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Role-play is a pedagogy that been used in a wide variety of contexts and content areas (Rao & Stupans, 2012). Essentially, it is the practice of having students take on specific roles - usually ones in which they are not familiar - and act them out in a case-based scenario for the purpose of learning course content or understanding “complex or ambiguous concepts” (Sogunro, 2004: 367). The guidelines for the role-play are usually modeled on realistic criteria so the students can get as close to “the real thing” as possible. Research on role-play’s effectiveness and best practices exists as far back as the 1970s; recently however, role-play has been touted as a tool better suited for the needs of today’s college student than more traditional teaching methods (see Rosa, 2012, and Bobbit et. al. , 2001).

Role-play pedagogy has been shown to be effective in reaching learning outcomes in three major learning domains: affective, cognitive, and behavioral (Maier, 2002; Rao & Stupans, 2012). By making students take on the role of another person, they practice empathy and perspective taking. This can lead to more self-reflection and awareness on the part of the student (Westrup & Planander, 2013; Sogunro, 2004). When students take the skills they have learned in theory and put them in practice, this creates a deeper cognitive link to the material, making it easier for students to learn (McEwen, et. al., 2014; Johnson & Johnson, 1997). Finally, using role-play as a training tool helps students change behaviors and use best practices in real-world settings (Beard, et. al., 1995).

Pavey and Donoghue (2003, p. 7) summarize the benefits of using role-play pedagogy:

“to get students to apply their knowledge to a given problem, to reflect on issues and the views of others, to illustrate the relevance of theoretical ideas by placing them in a real-world context, and to illustrate the complexity of decision-making.”

This pedagogical tool has been used in various fields, from medicine to law, from business to psychology (Westrup & Planander, 2013). Though role-play has traditionally been used in educational settings with an emphasis on the social dynamic of learning and fostering collaboration among students (Joyce & Weil, 2000), researchers have found role-play useful in getting students to better grasp practical cognitive skills as well (Shapiro & Leopold, 2012). Aspegren’s literature review (1999) on how medical student best learn communication skills revealed that experiential training produced much better results than simple one-way instruction. Using role-plays have been shown to better prepare student teachers and construction managers (Bhattacharjee, 2014). It can enhance second language learning (Livingstone, 1983) and reduce racial prejudice (McGregor, 1993). Not only does it increase student engagement, it increases knowledge retention. (Westrup & Planander, 2013)

Rao & Stupans (2012) have created a useful typology for organizing the various role-play activities that are used in higher education: ‘Role-Switch,’ ‘Acting,’ and ‘Almost Real Life.’ ‘Role-Switch’ requires the student to take on the role of another agent to understand the actions and motivations of someone else. ‘Acting’ role-plays allow students to practice newly-developed skills by simulating a scenario where that skill may be required. ‘Almost Real Live’ is a role-play “as close to the real experience as is possible” (431). This type of role-play lets students apply all their skills in a realistic, yet safe setting. Each of these categories focus on a different learning domain, though all overlap to some degree. The authors also surveyed the literature to collect best practices across all types of role-plays. Best practices include the instructor thinking deeply about the learning goals of the role-play and choosing a case that best reaches those goals; ensuring both the instructor and students are adequately prepared with case materials and familiar with the pedagogy; and allowing for sufficient and appropriate feedback and debriefing of the entire exercise (Rao & Stupans, 2012: 432-33).

These guidelines point to some of the drawbacks to using role-play, namely the amount of time necessary to properly prepare for the activity and the amount of knowledge one needs to have about both the content and the pedagogy (see House et. al. , 1983; Ments, 1989). However, if instructors do take the time to prepare, the benefits can far outweigh the effort.

Written by Lauren Britt Elmore , Ed.D., Harvard Graduate School of Education

Aspegren, K. (1999). BEME Guide No. 2: Teaching and learning communication skills in medicine-a review with quality grading of articles. Medical Teacher, 21 (6), 563-570.

Beard, R.L., Salas, E., & Prince, C. (1995). Enhancing transfer of training: Using role-play to foster teamwork in the cockpit. The International Journal of Aviation Psychology, 5 (2), 131-143.

Bhattacharjee, S. (2014). Proceedings from the 50th ASC Annual International Conference: Effectiveness of role-playing as a pedagogical approach in construction education.

Bobbit, L.M., Inks, S.A., Kemp, K.J. & Mayo, D.T. (2000). Integrating marketing courses to enhance team-based experiential learning. Journal of Marketing Education, 22 (1), 15-24.

House, R.J., Schuler, R.S. & Levanoni, E. (1983). Role conflict and ambiguity scales: Reality or artifact?. Journal of Applied Psychology, 68 , 334-337.

Johnson, D.W. & Johnson, F.P. (1997). Joining Together: Group Theory and Group Skills, 6th ed. Boston, MA: Allyn & Bacon.

Kettula, K. & Berghall, S. (2013). Drama-based role-play: A tool to supplement work-based learning in higher education. Journal of Workplace Learning, 25 (8), 556-575.

Maier, H.W. (January 2002). Role playing: structures and educational objectives. CYC-online, 36 . Retrived from www.cyc-net.org/cyc-online/cycol-0102-roleplay.html .

Ments, M.V. (1989), The Effective Use of Role-play: A Handbook for Teachers and Trainers, rev. ed. London: Kogan Page.

Rao, D. & Stupans, I. (2012). Exploring the potential of role play in higher education: development of a typology and teacher guidelines. Innovations in Education and Teaching International, 49 (4), 427-436.

Rosa, J.A. (2012). Marketing education for the next four billion: Challenges and innovations. Journal of Marketing Education, 34 (1), 44-54.

Sogunro, O.A. (2004). Efficacy of role-playing pedagogy in training leaders: Some reflections. Journal of Management Development, 23 (4), 355-371.

Westrup, U. & Planander, A. (2013). Role-play as a pedagogical method to prepare students for practice: The students’ voice. Ogre utbildning, 3 (3), 199-210.

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Gaming Intentionally: A Literature Review of the Viability of Role-Playing Games as Drama-Therapy-Informed Interventions

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Library Guide to Capstone Literature Reviews: Role of the Literature Review

The role of the literature review.

Your literature review gives readers an understanding of the scholarly research on your topic.

In your literature review you will:

demonstrate that you are a well-informed scholar with expertise and knowledge in the field by giving an overview of the current state of the literature
find a gap in the literature, or address a business or professional issue, depending on your doctoral study program; the literature review will illustrate how your research contributes to the scholarly conversation
provide a synthesis of the issues, trends, and concepts surrounding your research

Be aware that the literature review is an iterative process. As you read and write initial drafts, you will find new threads and complementary themes, at which point you will return to search, find out about these new themes, and incorporate them into your review.

The purpose of this guide is to help you through the literature review process. Take some time to look over the resources in order to become familiar with them. The tabs on the left side of this page have additional information.

Short video: Research for the Literature Review

Short Video: Research for the Literature Review

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Literature review as a dinner party

To think about the role of the literature review, consider this analogy: pretend that you throw a dinner party for the other researchers working in your topic area. First, you’d need to develop a guest list.

The guests of honor would be early researchers or theorists; their work likely inspired subsequent studies, ideas, or controversies that the current researchers pursue.
Then, think about the important current researchers to invite. Which guests might agree with each other? Which others might provide useful counterpoints?
You likely won’t be able to include everyone on the guest list, so you may need to choose carefully so that you don’t leave important figures out.
Alternatively, if there aren’t many researchers working in your topic area, then your guest list will need to include people working in other, related areas, who can still contribute to the conversation.

After the party, you describe the evening to a friend. You’ll summarize the evening’s conversation. Perhaps one guest made a comment that sparked a conversation, and then you describe who responded and how the topic evolved. There are other conversations to share, too. This is how you synthesize the themes and developments that you find in your research. Thinking about your literature research this way will help you to present your dinner party (and your literature review) in a lively and engaging way.

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Here are some useful resources from the Writing Center, the Office of Research and Doctoral Services, and other departments within the Office of Academic Support. Take some time to look at what is available to help you with your capstone/dissertation.

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What is a Literature Review?

A literature or narrative review is a comprehensive review and analysis of the published literature on a specific topic or research question. The literature that is reviewed contains: books, articles, academic articles, conference proceedings, association papers, and dissertations. It contains the most pertinent studies and points to important past and current research and practices. It provides background and context, and shows how your research will contribute to the field.

A literature review should:

Provide a comprehensive and updated review of the literature;
Explain why this review has taken place;
Articulate a position or hypothesis;
Acknowledge and account for conflicting and corroborating points of view

From S age Research Methods

Purpose of a Literature Review

A literature review can be written as an introduction to a study to:

Demonstrate how a study fills a gap in research
Compare a study with other research that's been done

Or it can be a separate work (a research article on its own) which:

Organizes or describes a topic
Describes variables within a particular issue/problem

Limitations of a Literature Review

Some of the limitations of a literature review are:

It's a snapshot in time. Unlike other reviews, this one has beginning, a middle and an end. There may be future developments that could make your work less relevant.
It may be too focused. Some niche studies may miss the bigger picture.
It can be difficult to be comprehensive. There is no way to make sure all the literature on a topic was considered.
It is easy to be biased if you stick to top tier journals. There may be other places where people are publishing exemplary research. Look to open access publications and conferences to reflect a more inclusive collection. Also, make sure to include opposing views (and not just supporting evidence).

Source: Grant, Maria J., and Andrew Booth. “A Typology of Reviews: An Analysis of 14 Review Types and Associated Methodologies.” Health Information & Libraries Journal, vol. 26, no. 2, June 2009, pp. 91–108. Wiley Online Library, doi:10.1111/j.1471-1842.2009.00848.x.

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In This Article Expand or collapse the "in this article" section Literature Reviews

Introduction, what is a literature review.

Literature Reviews for Thesis or Dissertation
Stand-alone and Systemic Reviews
Purposes of a Literature Review
Texts on Conducting a Literature Review
Identifying the Research Topic
The Persuasive Argument
Searching the Literature
Creating a Synthesis
Critiquing the Literature
Building the Case for the Literature Review Document
Presenting the Literature Review

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Literature Reviews by Lawrence A. Machi , Brenda T. McEvoy LAST REVIEWED: 27 October 2016 LAST MODIFIED: 27 October 2016 DOI: 10.1093/obo/9780199756810-0169

Literature reviews play a foundational role in the development and execution of a research project. They provide access to the academic conversation surrounding the topic of the proposed study. By engaging in this scholarly exercise, the researcher is able to learn and to share knowledge about the topic. The literature review acts as the springboard for new research, in that it lays out a logically argued case, founded on a comprehensive understanding of the current state of knowledge about the topic. The case produced provides the justification for the research question or problem of a proposed study, and the methodological scheme best suited to conduct the research. It can also be a research project in itself, arguing policy or practice implementation, based on a comprehensive analysis of the research in a field. The term literature review can refer to the output or the product of a review. It can also refer to the process of Conducting a Literature Review . Novice researchers, when attempting their first research projects, tend to ask two questions: What is a Literature Review? How do you do one? While this annotated bibliography is neither definitive nor exhaustive in its treatment of the subject, it is designed to provide a beginning researcher, who is pursuing an academic degree, an entry point for answering the two previous questions. The article is divided into two parts. The first four sections of the article provide a general overview of the topic. They address definitions, types, purposes, and processes for doing a literature review. The second part presents the process and procedures for doing a literature review. Arranged in a sequential fashion, the remaining eight sections provide references addressing each step of the literature review process. References included in this article were selected based on their ability to assist the beginning researcher. Additionally, the authors attempted to include texts from various disciplines in social science to present various points of view on the subject.

Novice researchers often have a misguided perception of how to do a literature review and what the document should contain. Literature reviews are not narrative annotated bibliographies nor book reports (see Bruce 1994 ). Their form, function, and outcomes vary, due to how they depend on the research question, the standards and criteria of the academic discipline, and the orthodoxies of the research community charged with the research. The term literature review can refer to the process of doing a review as well as the product resulting from conducting a review. The product resulting from reviewing the literature is the concern of this section. Literature reviews for research studies at the master’s and doctoral levels have various definitions. Machi and McEvoy 2016 presents a general definition of a literature review. Lambert 2012 defines a literature review as a critical analysis of what is known about the study topic, the themes related to it, and the various perspectives expressed regarding the topic. Fink 2010 defines a literature review as a systematic review of existing body of data that identifies, evaluates, and synthesizes for explicit presentation. Jesson, et al. 2011 defines the literature review as a critical description and appraisal of a topic. Hart 1998 sees the literature review as producing two products: the presentation of information, ideas, data, and evidence to express viewpoints on the nature of the topic, as well as how it is to be investigated. When considering literature reviews beyond the novice level, Ridley 2012 defines and differentiates the systematic review from literature reviews associated with primary research conducted in academic degree programs of study, including stand-alone literature reviews. Cooper 1998 states the product of literature review is dependent on the research study’s goal and focus, and defines synthesis reviews as literature reviews that seek to summarize and draw conclusions from past empirical research to determine what issues have yet to be resolved. Theoretical reviews compare and contrast the predictive ability of theories that explain the phenomenon, arguing which theory holds the most validity in describing the nature of that phenomenon. Grant and Booth 2009 identified fourteen types of reviews used in both degree granting and advanced research projects, describing their attributes and methodologies.

Bruce, Christine Susan. 1994. Research students’ early experiences of the dissertation literature review. Studies in Higher Education 19.2: 217–229.

DOI: 10.1080/03075079412331382057

A phenomenological analysis was conducted with forty-one neophyte research scholars. The responses to the questions, “What do you mean when you use the words literature review?” and “What is the meaning of a literature review for your research?” identified six concepts. The results conclude that doing a literature review is a problem area for students.

Cooper, Harris. 1998. Synthesizing research . Vol. 2. 3d ed. Thousand Oaks, CA: SAGE.

The introductory chapter of this text provides a cogent explanation of Cooper’s understanding of literature reviews. Chapter 4 presents a comprehensive discussion of the synthesis review. Chapter 5 discusses meta-analysis and depth.

Fink, Arlene. 2010. Conducting research literature reviews: From the Internet to paper . 3d ed. Los Angeles: SAGE.

The first chapter of this text (pp. 1–16) provides a short but clear discussion of what a literature review is in reference to its application to a broad range of social sciences disciplines and their related professions.

Grant, Maria J., and Andrew Booth. 2009. A typology of reviews: An analysis of 14 review types and associated methodologies. Health Information & Libraries Journal 26.2: 91–108. Print.

DOI: 10.1111/j.1471-1842.2009.00848.x

This article reports a scoping review that was conducted using the “Search, Appraisal, Synthesis, and Analysis” (SALSA) framework. Fourteen literature review types and associated methodology make up the resulting typology. Each type is described by its key characteristics and analyzed for its strengths and weaknesses.

Hart, Chris. 1998. Doing a literature review: Releasing the social science research imagination . London: SAGE.

Chapter 1 of this text explains Hart’s definition of a literature review. Additionally, it describes the roles of the literature review, the skills of a literature reviewer, and the research context for a literature review. Of note is Hart’s discussion of the literature review requirements for master’s degree and doctoral degree work.

Jesson, Jill, Lydia Matheson, and Fiona M. Lacey. 2011. Doing your literature review: Traditional and systematic techniques . Los Angeles: SAGE.

Chapter 1: “Preliminaries” provides definitions of traditional and systematic reviews. It discusses the differences between them. Chapter 5 is dedicated to explaining the traditional review, while Chapter 7 explains the systematic review. Chapter 8 provides a detailed description of meta-analysis.

Lambert, Mike. 2012. A beginner’s guide to doing your education research project . Los Angeles: SAGE.

Chapter 6 (pp. 79–100) presents a thumbnail sketch for doing a literature review.

Machi, Lawrence A., and Brenda T. McEvoy. 2016. The literature review: Six steps to success . 3d ed. Thousand Oaks, CA: Corwin.

The introduction of this text differentiates between a simple and an advanced review and concisely defines a literature review.

Ridley, Diana. 2012. The literature review: A step-by-step guide for students . 2d ed. Sage Study Skills. London: SAGE.

