This paper is the first studying on designing exponentially passive analysis for T-S fuzzy of dynamic systems with various time-varying delays such as neutral, discrete, and distributed time-varying delays. Constructing the new Lyapunov-Krasovskii function and the Newton-Leibniz theory, the zero equations, and the matrix inequality techniques, the multiple delay-dependent criteria, with assuring exponentially passive on the discussed T-S fuzzy system, are defined in respect of linear matrix inequalities (LMIs) that can be checked easily using the LMI toolbox of MATLAB. Those approaches give less conservative, exponentially passive criteria for special cases of general stability of a neutral differential system. Furthermore, the results of this study are delay-dependent, which depend on the lower and upper bound with the time-varying delay. Lastly, some numerical examples illustrate the performance of our criteria based on the results obtained and summarize some of the previous achievements. The research of Takagi and Sugeno created the Takagi-Sugeno (T-S) fuzzy system , which eTime delays is of significance both in theory and application due to its detrimental effects on stability and performance of systems and its wide existence in practical dynamic processes. The cases of delays can be usually considered as time delay, multiple delays, interval delay, input and state delays and so on. All of them were discussed around two basic group, i.e. delay-independent and delay-dependent. The delay-dependent stability criterion are investigated with the extent upper bound of delay. Hence, the criterion of delay-dependent stabilization are proposed to guarantee that the delay system is stable for any value of time delay less than the provided upper bound. In different circumstances, the delay-independent stability criteria are proposed without consideration of the extent for time delay. In ordinary, the delay-dependent conditions are preferable than the delay-independent conditions while the effect of time delay is not acute. According to Zhu and Yang  illustraIn addition, passivity theory is another proficient tool for analyzing system stability. The passive theory is the main pointed to the system can keep the system’s internal stability which is the passive properties. So that, the problem of inactivity is therefore an important part of recent research. Then, the passive control uses the product of output and input as the power rating, which captures the attenuation properties of the system under the bounded input. In particular, passivity theory is more general than stability theory because it can be illustrated Lyapunov function under the theory of stabilization. This theory is used for issue of engineering i.e. electric circuits and heat energy systems. Nowadays many researchers have studied passive theory and passive control problems extensively, for instance, Zhang et al. who studiDespite, in a specific physical system, mathematical models are described by functional differential equations of the neutral type. The neutral type of functional differential equation depends on the lag of the state and state derivatives. Approximately, neutral-type phenomena often appear in automatic control studies, chemical reactor, distributed network, the dynamic process such as steam pipes and water pipes. Also, population ecology, heat exchange, microwave oscillator, turbojet engine system, lossless transmission line, vibrating mass attached to an elastic band, etc. Likewise, the research of Zhou et al.  examinedThis study is the first ever exponentially passive analysis for Takagi-Sugeno fuzzy system of a dynamic system  consistiCi + ΔCi(t) = 0, Di + ΔDi(t) = 0 and Ei + ΔEi(t) = 0, The system  = 0 and Ei + ΔEi(t) = 0, Also, the system  method. Also, the systems created by stability theory and integral inequality techniques. The all of delays consist of discrete, neutral, and distributed delays that vary with time. In addition, this research offers a new approach to the resulting manipulation of exponential and inertial steady-states and more efficient compared to existing methods. The following topics to promote a clear understanding and objectives of this study are givenRemark 1This study constructs the suitable Lyapunov-Krasovskii functional, which consists of single, double, triple, and quadruple integral terms containing information about the lower and upper bounds of the delaysσ2, τ2and a statex(t). Furthermore, the LKF contains new triple integral terms as follows:and new quadruple integral termsthat do not appear in T = T, which shows that the T-S fuzzy for dynamical system is stablel system  whereCiExample 4Analyze the uncertainty neutral of T-S fuzzy dynamic system by the parameters as following:WhereLMI (is solved wheret)).LMI  is solveIn example 4, we used to discuss the stability criterion and passivity performance of the T-S fuzzy for dynamical system (whereCi + ΔCi(t) = 0 andDi + ΔDi(t) = 0. LMIs in Theorem 3 is solved by the MATLAB control toolbox to obtain the largest allowable bounds ofσ2for dissimilar values ofσd, αin example 4 are shown inl system  whereCigives the state trajectory of the T-S fuzzy for dynamical system (whereCi + ΔCi(t) = 0 andDi + ΔDi(t) = 0 with parameter in Example 4 where the initial condition T = T, which shows that the T-S fuzzy for dynamical system is stable.l system  whereCiExample 5Analyze the uncertainty neutral of T-S fuzzy dynamic system by the parameters as ollowing:whereLMI  = 0. LMIs in Theorem 4 is solved by MATLAB control toolbox to obtain the largest allowable bounds ofσ2for dissimilar values ofτd, α, σdin example 5 are shown inl system  whereDiExample 6Analyze the uncertainty of T-S fuzzy dynamic system presented in ”We note that you have provided additional information within the Acknowledgements Section that is not currently declared in your Funding Statement. 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Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: We will update your Data Availability statement to reflect the information you provide in your cover letter.[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to Questions  Comments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********  2. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #1: YesReviewer #2: Yes**********  3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.  The Reviewer #1: YesReviewer #2: Yes**********  4. Is the manuscript presented in an intelligible fashion and written in standard English?  PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********  5. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This study is relevant to designing reliable exponentially passive analysis for T-S fuzzy of dynamic systems with various time-varying delays such as neutral, discrete, and distributed time-varying delays. By using the Lyapunov-Krasovskii function, The Newton–Leibniz theory, the zero equations, and the matrix inequality technique. The multiple delay-dependent criterion with assure exponential stability and passive performance on the discussed T-S fuzzy system, are defined in respect of linear matrix inequalities (LMIs) that can be checked easily using LMI toolbox of MATLAB. A less conservative exponentially passive criterion given for special cases of general stability of a neutral differential system, by those approaches. The results of this study are delay-dependent, which depend on the lower bound and the upper bound with the time-varying delay. Lastly, the examples of Numerical are presented the performance of our criteria with the results obtained summarize some of the previous results as well.I think the readers of this journal will appreciate the results of this manuscript. Generally speaking, the manuscript is well written, the material is judiciously divided and organized and correct from scientific point of view.Reviewer #2: In this study, the authors investigate an exponentially passive analysis for T-S fuzzy dynamical systems with various time-varying delays, including neutral, discrete, and distributed time-varying delays using the Lyapunov-Krasovskii function, Newton-Leibniz theory, zero equations, and matrix inequality. As compared to literature, they obtained less conservative results.The theoretical analysis appears to be correct, but the paper must undergo careful and critical editing of both the English language and English grammar. There are many linguistic omissions, errors, and oversights throughout. There are several such errors scattered throughout the manuscript, so it is very important to check it carefully.**********  6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, Attachmentreview.docxSubmitted filename: Click here for additional data file. 7 Apr 2022Original Article Title: “A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delays”To: PLOS ONE EditorRe: Response to reviewersDear Editor,Thank you for allowing a resubmission of our manuscript, with an opportunity to address the reviewers’ comments.We are uploading (a) our point-by-point response to the comments (below) (response to reviewers), (b) an updated manuscript with yellow highlighting indicating changes, and (c) a clean updated manuscript without highlights (PDF main document).Best regards,<Thongchai Botmart> et al.Reviewer #1 This study is relevant to designing reliable exponentially passive analysis for T-S fuzzy of dynamic systems with various time-varying delays such as neutral, discrete, and distributed time-varying delays. By using the Lyapunov-Krasovskii function, The Newton–Leibniz theory, the zero equations, and the matrix inequality technique. The multiple delay-dependent criterion with assure exponential stability and passive performance on the discussed T-S fuzzy system, are defined in respect of linear matrix inequalities (LMIs) that can be checked easily using LMI toolbox of MATLAB. A less conservative exponentially passive criterion given for special cases of general stability of a neutral differential system, by those approaches. The results of this study are delay-dependent, which depend on the lower bound and the upper bound with the time-varying delay. Lastly, the examples of Numerical are presented the performance of our criteria with the results obtained summarize some of the previous results as well.  I think the readers of this journal will appreciate the results of this manuscript. Generally speaking, the manuscript is well written, the material is judiciously divided and organized and correct from scientific point of view. For these reasons I can recommend the acceptance of this paper after some corrections presented below:Answer : We really appreciate your suggestion. We have revised all of them as the follows: It seems that the proof of theorem 1 is so complicated, and for such many complex and large-scale matrices, how to guarantee the existence of the LMI problem for eq. (2).Author response: The stability criterion of Theorem 1 in the form LMIs (2) can be easily to examine by using LMI toolbox in MATLAB. The improved stability conditions by constructing new Lyapunov functionals is based on LMIs and the dimension of the LMIs depends on the number of premise variables of fuzzy set . Thus, the computational burden problem goes up. This problem is the issue in studying needs of LMI optimization in applied mathematics and the optimization research. Hence, in the further, new techniques to reduce the conservativeness caused by the time-delays such as the delay-fractioning approach and so on. Moreover, the vectors can be solve directly solution of LMI approach. Moreover, the effectiveness of computer should update the performance computer which can be helpful a computational problem.Author action: - The novelty of this paper should be highlighted in the main contributions through comparing it with the existing works.Author response: We have already rewritten by added the main contribution of our paper.Author action: We updated the manuscript in paragraph 5 of the introduction by adding the main contribution of our paper as follows: • We construct the suitable Lyapunov-Krasovskii functional, which consists of single, double, triple, and quadruple integral terms containing information about the lower and upper bounds of the delays σ_2,τ_2 and a state x(t). Furthermore, the LKF contains a new triple integral term σ_2^2 ∫_(-σ_2)^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)W_1 x ˙(s)dsdβdθ〗,τ_2^2 ∫_(-τ_2)^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)W_2 x ˙(s)dsdβdθ〗and a new quadruple integral term σ_2^3 ∫_(-σ_2)^0▒∫_v^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)U_1 x ˙(s)dsdβdθdv〗,τ_2^3 ∫_(-τ_2)^0▒∫_v^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)U_2 x ˙(s)dsdβdθdv〗that do not appear in . • For the first time, an improved Wirtinger inequality, a new triple integral inequality, and zero equation together with convex combination approach are used in this work; as a result, we obtain more general results and maximum allowable delay bounds greater than in previous literature . 3. The linguist should be thoroughly examined and corrected. Numerous typos and grammatical errors appear in the manuscript. For example, 3.1 On page 11, line 14, "-D∫_(t-h(t))^t▒〖x(s)ds- ├ ├ Eu(t))]0〗 " should be "-D∫_(t-h(t))^t▒〖x(s)ds- ├ ├ Eu(t))] 〗 ". 3.2 On page 19, line 143, “since lemma 5” should be “Since lemma 5”. 3.3 On page 29, line 181, "D+∆D_i (t)=0 and E+∆E_i (t)=0" should be "D_i+∆D_i (t)=0 and E_i+∆E_i (t)=0". 3.4. On page 33, line 214, "C+∆C_i (t)=0, D+∆D_i (t)=0 and E+∆E_i (t)=0" should be "C_i+∆C_i (t)=0, D_i+∆D_i (t)=0 and E_i+∆E_i (t)=0".Author response: Thanks for the suggestion we have already and carefully rechecked and revised the entire paper.Author action: We have corrected the manuscript by rewriting it as follows: 1. On page 1, line 4, “exponential stability and passive performance” should be “exponentially passive”.  2. On page 3, line 105, “exponential stability and passivity criteria” should be “exponentially passive criteria”. 3. On page 3, line 107, “exponential stability and passive performance” should be “exponentially passive”. 4. On page 3, line 109, “the general phase value system of the neutral differential system” should be “the general phase value system for the neutral dynamic system”. 5. On page 3, line 112, “the neutral differential system” should be “the neutral dynamic system”. 6. On page 11, line 14, "-D∫_(t-h(t))^t▒〖x(s)ds- ├ ├ Eu(t))]0〗 " should be "-D∫_(t-h(t))^t▒〖x(s)ds- ├ ├ Eu(t))] 〗 ". 7. On page 12, line 8, " who studied the passive controller design issue with both state and input delays for a class of continuous-time T-S fuzzy systems. Another researcher such as Wu et al. [12] identified the problem of passive control for fuzzy network systems, considering the random uncertainty variable sampling interval and the delay caused by the fixed network. Similarly, Song and He [13] who researched the robust passive control is offered for a limited time for nonlinear systems with time-delay. The studied of Yu et al. [14] focused both passive analysis and passive control for erratic intermittent switching delay systems through a simple switching signal design. Likewise, Yotha et al. Improved delay-dependent approach to passivity analysis for uncertain neural networks with discrete interval and distributed time-varying delays [15]. So, it is challenging to solve exponentially passive for T-S fuzzy of neutral dynamic system with various time-varying delays.”