical methods for the analysis and the synthesis of nonlinear systems. Although the Lyapunov-based approach offers the methods for the analysis and the synthesis, the construction of Lyapunov functions is often a difficult task. The SOS approach provides a technique to find Lyapunov functions by formulating the Lyapunov inequality conditions into the SOS conditions. The stability of nonlinear systems is analyzed by a direct application of SOS decompositions to the Lyapunov stability analysis. However, applications of the SOS approach to Lyapunov-based feedback design are much complicated because decision variables do not enter the Lyapunov inequalities conditions linearly. So far, two main approaches have been proposed. One is a method in [8], which formulates the design conditions into state-dependent linear matrix inequalities (SDLMIs) conditions. The SDLMIs are solved by the SOS decompositions. The other method is based on an iterative algorithm shown in reference [7], which also considers the enlargement of the regions of attraction of the

In the actual control problems, we often cannot measure all the values of the state variables of control systems. This fact leads to the necessity of the design of output feedback laws. The design of output feedback laws is more complicated task than that of state feedback laws because the stability conditions of the closed-loop systems become complex. As far as the authors know, so far, a few output feedback design methods have been proposed, for example, [[7], Section 3.5] and [13–15]. The further developments of design methods for output feedback

It is well known that we often can design dynamic feedback laws even when the design of static output feedback laws is difficult. This leads to the motivation of developing a design method based on the SOS approach for the design of dynamic output feedback laws. In reference [7], an iterative method for the design of dynamic output feedback laws has been shown. However, we need to give control Lyapunov functions (CLFs) to start the iteration in the method, and this might be a difficult task especially for complex or high-dimensional systems. The state-dependent LMI approach can be an alternative approach because it does not need to give any CLF. However, a concrete method for dynamic output feedback laws has

We provide the design methods of dynamic output feedback laws for the stabilization based on the SDLMI approach. This method is based on the design method of state feedback laws based on the SDLMI approach [8]. The proposed method employs a two-step algorithm. We first design a virtual state feedback law for a given system using the method of reference [8]. Then, we design a dynamic output feedback by using an SDLMI again based on the virtual state feedback law. The use of the virtual state feedback inherits the design approach of output feedback laws in reference [16], which indicates the general design approach of output feedback laws not necessarily for the SOS approach. We also show some numerical examples to demonstrate the effectiveness of the proposed method to the actual control problems.

systems are found in reference [11, 12].

320 Nonlinear Systems - Design, Analysis, Estimation and Control

closed-loop systems.

laws have been desired.

not been shown in this direction yet.

This section provides the stability theory of nonlinear systems. We present the definitions of stability, and then, we introduce the Lyapunov stability theory. The Lyapunov stability theory forms the basis for the analysis and synthesis of the stability of dynamical systems. The theory states that the existence of a kind of functions implies the stability.

This section considers the stability of an autonomous nonlinear system

$$
\dot{\mathbf{x}} = f(\mathbf{x}), \quad \mathbf{x}(\mathbf{t}\_0) = \mathbf{x}\_0 \tag{1}
$$

where *x*∈ℝ*n* is the state, *f*:ℝ*n* → ℝ*n* is the vector fields, and *x*0 ∈ ℝ*n* is the initial value of the state. In the following, we assume that the origin *x* = 0 is the equilibrium of system (1), that is, *f*(0) = 0, and we consider the stability of the origin.

To begin with, we show the definitions of the stability.

**Definition 1 (stability).** The equilibrium *x* = 0 is said to be Lyapunov stable if for any > 0, there exists *δ* = *δ*( ) > 0, such that for any *‖x*0‖ < *δ*, the solution *x*(*t*) of (1) satisfies that

$$\|\ x(t) \| < \epsilon, \quad \forall \ t \in [t\_0, \infty).$$

**Definition 2 (asymptotic stability).** The equilibrium *x* = 0 is said to be asymptotically stable if it is stable and there exists *δ* > 0, such that for any ‖*x*0‖ < *δ*, the solution of (1) satisfies that

$$\mathbf{x}(t) \to \mathbf{0} \text{ as } t \to \infty.$$

**Definition 3 (global asymptotic stability**). The equilibrium *x* = 0 is said to be globally asymptotically stable if it is stable and for any *x*0 ∈ ℝ*n*, the solution *x*(*t*) of (1) satisfies that

$$\mathbf{x}(t) \to \mathbf{0} \text{ as } t \to \infty.$$

To introduce the Lyapunov stability theory, we provide the definitions of the properties of functions.

**Definition 4 (positive definiteness).** A function *h:* ℝ*n* → ℝ is said to be positive definite if *h*(*x*) > 0 for any *x* ≠ 0 and *h*(0) = 0.

**Definition 5 (positive semidefiniteness).** A function *h:* ℝ*n* → ℝ is said to be positive semidefinite if *h*(*x*) ≥ 0 for any *x* ∈ ℝ*n*.

We say that a function *h*(*x*) is negative definite (negative semidefinite) if the function −*h*(*x*) is positive definite (respectively, positive semidefinite).

**Definition 6 (properness).** A function *h:* ℝ*n* → ℝ is said to be proper if for any *K* ∈ ℝ, the sublevel set

$$\{x \in \mathbb{R}^n \mid h(x) \le \kappa\}$$

is bounded.

The Lyapunov stability theory is stated as follows [17].

**Theorem 1.** Let *U* be an open subset of ℝ*n* which contains the origin. Suppose that a function *V*:*U* → ℝ is continuously differentiable, positive definite, and proper. The equilibrium of system (1), *x* = 0, is stable if and only if the function *V*(*x*) satisfies that

$$\frac{dV}{dt}(\chi) = \frac{\partial V}{\partial \chi}(\chi) f(\chi) \le 0, \ \forall \ x \in \mathbb{R}^n.$$

Moreover, the equilibrium of system (1), *x* = 0, is asymptotically stable if and only if the function *V*(*x*) satisfies that

$$\frac{dV}{dt}(\mathbf{x}) = \frac{\partial V}{\partial \mathbf{x}}(\mathbf{x}) f(\mathbf{x}) < 0, \ \forall \ \mathbf{x} \neq \mathbf{0}.$$

When *U* = ℝ*n*, the global asymptotic stability holds.

The Lyapunov theory is used to investigate the stability of nonlinear systems. However, to investigate the stability of each system by Lyapunov theory, we need to find a Lyapunov function for it. However, to find the Lyapunov functions is often a difficult task. Further, when we try to design stabilizing feedback laws based on the Lyapunov theory, we also need to find the Lyapunov function candidates for the closed-loop systems. Therefore, we require a method to find Lyapunov functions for each nonlinear system. The SOS approach provides Lyapunov functions as solutions to the SOS conditions.


*2.3. Methodological Quality Assessment*

The Methodological Index for Non-Randomized Studies (MINORS) was used to assess the methodological quality of the included articles [41]. MINORS is a valid instrument designed to assess the methodological quality of non-randomized surgical studies and is based on eight items for noncomparative studies and 12 items for studies with a control group.