In the introductory chapter, Ridley reviews many definitions of the literature review, literature reviews at the master’s and doctoral level, and placement of literature reviews within the thesis or dissertation document. She also defines and differentiates literature reviews produced for degree-affiliated research from the more advanced systematic review projects.

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Lau F, Kuziemsky C, editors. Handbook of eHealth Evaluation: An Evidence-based Approach [Internet]. Victoria (BC): University of Victoria; 2017 Feb 27.

Cover of Handbook of eHealth Evaluation: An Evidence-based Approach

Handbook of eHealth Evaluation: An Evidence-based Approach [Internet].

Chapter 9 methods for literature reviews.

Guy Paré and Spyros Kitsiou .

9.1. Introduction

Literature reviews play a critical role in scholarship because science remains, first and foremost, a cumulative endeavour ( vom Brocke et al., 2009 ). As in any academic discipline, rigorous knowledge syntheses are becoming indispensable in keeping up with an exponentially growing eHealth literature, assisting practitioners, academics, and graduate students in finding, evaluating, and synthesizing the contents of many empirical and conceptual papers. Among other methods, literature reviews are essential for: (a) identifying what has been written on a subject or topic; (b) determining the extent to which a specific research area reveals any interpretable trends or patterns; (c) aggregating empirical findings related to a narrow research question to support evidence-based practice; (d) generating new frameworks and theories; and (e) identifying topics or questions requiring more investigation ( Paré, Trudel, Jaana, & Kitsiou, 2015 ).

Literature reviews can take two major forms. The most prevalent one is the “literature review” or “background” section within a journal paper or a chapter in a graduate thesis. This section synthesizes the extant literature and usually identifies the gaps in knowledge that the empirical study addresses ( Sylvester, Tate, & Johnstone, 2013 ). It may also provide a theoretical foundation for the proposed study, substantiate the presence of the research problem, justify the research as one that contributes something new to the cumulated knowledge, or validate the methods and approaches for the proposed study ( Hart, 1998 ; Levy & Ellis, 2006 ).

The second form of literature review, which is the focus of this chapter, constitutes an original and valuable work of research in and of itself ( Paré et al., 2015 ). Rather than providing a base for a researcher’s own work, it creates a solid starting point for all members of the community interested in a particular area or topic ( Mulrow, 1987 ). The so-called “review article” is a journal-length paper which has an overarching purpose to synthesize the literature in a field, without collecting or analyzing any primary data ( Green, Johnson, & Adams, 2006 ).

When appropriately conducted, review articles represent powerful information sources for practitioners looking for state-of-the art evidence to guide their decision-making and work practices ( Paré et al., 2015 ). Further, high-quality reviews become frequently cited pieces of work which researchers seek out as a first clear outline of the literature when undertaking empirical studies ( Cooper, 1988 ; Rowe, 2014 ). Scholars who track and gauge the impact of articles have found that review papers are cited and downloaded more often than any other type of published article ( Cronin, Ryan, & Coughlan, 2008 ; Montori, Wilczynski, Morgan, Haynes, & Hedges, 2003 ; Patsopoulos, Analatos, & Ioannidis, 2005 ). The reason for their popularity may be the fact that reading the review enables one to have an overview, if not a detailed knowledge of the area in question, as well as references to the most useful primary sources ( Cronin et al., 2008 ). Although they are not easy to conduct, the commitment to complete a review article provides a tremendous service to one’s academic community ( Paré et al., 2015 ; Petticrew & Roberts, 2006 ). Most, if not all, peer-reviewed journals in the fields of medical informatics publish review articles of some type.

The main objectives of this chapter are fourfold: (a) to provide an overview of the major steps and activities involved in conducting a stand-alone literature review; (b) to describe and contrast the different types of review articles that can contribute to the eHealth knowledge base; (c) to illustrate each review type with one or two examples from the eHealth literature; and (d) to provide a series of recommendations for prospective authors of review articles in this domain.

9.2. Overview of the Literature Review Process and Steps

As explained in Templier and Paré (2015) , there are six generic steps involved in conducting a review article:

formulating the research question(s) and objective(s),
searching the extant literature,
screening for inclusion,
assessing the quality of primary studies,
extracting data, and
analyzing data.

Although these steps are presented here in sequential order, one must keep in mind that the review process can be iterative and that many activities can be initiated during the planning stage and later refined during subsequent phases ( Finfgeld-Connett & Johnson, 2013 ; Kitchenham & Charters, 2007 ).

Formulating the research question(s) and objective(s): As a first step, members of the review team must appropriately justify the need for the review itself ( Petticrew & Roberts, 2006 ), identify the review’s main objective(s) ( Okoli & Schabram, 2010 ), and define the concepts or variables at the heart of their synthesis ( Cooper & Hedges, 2009 ; Webster & Watson, 2002 ). Importantly, they also need to articulate the research question(s) they propose to investigate ( Kitchenham & Charters, 2007 ). In this regard, we concur with Jesson, Matheson, and Lacey (2011) that clearly articulated research questions are key ingredients that guide the entire review methodology; they underscore the type of information that is needed, inform the search for and selection of relevant literature, and guide or orient the subsequent analysis. Searching the extant literature: The next step consists of searching the literature and making decisions about the suitability of material to be considered in the review ( Cooper, 1988 ). There exist three main coverage strategies. First, exhaustive coverage means an effort is made to be as comprehensive as possible in order to ensure that all relevant studies, published and unpublished, are included in the review and, thus, conclusions are based on this all-inclusive knowledge base. The second type of coverage consists of presenting materials that are representative of most other works in a given field or area. Often authors who adopt this strategy will search for relevant articles in a small number of top-tier journals in a field ( Paré et al., 2015 ). In the third strategy, the review team concentrates on prior works that have been central or pivotal to a particular topic. This may include empirical studies or conceptual papers that initiated a line of investigation, changed how problems or questions were framed, introduced new methods or concepts, or engendered important debate ( Cooper, 1988 ). Screening for inclusion: The following step consists of evaluating the applicability of the material identified in the preceding step ( Levy & Ellis, 2006 ; vom Brocke et al., 2009 ). Once a group of potential studies has been identified, members of the review team must screen them to determine their relevance ( Petticrew & Roberts, 2006 ). A set of predetermined rules provides a basis for including or excluding certain studies. This exercise requires a significant investment on the part of researchers, who must ensure enhanced objectivity and avoid biases or mistakes. As discussed later in this chapter, for certain types of reviews there must be at least two independent reviewers involved in the screening process and a procedure to resolve disagreements must also be in place ( Liberati et al., 2009 ; Shea et al., 2009 ). Assessing the quality of primary studies: In addition to screening material for inclusion, members of the review team may need to assess the scientific quality of the selected studies, that is, appraise the rigour of the research design and methods. Such formal assessment, which is usually conducted independently by at least two coders, helps members of the review team refine which studies to include in the final sample, determine whether or not the differences in quality may affect their conclusions, or guide how they analyze the data and interpret the findings ( Petticrew & Roberts, 2006 ). Ascribing quality scores to each primary study or considering through domain-based evaluations which study components have or have not been designed and executed appropriately makes it possible to reflect on the extent to which the selected study addresses possible biases and maximizes validity ( Shea et al., 2009 ). Extracting data: The following step involves gathering or extracting applicable information from each primary study included in the sample and deciding what is relevant to the problem of interest ( Cooper & Hedges, 2009 ). Indeed, the type of data that should be recorded mainly depends on the initial research questions ( Okoli & Schabram, 2010 ). However, important information may also be gathered about how, when, where and by whom the primary study was conducted, the research design and methods, or qualitative/quantitative results ( Cooper & Hedges, 2009 ). Analyzing and synthesizing data : As a final step, members of the review team must collate, summarize, aggregate, organize, and compare the evidence extracted from the included studies. The extracted data must be presented in a meaningful way that suggests a new contribution to the extant literature ( Jesson et al., 2011 ). Webster and Watson (2002) warn researchers that literature reviews should be much more than lists of papers and should provide a coherent lens to make sense of extant knowledge on a given topic. There exist several methods and techniques for synthesizing quantitative (e.g., frequency analysis, meta-analysis) and qualitative (e.g., grounded theory, narrative analysis, meta-ethnography) evidence ( Dixon-Woods, Agarwal, Jones, Young, & Sutton, 2005 ; Thomas & Harden, 2008 ).

9.3. Types of Review Articles and Brief Illustrations

EHealth researchers have at their disposal a number of approaches and methods for making sense out of existing literature, all with the purpose of casting current research findings into historical contexts or explaining contradictions that might exist among a set of primary research studies conducted on a particular topic. Our classification scheme is largely inspired from Paré and colleagues’ (2015) typology. Below we present and illustrate those review types that we feel are central to the growth and development of the eHealth domain.

9.3.1. Narrative Reviews

The narrative review is the “traditional” way of reviewing the extant literature and is skewed towards a qualitative interpretation of prior knowledge ( Sylvester et al., 2013 ). Put simply, a narrative review attempts to summarize or synthesize what has been written on a particular topic but does not seek generalization or cumulative knowledge from what is reviewed ( Davies, 2000 ; Green et al., 2006 ). Instead, the review team often undertakes the task of accumulating and synthesizing the literature to demonstrate the value of a particular point of view ( Baumeister & Leary, 1997 ). As such, reviewers may selectively ignore or limit the attention paid to certain studies in order to make a point. In this rather unsystematic approach, the selection of information from primary articles is subjective, lacks explicit criteria for inclusion and can lead to biased interpretations or inferences ( Green et al., 2006 ). There are several narrative reviews in the particular eHealth domain, as in all fields, which follow such an unstructured approach ( Silva et al., 2015 ; Paul et al., 2015 ).

Despite these criticisms, this type of review can be very useful in gathering together a volume of literature in a specific subject area and synthesizing it. As mentioned above, its primary purpose is to provide the reader with a comprehensive background for understanding current knowledge and highlighting the significance of new research ( Cronin et al., 2008 ). Faculty like to use narrative reviews in the classroom because they are often more up to date than textbooks, provide a single source for students to reference, and expose students to peer-reviewed literature ( Green et al., 2006 ). For researchers, narrative reviews can inspire research ideas by identifying gaps or inconsistencies in a body of knowledge, thus helping researchers to determine research questions or formulate hypotheses. Importantly, narrative reviews can also be used as educational articles to bring practitioners up to date with certain topics of issues ( Green et al., 2006 ).

Recently, there have been several efforts to introduce more rigour in narrative reviews that will elucidate common pitfalls and bring changes into their publication standards. Information systems researchers, among others, have contributed to advancing knowledge on how to structure a “traditional” review. For instance, Levy and Ellis (2006) proposed a generic framework for conducting such reviews. Their model follows the systematic data processing approach comprised of three steps, namely: (a) literature search and screening; (b) data extraction and analysis; and (c) writing the literature review. They provide detailed and very helpful instructions on how to conduct each step of the review process. As another methodological contribution, vom Brocke et al. (2009) offered a series of guidelines for conducting literature reviews, with a particular focus on how to search and extract the relevant body of knowledge. Last, Bandara, Miskon, and Fielt (2011) proposed a structured, predefined and tool-supported method to identify primary studies within a feasible scope, extract relevant content from identified articles, synthesize and analyze the findings, and effectively write and present the results of the literature review. We highly recommend that prospective authors of narrative reviews consult these useful sources before embarking on their work.

Darlow and Wen (2015) provide a good example of a highly structured narrative review in the eHealth field. These authors synthesized published articles that describe the development process of mobile health ( m-health ) interventions for patients’ cancer care self-management. As in most narrative reviews, the scope of the research questions being investigated is broad: (a) how development of these systems are carried out; (b) which methods are used to investigate these systems; and (c) what conclusions can be drawn as a result of the development of these systems. To provide clear answers to these questions, a literature search was conducted on six electronic databases and Google Scholar . The search was performed using several terms and free text words, combining them in an appropriate manner. Four inclusion and three exclusion criteria were utilized during the screening process. Both authors independently reviewed each of the identified articles to determine eligibility and extract study information. A flow diagram shows the number of studies identified, screened, and included or excluded at each stage of study selection. In terms of contributions, this review provides a series of practical recommendations for m-health intervention development.

9.3.2. Descriptive or Mapping Reviews

The primary goal of a descriptive review is to determine the extent to which a body of knowledge in a particular research topic reveals any interpretable pattern or trend with respect to pre-existing propositions, theories, methodologies or findings ( King & He, 2005 ; Paré et al., 2015 ). In contrast with narrative reviews, descriptive reviews follow a systematic and transparent procedure, including searching, screening and classifying studies ( Petersen, Vakkalanka, & Kuzniarz, 2015 ). Indeed, structured search methods are used to form a representative sample of a larger group of published works ( Paré et al., 2015 ). Further, authors of descriptive reviews extract from each study certain characteristics of interest, such as publication year, research methods, data collection techniques, and direction or strength of research outcomes (e.g., positive, negative, or non-significant) in the form of frequency analysis to produce quantitative results ( Sylvester et al., 2013 ). In essence, each study included in a descriptive review is treated as the unit of analysis and the published literature as a whole provides a database from which the authors attempt to identify any interpretable trends or draw overall conclusions about the merits of existing conceptualizations, propositions, methods or findings ( Paré et al., 2015 ). In doing so, a descriptive review may claim that its findings represent the state of the art in a particular domain ( King & He, 2005 ).

In the fields of health sciences and medical informatics, reviews that focus on examining the range, nature and evolution of a topic area are described by Anderson, Allen, Peckham, and Goodwin (2008) as mapping reviews . Like descriptive reviews, the research questions are generic and usually relate to publication patterns and trends. There is no preconceived plan to systematically review all of the literature although this can be done. Instead, researchers often present studies that are representative of most works published in a particular area and they consider a specific time frame to be mapped.

An example of this approach in the eHealth domain is offered by DeShazo, Lavallie, and Wolf (2009). The purpose of this descriptive or mapping review was to characterize publication trends in the medical informatics literature over a 20-year period (1987 to 2006). To achieve this ambitious objective, the authors performed a bibliometric analysis of medical informatics citations indexed in medline using publication trends, journal frequencies, impact factors, Medical Subject Headings (MeSH) term frequencies, and characteristics of citations. Findings revealed that there were over 77,000 medical informatics articles published during the covered period in numerous journals and that the average annual growth rate was 12%. The MeSH term analysis also suggested a strong interdisciplinary trend. Finally, average impact scores increased over time with two notable growth periods. Overall, patterns in research outputs that seem to characterize the historic trends and current components of the field of medical informatics suggest it may be a maturing discipline (DeShazo et al., 2009).

9.3.3. Scoping Reviews

Scoping reviews attempt to provide an initial indication of the potential size and nature of the extant literature on an emergent topic (Arksey & O’Malley, 2005; Daudt, van Mossel, & Scott, 2013 ; Levac, Colquhoun, & O’Brien, 2010). A scoping review may be conducted to examine the extent, range and nature of research activities in a particular area, determine the value of undertaking a full systematic review (discussed next), or identify research gaps in the extant literature ( Paré et al., 2015 ). In line with their main objective, scoping reviews usually conclude with the presentation of a detailed research agenda for future works along with potential implications for both practice and research.

Unlike narrative and descriptive reviews, the whole point of scoping the field is to be as comprehensive as possible, including grey literature (Arksey & O’Malley, 2005). Inclusion and exclusion criteria must be established to help researchers eliminate studies that are not aligned with the research questions. It is also recommended that at least two independent coders review abstracts yielded from the search strategy and then the full articles for study selection ( Daudt et al., 2013 ). The synthesized evidence from content or thematic analysis is relatively easy to present in tabular form (Arksey & O’Malley, 2005; Thomas & Harden, 2008 ).

One of the most highly cited scoping reviews in the eHealth domain was published by Archer, Fevrier-Thomas, Lokker, McKibbon, and Straus (2011) . These authors reviewed the existing literature on personal health record ( phr ) systems including design, functionality, implementation, applications, outcomes, and benefits. Seven databases were searched from 1985 to March 2010. Several search terms relating to phr s were used during this process. Two authors independently screened titles and abstracts to determine inclusion status. A second screen of full-text articles, again by two independent members of the research team, ensured that the studies described phr s. All in all, 130 articles met the criteria and their data were extracted manually into a database. The authors concluded that although there is a large amount of survey, observational, cohort/panel, and anecdotal evidence of phr benefits and satisfaction for patients, more research is needed to evaluate the results of phr implementations. Their in-depth analysis of the literature signalled that there is little solid evidence from randomized controlled trials or other studies through the use of phr s. Hence, they suggested that more research is needed that addresses the current lack of understanding of optimal functionality and usability of these systems, and how they can play a beneficial role in supporting patient self-management ( Archer et al., 2011 ).