“ConclusionThis study rectify the exponentially passive analysis for the neutral difference of the uncertain Takagi-Sukeno fuzzy system with neutral, discrete and distributed interval time-varying delayed. By spending the Newton-Leibniz formulas, Lyapunov-Krasovskii functions (LKF), zero equations and matrix inequality techniques. The form of linear matrix inequalities (LMIs) is constructed from the exponentially passive which the numerical efficiency can be verified. Hence, this study shows the example of numbers to demonstrate the effectiveness of our theoretical results, and to illustrate, the results we have obtained are less conservative than the results available in other works. In the future work, the derived results and methods in this paper are expected to be applied to other systems such as fuzzy generalized complex-valued, guaranteed cost, pinning control of neural networks for impulsive effects on stability and passivity analysis, and so on [40–44].”Reviewer #2: In this study, the authors investigate an exponentially passive analysis for T-S fuzzy dynamical systems with various time-varying delays, including neutral, discrete, and distributed time-varying delays using the Lyapunov-Krasovskii function, Newton-Leibniz theory, zero equations, and matrix inequality. As compared to literature, they obtained less conservative results.The theoretical analysis appears to be correct, but the paper must undergo careful and critical editing of both the English language and English grammar. There are many linguistic omissions, errors, and oversights throughout. There are several such errors scattered throughout the manuscript, so it is very important to check it carefully.Answer : We really appreciate your suggestion. We have checked the grammatical problems throughout the manuscript thoroughly already.AttachmentPLoS-ONE-Response-to-Reviewers pang.docxSubmitted filename: Click here for additional data file. 30 Jun 2022
 PONE-D-22-00021R1

 A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delays

 PLOS ONEDear Dr. Botmart,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Aug 14 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at
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If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #2: (No Response)Reviewer #3: (No Response)**********  2. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: YesReviewer #3: Yes**********  3. Has the statistical analysis been performed appropriately and rigorously?   Reviewer #2: I Don't KnowReviewer #3: Yes**********  4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.  The Reviewer #2: YesReviewer #3: Yes**********  5. Is the manuscript presented in an intelligible fashion and written in standard English?  PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #2: NoReviewer #3: Yes**********  6. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #2: The authors have improved the revised manuscript based on the reviewers' comments, but some additional corrections are needed. Please see the attached file.Reviewer #3: 1. The abstract needs to be written in a more clarified way indicating the contribution.2. The authors have to state the weakness in previous works which motivated this study.3. The authors did not explain the difference between the work in the following paper [New results on robust exponential stability ofTakagi–Sugeno fuzzy for neutral differential systems with mixed time-varying delays] and the work in this paper.4. The novelty of this study has been explicitly stated.5. What is the research object in this paper?6. The format and English writing of the paper should be improved.7. The conclusion is descriptive. It is void of quantitative and numerical improvement and comparison.**********  7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Reviewer #2: NoReviewer #3: No**********https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
 While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, AttachmentPONE-D-22-00021_R1 (1).pdfSubmitted filename: Click here for additional data file. 26 Jul 2022Original Manuscript ID: PONE-D-22-00021R1Original Article Title: “A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delays”To: PLOS ONE EditorRe: Response to reviewersDear Editor,Thank you for allowing a resubmission of our manuscript, with an opportunity to address the reviewers’ comments.We are uploading (a) our point-by-point response to the comments (below) (response to reviewers), (b) an updated manuscript with yellow highlighting indicating changes, and (c) a clean updated manuscript without highlights (PDF main document).Best regards,<Thongchai Botmart> et al.Reviewer #2: The authors have improved the revised manuscript based on the reviewers' comments, but some additional corrections are needed. Please see the attached file.Answer : We appreciate your suggestion. We revised as the suggestion already and the English of the whole paper is carefully checked in the revised paper.Reviewer #3:1. The abstract needs to be written in a more clarified way indicating the contribution.Author response: We have already rewritten the abstract.Author action: We updated the manuscript in the abstract part as follows: This paper is the first studying on designing exponentially passive analysis for T-S fuzzy of dynamic systems with various time-varying delays such as neutral, discrete, and distributed time-varying delays. Constructing the new Lyapunov-Krasovskii function and the Newton-Leibniz theory, the zero equations, and the matrix inequality techniques, the multiple delay-dependent criteria, with assuring exponentially passive on the discussed T-S fuzzy system, are defined in respect of linear matrix inequalities (LMIs) that can be checked easily using the LMI toolbox of MATLAB. Those approaches give less conservative, exponentially passive criteria for special cases of general stability of a neutral differential system. Furthermore, the results of this study are delay-dependent, which depend on the lower and upper bound with the time-varying delay. Lastly, some numerical examples illustrate the performance of our criteria based on the results obtained and summarize some of the previous achievements.2. The authors have to state the weakness in previous works which motivated this study.Author response: Many thanks for your valuable remarks. Author action: We have revised in introduction part and added a Remark 1. as follows the above mentioned, there is still room for further improvement: the fuzzy T-S method with delay-dependent based on latency to the possible extent of the thresholds for exponential stability and passivity performance. Remark 1 This study constructs the suitable Lyapunov-Krasovskii functional, which consists of single, double, triple, and quadruple integral terms containing information about the lower and upper bounds of the delays σ_2,τ_2 and a state x(t). Furthermore, the LKF contains a new triple integral term as follows:σ_2^2 ∫_(-σ_2)^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)W_1 x ˙(s)dsdβdθ〗,τ_2^2 ∫_(-τ_2)^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)W_2 x ˙(s)dsdβdθ〗and a new quadruple integral term σ_2^3 ∫_(-σ_2)^0▒∫_v^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)U_1 x ˙(s)dsdβdθdv〗,τ_2^3 ∫_(-τ_2)^0▒∫_v^0▒∫_θ^0▒∫_(t+β)^t▒〖e^2α(s-t) x ˙^T (s)U_2 x ˙(s)dsdβdθdv〗that do not appear in . These improvement techniques enhance to get better results.3. The authors did not explain the difference between the work in the following paper [New results on robust exponential stability of Takagi–Sugeno fuzzy for neutral differential systems with mixed time-varying delays] and the work in this paper.Author response: Many thanks for your valuable suggestion. We have added in the Remark 7 and add referent.Author action:  Remark 7 New results on robust exponential stability of Takagi - Sugeno fuzzy for neutral differential systems with mixed time-varying delays [40] only focus on exponential stability for neutral differential equations of the uncertain Takagi - Sugeno fuzzy system. This paper studies exponential stable and exponentially passive neutral differential equations of the uncertain Takagi - Sugeno fuzzy system for further improvement. Furthermore, we consider mixed interval time-varying delays: mixed interval discrete time-varying delay, interval distributed time-varying delay, and interval neutral time-varying delay, i.e., σ(t) interval discrete time-varying delay which satisfies 0≤σ_1≤σ(t)≤σ_2, h(t) is interval distributed time-varying delays which satisfy 0≤h_1 ≤ h(t)≤h_2. and τ(t) is interval neutral time-varying delay which satisfy 0≤τ_1≤τ(t) ≤ τ_2.  [40] Tranthi J, Botmart T, Weera W, La-inchua T, Pinjai S. New results on robust exponential stability of Takagi - Sugeno fuzzy for neutral differential systems with mixed time-varying delays. Math Comput Simul. 2022; 201 : 714-738.4. The novelty of this study has been explicitly stated.Author response: We appreciate your compliments.Author action: -5. What is the research object in this paper?Author response: this paper investigates the delay-dependent approach to exponential passive of T-S fuzzy for uncertain neutral dynamical system with discrete interval and distributed time-varying delays. Based on delay partitioning, a LKF is constructed to obtain several improved delay-dependent passivity conditions which guarantee the passivity of T-S fuzzy for uncertain neutral dynamical system. We consider the additional useful terms with the distributed delays and estimate some integral terms by Wirtinger’s inequality provided a tighter lower bound than Jensen’s inequality. The Lyapunov–Krasovskii functional contains single, double, triple, and quadruple integral terms, in which full information on the delays and a state variable is used. Therefore, the construction and the technique for computation of the Lyapunov–Krasovskii functional are the main keys to improving the results of this work. In the proof of Theorems 1 improved Wirtinger’s single integral inequality, a novel triple integral inequality, and convex combination technique are used to bound the derivative of Lyapunov– Krasovskii functional, which provide a tighter bound than the inequalities. All of these lead to a reduction of the conservatism of our results compared to those in some exciting works and, in particular, numerical examples. However, the complex computation of the Lyapunov–Krasovskii functional leads to the LMI derived in this work which contains much information about the system. Hence, for further work, it is interesting for researchers to improve the technique for a simple Lyapunov–Krasovskii functional and also achieve better results.Author action: -6. The format and English writing of the paper should be improved.Author response: We really appreciate your suggestion. We have checked the grammatical problems already in this paper.Author action: We have corrected the manuscript by rewriting it as follows: 1. On page 1, line 3 “The Newton-Leibniz theory” should be “the Newton-Leibniz theory” 2. On page 1, line 10 “Lastly, the examples of Numerical are presented the performance of our criteria with the results obtained summarize some of the previous results as well.” should be “Lastly, some numerical examples illustrate the performance of our criteria base on the results obtained and summarize some of the previous achievement as well.” 3. On page 3, line 95 “Fang Liu, et al. [?], Li et al. [?], Lien et al.  and Pin-Lin Liu [?].” should be “by Fang Liu, et al. [26], Li et al. [27], Lien et al.  and Pin-Lin Liu [29].” 4. On page 3, line 106 “that do not appear in .” should be “that do not appear in .” 5. On page 4, line 110 “previous literature .” should be “previous literature .” 6. On page 5, line 133 “Definition 1 [?] The system (1)” should be “Definition 1 [31] The system (1)” 7. On page 6, line 1 “Lemma 1 [?]” should be “Lemma 1 [32]” 8. On page 6, line 6 “Lemma 2 [?], [?]” should be “Lemma 2 [33], [34]” 9. On page 6, line 7 “the following inequality hold:” should be “the following inequality holds:” 10. On page 6, line 14 “Lemma 3 [?]” should be “Lemma 3 [35]” 11. On page 6, line 15 “the following inequality hold:” should be “the following inequality holds:” 12. On page 6, line 21 “Lemma 4 [?]” should be “Lemma 4 [36]” 13. On page 6, line 22 “the following inequality hold:” should be “the following inequality holds:” 14. On page 18, line 142 “The proof is completes” should be “The proof is completed” 15. On page 20, line 155 “exponential stability” should be “exponential stable”7. The conclusion is descriptive. It is void of quantitative and numerical improvement and comparison.Author response: We appreciate your valuable remark. We have already rewritten the conclusion part.Author action: We updated the manuscript as follows: This study rectifies the exponentially passive analysis of the neutral difference of the uncertain Takagi-Sukeno fuzzy system with neutral, discrete, and distributed interval time-varying delay. By spending the Newton-Leibniz formulas, Lyapunov-Krasovskii Functions (LKF), zero equations, and matrix inequality techniques. The form of linear matrix inequalities (LMIs) is constructed from the exponentially passive, in which the numerical efficiency can be verified. Hence, this study shows the example of numbers to demonstrate the effectiveness of our theoretical results and to illustrate the results we have obtained are less conservative than the results available in other works: according to Corollary 2, we get the upper bounds of the time-varying delay σ_2for various σ_d and α. Summarize them in Table 3 for comparison with the results obtained in . It is concluded that our results have the upper bounds of the time-varying delay σ_2 at the amount of 1.1121 for σ_d = 0.9 and α = 0.9. Moreover, in Corollary 3, we get the upper bounds of the time-varying delay〖 σ〗_2. Summarize them in Table 6 for comparison with the results obtained in [30]. It is concluded that our results have the upper bounds of the time-varying delay σ_2 at the amount of 0.5021 for τ= 0.2450 and α = 0.23. We can see that our obtained results are less conservative than some existing results. In future work, the derived results and methods in this paper are expected to be applied to other systems such as fuzzy generalized complex-valued, guaranteed cost, pinning control of neural networks for impulsive effects on stability and passivity analysis, and so on [41-45].Finally, authors are once again thankful to anonymous reviewer, editor in chief, associate editor and editorial staff for their time, help, efforts and support.Corresponding authorThongchai BotmartAttachmentPLoS-ONE-Response-to-Reviewers.docxSubmitted filename: Click here for additional data file. 23 Aug 2022