9.3.4. Forms of Aggregative Reviews

Healthcare providers, practitioners, and policy-makers are nowadays overwhelmed with large volumes of information, including research-based evidence from numerous clinical trials and evaluation studies, assessing the effectiveness of health information technologies and interventions ( Ammenwerth & de Keizer, 2004 ; Deshazo et al., 2009 ). It is unrealistic to expect that all these disparate actors will have the time, skills, and necessary resources to identify the available evidence in the area of their expertise and consider it when making decisions. Systematic reviews that involve the rigorous application of scientific strategies aimed at limiting subjectivity and bias (i.e., systematic and random errors) can respond to this challenge.

Systematic reviews attempt to aggregate, appraise, and synthesize in a single source all empirical evidence that meet a set of previously specified eligibility criteria in order to answer a clearly formulated and often narrow research question on a particular topic of interest to support evidence-based practice ( Liberati et al., 2009 ). They adhere closely to explicit scientific principles ( Liberati et al., 2009 ) and rigorous methodological guidelines (Higgins & Green, 2008) aimed at reducing random and systematic errors that can lead to deviations from the truth in results or inferences. The use of explicit methods allows systematic reviews to aggregate a large body of research evidence, assess whether effects or relationships are in the same direction and of the same general magnitude, explain possible inconsistencies between study results, and determine the strength of the overall evidence for every outcome of interest based on the quality of included studies and the general consistency among them ( Cook, Mulrow, & Haynes, 1997 ). The main procedures of a systematic review involve:

Formulating a review question and developing a search strategy based on explicit inclusion criteria for the identification of eligible studies (usually described in the context of a detailed review protocol).
Searching for eligible studies using multiple databases and information sources, including grey literature sources, without any language restrictions.
Selecting studies, extracting data, and assessing risk of bias in a duplicate manner using two independent reviewers to avoid random or systematic errors in the process.
Analyzing data using quantitative or qualitative methods.
Presenting results in summary of findings tables.
Interpreting results and drawing conclusions.

Many systematic reviews, but not all, use statistical methods to combine the results of independent studies into a single quantitative estimate or summary effect size. Known as meta-analyses , these reviews use specific data extraction and statistical techniques (e.g., network, frequentist, or Bayesian meta-analyses) to calculate from each study by outcome of interest an effect size along with a confidence interval that reflects the degree of uncertainty behind the point estimate of effect ( Borenstein, Hedges, Higgins, & Rothstein, 2009 ; Deeks, Higgins, & Altman, 2008 ). Subsequently, they use fixed or random-effects analysis models to combine the results of the included studies, assess statistical heterogeneity, and calculate a weighted average of the effect estimates from the different studies, taking into account their sample sizes. The summary effect size is a value that reflects the average magnitude of the intervention effect for a particular outcome of interest or, more generally, the strength of a relationship between two variables across all studies included in the systematic review. By statistically combining data from multiple studies, meta-analyses can create more precise and reliable estimates of intervention effects than those derived from individual studies alone, when these are examined independently as discrete sources of information.

The review by Gurol-Urganci, de Jongh, Vodopivec-Jamsek, Atun, and Car (2013) on the effects of mobile phone messaging reminders for attendance at healthcare appointments is an illustrative example of a high-quality systematic review with meta-analysis. Missed appointments are a major cause of inefficiency in healthcare delivery with substantial monetary costs to health systems. These authors sought to assess whether mobile phone-based appointment reminders delivered through Short Message Service ( sms ) or Multimedia Messaging Service ( mms ) are effective in improving rates of patient attendance and reducing overall costs. To this end, they conducted a comprehensive search on multiple databases using highly sensitive search strategies without language or publication-type restrictions to identify all rct s that are eligible for inclusion. In order to minimize the risk of omitting eligible studies not captured by the original search, they supplemented all electronic searches with manual screening of trial registers and references contained in the included studies. Study selection, data extraction, and risk of bias assessments were performed independently by two coders using standardized methods to ensure consistency and to eliminate potential errors. Findings from eight rct s involving 6,615 participants were pooled into meta-analyses to calculate the magnitude of effects that mobile text message reminders have on the rate of attendance at healthcare appointments compared to no reminders and phone call reminders.

Meta-analyses are regarded as powerful tools for deriving meaningful conclusions. However, there are situations in which it is neither reasonable nor appropriate to pool studies together using meta-analytic methods simply because there is extensive clinical heterogeneity between the included studies or variation in measurement tools, comparisons, or outcomes of interest. In these cases, systematic reviews can use qualitative synthesis methods such as vote counting, content analysis, classification schemes and tabulations, as an alternative approach to narratively synthesize the results of the independent studies included in the review. This form of review is known as qualitative systematic review.

A rigorous example of one such review in the eHealth domain is presented by Mickan, Atherton, Roberts, Heneghan, and Tilson (2014) on the use of handheld computers by healthcare professionals and their impact on access to information and clinical decision-making. In line with the methodological guidelines for systematic reviews, these authors: (a) developed and registered with prospero ( www.crd.york.ac.uk/ prospero / ) an a priori review protocol; (b) conducted comprehensive searches for eligible studies using multiple databases and other supplementary strategies (e.g., forward searches); and (c) subsequently carried out study selection, data extraction, and risk of bias assessments in a duplicate manner to eliminate potential errors in the review process. Heterogeneity between the included studies in terms of reported outcomes and measures precluded the use of meta-analytic methods. To this end, the authors resorted to using narrative analysis and synthesis to describe the effectiveness of handheld computers on accessing information for clinical knowledge, adherence to safety and clinical quality guidelines, and diagnostic decision-making.

In recent years, the number of systematic reviews in the field of health informatics has increased considerably. Systematic reviews with discordant findings can cause great confusion and make it difficult for decision-makers to interpret the review-level evidence ( Moher, 2013 ). Therefore, there is a growing need for appraisal and synthesis of prior systematic reviews to ensure that decision-making is constantly informed by the best available accumulated evidence. Umbrella reviews , also known as overviews of systematic reviews, are tertiary types of evidence synthesis that aim to accomplish this; that is, they aim to compare and contrast findings from multiple systematic reviews and meta-analyses ( Becker & Oxman, 2008 ). Umbrella reviews generally adhere to the same principles and rigorous methodological guidelines used in systematic reviews. However, the unit of analysis in umbrella reviews is the systematic review rather than the primary study ( Becker & Oxman, 2008 ). Unlike systematic reviews that have a narrow focus of inquiry, umbrella reviews focus on broader research topics for which there are several potential interventions ( Smith, Devane, Begley, & Clarke, 2011 ). A recent umbrella review on the effects of home telemonitoring interventions for patients with heart failure critically appraised, compared, and synthesized evidence from 15 systematic reviews to investigate which types of home telemonitoring technologies and forms of interventions are more effective in reducing mortality and hospital admissions ( Kitsiou, Paré, & Jaana, 2015 ).

9.3.5. Realist Reviews

Realist reviews are theory-driven interpretative reviews developed to inform, enhance, or supplement conventional systematic reviews by making sense of heterogeneous evidence about complex interventions applied in diverse contexts in a way that informs policy decision-making ( Greenhalgh, Wong, Westhorp, & Pawson, 2011 ). They originated from criticisms of positivist systematic reviews which centre on their “simplistic” underlying assumptions ( Oates, 2011 ). As explained above, systematic reviews seek to identify causation. Such logic is appropriate for fields like medicine and education where findings of randomized controlled trials can be aggregated to see whether a new treatment or intervention does improve outcomes. However, many argue that it is not possible to establish such direct causal links between interventions and outcomes in fields such as social policy, management, and information systems where for any intervention there is unlikely to be a regular or consistent outcome ( Oates, 2011 ; Pawson, 2006 ; Rousseau, Manning, & Denyer, 2008 ).

To circumvent these limitations, Pawson, Greenhalgh, Harvey, and Walshe (2005) have proposed a new approach for synthesizing knowledge that seeks to unpack the mechanism of how “complex interventions” work in particular contexts. The basic research question — what works? — which is usually associated with systematic reviews changes to: what is it about this intervention that works, for whom, in what circumstances, in what respects and why? Realist reviews have no particular preference for either quantitative or qualitative evidence. As a theory-building approach, a realist review usually starts by articulating likely underlying mechanisms and then scrutinizes available evidence to find out whether and where these mechanisms are applicable ( Shepperd et al., 2009 ). Primary studies found in the extant literature are viewed as case studies which can test and modify the initial theories ( Rousseau et al., 2008 ).

The main objective pursued in the realist review conducted by Otte-Trojel, de Bont, Rundall, and van de Klundert (2014) was to examine how patient portals contribute to health service delivery and patient outcomes. The specific goals were to investigate how outcomes are produced and, most importantly, how variations in outcomes can be explained. The research team started with an exploratory review of background documents and research studies to identify ways in which patient portals may contribute to health service delivery and patient outcomes. The authors identified six main ways which represent “educated guesses” to be tested against the data in the evaluation studies. These studies were identified through a formal and systematic search in four databases between 2003 and 2013. Two members of the research team selected the articles using a pre-established list of inclusion and exclusion criteria and following a two-step procedure. The authors then extracted data from the selected articles and created several tables, one for each outcome category. They organized information to bring forward those mechanisms where patient portals contribute to outcomes and the variation in outcomes across different contexts.

9.3.6. Critical Reviews

Lastly, critical reviews aim to provide a critical evaluation and interpretive analysis of existing literature on a particular topic of interest to reveal strengths, weaknesses, contradictions, controversies, inconsistencies, and/or other important issues with respect to theories, hypotheses, research methods or results ( Baumeister & Leary, 1997 ; Kirkevold, 1997 ). Unlike other review types, critical reviews attempt to take a reflective account of the research that has been done in a particular area of interest, and assess its credibility by using appraisal instruments or critical interpretive methods. In this way, critical reviews attempt to constructively inform other scholars about the weaknesses of prior research and strengthen knowledge development by giving focus and direction to studies for further improvement ( Kirkevold, 1997 ).

Kitsiou, Paré, and Jaana (2013) provide an example of a critical review that assessed the methodological quality of prior systematic reviews of home telemonitoring studies for chronic patients. The authors conducted a comprehensive search on multiple databases to identify eligible reviews and subsequently used a validated instrument to conduct an in-depth quality appraisal. Results indicate that the majority of systematic reviews in this particular area suffer from important methodological flaws and biases that impair their internal validity and limit their usefulness for clinical and decision-making purposes. To this end, they provide a number of recommendations to strengthen knowledge development towards improving the design and execution of future reviews on home telemonitoring.

9.4. Summary

Table 9.1 outlines the main types of literature reviews that were described in the previous sub-sections and summarizes the main characteristics that distinguish one review type from another. It also includes key references to methodological guidelines and useful sources that can be used by eHealth scholars and researchers for planning and developing reviews.

Typology of Literature Reviews (adapted from Paré et al., 2015).

As shown in Table 9.1 , each review type addresses different kinds of research questions or objectives, which subsequently define and dictate the methods and approaches that need to be used to achieve the overarching goal(s) of the review. For example, in the case of narrative reviews, there is greater flexibility in searching and synthesizing articles ( Green et al., 2006 ). Researchers are often relatively free to use a diversity of approaches to search, identify, and select relevant scientific articles, describe their operational characteristics, present how the individual studies fit together, and formulate conclusions. On the other hand, systematic reviews are characterized by their high level of systematicity, rigour, and use of explicit methods, based on an “a priori” review plan that aims to minimize bias in the analysis and synthesis process (Higgins & Green, 2008). Some reviews are exploratory in nature (e.g., scoping/mapping reviews), whereas others may be conducted to discover patterns (e.g., descriptive reviews) or involve a synthesis approach that may include the critical analysis of prior research ( Paré et al., 2015 ). Hence, in order to select the most appropriate type of review, it is critical to know before embarking on a review project, why the research synthesis is conducted and what type of methods are best aligned with the pursued goals.

9.5. Concluding Remarks

In light of the increased use of evidence-based practice and research generating stronger evidence ( Grady et al., 2011 ; Lyden et al., 2013 ), review articles have become essential tools for summarizing, synthesizing, integrating or critically appraising prior knowledge in the eHealth field. As mentioned earlier, when rigorously conducted review articles represent powerful information sources for eHealth scholars and practitioners looking for state-of-the-art evidence. The typology of literature reviews we used herein will allow eHealth researchers, graduate students and practitioners to gain a better understanding of the similarities and differences between review types.

We must stress that this classification scheme does not privilege any specific type of review as being of higher quality than another ( Paré et al., 2015 ). As explained above, each type of review has its own strengths and limitations. Having said that, we realize that the methodological rigour of any review — be it qualitative, quantitative or mixed — is a critical aspect that should be considered seriously by prospective authors. In the present context, the notion of rigour refers to the reliability and validity of the review process described in section 9.2. For one thing, reliability is related to the reproducibility of the review process and steps, which is facilitated by a comprehensive documentation of the literature search process, extraction, coding and analysis performed in the review. Whether the search is comprehensive or not, whether it involves a methodical approach for data extraction and synthesis or not, it is important that the review documents in an explicit and transparent manner the steps and approach that were used in the process of its development. Next, validity characterizes the degree to which the review process was conducted appropriately. It goes beyond documentation and reflects decisions related to the selection of the sources, the search terms used, the period of time covered, the articles selected in the search, and the application of backward and forward searches ( vom Brocke et al., 2009 ). In short, the rigour of any review article is reflected by the explicitness of its methods (i.e., transparency) and the soundness of the approach used. We refer those interested in the concepts of rigour and quality to the work of Templier and Paré (2015) which offers a detailed set of methodological guidelines for conducting and evaluating various types of review articles.

To conclude, our main objective in this chapter was to demystify the various types of literature reviews that are central to the continuous development of the eHealth field. It is our hope that our descriptive account will serve as a valuable source for those conducting, evaluating or using reviews in this important and growing domain.

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Cite this Page Paré G, Kitsiou S. Chapter 9 Methods for Literature Reviews. In: Lau F, Kuziemsky C, editors. Handbook of eHealth Evaluation: An Evidence-based Approach [Internet]. Victoria (BC): University of Victoria; 2017 Feb 27.
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Types of Review Articles and Brief Illustrations
Concluding Remarks

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Published: 14 April 2024

Role of reactive oxygen species in myelodysplastic syndromes

Qiangan Jing 1 , 2 na1 ,
Chaoting Zhou 1 na1 ,
Junyu Zhang 3 na1 ,
Ping Zhang 1 ,
Yunyi Wu 1 ,
Junyu Zhou 1 ,
Xiangmin Tong 4 ,
Yanchun Li 4 ,
Jing Du ORCID: orcid.org/0000-0001-7519-8531 1 &
Ying Wang 4

Cellular & Molecular Biology Letters volume 29 , Article number: 53 ( 2024 ) Cite this article

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Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy.