 PONE-D-22-00021R2

 A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delays

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 While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  27 Aug 2022Original Manuscript ID: PONE-D-22-00021R2Original Article Title: “A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delays”To: PLOS ONE EditorRe: Response to reviewersDear Editor,Thank you for allowing a resubmission of our manuscript, with an opportunity to address the reviewers’ comments.We are uploading (a) our point-by-point response to the comments (below) (response to reviewers), (b) an updated manuscript with yellow highlighting indicating changes, and (c) a clean updated manuscript without highlights (PDF main document).Best regards,<Thongchai Botmart> et al.Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.Answer: We have added the referent [40] because a reviewer requires us to compare the difference between the work in the following paper [New results on robust exponential stability of Takagi–Sugeno fuzzy for neutral differential systems with mixed time-varying delays] and the work in this paper. I.e., New results on robust exponential stability of Takagi - Sugeno fuzzy for neutral differential systems with mixed time-varying delays [40] only focus on exponential stability for neutral differential equations of the uncertain Takagi - Sugeno fuzzy system. This paper studies exponential stable and exponentially passive neutral differential equations of the uncertain Takagi - Sugeno fuzzy system for further improvement. Furthermore, we consider mixed interval time-varying delays: mixed interval discrete time-varying delay, interval distributed time-varying delay, and interval neutral time-varying delay, i.e., σ(t) is interval discrete time-varying delay which satisfies 0≤σ_1≤σ(t)≤σ_2, h(t) is interval distributed time-varying delays which satisfy 0≤h_1≤h(t)≤h_2. And τ(t) is an interval neutral time-varying delay that satisfies 0≤τ_1≤τ(t)≤τ_2.  [40] Tranthi J, Botmart T, Weera W, La-inchua T, Pinjai S. New results on robust exponential stability of Takagi - Sugeno fuzzy for neutral differential systems with mixed time-varying delays. Math Comput Simul. 2022; 201 : 714-738.Review Comments to the AuthorReviewer #2: In response to the reviewers' comments, the authors improved their revised manuscript, and now it can be published.Answer: we greatly appreciate your kind comments and acceptance for our manuscript.Reviewer #3: The authors have improved the revised manuscript based on the reviewers' comments, All my comments have been addressed—no further comments.Answer: we greatly appreciate your kind comments and acceptance for our manuscript.AttachmentOriginal Manuscript ID round 3.pdfSubmitted filename: Click here for additional data file. 12 Sep 2022A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delaysPONE-D-22-00021R3Dear Dr. Botmart,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. 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The manuscript can be accepted in the present form.**********  7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose “no”, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.  Reviewer #2: NoReviewer #3: No********** 27 Sep 2022PONE-D-22-00021R3 A novel criteria on exponentially passive analysis for Takagi-Sugeno fuzzy of neutral dynamic system with various time-varying delays Dear Dr. Botmart:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! 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Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood.The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (n = 125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias , a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups.C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established.After sDTI measurement at FA (p < 0.001), elevated PTRD (p = 0.002) and reduced PTMD (p = 0.003) compared to healthy controls. Furthermore, FA was significantly reduced in DCFA (p < 0.001) with no differences in AH. In a genetically homogeneous subgroup of SPG4 patients (n = 12) with affection of the dorsal columns, DCRD significantly correlated with the overall disease severity as measured by the Spastic Paraplegia Rating Scale (SPRS) .In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTWith the most extensive sDTI study in vivo to date, we showed that axial sDTI combined with motion correction and advanced data post-processing strategies enables robust measurements and is ready to use, allowing recognition and quantification of disease- and age-related changes of the PT, DC, and AH. These results may also encourage the usage of sDTI in other neurodegenerative diseases with spinal cord involvement to explore its capability as selective biomarkers. This technique is limited in detecting and quantifying the axonal degeneration of the long spinal fiber tracts, which is needed to provide outreaching information on the etiology of neurodegeneration and immediately impact clinical decision-making. Diffusion tensor imaging (DTI) is a promising imaging technology to investigate the microstructure of white matter in the spinal cord . It poteSPAST gene, SPG4. MRI studies of the spinal cord are lacking but include structural cortical MRI (15-positron emission tomography (PET) of the motor cortex (Hereditary spastic paraplegia (HSP) is an incurable degenerative motor neuron disease that primarily affects the upper motor neuron and leads to loss of ambulation. HSP is genetically heterogeneous with common clinical core symptoms: spastic gait disorder with paraparesis often accompanied by neurogenic bladder disorder. But HSP is not restricted to the motor system. It also affects the sensory system in a substantial portion of HSP patients including the long fiber tracts of the dorsal columns . Histopaical MRI , regionaical MRI , diffusiical MRI , restingical MRI , and O15r cortex .The purpose of this study was the implementation of a high-resolution sDTI that is suitable for the selective evaluation of the pyramidal tracts (PT) and dorsal columns (DC) and detection of spinal degeneration at the cervical level where all of these long spinal tracts pass at the same level simultaneously. We hypothesized that diffusivity, especially of FA, RD, AD and MD would be significantly altered with definite illness and known pyramidal degeneration in HSP, compared to a database of normal DTI parameters gained from healthy controls . With a 2The local institutional ethics committee approved this single-center, cross-sectional prospective study . Before enrollment, written informed consent was obtained from all participating HSP patients and healthy controls.2.1Recruitment of study participants with known HSP  was coordinated through our specialized neurologic outpatient clinic. Healthy controls were taken from an in-house healthy control cohort . Partici2.2sec, and a 32-channel head coil. The acquisition protocol for healthy controls comprised the study protocol for sDTI and 3D brain scans with T1 and T2-FLAIR contrast according to our standard clinical protocol to screen for any pathological conditions, which were excluded. Age-related typical microangiopathy was not considered a pathological condition. MR examinations of participants with HSP included the standard clinical protocol and the above-mentioned sequences.Acquisition protocol for sDTI is provided in 2.2.1EPI) sequence with double spin-echo diffusion preparation at the height of cervical vertebra two (C2)  pulsation artifacts. The