Graphical Abstract

Introduction

Over the past few decades, despite great advancements in therapy, cancer remains a key challenge to human health and a leading cause of death globally [ 1 ]. Triggering apoptotic signaling pathways using anticancer drugs to induce apoptosis is one of the principal strategies for cancer treatment [ 2 , 3 ]. However, the complicated pathogenesis and acquired or intrinsic resistance of several cancers make it difficult to kill cancer cells effectively using therapeutic avenues, such as chemotherapy and radiotherapy [ 4 ]. Therefore, insights into the endogenous or exogenous factors influencing the etiology are important for eliminating cancer cells. Reactive oxygen species (ROS) are byproducts of cell growth under aerobic conditions and are mainly derived from mitochondrial metabolism [ 5 ]. Specifically, ROS encompass a group of derivatives of molecular oxygen [e.g., superoxide anion radical (O ⋅ − 2 ), hydroxyl radicals (OH ⋅ ), hydrogen peroxide (H 2 O 2 ), and singlet oxygen ( 1 O 2 )], which are formed by redox reactions or electron transfer in the mitochondrial electron transport chain (ETC) [ 6 ]. One of the prominent hallmarks of cancer cells is their high metabolic rate and uncontrolled proliferation [ 7 ]; therefore, they maintain higher ROS production and exhibit more aberrant redox homeostasis than noncancerous cells [ 8 ]. Several studies have emphasized that many transcription factors involved in the regulation of redox homeostasis are activated by ROS [ 9 ]. In some cancers, low or moderate levels of ROS could promote cell proliferation, differentiation, metastasis, and even chemoresistance, protecting cells from cytotoxic ROS by acting as signaling molecules to activate antioxidant systems in response to stress [ 5 , 10 , 11 , 12 ]. ROS, which are important signaling molecules, are often closely involved in the pathogenesis of numerous diseases and influence tumorigenesis, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML) [ 13 , 14 , 15 , 16 , 17 ].

In all healthy cells, the regulation of redox homeostasis is essential for cellular maintenance, proper execution, and survival. However, numerous pathological states are characterized by an aberrant redox state in which the generation and elimination of ROS are imbalanced, leading to oxidative stress (OS) [ 18 ]. OS is closely associated with many pathological conditions, such as aging [ 19 ], Parkinson’s disease [ 20 ], Alzheimer disease [ 21 , 22 ], rheumatoid arthritis [ 23 ], cardiovascular diseases [ 24 , 25 ], neurodegenerative diseases [ 26 , 27 ], diabetes [ 28 ], and cancer [ 29 ]. Compelling evidence has highlighted that chronic OS affects the progression of several hematological malignancies, including MDS and leukemia [ 30 , 31 , 32 ]. In this context, ROS are significant factors in tumor formation and the response to antineoplastic therapy, and the role of ROS in inhibiting or promoting malignant tumor onset may be determined by OS. This review aims to investigate the role of ROS in MDS and discuss whether ROS is an attractive therapeutic target for MDS treatment.

Formation of ROS and OS

Numerous physiological processes are accompanied by the formation of ROS and reactive nitrogen species (RNS), which are unavoidable consequences of cellular metabolism. ROS can be defined as nonradicals and free radicals (with one or more unpaired electrons) derived from diatomic oxygen. Highly reactive superoxide radicals (O ⋅ − 2 ) derived from the monovalent reduction of oxygen are at the heart of a range of potential chemical reactions [ 9 ], as well as the first step of ROS production (Fig. 1 ); For example, superoxide radicals can react with nitric oxide and mediate RNS production. Commonly, rapid superoxide reactions with superoxide dismutases (SODs) yield the versatile signaling molecule hydrogen peroxide (H 2 O 2 ). H 2 O 2 , a membrane-permeable and moderately prooxidant molecule, is a key agent in redox signaling, and its production is controlled by metabolic cues or numerous stress factors, including growth factors, chemokines, and physical stressors [ 33 ]. The elimination of H 2 O 2 is implemented by peroxiredoxins (PRX), glutathione peroxidase (GPX), and catalase (CAT) in the thioredoxin (Trx) and glutathione (GSH) systems [ 34 ]. In the low nanomolar range (intracellular concentrations below 100 nM), H 2 O 2 mediates the reversible oxidation of cysteine residues via specific protein targets and participates in the regulation of metabolic activity in response to external stress [ 9 , 35 , 36 ]. However, a supraphysiological concentration of H 2 O 2 (above 100 nM) can irreversibly modify and cause permanent impairment of DNA, proteins, or biomolecules [ 36 , 37 ], eventually leading to cell growth arrest or even senescence and death, a condition known as OS (Fig. 2 a), which is why cells have evolved professional defense mechanisms to control and scavenge the accumulation of H 2 O 2 and often maintain it at low or nontoxic threshold concentrations. Furthermore, the Fenton reaction, which mostly involves the decomposition of excess H 2 O 2 catalyzed by redox metals (e.g., Fe 2+ and Cu + ), is the primary source of deleterious hydroxyl radicals (OH ⋅ ) [ 38 ]. The accumulation of hydroxyl radicals can damage DNA, resulting in genomic instability, which is significant in the etiology and pathogenesis of multiple tumors as well as in protein structure and cellular membrane devastation by initiating lipid peroxidation [ 39 ]. Thus, maintaining the homeostasis of free labile ferrous iron and cuprous ions is critical for cells to take precautions against the formation of hydroxyl radicals. The more perturbed the homeostasis of transition metal cations, the more cellular impairment is induced by toxic hydroxyl radicals or metal ions.

Basics of ROS. The formation of intracellular O ⋅ − 2 could be deemed as a result of the activity of NOXs, or oxidative phosphorylation in mitochondria. Superoxide molecule as a reductant or an oxidant lies at the hub of a series of redox reactions. Mostly, superoxide radicals are catalyzed to H 2 O 2 by superoxide dismutases, including cytosolic SOD1, mitochondrial SOD2, and extracellular SOD3. Alternatively, superoxide reacts with NO ⋅ to form strong oxidative ONOO − , which can mediate oxidative modification of protein residues and induce RNS production. Physiological levels of H 2 O 2 are strictly regulated by multiple mechanisms, such as acting with PRX, GPX, and CAT to form H 2 O, while H 2 O 2 is also able to oxidation cysteine residues on proteins for signaling transduction. If, however, excessive H 2 O 2 is not controlled, it will be decomposed into OH ⋅ in the presence of metal cations (e.g., Fe 2+ and Cu + ). OH ⋅ can react with DNA and irreversibly damage DNA base units and also reacts with RH, forming R ⋅ . R ⋅ further reacts with O 2 , building up RO ⋅ or ROO ⋅ , which can cause lipid peroxidation by a series of reaction steps and ultimately subvert membrane stability and permeabilization

Intracellular concentration of H 2 O 2 , ROS levels, and OS. a Estimated ranges of H 2 O 2 concentration concerning OS cellular responses. The intracellular physiological range of H 2 O 2 boasts a wide span from 1 to 100 nM, and cellular proliferation, differentiation, migration, and angiogenesis rely heavily on that appropriate range. High concentrations of H 2 O 2 trigger cellular adaptive stress responses. Even higher levels result in inflammatory responses, growth retardation, tumor growth, metastasis, and cell death through different mechanisms. Green and orange coloring stands for principally eustress and distress responses, respectively. It is estimated that a 100-fold concentration gradient, which varies with cell type, the location inside cells, and the activity of enzymatic sinks, gives a rough orientation from extracellular to intracellular [ 18 , 279 ]. b Imbalance between oxidants and antioxidants causes OS and influences tumorigenesis. Excessive ROS generation leads to prooxidative/antioxidative imbalance and OS, which could be detrimental and result in cellular dysfunction or cell death. For tumor cells, a higher generation of ROS and an elevated redox state are crucial for tumorigenesis. In addition, tumor cells are able to increase the antioxidant levels to alleviate the cytotoxic effect of ROS and counteract OS-induced cell death

OS can be considered to be a disorder in which ROS generation and elimination are unbalanced, being inextricably linked to the pathology of many diseases [ 40 ], including various carcinomas. Cells have complicated biochemical and epigenetic mechanisms that maintain a relatively steady condition between prooxidative and antioxidative systems, and their disruption can result in physiological and pathological implications. Through antioxidant defense mechanisms involving both enzymatic and nonenzymatic antioxidants [ 41 , 42 ], cells maintain low or moderate ROS levels under normal physiological conditions, enabling cell growth and development. Further, in the functionality of cells, ROS serve as signaling agents that can drive gene and protein expression also but are protumorigenic [ 43 , 44 ]. As overproliferation and aberrant metabolism of tumors are commonly accompanied by high ROS generation, tumor cells adapt to the oxidative burden and maintain a high antioxidant status to avoid the cytotoxicity of high ROS levels [ 29 ]. However, excessive ROS reaching an uncontrolled or unscavenging status results in senescence and cellular death. Therefore, antioxidative defenses are of great significance in both signal transduction and counteracting ROS, which can maximally protect biomolecules against oxidative damage. It is noteworthy that many cellular physiological processes, such as proliferation and differentiation, cell growth, inflammation, and host defense, are subject to high ROS levels to a large extent, and those processes can be destroyed when the balance between uncontrolled ROS and antioxidants is affected (Fig. 2 b).

Typically, cells contain a spectrum of endogenous antioxidant enzymes, such as GSH, GPX, SOD, CAT, PRX, and Trx, which can directly scavenge dangerous ROS (hydroxyl radicals, peroxyl radicals, superoxides, and lipid peroxides) and maintain intracellular redox homeostasis [ 45 , 46 ]. GSH, a tripeptide composed of glutamate, glycine, and cysteine, is the most abundant intracellular antioxidant that participates in antioxidant defense, subdues ROS to homeostatic levels, and maintains the essential thiol status of proteins [ 47 ]. Two forms of GSH are possible: oxidized glutathione (GSSG), which is generated by GSH and interacts with H 2 O 2 ; meanwhile, GSSG can be biotransformed into the reduced form of GSH in the presence of reductase catalyzed by nicotinamide adenine dinucleotide phosphate (NADPH) as an electron donor. Significant changes in the intracellular ratio of GSH to GSSG can be regarded as indicators of oxidative damage [ 48 ]. GSH levels play a paramount role in malignant tumor development, which is typically linked to proliferative responses and influences cell cycle progression, metastatic invasion, and resistance to chemotherapy [ 48 , 49 , 50 ]. In addition, clinical survival outcomes of patients with certain diseases are closely associated with GSH levels. The majority of the intracellular GSH content of some neoplastic cells is commonly regulated by GSH-related enzymes, and increased GSH levels are closely related to the activities of γ-glutamylcysteine ligase and γ-glutamyl-transpeptidase, as well as high expression of GSH-transporting export pumps.

As elevated GSH levels are capable of boosting antioxidative ability and resistance to OS, previous studies have observed that GSH levels tend to be elevated in a variety of malignant tumors, including pancreatic adenocarcinoma [ 51 ] and liver [ 52 ], ovarian [ 53 ], breast [ 54 ], and lung cancers [ 55 ]. In contrast, studies have observed reduced intracellular GSH content and high ROS levels in bone marrow cells from patients with MDS [ 56 ], indicating that these cells are under OS. These results suggest that the depletion of glutathione or inhibition of GSH-related enzymes and enhanced cell OS may be effective methods for MDS treatment. Rasool et al. [ 57 ] analyzed 50 patients with leukemia, including those with ALL and AML, and 20 healthy controls to explore various circulating biomarkers (OS markers, electrolytes, and vitamin E). They showed that enzymatic and nonenzymatic antioxidant levels (GSH, SOD, CAT, GPX, and vitamin E), platelets, and electrolytes (Ca and Mg) were decreased when compared with controls, whereas malondialdehyde levels, which can reflect OS, were significantly enhanced in the disease subtypes of leukemia. These results indicate that the pathological state in patients with MDS and those with leukemia was inextricably associated with OS.

Source of ROS generation in hematopoietic cells

Mitochondria and mitochondrial etc.

Mitochondria are the metabolic centers of cells, play an essential role in various fundamental organismal processes, and serve as integral participants in the regulation of cell signaling pathways. For instance, they are the major site of adenosine triphosphate (ATP) generation by oxidative phosphorylation (OXPHOS), as well as participating in ROS generation and consumption, heme synthesis, the tricarboxylic acid (TCA) cycle, calcium signaling, epigenetic regulation, mitophagy, and apoptosis [ 58 , 59 ]. Hematopoietic stem cells (HSCs) are also regulated by these mitochondrial processes (Fig. 3 a). Mitochondrial ROS (mROS), a consequence of electron leakage during OXPHOS and molecular O 2 reduction, are typical byproducts of mitochondrial respiration [ 60 , 61 ]. It is well known that mROS encompass a series of major ROS, such as highly reactive superoxide radicals (O ⋅ − 2 ), noxious hydroxyl radicals (OH ⋅ ), H 2 O 2 , and singlet molecular oxygen ( 1 O 2 ). It is worth mentioning that there at least ten sites for O ⋅ − 2 generation in mitochondria, and the complexes I, II, and III of the ETC are most conspicuous [ 62 , 63 ]. Incomplete electron transport via ETC complexes I and II leads to the generation of O ⋅ − 2 in the mitochondrial matrix, as well as production in both the mitochondrial matrix and the intermembrane when electronic leakage occurs at complex III [ 64 , 65 ]. Under pathological conditions, complex III-generated O ⋅ − 2 commonly results from hypoxic signaling and the activation of hypoxia-inducible factors [ 66 ]. In addition, the intermembrane space O ⋅ − 2 is highly likely to engage in cellular signals transduction events, such as DNA and protein modifications, as they can travel to the cytosol easily [ 62 , 67 , 68 ].

a Multiple mitochondrial processes regulate HSCs. HSCs are exceedingly sensitive to ROS (mainly generated by mitochondrial metabolism) levels, which can directly influence their differentiation and commitment. Excessive ROS levels invariably cause HSC pool exhaustion. Metabolites (e.g., fumarate, succinate, NAD, and acetyl-CoA), produced by mitochondria through OXPHOS and the TCA cycle, could impact the epigenetic landscape. For example, fatty acid oxidation in HSCs is required to support acetyl-CoA production. Meanwhile, the mitochondrial dynamic regulatory protein Mfn2 inhibits NFAT activity by a negative effect on intracellular calcium ions, thereby maintaining HSCs. Heightened calcium signaling prompts mitochondrial activity and participates in HSC division. In addition, mitochondrial dynamics and mitophagy are an integral part of HSC maintenance. Specifically, mitochondrial dynamics (e.g., fusion, fission, and motility) together determine mitochondrial morphology and are conducive to mitochondrial quality control and cellular stress response, while mitophagy can sweep away impaired mitochondria and contribute to the normal function of HSCs. Red arrows represent mitochondrial-related processes, while blue arrows stand for secondary effects. b Assembly of NOX isoforms. The NOX2 complex is composed of cytosolic subunits (p47 phox , p40 phox , and p67 phox ), a small GTPase Rac1/2, and membrane subunits (gp91 phox , and p22 phox ). NOX1 is constituted of the NOX1 catalytic subunit (a homolog of gp91 phox ), NOXO1 (a homolog of p47 phox ), NOXA1 (a homolog of p67 phox ), and Rac1 subunit. The structure of NOX3 is similar to NOX1/2. However, NOX4 constitutes membrane subunits p22 phox , and poldip2 is significantly different from other NOXs. NOX5 boasts a special N-terminal domain that harbors four Ca 2+ binding sites and an EF-hand domain. The DUOX1/2 has a unique N-terminal domain and EF hand-type Ca 2+ -binding pockets. The activation of NOX1-3 needs cytosolic subunits, while NOX4 requires p22 phox and poldip2. Ca 2+ that binds to the EF-hand domains is demanded in the activation of NOX5 and DUOX1/2

To maintain redox homeostasis within the mitochondria, superoxide radicals in the cytosol, mitochondrial matrix, or intermembrane space are rapidly biotransformed to H 2 O 2 in the presence of SODs. As noted above, H 2 O 2 decomposes to form OH ⋅ via the Fenton reaction, and the elimination of OH ⋅ is regulated by catalase and peroxidase in the Trx and GSH antioxidant systems. Approximately 90% of intracellular ROS are produced by mitochondrial metabolism; mROS and related signaling pathways are integral participants in a diverse array of processes, including senescence, apoptosis, tumorigenesis, and development [ 69 ]. Previous studies have reported the critical role of mitochondria and ROS in self-renewal [ 70 , 71 ], differentiation [ 72 ], fate [ 73 ], and function [ 74 ].