best individual trigger delay was visually estimated on b0 images at the same location as the sDTI acquisition . The diffusion encoding gradients of the DTI sequence were applied along the directions e1 = , e2 = , e3 = , e4 = , e5 =  and e6 = . The reported coordinates  are relative to the scanner frame of reference; the spinal cord is parallel to the z-axis in the supine position. Two neuroradiologists evaluated diagnostic image quality with expertise in neuroanatomy on MRI scans of 13 years and 15 years. Further technical details of the sDTI sequence parameters are given in Diffusion-weighted images were acquired using an optimized monopolar, echo-planar imaging (two (C2)  (Stejskatwo (C2) . At C2 t2.2.22 before placement of the ROI. To allow a semi-automated, bilateral ROI evaluation (1.05 mm in diameter) of the pyramidal tracts (PT), the dorsal columns (DC), and the anterior horns (AH), ROIs were adjusted along a manually defined ellipsoid aligned on the individual FA image of each subject’s spinal cord . The acquired slices with the original field of view (FOV) were manually centered and cropped to the intra-spinal space at the outer margins of the cerebrospinal fluid. After exclusion of relevant eddy-current induced distortions by visual inspection, no eddy-current correction was performed. The basic diffusion measures axial diffusivity (AD) and radial diffusivity (RD) were created by fitting a tensor model to the raw diffusion data. The thereof derived diffusion measures fractional anisotropy (FA) and mean diffusivity (MD) were calculated. Since scans suffer from breathing artifacts with slice displacement in the anterior-posterior direction, an automatic movement correction was added based on midsagittal intensity profiles aligned for each direction on the b0 image. To reduce partial volume effects DTI metric maps were interpolated to 0.2×0.2 mmnal cord . Both, t2.3t-test in case of equal variance or Welch’s t-test in case of unequal variance. A corrected p-value of <0.05 was considered statistically significant. Bonferroni correction was applied when multiple comparisons were calculated from the same data set. Cohen’s d effect sizes were calculated for each right and left fiber tract between HSP patients and healthy controls based on estimated marginal means , and interpreted according to the following criteria: small |d| = 0.20–0.49; medium |d| = 0.50–0.79; large |d| ≥ 0.80. Univariate GLMs with age and sex as co-founding factors and subject group  as fixed factor were performed for in-between group differences. Linear (Pearson) correlation and quadratic regression were performed to check for a dependency of DTI measurement parameters on age, age of onset, disease duration, and SPRS.JMP 14.2  and SPSS  were used for statistical analysis. After evaluating variance between healthy controls and HSP patients with a Levene-test of equal variance, group differences were compared either with a Student’s 2.4The datasets generated from the statistical analyses during the current study are available from the corresponding author on reasonable request.33.1Demographic and clinical characteristics of HSP patients and healthy controls are presented in A control group of 126 healthy participants with a similar age and sex distribution was enrolled, of which 11 scans had to be excluded due to motion artifacts (9 %). The healthy control group consisted of 60 women (median age (IQR) 36.5 years (27)) and 55 men (median age (IQR) 37 years (27)). No imaging or clinical data were suspicious for an underlying neurodegenerative process.3.23.3FA) is 0.54 ± 0.03 (r(115) = − 0.005, p = 0.958), PTRD 0.16 ± 0.04 10−3 mm2/s (r(115) = 0.003, p = 0.971) and PTMD 0.3 ± 0.04 10−3 mm2/s (r(115) = 0.038, p = 0.69), whereas DCFA is 0.56 ± 0.03 (r(115) = 0.057, p = 0.549), DCRD 0.16 ± 0.04 10−3 mm2/s (r(115) = 0.023, p = 0.81) and DCMD 0.30 ± 0.04 10−3 mm2/s (r(115) = 0.049, p = 0.606). Observed measurement parameters of the AHFA are 0.37 ± 0.04 (r(115) = − 0.102, p = 0.282), AHRD 0.22 ± 0.04 10−3 mm2/s (r(115) = 0.049, p = 0.607) and AHMD 0.28 ± 0.04 10−3 mm2/s (r(115) = 0.052, p = 0.58). There were no sex related differences of FA, RD and MD in healthy controls either, except for AHMD with p = 0.047  in contrast to the relatively closely packed values of FA, RD and MD  in patients with HSP compared to healthy controls.DTI parameters including FA, RD and MD in the three investigated fiber tract regions PT, DC and AH were compared between healthy controls and HSP patients , Fig. 4.−3 mm2/s, p = 0.002) whereas there is no significant difference in the DCRD . Significant differences could also be detected for MD in the PT  but not in DCMD .Furthermore, RD is significantly increased in the PT  and MD  could be observed in AH.No significant change of mean FA , RD (0.20 ± 0.04 vs 0.22 ± 0.04 103.5FA (r(32) = − 0.169, p = 0.354), for RD in DC (r(32) = 0.027, p = 0.883) and PTRD (r(32) = 0.003, p = 0.984) as well as for MD in DC (r(32) = 0.139, p = 0.447) and PTMD (r(32) = − 0.05, p = 0.787). Furthermore, no significant correlation could be detected between these DTI parameters neither with age of onset nor disease duration.No significant correlation between the Spastic Paraplegia Rating Score (SPRS) and the DTI parameters FA, RD and MD could be shown in pyramidal tracts and dorsal columns across all study participants . In HSP RD with good correlation to the SPRS score in SPG4 (r(12) = − 0.713, p = 0.009). No significant correlations could be detected for PTRD of the SPG4 subgroup (r(12) = − 0.397, p = 0.201).To check whether the homogeneous SPG4 subgroup shows different results than a heterogenous group of HSP patients, diffusion parameters were evaluated for SPG4 n = 12,  patients4HSP is the prototype disease of a continuous and slow degeneration of the first motor neuron not detectable by conventional MRI. In this study, the value of an improved sDTI and its quantitative parameters could be demonstrated by confirming spinal pyramidal and dorsal column degeneration in HSP patients. A significant decline in fractional anisotropy and mean diffusivity together with corresponding increase in radial diffusivity could be shown in the pyramidal tracts compared to healthy controls. Moreover, improved sDTI enables the selective evaluation not only of the pyramidal tracts but also of the dorsal columns and the anterior horns in line with high prevalence of sensory and low prevalence of second motor neuron involvement in HSP especially in the majority of cases included in this study .4.1The biological basis of these specific changes can be explained by neuropathological post mortem studies in HSP. These studies report axon degeneration involving lateral corticospinal tracts that is less severe in the cervical spinal cord and most severe in the thoracic spinal cord  . In addi. In line4.2The findings of this study are an important advancement beyond conventional MRI and previous studies of sDTI. The results of this study highlight the importance of column-specific analysis in applying DTI in evaluation of spinal cord disorders. For the most part, previous studies lack both the size of the collective comparable to ours and a high-resolution representation of the myelon. This study revealed no significant age-related changes in standard DTI parameters in the healthy control group. Previous sDTI studies show different results regarding age dependency . One stuMultiple technical factors influence the quality of sDTI. The sDTI sequence used in this study with a low FOV, high axial in-plane resolution