NADPH oxidase (NOX) family proteins

NOX are multi-subunit protein complexes that belong to the NOX family. The classical NOX structure is composed of two membrane catalytic subunits (gp91 phox referred to as NOX2 and p22 phox ), three cytosolic proteins (p47 phox , p40 phox , and p67 phox ), and the G-protein Rac [ 75 ]. Seven NOX isoforms have been identified, including NOX2 and its homologs (NOX1, NOX3, NOX4, and NOX5), dual oxidase 1 (DUOX1), and dual oxidase 2 (DUOX2) [ 76 ]. The NOX family was initially discovered in the phagocytic membrane, and NOX2 was the first identified member of this family. NOXs are important for mature phagocytes to exterminate pathogens and regulate immune defense and inflammation [ 77 ]. Professional phagocytic cells (neutrophils, eosinophils, monocytes, and macrophages) can use superoxide-produced NOXs as part of the antimicrobial mechanisms to derive large amounts of ROS [ 75 ]. The NOX family is one of the major endogenous enzymes that can induce the cellular production of O ⋅ − 2 and H 2 O 2 by transferring electrons from the cytosolic donor NADPH to the acceptor O 2 [ 75 ]. They are ubiquitously present in virtually all organs, tissues, and cells, and are closely linked to cellular proliferation and differentiation, aging, apoptosis, and even the pathological mechanisms of many diseases.

The subcellular localization of NOXs is significantly different, which is conducive to local ROS production and cellular signal transduction. For instance, NOX1, NOX2, NOX3, DUOX1, and DUOX2 are mainly found in the plasma membrane (PM); NOX5 is distributed in the endoplasmic reticulum (ER); and NOX4 is observed in the PM, ER, and nucleus (N) [ 18 ]. In addition, there are marked distinctions in the tissue distribution of the NOX family proteins: the colon boasts the most abundant expression of NOX1, and NOX2 is primarily expressed in mature phagocytes; concurrently, the most abundant tissues of NOX3, NOX4, NOX5, and DUOX proteins are the inner ear, kidney, spleen and testis, and thyroid, respectively (Table 1 ) [ 78 , 79 ].

Some NOXs (NOX1–4) require association with the transmembrane subunit p22 phox to ensure correct posttranslational modification, membrane targeting, long-term stability, and enzymatic activity; however, the structures and regulatory mechanisms of the seven enzymes greatly vary (Fig. 3 b). NOX1 activation, which leads to the reduction of O 2 to superoxide, is completed by forming a complex with NADPH oxidase activator 1 (NOXA1), NADPH oxidase organizer 1 (NOXO1), and Rac1 GTPase [ 80 ]. The activation of NOX2 is regulated by a set of complex protein–protein interactions (p22 phox , p47 phox , p67 phox , p40 phox , and Rac), as previously reported [ 81 ]. Intriguingly, both the cytosolic subunits (p47 phox and p67 phox ) and activators (NOXA1 and NOXO1) can mediate NOX3 activation and are required for the p22 phox subunit in NOX3 activation and superoxide formation [ 82 ]. It is distinct from other NOXs. NOX4 with compositional activity does not require cytoplasmic subunits to function, and it merely hinges on the p22 phox protein for ROS production. Studies have shown that NOX5 activation is mediated by the intracellular Ca 2+ concentration, as it boasts a special N-terminal domain that contains Ca 2+ -binding pockets that prompt NOX5 activation by extra elongation factor (EF)-hand motifs [ 75 , 83 ]. Similar to NOX5, DUOX1/2 protein activation is dependent on Ca 2+ because their structures have additional N-terminal domains with peroxidase activity and intracellular EF hand-type Ca 2+ binding sites [ 84 ]. Additionally, dual oxidase maturation factors play a paramount role in the posttranslational modification and membrane targeting of DUOX1/2 [ 78 ]. Although each member of the NOX family produces ROS, distinct types of ROS are generated. NOX1, NOX2, NOX3, and NOX5 mainly produce highly reactive O ⋅ − 2 and NOX4, whereas DUOX1/2 enzymes principally generate H 2 O 2 (Table 1 ).

The NOX family has attracted considerable attention because of its involvement in the pathogenesis and progression of numerous diseases, including various neoplasias. In particular, the redox signaling molecule H 2 O 2 , which originates from the NOXs, plays a critical role in hematopoiesis [ 85 ] and hematopoietic growth factor signaling [ 86 ]. Hole et al. [ 87 ] reported that the constitutive activation of NOXs caused the generation of extracellular ROS to be significantly augmented in more than 60% of patients with AML and that the increased ROS prompted the proliferation of AML cells, as well as normal CD34 + cells, to a lesser extent. Demircan et al. [ 88 ] analyzed the important role of the NOX family member NOX4 in AML using human AML cells and mouse models. They revealed that the proliferation ability and cell competition were reduced in fms-like receptor tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive human AML cells upon inhibition of the enzymatic activity of NOX4 and p22 phox . In contrast, an augmented myeloproliferative phenotype was observed in the FLT3-ITD-triggered knock-in mouse model after the deliberate deletion of NOX4. Meanwhile, NOX4 inactivation leads to increased HSC numbers, and the reconstitution ability decreases slightly in normal hematopoietic stem and progenitor cells (HSPCs).

Metabolic pathways

Specific metabolic pathways or enzyme activities are associated with cellular ROS generation, including polyamine metabolism, purine catabolism, activities of xanthine oxidoreductase (XOR), myeloperoxidase (MPO), and cytochrome P450 (CYP) monooxygenase enzymes. Mounting evidence strongly indicates that tumors contain higher levels of polyamines and amine oxidases (AOs) than normal tissues; using primary amines as electron donors, AOs can catalyze polyamines to form aldehydes, ammonia, and H 2 O 2 in response to cellular signals and stress [ 89 ]. XOR is a rate-limiting enzyme that converts hypoxanthine to xanthine and xanthine to uric acid [ 90 ]. Two interconvertible forms of XOR are possible: mammalian XOR, which is constitutively a nicotinamide adenine dinucleotide (NAD + )-dependent xanthine dehydrogenase, can be transformed to xanthine oxidase (XO) either reversibly by the oxidation of two cysteine residues or irreversibly by proteolysis [ 91 ]. XO catalyzes the reduction of O 2 to generate O ⋅ − 2 and H 2 O 2 by transferring monovalent and divalent electrons [ 92 ]. Previous studies have illustrated that XO can be activated by inflammatory stimuli or stem cell growth factors and is essential for the maintenance of mammalian target of rapamycin (mTOR)-dependent translational regulation in human myeloid cells [ 93 ]. Moreover, XOR-derived ROS can induce OS and enhance the interactions between leukocytes and endothelial cells by increasing phagocytic adhesion [ 92 ].

MPO is a heme peroxidase that mainly exists in primary azurophilic granules, whereas very small amounts of MPO are found in monocytes and certain macrophage subpopulations. MPO can catalyze chlorides to form hypochlorous acids that participate in other types of ROS production, including OH ⋅ and NO 2 Cl [ 10 ]. Notably, a recent study has reported that the expression level of MPO strongly interferes with the sensitivity of AML cells to cytarabine and plays a pivotal role in maintaining mitochondrial metabolism and redox homeostasis [ 15 ]. The measurement of neutrophil MPO expression in peripheral blood can effectively exclude patients with suspected MDS [ 94 ]. In addition, CYPs, which are part of the electron transport chain in the ER, are capable of inducing ROS generation upon breakdown or uncoupling of the P450 catalytic cycle [ 95 ]. As one of the primary sources of ROS, CYPs play a significant role in the oxidative metabolism of several endogenous and exogenous compounds [ 96 ].

Functions of ROS in the hematological niche

Basics of the hematological niche.

In the bone marrow (BM), HSCs and progenitor cells dwell within the so-called hemopoietic niche, which is defined as cellular and molecular microenvironments that ensure hematopoietic homeostasis, maintenance and regulation of HSC functions, control of their normal growth, self-renewal proliferation and differentiation, and migration through the collaboration of cellular mechanisms. Typically, the hematological niche is divided into two distinct compartments, viz. the osteoblastic marrow compartment and the vascular marrow compartment, which are essential for hematopoiesis [ 97 ]. On the basis of transgenic mouse models, various BM stromal, nonhematopoietic and hematopoietic cell types, niche factors, and their receptors have been implicated in the regulation of intricate hemopoietic niche activity (Fig. 4 a) [ 98 , 99 ].

a Cellular and molecular components of the HSC niche. The activity of HSC is regulated by various nonhematopoietic and hematopoietic cell types and niche regulatory factors. The target map shows how BM niche cells are indirectly or directly implicated in the regulation of HSCs through the synthesis of niche factors in the form of cell-bounding or secretory molecules. The color of radial spokes represents the affected HSC activity. Molecules with asterisks stand for involvement in BM regeneration after ablation. The bold molecules indicate molecules for which functional data were obtained via cell-specific genetic evidence. b The adult bone marrow HSC niche in homeostasis. Multiple cell types and niche regulatory factors are implicated in the regulation of HSC activity in a direct or indirect manner. Vasculature and associated stromal cells, including periarteriolar Nes -GFP high cells, NG2 + cells, and MYH11 + cells, as well as perisinusoidal Nes -GFP low cells, CAR cells, and LEPR + cells, are the essential regulators for HSC maintenance. The sympathetic nervous system nerves are involved in the mobilization of HSC, adipocytes perhaps negatively impact HSC maintenance, and nonmyelinating Schwann cells may lead to HSC quiescence. Osteoblasts not only take part in HSC regulation but also may play a prominent role in lymphoid progenitor regulation. Macrophages, neutrophils, T reg cells, megakaryocytes, and other hematopoietic cells are the progeny that differentiate from HSC. In addition, platelet-biased Vwf -GFP + HSCs are distributed in and regulated by separate BM niches containing megakaryocytes, while myeloid-biased Vwf -GFP – HSCs are localized in and regulated by separate BM niches containing arterioles. c The relationship between ROS levels and HSCs destiny. Maintenance of low ROS levels is associated with hypoxic conditions and some regulators, such as HIF1, COX2, PGE2, CXCR4, and CXCL12. Raised ROS could drive HSCs out of the quiescent state and differentiation into short-term repopulating cells, and further differentiation into myeloid cells (e.g., erythrocytes, leukocytes, neutrophils, basophils, eosinophils, monocytes, lymphocytes, and platelets). However, excessive ROS levels can prompt the exhaustion of HSCs and then apoptosis/ferroptosis

Mature blood cells originate from a population of pluripotent HSCs that are mostly quiescent while sporadically dividing and self-renewing to sustain the stem cell pool and ensure continued blood cell replenishment [ 58 , 100 ]. The growth of HSCs can be divided into two phases: quiescent (cell cycle in the G0 phase) and activated (cell cycle in the G1–G2–S–M phase). Notably, during cell cycle progression triggered by elevated intracellular ROS levels, activated HSCs can not only choose to proliferate and differentiate to form multilineage blood cells but also reenter a quiescent state. The anatomical location of endogenous HSCs is mainly adjacent to sinusoidal blood vessels and away from arterioles after activation and proliferation [ 101 , 102 ], whereas quiescent HSCs are located in proximity to megakaryocytes and osteoblastic cell compartments [ 103 , 104 ]. The distribution of HSCs in hematological niches may not be random and is likely affected by the anfractuous cellular and molecular microenvironments in the BM. It is becoming increasingly apparent that a variety of BM stromal cells, HSCs’ progeny, and other cell types are involved in the regulation of HSC activity. Endothelial cells, perivascular mesenchymal stromal cells (MSCs), adipose cells, and macrophages can produce stem cell factor, CXC-chemokine ligand 12 cytokines, and other regulatory factors that promote HSC self-renewal and are required for HSC maintenance [ 105 , 106 , 107 , 108 ]. Crosstalk between nonhematopoietic and hematopoietic cell types and niche regulatory factors ensures optimal growth of HSCs (Fig. 4 b) [ 109 ].

Fate of ROS and HSCs

In addition to the various cell types and regulatory factors in the BM niche microenvironment, intracellular ROS are also implicated in the regulation of HSC activity. Several studies have elucidated the prominence of ROS management in HSC functions, including hematopoiesis, self-renewal, proliferation, differentiation, maturation, migration, and chronological aging. Specifically, HSCs are extremely sensitive to the intracellular redox state; thus, maintaining extremely low cellular ROS levels and NOX expression levels is essential for HSCs to maintain quiescence [ 110 ]. Evidence suggests that quiescent, proliferative, and differentiated stem cells boast distinct amounts of intracellular ROS owing to their different metabolism. Low ROS levels, which are regulated by both endogenous and exogenous factors, are required for the maintenance of stem cell self-renewal, migration, and development, and the cell cycle state [ 111 , 112 ]. However, increased ROS seemingly drive HSCs out of quiescence and trigger HSC differentiation, reducing their capacity for self-renewal, disrupting the balance between self-renewal and differentiation, and exhausting the HSC pool if not remedied, which, in turn, may promote the onset of certain types of disease [ 71 , 97 , 113 , 114 ]. Therefore, intracellular ROS levels may determine the fate of stem cells (Fig. 4 c).

Regulation of hematopoietic homeostasis

Numerous scientific studies have shown that abnormal differentiation and self-renewal of HSC can cause certain types of diseases. For example, MDS or leukemia results from insufficient differentiation or uncontrolled self-renewal of HSC, whereas excessive differentiation or insufficient self-renewal can contribute to the depletion of the HSC pool [ 99 ]. To maintain hematopoietic homeostasis throughout the life cycle, the differentiation, self-renewal, and aging of HSCs must be regulated. The forkhead box O (FOXO) family of transcription factors (especially FOXO3), which serve as crucial regulators of ROS levels in cellular antioxidative defense systems, is essential for maintaining the HSC pool [ 115 , 116 , 117 ]. Yalcin et al. [ 118 ] studied FOXO3(−/−) mice and demonstrated that FOXO3 regulation of HSC occurs mostly by regulating the redox state of HSC, in which the loss of FOXO3 leads to elevated ROS accumulation and myeloproliferative syndrome that can be partially rescued by antioxidant therapy. Furthermore, FOXO3 loss in HSCs reduced the competitive repopulation ability and induced exhaustion of the HSC pool in an in vitro model [ 115 ]. Importantly, previous studies have shown that FOXO3 is involved in the regulation of mitochondrial metabolism in HSCs [ 119 , 120 , 121 ]. These findings indicate that FOXO3(−/−) HSCs can cause fragmented mitochondria, increased mitochondrial content, mitochondrial membrane potential (MMP), and glycolysis, but reduced OXPHOS and ATP; the mitochondrial defects of HSC (rather than increased ROS levels) are associated with the long-term competitive repopulation activity of HSCs. Additionally, these studies also singled out the possibility that enhanced activity of glycolysis may have a bearing on exit from quiescence and HSC activation in at least some contexts [ 119 ], although the majority of literature has revealed that normal HSCs reside in a low-oxygen niche environment and their energy demands are highly dependent on the glycolytic pathway [ 122 , 123 , 124 ].

In addition to FOXO3 , several other genes participate in the regulation of mitochondrial metabolism and affect the function and fate of HSCs. Maryanovich et al. [ 125 ] demonstrated that the ataxia–telangiectasia mutated (ATM)-mediated BH3 interacting domain death agonist (BID) pathway plays a critical role in the self-renewal and quiescence maintenance of HSCs by regulating OS. Loss of BID phosphorylation results in HSC escape from the quiescent phase, HSC pool depletion, and a significant reduction in HSC reproductive potential. In parallel, they found that the mitochondrial carrier homologue 2 (MTCH2), downstream of BID, negatively regulates mitochondrial OXPHOS and is indispensable for HSC homeostasis. Loss of MTCH2 enhances the mitochondrial size and OXPHOS, increases ATP and ROS levels, and triggers HSPC cycle entry [ 126 ]. Tai-Nagara et al. [ 127 ] demonstrated that mortalin and DJ-1 act synergistically and are imperative for HSCs to maintain normal physiological ROS concentrations and HSC numbers. Furthermore, a study on the tuberous sclerosis complex (TSC)/mTOR signaling pathway showed that HSCs with TSC1 deletion escaped quiescence and mitochondrial biogenesis, as well as a marked reduction in hematopoiesis and self-renewal capability [ 128 ]. TSC1(−/−) activates mTOR signaling in response to ROS generation in HSC. These findings indicate that mitochondrial metabolism and intracellular ROS levels are important regulators of HSC function and must be precisely regulated.

Pathophysiology of MDS

Classification of mds.

MDS is a hematological neoplasm with limited treatment strategies, being characterized by clonal propagation of HSCs, recurrent genetic abnormalities, myelodysplasia, ineffective hematopoiesis, abnormalities in the peripheral blood, and a high intrinsic risk of progression to AML [ 129 , 130 ]. Patients with MDS have been stratified into five risk groups according to the revised International Prognostic Scoring System (IPSS-R), including IPSS-R very low, low, intermediate (up to 3.5 IPSS-R score points), high, and very high risk, with distinct clinic outcomes in terms of survival and AML evolution [ 131 ]. Recently, the World Health Organization and the International Consensus Classification have updated the latest classification of MDS, which is in favor of more holistic risk-stratification schemes (e.g., IPSS-R). Notably, the new classification divides MDS entities into those with well-defined genetic abnormalities and those with morphological definitions, and places more emphasis on defining MDS typing from a genetic perspective than the previous version of risk-based typing (Table 2 ) [ 132 , 133 ].

Molecular pathogenesis of MDS

MDS develops from the growth and spread of a clone with somatic mutations of hematopoietic cells and generally evolves into AML (Fig. 5 ) [ 129 ]. The selection advantage of clones is conferred by somatic genetic lesions described as driver mutations [ 134 ], and the initial mutation takes place in HSCs with self-renewal capability. Meanwhile, additional mutations that pertain to clonal progression may also occur in progenitor cells, thereby bestowing the ability to self-renew [ 135 ]. Some mutation driver genes that belong to distinct biological pathways can contribute to myelodysplastic neoplasm, and the majority of patients with MDS exhibit combinations of pathway mutations, which is responsible for the heterogeneity of MDS [ 136 , 137 , 138 , 139 ].

Occurrence and manifestations of myelodysplastic hematopoiesis. MDS develops from the growth and propagation of a clone with somatic mutations of hematopoietic cells and generally evolves into AML. The characteristics and clinical manifestations vary in different phases. First, an initial mutation occurs in HSC, and additional mutations that pertain to clonal progression occur in progenitor or precursor cells, collectively forming a local clone. Next, as time elapses, mutant stem cells migrate and dwell within other BM regions (e.g., sternum, femur, and ilium) through peripheral blood to form local clones, and the condition is defined as the clonal hematopoiesis of indeterminate potential (CHIP) phase when hematopoietic cells harboring somatic mutations represent a minimum of 4% of all BM cells (corresponding to a minimum of 2% of the mutation allelic frequency). Subsequently, clonal hematopoiesis gradually increases and ultimately becomes the predominant cell population in the BM, which is called MDS or clonal cytopenia of undetermined significance (CCUS). The abnormal hematopoiesis caused by clonal dominance is frequently linked to additional somatic mutations. Ultimately, the emergence of additional driver mutations acquirement or preexisting mutations results in the selection and leukemic transformation of subclones of hematopoietic cells (highlighted in pale pink) with progressively damaged capacity for differentiation

Pathophysiology of MDS with isolated del(5q)

MDS with isolated del(5q) is caused by the deletion of the DNA region in the long arm of chromosome 5. This genetic lesion is the initial driver mutation that results in the haploinsufficiency of several genes, which subsequently drives clinical symptoms. Typically, ribosomal protein S14 (RPS14) and casein kinase 1 alpha 1 (CSNK1A1) are associated with the dysplasia of erythrocytes, and RPS14 haploinsufficiency contributes to macrocytic anemia in mutant erythroblasts [ 140 ]. CSNK1A1 haploinsufficiency is capable of endowing del(5q)-heterozygous stem cells with clonal growth superiority and then expansion [ 141 ], which is responsible for the efficiency and high clinical remission rate of lenalidomide in MDS with isolated del(5q) [ 142 ].

Mutation driver genes

In MDS patients, there are numerous mutation driver genes, which, through diverse mechanisms, lead to clonal outgrowth, myeloproliferation, and propagation of myelodysplastic hematopoiesis (Fig. 5 ). Only ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3 alpha (DNMT3A), RUNX family transcription factor 1 (RUNX1), splicing factor 3b subunit 1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and tet methylcytosine dioxygenase 2 (TET2) exhibit mutations in a minimum of 10% patients [ 138 , 139 , 143 ]. The most frequently mutated genes in MDS, TET2, and DNMT3A are essential for the differentiation of HSCs [ 144 ]. The heterozygous inactivation of TET2 augments self-renewal and damage differentiation, resulting in clonal growth of mutant stem cells and myeloproliferation [ 145 ]. DNMT3A ablation in the hematopoietic system leads to myeloid transformation, affecting stem cell self-renewal, myeloid differentiation, tissue tropism, and restricting progenitor expansion [ 146 ].

Abnormality of RNA splicing and aberrant gene transcripts

According to recent studies, SF3B1 mutation has been identified as a unique subtype of MDS that encompasses more than 90% of MDS cases with ineffective erythropoiesis, and at least 5% ring sideroblasts [ 147 , 148 ]. In proven cases, specific mutations or comutations and the amount and type of mutations mostly tend to be unfavorable to the prognosis of MDS patients, with certain exceptions where SF3B1 mutation confers a superior outcome and prolonged survival [ 148 , 149 , 150 ]. In hematopoietic cells, roughly half of the splicing events are performed by spliceosomes containing a mutant SF3B1 splicing factor, which alters the recognition of RNA branch points and renders the preferred usage of cryptic 3′ splice sites, finally causing aberrant transcripts of several genes or in-frame isoform production (Fig. 6 a) [ 151 , 152 , 153 ]. The situation involves erythroferrone (ERFE): variant ERFE protein is conducive to increased iron absorption or parenchymal iron loading [ 153 ]. Furthermore, mutation driver genes SRSF2, U2 small nuclear RNA auxiliary factor 1 (U2AF1), and the epigenetic regulator isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) are recurrently mutated in numerous myeloid neoplasms and are associated with unfavorable clinical prognosis [ 154 , 155 , 156 , 157 , 158 , 159 ]. Compared with spliceosome gene SF3B1 mutations, SRSF2 and U2AF1 mutations result in different splicing abnormalities, mainly alterations in exon usage [ 151 , 152 , 160 ]. Their mutation is concerned with augmented R-loop formation, which results in genomic instability and is always associated with combinatorial mutation patterns [ 152 , 161 ], such as the comutation of SRSF2 (P95H)–IDH2 (R140Q) found in MDS and AML [ 138 , 162 , 163 ]. Collectively, the interaction between abnormality RNA splicing and epigenetic regulation control drives the malignant advancement of MDS or AML (Fig. 6 b).

a Role of abnormality of RNA splicing in the pathogenesis of SF3B1-mutated MDS. In hematopoietic cells, normal spliceosomes implement roughly half of the splicing events, while the other half is performed by spliceosomes containing a mutant SF3B1 splicing factor, which alters the recognition of RNA branch points and renders the preferred usage of cryptic 3′ splice sites located 10–30 base pairs farther upstream of canonical sites, finally causing aberrant transcripts of several genes or in-frame isoforms production. However, just small quantities of abnormal transcripts are detectable in SF3B1-mutated myelodysplastic cells owing to the bulk of abnormal transcripts’ rapid degradation through nonsense-mediated decay, which is primarily caused by the inserted nucleotide sequence containing a premature termination codon. b Synergistic interaction of aberrant splicing and epigenetic dysregulation in MDS. Mutation of SRSF2 renders the preference alteration of the neomorphic splicing factor to specific exonic splicing enhancer motifs, in turn causing alternative exon usage. Aberrant transcripts with a premature stop codon will be generated in the process, with rapid degradation through nonsense-mediated decay or the production of mutated proteins, resulting in different pathological outcomes. Mutation of IDH2 (R140Q) gives rise to the activation of the neomorphic enzyme and, in turn, DNA hypermethylation, which sabotages epigenetic regulators’ function and drives the malignant advancement of the disease

ROS in the pathophysiology of MDS

Substantial literature supports that ROS play a paramount role in the occurrence of numerous diseases, as they take part in the regulation of essentially all aspects of cellular function (gene or protein expression, cellular growth, proliferation and differentiation, and epigenetic modifications) [ 9 ]. More recently, enhanced ROS levels have been observed in a wide variety of pathological states, such as neurodegenerative, autoimmune, cardiovascular, and metabolic diseases [ 21 , 28 , 164 , 165 ], atherosclerosis [ 166 , 167 ], cataracts [ 168 ], Fanconi anemia (FA), and hematological malignancies such as MDS, and AML. Notably, patients with FA frequently develop MDS or AML. In this subsection, we focus on the role of ROS in MDS development.

Generation of ROS in MDS

Pioneering studies have found that the presence of oxidized pyrimidine nucleotides in the CD34 + cells of patients with MDS and the oxidized pyrimidines were closely related to increased plasma tumor necrosis factor-α and low concentration of GSH in BM mononuclear cells [ 169 ]. It is currently clear that the oxidized purine and pyrimidine nucleotides (DNA oxidative damage) are ubiquitously present in the BM CD34 + cells of patients with MDS when compared with controls [ 170 ], and enhanced ROS levels and oxidative damage markers are also commonly detected. Furthermore, increased activity of several antioxidant enzymes and reduced GSH levels have been observed in patients with MDS [ 56 , 171 ]. These observations suggest that these patients were under OS.

A plethora of studies suggest that inflammation and the inflammasome, pyroptosis, ferroptosis, mitophagy, and even necroptosis are inextricably linked with ROS generation and affect the pathophysiology of MDS [ 172 , 173 , 174 ]. It is becoming more widely recognized that inflammation is a characteristic of MDS, and previous studies have confirmed that activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is redox dependent as well as a hallmark of patients with MDS, which causes clonal expansion and pyroptosis upon activation [ 175 , 176 ]. Specifically, there is excessive protein content of alarmin S100A9 in MDS HSPCs and BM plasma, and S100A9 is capable of triggering pyroptosis through the activation of NOX, augmenting ROS levels, and the activation of NLRP3 and β-catenin. Meanwhile, knockdown of or pharmacologically inhibiting NLRP3, neutralizing S100A9, can alleviate pyroptosis, ROS accumulation, and nuclear β-catenin in MDS, rendering restoration of colony-forming capacity and efficient hematopoiesis [ 176 ]. Cluzeau et al. [ 177 ] reported that S100A9 directly inhibits the elaboration of erythropoietin and the endocrine response to anemia, while neutralization or suppression of S100A9 could reverse the processes and thus erythropoiesis enhancement in patients with low-risk MDS (LR-MDS). Ji et al. [ 178 ] showed that pathologic levels of tumor necrosis factor-alpha and interleukin 6 suppressed erythroid colony formation and drive ineffective erythropoiesis via ROS-induced caspase-3 activation and apoptosis in a double knockout of mDia1 and mir-146a mouse model (mimicking del(5q) MDS). Emerging data indicate that decitabine treatment causes ROS to augment, GSH depletion, GPX4 reduction, and subsequently ferroptosis and necroptosis in MDS cells, and these results are also confirmed in iron overload (IOL) MDS mouse models [ 179 ]. Ferroptosis or necroptosis induced by decitabine can be abrogated by ferroptosis or necroptosis inhibitors. Crucially, iron chelators also enhanced the effects of decitabine, indicating that ROS is an essential regulator of treatment outcomes.

Mitophagy is an evolutionarily conserved intracellular process that obviates dysfunctional mitochondria to avoid their accumulation and is eminent in tumorigenesis and treatment [ 180 ]. Caspase-dependent apoptosis, ROS-induced mitophagy/autophagy, and accumulation of DNA and mitochondrial damage have been well demonstrated in MDS [ 181 , 182 ]. Studies indicate that mice manifest loss of HSC functions, myeloproliferation, augmented mitochondria and ROS in the HSPC compartment, and elevated DNA impairment when conditionally deleting autophagy related 7 (Atg7) in the hematopoietic system, indicating that Atg7 is a crucial modulator of HSC maintenance [ 183 , 184 ]. Additionally, Jiang et al. [ 185 ] observed that impairment in NIX-mediated mitophagy is linked to the accumulation of ROS and damaged mitochondria in BM nucleated RBC of MDS patients. Experiments in MDS mouse models showed elevated ROS levels caused by dysregulated mitochondrial dynamics. To be specific, Aoyagi et al. [ 186 ] reported that substantial dynamin-related protein 1 (DRP1)-dependent mitochondrial fragmentation in HSPCs results in excessive ROS generation, inducing inflammatory signaling activation and ineffective hematopoiesis, which can be attenuated via DRP1 inhibition. Deactivation of DRP1 in mitochondria can contribute to loss of regenerative potential of HSCs while maintaining their quiescent state [ 187 ]. In addition, mitochondrial DNA mutations that are tightly entangled with poor ETC function and increased ROS levels are commonly detected in MDS. The importance of necroptosis in the pathogenesis of MDS has been emphasized. Montalban Bravo et al. [ 174 ] reported that receptor interacting serine/threonine kinase 1 (RIPK1, a member of the necroptosis complex component) is highly expressed and associated with poor survival outcomes in MDS patients. Zinkel’s group also presented similar results that necroptosis (predominantly RIPK1 expression) is upregulated in MDS patients compared with control participants [ 188 ]. In summary, ROS and OS are capable of inducing cell death (e.g., apoptosis, ferroptosis, pyroptosis, necroptosis, and autophagy) and have been implicated in the pathogenesis and progression of MDS.

Inevitable IOL and iron chelation therapy (ICT)

Anemia-related symptoms, such as fatigue, resulting from hematopoietic dysplasia or pancytopenia, commonly occur in most patients with low-risk MDS and lead to red blood cell (RBC) transfusion dependence [ 189 , 190 , 191 ], which subsequently results in IOL [ 192 ]. IOL is deleterious to cells and can catalyze H 2 O 2 to easily decompose into highly reactive OH ⋅ by the Fenton chemistry reaction and are involved in the OS of patients with MDS. Importantly, the accumulation of iron and ROS within BM CD34 + cells may contribute to genetic and chromosomal abnormalities, which, in turn, accelerate blast proliferation and prompt MDS transformation into AML [ 192 ]. Therefore, it is not surprising that IOL is considered the primary cause of OS in patients with MDS [ 17 , 193 ]. In addition, IOL is closely associated with the survival outcome of patients with MDS, which negatively affects organ function and clinical survival time [ 191 , 194 ]. ICT is effective and feasible for the management of patients with MDS and can restore iron balance and improve organ function and survival to near-normal levels, particularly in patients with LR-MDS who are IOL [ 194 , 195 , 196 ].

The TELESTO trial found that, compared with placebo, IOL patients with low- to intermediate-1-risk MDS show longer event-free survival without differences in overall survival upon ICT (deferasirox dispersible tablets) [ 197 ]. Leitch et al. reported that patients with transfusion-dependent LR-MDS had significantly longer median overall survival time after receiving ICT from the onset of transfusion dependence compared with those who did not [ 198 ], and the survival advantage persisted even after conducting a matched pair analysis that accounted for age, frailty, comorbidities, and R-IPSS [ 199 ]. Recent studies of 2200 patients with MDS, of whom 224 received ICT, also confirmed that ICT can ameliorate the overall survival and hematopoiesis of transfused patients with LR-MDS. ICT’s benefits for MDS patients vary depending on the circumstances, and National Comprehensive Cancer Network (NCCN) guidelines recommend its usage when ferritin levels surpass 2500 ng/mL [ 200 ].

Is targeting ROS for MDS therapy feasible?

Possible clinical implications of ros activity in the hemopoietic system.

Hematological malignancies resulting from abnormalities in the hematopoietic system are highly correlated with altered ROS levels. Specifically, ROS are involved in crucial aspects of hematopoiesis, including clonal evolution, hematological improvement, and hematopoietic cell transplantation engraftment. MDS is a well-known clonal disease characterized by elevated genetic instability [ 136 ]. In an expanded clone, the continuous acquisition of mutations can first result in a myelodysplastic phenotype and then in a leukemic phenotype through additional mutations [ 201 , 202 ]. In patients with MDS, IOL can lead to the disruption of ROS homeostasis and genomic instability of pre-leukemia clones, which may be one of the possible reasons for clonal evolution to AML. However, ICT is capable of improving hematopoietic insufficiency in MDS and slowing the progression to AML [ 192 , 193 , 203 ]. In terms of ROS in hematological improvement, studies have revealed that IOL significantly increases ROS levels in HSPCs, reduces the immature hematopoietic cell ratio, and blunts their clonogenic capacity [ 204 , 205 ]. IOL also increases ROS levels in MSCs of patients with high-risk MDS (HR-MDS) and triggers oxidative injury through the activation of Wnt/β-catenin signaling pathways [ 206 ]. Notably, the above effects can be rescued by the administration of iron chelators or antioxidants [ 206 , 207 ], implying that ROS activity may represent a potential target for therapy. Overall, there is plentiful evidence that excessive free iron adversely affects the hematopoietic microenvironment, resulting in ROS accumulation and affecting the expression of genes that regulate and disrupt hematopoiesis [ 208 ]. In addition, several major studies have elucidated the correlation between ROS activity and hematopoietic impairment (Table 3 ).