and motion correction represents a strong advance compared to other studies which frequently use sagittal acquisitions with low axial resolution and freehand-ROI placement onto an axial fractional anisotropy map for whole cord DTI metrics or estimated location of spinal tracts which might lead to incorrect results . Data pr4.3C2 – C4 in patients compared to healthy controls with SPG4 and SPG11 but not for patients with SPG7. An association of the duration and severity of clinical disability with reduced gray matter area could only be shown at the level of C4  have already ceased, to a stage of the disease in which patients can still walk, the further progression of the disease can no longer be monitored with electrophysiology . A recenel of C4 . ChangesThis study shows, using the homogeneous SPG4 subgroup, that there is a correlation of RD from the dorsal columns to disease severity as measured by the SPRS score. It must be noted, however, that there were nearly twice as many movement artifacts in the study group with HSP as in the comparison group. This can be explained by the onset of spasticity during the measurements, which makes it difficult for patients with this condition to lie still permanently. The results of this study highlight the importance of column-specific analysis in applying DTI in evaluation of spinal cord disorders. With DTI analysis only as in a whole cord region, details within each white matter column cannot be sufficiently revealed. In a whole cord analysis, subtle abnormalities of DTI parameters caused by minor microstructure impairment in a small region may be missed. A recent study by Navas-Sanchez et al. evaluated the SPG4 subset of 12 patients and found FA changes which were significantly related to disease severity as measured by SPRS . The dat4.4This study has several limitations. First, with HSP being a rare disease the access to affected patients is limited. Second, a longitudinal study for a correlation of DTI parameters to individual changes in clinical severity of the disease measured by the Spastic Paraplegia Rating Scale (SPRS) is still lacking. Third, the number of diffusion directions are important for fiber tracking and advanced diffusion parameters. In this study only 6 directions were used as the basic parameters  have been shown to be similar independent of the number of diffusion directions for different tracts . Nonethe4.5In conclusion, the results of this study demonstrate a pattern of robust alterations of pyramidal tracts and dorsal columns within HSP and reveal unique features including the distinction of normal ageing and pathologic conditions of the myelon compared to a healthy control group using an improved sDTI sequence. Therefore, it could have an important impact on patient management from diagnosis to therapy. As HSP is the prototype disease of the degenerating first motor neuron, the measured increase of radial diffusivity and decline of fractional anisotropy and mean diffusivity in the pyramidal tracts reflect well this pathologic condition. These patterns may help to detect a measurable correlate in patients with suspected motoneuron disease as well as the extent of microstructural changes, degeneration and outcome.An ideal future study would further investigate sDTI as a graduation and prognostic tool for further disease development and evaluation of response to therapy in myelon diseases affecting the long fiber tracts such as HSP, amyothrophic lateral sclerosis, Friedreich ataxia, spinal cord ischemia, spinal tumors or multiple sclerosis.Competing interests.BB is co-founder and share-holder of AIRAmed and has received consultancy fees from Medtronic; TL is co-founder, CEO and share-holder of AIRAmed, he has received grants from the Alzheimer Forschung Initiative e.V., travel grants from Bayer and presentation fees from Roche. The other authors report no competing interests.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Although the seized samples analyses revealed the presence of well-established adulterants such as levamisole for cocaine or paracetamol/acetaminophen for heroin, the reported data disclosed new adulteration practices, such as the use of NPS as cutting agents for classic drugs of abuse and other NPS. For example, heroin adulterated with synthetic cannabinoids or cocaine adulterated with fentanyl/fentalogues raised particular concern. Notably, adulterants play a role in some adverse effects commonly associated with the primary drug, such as levamisole-adulterated cocaine that may induce vasculitis via an autoimmune process. It is essential to constantly monitor adulterants due to their changing availability that may threaten drug consumers’ health. Adulteration is a well-known practice of drug manufacturers at different stages of drug production. The intentional addition of active ingredients to adulterate the primary drug may enhance or mask pharmacological effects or may produce more potent drugs to increase the number of available doses and the dealer’s profit. Adulterants found in different drugs change over time in response to different factors. A systematic literature search in PubMed and Scopus databases and official international organizations’ websites according to PRISMA guidelines was performed. A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as “non-biological” ( In 2020, about 284 million people consumed drugs within the previous year, representing an increase of 26% compared to 2010. Cannabis products remain the most abused compounds all over the world, while the highest prevalence of drug-related deaths is attributed to opioids . AlthougBesides the threat of illicit drug consumption, adulteration with other active compounds represents an additional risk for drug users, exposing them to unanticipated intake of a wide range of pharmacologically active substances. Adulteration is a well-known practice of drug manufacturers at different stages of drug production ,5. DiffeRecently, concerns were raised by the adulteration of low ∆-9-tetrahydrocannabinol (THC) cannabis products with more powerful synthetic cannabinoids ,11.Here, we review the most recent reports of adulterants detected in seized drugs of abuse including NPS. Furthermore, we reviewed reported cases of adulterated drug intoxications published in the literature from 2017 to 2022, focusing on clinical signs, pharmacological peculiarities, reported intoxication symptoms, and toxicological analyses performed on different human specimens.n = 35) or “biological”  according to the samples investigated. All results are summarised in A total of 724 studies were initially screened, with 145 articles from PubMed and 462 from Scopus excluded according to the criteria described in the Method Section. The remaining 117 records were further assessed for eligibility to exclude articles without sufficient data. Finally, 79 studies were classified as “non-biological” (n = 20), opioids (n = 14), amphetamine-like stimulants (n = 8), NPS (n = 2), and THC (n = 2). Although most manuscripts considered one adulterated drug, different substance classes were investigated in 7 studies [The literature search yielded 35 studies  on seizeoids n = , ampheta studies ,16,17. C studies .Levamisole and phenacetin were the most prevalent cocaine adulterants, followed by caffeine. The reported adulteration with local anaesthetics such as lidocaine, benzocaine, or procaine ,23,24,25Amphetamine-type stimulants were adulterated with the most varied compounds, primarily other stimulants, most likely to boost the expected effect. Furthermore, the highest number of NPS  were detected in MDMA and methamphetamine seized in the USA and Canada ,32.Only 3 studies investigating NPS composition revealed that these adulteration practices also occurred with these compounds that were also used as adulterants of classic drugs ,31,33 AlCannabis adulteration was the least investigated phenomenon since it was reported in only 2 studies. In this regard, Oomen et al. analysed a large number of samples recently seized in Europe, showing 24% of samples were adulterated with a potent synthetic cannabinoid, MDMB-4en PINACA, . It was The quality and quantity of adulterants identified in psychotropic drugs are affected by the analytical approach, as typical targeted methods do not reveal unexpected molecules ,35. Examn = 7), 5F-MDMB-PICA (n = 1); lead (n = 1); sildenafil (n = 1); etizolam and caffeine (n = 1), and lysergic acid diethylamide (LSD) (n = 4) [n = 10), methaqualone and several benzodiazepines, caffeine and acetaminophen (n = 1), 5F-MDMB- PINACA (n = 7) and phenethylamine (n = 1), asbestos (n = 1) [n = 17 cases) [A total of 35 case reports of drug adulterants’ intoxications are included . Adulter (n = 4) ,50,51,52 (n = 1) ,54,55,567 cases) ,60,61,62n = 5) [n = 8) [n = 4) [n = 1) [n = 1) [n = 1) [In this regard, the most interesting association between an adulterant and resultant disease occurred with levamisole and perinuclear or cytoplasmic anti-neutrophil cytoplasmic antibodies (p- or c-ANCA) positivity. P- or c-ANCA are two autoantibodies which target different neutrophil proteins: myeloperoxidase (MPO) associated with p-ANCA and proteinase3 (PR3) associated with c-ANCA. Generally, ANCA positivity is a marker of autoimmune pathologies including systemic autoimmune vasculitis, necrotising crescentic glomerulonephritis, inflammatory bowel disease and other autoimmune pathologies . In levan = 5) ,57, vasc [n = 8) ,59,60,61 [n = 4) ,62, pyod [n = 1) , neutrop [n = 1) , and cer [n = 1) . These a [n = 1) . Vasculi [n = 1) .The average age of the cocaine users that experienced levamisole toxicity due to adulteration was 44 years, including 11 males (average age: 41.8 years) and 7 females (average age: 45.3 years). Age and sex were factors related to levamisole and cocaine exposure in the different pathologies. CIMDL was associated with younger age and female sex , older women experienced more vasculitis  and older men more glomerulonephritis (42 years). n = 5), while the quantitative confirmatory analysis was performed on hair (n = 2) with segmental analysis. Levamisole-adulterated cocaine produced toxicity in the nasal septum including CIMDL (2), kidney (2), brain (1) and skin vessels (2). Levamisole was analytically confirmed in only 7 cases, with suspected exposure based on the clinical manifestations and confirmed cocaine exposure ,45,58,59n = 8) [n = 7), fentanyl (n = 5), and cocaine (n = 3) [Adulterated opioids were found in 10 intoxications. The most frequent adulterated opioid was heroin laced with 5F-MDMB-PINACA (n = 8) , while mn = 8) . Lead wan = 8) . Patient (n = 3) ,52,55. n = 6), fentanyl (n = 3) and heroin (n = 3), while 5F-MDMB- PICA and cocaine were positive for 1 case [n = 7), fentanyl (n = 6) as the most detected analytes. [n = 5), followed by blood (n = 4), serum (n = 3) and hair (n = 1). In all these cases, quantification was accomplished with sophisticated analytical methods. The adulterants were THC and MDMA for LSD (n = 3), sildenafil (n = 1) for GHB, etizolam (n = 1) for alprazolam and phenylethylamine (n = 1) for kratom [The most frequent substances detected in serum were 6-acetylmorphine . Interestingly, levamisole was more concentrated in brain tissue than in the other matrices (128 ng/mg) suggesting an accumulation in the parenchyma and facilitated passage through the blood–brain barrier [In 2019, Handley et. al. found higher levamisole concentration in urine than in plasma (565 ng/mL vs 10.6 ng/mL), due to its rapid metabolism (t barrier .n = 40), urine (n = 30), and oral fluid (n = 30). Concentrations in hair were 2.3–8600 pg/mg for fentanyl  and 2.1–3200 pg/mg for acetylfentanyl [In the series of heroin cases, acetylfentanyl, furanylfentanyl, U-47700, and norfentanyl were the adulterants identified in segmented hair  and sold under the name “Krypton” . ODT, a Although the reported data covered a limited time range, more recent evidence confirms the changing nature of adulteration practices, such as the xylazine-laced heroin seized in the USA ,82.Adulterants may play a role in the adverse effects commonly related to the primary drug, such as vasculitis induced by levamisole-adulterated cocaine . P/c-ANCAlthough other adulterants were detected in seized samples, such as phenacetin, benzocaine and lidocaine, these substances were not reported in clinical cases, probably due to the lack of specific analyses of compounds other than principal drugs causing health threats. Noteworthy is the alarming increase in cocaine-related deaths due to fentanyl-adulterated cocaine . Huhn etApparently, lead adulteration of drugs such as opium, heroin and methamphetamine is a common practice in Iran . In leadRarely, cases of LSD-adulterated methamphetamine were reported, characterized by the inconsistency between the type of symptoms appearing in the acute intoxication phase and the substance reportedly taken by the patient. This inconsistency led to toxicological research to detect LSD and adulterants . The sta(1)Articles not written in English(2)Commentary; editorial letters; and surveys(3)Duplicates were removed(4)Irrelevant studiesA systematic literature search was performed in PubMed and Scopus databases and official international organizations’ websites; according to PRISMA guidelines (12). Keywords “drug of abuse”; “new psychoactive substances”; “fentanyl analogues”; “heroin”; “cocaine”; “amphetamine”; “THC”; “cannabis”; “stimulants”; “synthetic cathinones”; “synthetic opioids”; “opioids”; “opiates”; “phenethylamine”; “synthetic cannabinoids”; were combined with “adulteration”; “adulterants”; and “contaminated”. A total of 3604 scientific articles (1250 from PubMed and 2354 from Scopus) published from 2017 to 2021 were initially screened for eligibility. Two scientists individually evaluated each entry from one database; considering for full text reading only titles and abstracts mentioning analytical assessment of drugs and adulterants in seized materials and/or in drug-related intoxications. Further screening excluded studies according to the following criteria:Articles were classified by matrix investigated as “biological specimens” or “non biological specimens”. Finally, articles were excluded for insufficient data.Drug of abuse adulteration is a common practice involving a wide range of different active substances added to the primary drugs for pharmacological or profit purposes. The data showed that adulterants are widely added to all the classes of drugs of abuse, including NPS. Furthermore, NPS may be used as adulterants to potentiate the primary drug effect or obtain cocktails exerting unexpected effects on the abusers. However, they represent an additional threat to the users’ health since a synergistic effect is observed in the comparison of certain intoxication symptoms. Moreover, the unexpected presence of certain psychotropic drugs may lead to incorrect treatment of intoxication cases. For these reasons, adulteration practices must be monitored to assess changes in the drug supply and adulterants should be analytically assessed in intoxication cases.