Is there a case for targeting ROS in MDS?

Considering the continued interest in redox chemotherapeutics in recent years [ 209 , 210 ] and the extensive impact of ROS on MDS pathophysiology and progression, ROS may represent a novel potential therapeutic target for MDS. As discussed above, malignant cells frequently harbor higher ROS levels than their normal counterparts. Increased ROS production leads to hyperactivation of ROS signaling pathways, exhaustion of antioxidant defenses, and nonspecific oxidative damage to biomolecules, particularly DNA and proteins [ 37 ]. Therefore, two approaches (prooxidant and antioxidant) can be used to manipulate ROS in malignant cells to achieve therapeutic effects. In this section, we discuss the application of prooxidant and antioxidant approaches in MDS treatment (Fig. 7 ).

Manipulating ROS levels in MDS cells for therapeutic effects. Schematic representation of prooxidant and antioxidant treatment as a therapy for MDS. The effects of prooxidant treatment are augmented ROS generation, exhausting antioxidant defenses, subsequent unavoidable contributions to oxidative stress, lipid peroxidation, DNA damage, and oxidation of proteins that contain redox-sensitive residues. Moreover, enhanced ROS levels may be conducive to cell cycle progression in some situations, and also promote DNA mutation, which may cause malignant cells to resist apoptosis. However, the application of antioxidants acts against excessive ROS and reduces ROS signaling, oxidative stress, and proliferative drive. In addition, antioxidant treatment could reduce cell cycle progression, and protect nonmalignant cells from oxidative injury, especially when used in combination with chemotherapy

The prooxidant approach

The prooxidant approach refers to the amplification of existing oxidative stress and the disruption of redox homeostasis through the administration of prooxidants, which can cause catastrophic oxidative injury and malignant cell death. For many years, cytotoxic drugs have been the mainstay of treatment for hematological malignancies, including MDS and AML. For instance, azacitidine (AZA), which acts as a pyrimidine nucleoside analog of cytidine, disrupts the synthesis of DNA, mRNA, and proteins [ 211 ]. Various mechanisms underlie the antineoplastic effects of AZA, such as cytotoxic effects on abnormal hematopoietic cells in the BM, alteration of the cellular redox status, and hypomethylation of DNA [ 212 , 213 ]. Interestingly, conflicting data exist regarding the effects of AZA on ROS production. A recent study suggested that AZA treatment increases oxidative stress (decreased GSH levels, elevated GSSG·GSH −1 ratio in the erythrocyte, and increased lipid peroxidation) in patients with MDS [ 214 ]. Klobuch [ 215 ] and colleagues showed that low-dose AZA combined with PPARγ agonist pioglitazone and all- trans retinoic acid stimulates ROS production and triggers phenotypical and functional differentiation of primary AML blasts into neutrophil-like cells. However, in a case report, Hasunuma et al. [ 216 ] observed decreased ROS levels in peripheral white blood cells and reduced dacron-reactive oxygen metabolites (d-ROMs) in the serum of patients with MDS following AZA treatment. The authors concluded that AZA therapy can ameliorate hematopoiesis and weaken ROS and d-ROM generation.

Decitabine (also known as 5-aza-2-deoxcytidine, DAC) is a commonly used drug with Food and Drug Administration (FDA) approval for the treatment of patients with MDS and AML [ 217 ]. DAC induces ROS accumulation, cell cycle blockage, and apoptosis in leukemic cells [ 218 , 219 , 220 ]. DAC promotes the expression of different NADPH oxidase isoforms and increases the protein expression level of NOX4 in an ATM-dependent manner [ 221 ]. Studies conducted by Wang et al. [ 222 ] revealed that DAC treatment leads to ROS production, cell growth arrest, MMP reduction, and apoptosis in MSCs derived from patients with MDS. Some chemical compounds with prooxidant properties are effective against MDS and leukemic cell lines. A prototype example is the application of arsenic trioxide (ATO) and all- trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) treatment [ 223 ]. The major effect of ATO is the induction of ROS accumulation, which alters cellular redox homeostasis by triggering electron leakage, irreversibly inhibiting thioredoxin reductase, and depleting PRX III [ 224 ]. Research has indicated that ATO augments ROS production via Trx inhibition and NOX activation, displaying encouraging results in treatment of relapsed APL [ 225 , 226 ]. In vitro results from Huang et al. [ 227 ] suggested that DAC combined with ATO can induce MDS cell line apoptosis via elevated ROS-related ER stress. Another in vitro study indicated that ATRA blocked the activation of Nrf2 by activating the RARα–Nrf2 complex, rendering ROS accumulation and ROS-dependent cytotoxicity in MDS and AML cells when combined with DAC [ 228 ]. Other studies have demonstrated that several drugs can induce MDS cell death by altering cellular ROS levels (Table 4 ).

The key role of antioxidants, particularly GSH and Trx, in all cells is to respond to oxidative stress and buffer excess ROS. Thus, inhibition of intracellular antioxidants is sufficient to subvert cellular redox homeostasis and kill tumor cells. Notably, many antioxidant molecules are upregulated in tumor cells, which can influence the therapeutic efficacy and augment drug resistance [ 49 ]. Taken together, introducing exogenous ROS or prompting their generation in MDS cells using drugs or chemotherapy may be attractive approaches for MDS treatment.

The antioxidant approach

The antioxidant approach aims to scavenge high physiological levels of ROS in some types of cancer using antioxidant molecules. The basic rationale behind this approach is that enhanced ROS accumulation facilitates carcinogenesis and tumorigenesis by inducing gene mutations, increasing genetic instability, and activating prooncogenic signaling [ 8 , 229 , 230 ]. High ROS levels caused by high-glucose conditions can promote the proliferation of pancreatic carcinoma cells [ 231 ]. However, there is still a dispute regarding the therapeutic effect of the antioxidant approach in cancer treatment. Some studies have argued that antioxidants protect not only healthy cells but also tumor cells to avoid or reduce oxidative damage, thereby contributing to the effectiveness of chemotherapy being seriously reduced. However, the endorsers believe that antioxidant therapy may counteract chemotherapy-related cytotoxicity, augment treatment response rates, and prolong patient survival. Indeed, several studies have supported antioxidant therapy as a viable option that reduces the toxicity of chemotherapy by damaging malignant cells and does not interfere with chemotherapy when the antioxidant is used concomitantly with chemotherapy [ 232 , 233 ]. Therefore, it is conceivable to harness an antitumor antioxidant approach with chemotherapy, although the effect of antioxidant therapy in reducing ROS levels has not been widely accepted [ 234 , 235 ].

Deferasirox (DFX), an iron-chelating drug, is commonly used to treat IOL in patients with LR-MDS [ 236 ]. It directly removes labile iron, reduces oxidative stress, improves hematopoiesis, and delays leukemic transformation [ 237 , 238 , 239 ]. In addition to this, several exogenous sources of natural or synthetic antioxidants have demonstrated therapeutic potential for tumor treatment. Zhang et al. [ 240 ] reported that the antioxidant azelaic acid can reduce ROS levels, elevate the total antioxidant capacity of AML cells, and exhibit antileukemic effects. In leukemic cells, the natural compound ascorbic acid (also referred to as vitamin C) has antiproliferative and proapoptotic activities [ 241 ], which have also been observed for other antioxidants [ 242 , 243 ]. Studies conducted by Jin et al. [ 244 ] showed that compound Kushen injection (CKI) decreased ROS levels, inhibited proliferation, and promoted apoptosis in AML cells. They also found that the expression of PRX I and PRX II was upregulated, while that of Trx1 was downregulated upon CKI administration. Meanwhile, the hematological parameters of patients with low- to intermediate-risk MDS can be improved by amifostine [ 245 , 246 ]. Notably, antioxidants combined with specific chemotherapeutic agents result in positive benefits and improved patient survival. Previous research has illustrated improved complete remission and prolonged overall survival in patients with AML when vitamin C was administered in combination with DCA [ 247 ]. Interestingly, GSH, vitamins, and N-acetylcysteine appear to be the most common dietary antioxidants used in cancer treatment when combined with chemotherapy/radiotherapy [ 232 , 248 ].

Collectively, oxidative stress caused by chemotherapy/radiotherapy not only leads to malignant tumor apoptosis but also augments genomic instability, which in turn accelerates disease progression. In particular, MDS and AML are associated with the escalation of oxidative stress [ 97 , 249 ]. Therefore, an antioxidant approach may be conducive to relaxing DNA impairment and slowing disease progression to a certain extent, and complementary effects may exist between chemotherapy and antioxidants.

Other therapeutic approaches for MDS

With the heterogeneous nature of MDS comes a need for complex and personalized treatment strategies, and the current treatment therapeutic approaches are based on risk-adapted therapy (by IPSS-R) (Fig. 8 ). Treatment for patients with LR-MDS (IPSS-R score ≤ 3.5) aims to decrease transfusion requirements, improve living quality and survival, and prevent AML transformation. In the case of patients with HR-MDS, therapy aims to prolong survival.

Proposed therapeutic algorithm for patients with MDS

Treatment options for LR-MDS patients

There are several agents for treating LR-MDS patients, including erythropoiesis-stimulating agents (ESAs), immunosuppressive agents, lenalidomide, hypomethylating agents (HMAs), luspatercept, azanucleosides, imetelstat, thrombomimetic agents, canakinumab, as well as allogeneic stem cell transplantation (AlloSCT).

Treatment with ESAs is common practice in patients with anemia and LR-MDS. Results from Platzbecker and colleagues showed a notable increase in erythropoiesis responses and a decrease in transfusion incidence in weeks 5–24 of darbepoetin alfa treatment compared with placebo in patients with LR-MDS, without differences among the groups in terms of the occurrence of thromboembolic events, and transformation to AML [ 250 ]. Notably, for eligible MDS patients with or having lost response to ESA, adding the granulocyte colony-stimulating factor can improve response rates [ 251 ]. A recognized characteristic of MDS is immune dysregulation, which results in ineffective hematopoiesis and accelerates disease progress [ 252 ]. Immune-modulating agent therapy may be therapeutically beneficial for patients with immune dysregulation. An immense amount of clinical trials have delved into immunosuppressive therapy using anti-thymocyte globulin alone or in combination with cyclosporine, displaying trilineage response rates between 16% and 67% [ 253 ], and immunosuppressive therapy with alemtuzumab (anti-CD52 antibody) exhibits significant activity and a high response rate in MDS patients [ 254 ]. Canakinumab, an interleukin 1 beta (IL-1β) inhibitor, has been explored in patients with LR-MDS. An ex vivo study revealed that the IL-1β-neutralizing antibody canakinumab markedly enhanced the colony-forming activity of HSPCs when cocultured with BM monocytes from SF3B1-mutated LR-MDS [ 255 ]. Results from phase II clinical trials confirmed that canakinumab is safe and effectively targets IL-1β signaling, and yielded durable response in LR-MDS patients with single somatic driver mutation in TET2 or DNMT3A [ 256 , 257 ]. Meanwhile, a multi-institution, open-label, phase 1b/2 clinical trial (NCT04798339) is being carried out to evaluate the toxicity and efficacy of canakinumab in combination with darbepoetin alfa in patients with LR-MDS who have failed prior treatment with an ESA; results are expected in 2024.

Although conventional or reduced-dose HMAs exhibit some activity in patients with LR-MDS, the limited activity and transient response of HMAs following the failure of ESAs as first-line therapy means they are seldom used [ 258 ]. Data show that CC-486 (an oral form of azacitidine) has a significant impact on RBC transfusion requirements and platelet responses, yet CC-486 treatment did not improve overall survival [ 259 , 260 ]. Importantly, there is currently no approval for the use of CC-486 in MDS, and oral HMAs may play a part in patients with LR-MDS in the future. Lenalidomide is considered the recommended therapy for patients with LR-MDS, anemia, good platelet count, and isolated del(5q). Results from a phase III study showed that nearly a third of lenalidomide-treated patients achieve RBC transfusion independence at greater than or equal to 8 weeks, with 8.2 months of median response duration in LR-MDS patients with non-del(5q) who are RBC transfusion dependent and ineligible for or refractory to ESAs [ 261 ]. Lenalidomide is capable of elevating the erythroid response rate when combined with ESA in LR-MDS patients with ESA resistance [ 262 ]. Notably, in patients with TP53-mutated del(5q) MDS, the response rate to lenalidomide is negatively impacted by TP53 mutation [ 263 , 264 ].

Luspatercept was approved for patients with LR-MDS by the US FDA in 2020; it can regulate the TGF-beta signaling to ameliorate erythropoiesis and promote late-stage erythroid maturation, and exhibits protracted clinical efficacy [ 265 , 266 ]. Recently, the COMMANDS trial, aimed at a comparative analysis of the effectiveness and safety of luspatercept and epoetin alfa in managing patients with LR-MDS, showed that luspatercept outperformed epoetin alfa in improving hemoglobin levels and attaining RBC transfusion independence (TI) in ESA-naïve patients with LR-MDS [ 267 ]. Nevertheless, these results require long-term follow-up and additional data to confirm. Several studies have evaluated the safety and effectiveness of thrombopoietin agonists for treating patients with LR-MDS. Data from these studies show an impressive rise in platelet responses and lower bleeding event episodes in eltrombopag (thrombopoietin agonist) treated patients when compared with the placebo group, but without significant difference in terms of leukemic transformation [ 268 ]. However, more data are needed to support these results. The telomerase inhibitor imetelstat also shows clinical efficacy for patients with LR-MDS. Clinical trials (NCT02598661) observed a significantly durable TI rate in transfusion-dependent patients with LR-MDS after imetelstat treatment, and patients with heavy transfusion and ineligible for or refractory to ESAs can also achieve durable TI and clinical benefit [ 269 , 270 ].

AlloSCT is currently the only potentially curative therapy for patients with MDS [ 271 ]. AlloSCT is not recommended for patients with less advanced disease because a good prognosis is achievable with standard care alone, and the potential favorable survival impact of AlloSCT cannot outweigh the early expected high mortality risk [ 272 ]. Patients who received multiple treatments (e.g., lenalidomide, HMAs, luspatercept, azanucleosides, imetelstat, etc.) should be considered for transplantation and clinical trials.

Treatment options for HR-MDS patients

Treatment options for patients with HR-MDS are relatively scarce (Fig. 8 ), and for the bulk of patients for whom intensive chemotherapy is not appropriate, azanucleosides (AZA and DAC) remain the most commonly prescribed medication. Although DAC is approved for MDS treatment in the USA, patients do not benefit from it in terms of survival based on clinical data, and the optimal dosage and treatment schedule of DAC remain uncertain [ 273 , 274 , 275 ]. Oral DAC/cedazuridine treatment has proven to be a safe and effective substitute for intravenous DAC for patients with MDS, as shown in a phase III clinical trial (NCT03306264) [ 276 ]. AZA has been studied in patients with HR-MDS. The registration trial (AZA-001) found that patients who received azacitidine showed a notable improvement in survival time compared with those who received standard of care, including intensive chemotherapy (24.5 months compared with 15 months) [ 277 ]. The progression of MDS to AML transformation was notably delayed, and the need for RBC transfusions and infection rates were also considerably ameliorated. As mentioned, oral azacitidine (CC-486) significantly affects platelet responses and the need for RBC transfusions, and treatment with CC-486 did not increase overall survival. CC-486 was proposed for maintenance therapy after AlloSCT in patients with HR-MDS [ 278 ]. In addition, AlloSCT therapy has been discussed above and will not be revisited in this subsection.

Conclusions and future perspectives

Despite advancements made in the field of medicine, MDS remains an intractable problem that imposes a high disease burden on patients. The heterogeneous nature of MDS necessitates sophisticated and personalized therapeutic strategies, and allogeneic hematopoietic stem cell transplantation remains the only potentially curative therapy for MDS among various approaches [ 236 ]. Therefore, the identification of novel therapeutic targets is of paramount importance.

ROS have been implicated in metabolic regulation, stress responses, and redox signaling. As ROS accumulation and oxidative damage are strongly associated with various pathologies, including MDS and several forms of myeloid leukemia, interest in ROS research has continued to grow in recent years. The observation of increased ROS and OS in MDS, especially in patients with LR-MDS, suggests that ROS may be an attractive therapeutic target and that ROS modulation therapy could be a useful approach for MDS treatment. Indeed, the prooxidant approach is the preferred choice for clinical first-line treatment because chemotherapy triggers malignant tumor regression and apoptosis by elevating ROS levels and OS. Furthermore, antioxidant approaches can augment the cytotoxicity of chemotherapy and protect nonmalignant cells from oxidative damage. Finally, identifying the source and species of ROS produced by MDS and targeting control-specific ROS-mediated signaling pathways by designing redox drugs may be viable strategies for the management of MDS in the future. This review highlights ROS production, which may play a pivotal role in the pathogenesis and treatment response of MDS.

Availability of data and materials

Not applicable.

Abbreviations

Singlet oxygen

Alpha lipoic acid

Allogeneic stem cell transplantation

Acute myeloid leukemia

Amine oxidases

Acute promyelocytic leukemia

ASXL transcriptional regulator 1

Autophagy related 7

Ataxia-telangiectasia mutated

Arsenic trioxide

All- trans retinoic acid

Azacitidine

B‑cell lymphoma 2 associated X protein

B‑cell lymphoma 2

BH3 interacting domain death agonist

Bone marrow

Bone marrow nucleated cells

CXCL12-abundant reticular

CCR4-NOT transcription complex subunit 1

Compound Kushen injection

Chronic myeloid leukemia

Coenzyme Q10

Mitochondrially encoded cytochrome C oxidase II

Casein kinase 1 alpha 1

CXC-chemokine ligand 12

CXC chemokine ligand 4

CXC-chemokine ligand 4

C-X-C motif chemokine receptor 4

Cytochrome P450

Cytochrome P450 2D6

Cytochrome P450 2E1

Cytochrome P450 3A4

Cytochrome P450 4A11

Duffy antigen receptor for chemokines

Deferasirox

DNA methyltransferase 3 alpha

Dacron-reactive oxygen metabolites

Dynamin-related protein 1

Dual oxidase 1/2

Elongation factor

Endoplasmic reticulum

Erythroferrone

Erythropoiesis-stimulating agents

Electron transport chain

Extracellular space

Fanconi anemia

Fibroblast growth factor 1

Fms-like receptor tyrosine kinase 3-internal tandem duplication

Forkhead box O

Glycoprotein 130

Glutathione peroxidase

Glutathione

Oxidized glutathione

Hydrogen peroxide

Hypoxia-inducible factor 1

Hypomethylating agents

Heme oxygenase 1

Hypobromous acid

Hypochlorous acid

Human pluripotent stem cells.

High-risk myelodysplastic syndromes

Hematopoietic stem cells

Hematopoietic stem and progenitor cells

Iron chelation therapy

Isocitrate dehydrogenase 1/2

Interleukin 1 beta

Interleukin-7/10

Iron overload

Revised international prognostic scoring system

Leptin receptor

Low-risk myelodysplastic syndromes

Myelodysplastic syndromes

Mitochondrial membrane potential

Myeloperoxidase

Mitochondrial ROS

Mesenchymal stromal cells

Mitochondrial electron transport chain

Mitochondrial carrier homologue 2

Mammalian target of rapamycin

Myosin heavy chain 11

N-acetylcysteine

Nicotinamide adenine dinucleotide

Nicotinamide adenine dinucleotide phosphate

Nuclear factor of activated T cells

Nuclear factor κB

Neural-glial antigen 2

NUP98-HOXD13

NLR family pyrin domain containing 3

Nitric oxide

NADPH oxidase

NADPH oxidase 1–5

NADPH oxidase activator 1

NADPH oxidase organizer 1

Nuclear factor erythroid-2 related factor 2

Superoxide anion radicals

Hydroxyl radicals

Peroxynitrite anion

Osteopontin

Oxidative stress

Oncostatin M

Oxidative phosphorylation

Prostaglandin E2

Plasma membrane

Peroxiredoxin

Hydrocarbon radicals

Retinoic acid receptor alpha

Red blood cell

Hydrocarbons

Receptor interacting serine/threonine kinase 1

Reactive nitrogen species

Alkoxyl radicals

Peroxyl radicals

Organic hydroperoxides

Reactive oxygen species

Ribosomal protein S14

RUNX family transcription factor 1

Stem cell factor

Splicing factor 3b subunit 1

Sympathetic nervous system

Superoxide dismutase

Serine and arginine rich splicing factor 2

Tricarboxylic acid

Thio-deoxycytidine

Tet methylcytosine dioxygenase 2

Transforming growth factor-β

Transfusion independence

Tumor necrosis factor

Regulatory T cells

Thioredoxin

Tuberous sclerosis complex

U2 small nuclear RNA auxiliary factor 1

Vascular cell adhesion molecule 1

Von Willebrand factor

Xanthine oxidase

Xanthine oxidoreductase

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This research was supported by the Zhejiang Provincial Natural Science Foundation of China (nos. LBY23H080004 and LBY23H080005), the National Natural Science Foundation of China (nos. 82102938 and 82202429), and the Medical and Health Science and Technology Project of Zhejiang Province (no. 2022KY455).

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Qiangan Jing, Chaoting Zhou, and Junyu Zhang contributed equally to this work.

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Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China

Qiangan Jing, Chaoting Zhou, Ping Zhang, Yunyi Wu, Junyu Zhou & Jing Du

HEALTH BioMed Research & Development Center, Health BioMed Co., Ltd, Ningbo, 315803, Zhejiang, China

Qiangan Jing

Department of Hematology, Lishui Central Hospital, Lishui, 323000, Zhejiang, China

Junyu Zhang

Department of Central Laboratory, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, China

Xiangmin Tong, Yanchun Li & Ying Wang

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Ying Wang, Jing Du, and Yanchun Li conceived the manuscript. Junyu Zhang and Xiangmin Tong revised the final manuscript. Ping Zhang, Yunyi Wu, and Junyu Zhou performed the critical literature review. Qiangan Jing and Chaoting Zhou wrote the final manuscript. All authors read and approved the final manuscript.

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Correspondence to Yanchun Li , Jing Du or Ying Wang .

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Jing, Q., Zhou, C., Zhang, J. et al. Role of reactive oxygen species in myelodysplastic syndromes. Cell Mol Biol Lett 29 , 53 (2024). https://doi.org/10.1186/s11658-024-00570-0

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Published: 08 November 2023

Policies to prevent zoonotic spillover: a systematic scoping review of evaluative evidence

Chloe Clifford Astbury 1 , 2 , 3 ,
Kirsten M. Lee 1 , 2 ,
Ryan Mcleod 1 ,
Raphael Aguiar 2 ,
Asma Atique 1 ,
Marilen Balolong 4 ,
Janielle Clarke 1 ,
Anastassia Demeshko 1 ,
Ronald Labonté 5 ,
Arne Ruckert 5 ,
Priyanka Sibal 6 ,
Kathleen Chelsea Togño 4 ,
A. M. Viens 1 , 3 ,
Mary Wiktorowicz 1 , 2 ,
Marc K. Yambayamba 7 ,
Amy Yau 8 &
Tarra L. Penney 1 , 2 , 3

Globalization and Health volume 19 , Article number: 82 ( 2023 ) Cite this article

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Emerging infectious diseases of zoonotic origin present a critical threat to global population health. As accelerating globalisation makes epidemics and pandemics more difficult to contain, there is a need for effective preventive interventions that reduce the risk of zoonotic spillover events. Public policies can play a key role in preventing spillover events. The aim of this review is to identify and describe evaluations of public policies that target the determinants of zoonotic spillover. Our approach is informed by a One Health perspective, acknowledging the inter-connectedness of human, animal and environmental health.

In this systematic scoping review, we searched Medline, SCOPUS, Web of Science and Global Health in May 2021 using search terms combining animal health and the animal-human interface, public policy, prevention and zoonoses. We screened titles and abstracts, extracted data and reported our process in line with PRISMA-ScR guidelines. We also searched relevant organisations’ websites for evaluations published in the grey literature. All evaluations of public policies aiming to prevent zoonotic spillover events were eligible for inclusion. We summarised key data from each study, mapping policies along the spillover pathway.

Our review found 95 publications evaluating 111 policies. We identified 27 unique policy options including habitat protection; trade regulations; border control and quarantine procedures; farm and market biosecurity measures; public information campaigns; and vaccination programmes, as well as multi-component programmes. These were implemented by many sectors, highlighting the cross-sectoral nature of zoonotic spillover prevention. Reports emphasised the importance of surveillance data in both guiding prevention efforts and enabling policy evaluation, as well as the importance of industry and private sector actors in implementing many of these policies. Thoughtful engagement with stakeholders ranging from subsistence hunters and farmers to industrial animal agriculture operations is key for policy success in this area.

This review outlines the state of the evaluative evidence around policies to prevent zoonotic spillover in order to guide policy decision-making and focus research efforts. Since we found that most of the existing policy evaluations target ‘downstream’ determinants, additional research could focus on evaluating policies targeting ‘upstream’ determinants of zoonotic spillover, such as land use change, and policies impacting infection intensity and pathogen shedding in animal populations, such as those targeting animal welfare.

The increasing incidence of zoonotic emerging infectious diseases (EIDs) has been attributed to behavioural practices and ecological and socioeconomic change, and is predicted to continue in the coming years [ 1 ]. Higher levels of anthropogenic activity, including agricultural intensification, urbanisation and other forms of land use change, have led to increased interactions between wildlife, humans and livestock, increasing the risk of cross-species transmission [ 2 , 3 , 4 ]. Meanwhile, accelerating rates of globalisation and urbanisation, leading to increased global movement of people and goods and more dense human settlements, have made outbreaks of disease in human populations more difficult to contain [ 5 ]. In response, a call has been issued by leading organisations and experts, including the United Nations Environment Programme, the International Livestock Research Institute and the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, to complement reactive policy responses with policies that prevent zoonotic EIDs [ 1 , 6 , 7 , 8 , 9 , 10 ]. This approach, sometimes called deep prevention, would need to target upstream drivers to reduce the risk of outbreaks occuring [ 11 ].

Zoonotic spillover, defined as the transmission of a pathogen from an animal to a human, depends on the alignment of ecological, epidemiological and behavioural factors [ 12 ]. Zoonotic pathogens must be transmitted across a spillover pathway (Fig. 1 ) in order to induce infections in humans [ 12 , 13 ]. This involves meeting a series of conditions including appropriate density and distribution of reservoir hosts, pathogen prevalence, infection intensity and human exposure [ 12 ]. Across this pathway, a number of drivers of zoonotic spillover have been identified, including changes in wildlife and livestock populations [ 14 ]; deforestation, urbanisation and other forms of land use change [ 15 , 16 ]; bushmeat consumption [ 17 , 18 , 19 ]; and a variety of human practices including hunting, farming, animal husbandry, mining, keeping of exotic pets and trade [ 8 , 9 , 20 , 21 , 22 ]. These large-scale changes have repeatedly given rise to spillover events [ 2 , 15 , 23 ], sometimes involving pathogens with epidemic or pandemic potential [ 24 ].

Spillover pathway adapted from Plowright et al. [ 12 , 13 ]

The responsibility for addressing zoonotic disease frequently spans multiple sectors of governance due to its relevance for both animals and humans. A One Health perspective, which recognises the health of humans, animals and the environment as being closely linked and inter-dependent [ 25 ], can be useful in understanding the spillover pathway and drivers of spillover events, as well as informing policy and governance approaches to address this cross-sectoral problem. At the international level, the World Health Organization, the Food and Agriculture Organization, the World Organisation for Animal Health and the United Nations Environment Programme have endorsed a One Health approach to policymaking to respond to zoonotic infectious diseases, emphasising collaboration between agencies [ 26 ].

Operationalising a One Health approach to policy

While One Health is a promising approach to preventing zoonotic EIDs, operationalising this concept remains a challenge. Evaluative evidence exists around the effectiveness of interventions to prevent spillover events [ 13 , 27 , 28 , 29 ], however these have often been implemented as short- to medium-term programmes or academic investigations [ 8 ]. In some cases, zoonoses have re-emerged after successful programmes have ended [ 29 ]. As a result, experts have argued for the incorporation of successful interventions into policy frameworks, providing interventions with the sustainability required for long-term disease control [ 8 , 10 ].

Operationalising a One Health approach to policy involves understanding the policy options, identifying the stakeholders involved and developing insights into how to successfully implement and evaluate these policies. Although the longevity and scope of government actions may make policy an effective vehicle for prevention of emerging diseases, implementing policy is a complex process involving numerous actors with competing views and interests [ 30 ]. This context presents challenges for policy development and implementation. Where relevant policies are designed and implemented in isolation, opportunities for co-benefits may be missed and interventions may produce unintended consequences [ 31 ]. Finally, while evaluative evidence is key to informing future policy decisions, the complex systems in which policies are often implemented make evaluation challenging [ 32 ].

Aims and scope

To provide insights around how to use policy to successfully prevent zoonotic spillover events, it is necessary to synthesise the available evaluative evidence. A One Health perspective allows this evidence synthesis to incorporate a wide range of policy instruments and actors and to identify approaches to successfully implementing and evaluating policies in this complex, multi-sectoral context.

Approaches to managing epidemic and pandemic infectious pathogens when they have entered human populations have been systematically catalogued in the medical literature [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. These measures include hand washing, face masks, school closures, contact tracing, vaccination and case isolation. Further upstream, systematic reviews of interventions targeting the spillover pathway have predominantly focused on programmes rather than policies, and have been restricted by various characteristics such as geographic region [ 28 ] or pathogen type [ 29 ], or focused on programmes with an explicit endorsement of a One Health approach [ 27 ]. In consequence, a comprehensive understanding of what policies to prevent zoonotic spillover have been evaluated, what actors are involved, and how to successfully implement and evaluate them, is lacking. To address these research gaps, our objective was to synthesise the existing evaluative evidence around policies that target the determinants of zoonotic spillover.

Our approach to identifying and analysing this literature was informed by a One Health perspective, acknowledging the inter-connectedness of human, animal and environmental health.

We conducted a systematic scoping review of evaluations of policies aimed at preventing zoonotic spillover events, based on a previously published protocol [ 40 ]. Results are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews [ 41 ]. The scoping review was conducted in line with guidelines published by Arksey and O’Malley and refined by Levac and colleagues [ 42 , 43 , 44 ], which emphasise an iterative approach suited to an exploratory research question.

The One Health perspective guided the development of the review methodology. This included the search strategy and inclusion criteria, which allow for the inclusion of policies focused on human, animal or environmental health (or any combination of these areas) and with leadership from one or more of these sectors, and the research questions, which seek to outline the policies and the range of sectors involved in implementation. While our focus on the spillover pathway meant we only included policies that had been evaluated in terms of their impacts on animal and human population distributions, health and interactions, we explicitly searched for environment-focused policies (e.g., protection of wetlands and other wildlife habitats) that might have been evaluated from this perspective. We also aimed to interrogate the One Health approach to governance, by assessing to what extent cross-sectoral collaboration – a key tenet of One Health practice [ 25 ] – emerged as a reason for policy success.

Stage 1: identifying the research question

Informed by our research objective, our research questions were:

What policies aimed at preventing zoonotic spillover (i.e., policies that target the determinants of zoonotic spillover included in the spillover pathway [ 12 ]: population distribution, health and interactions) have been evaluated?

What are the types of policies?

Which policy actors (single department, multi-sectoral, whole of government) are involved?

What are the reasons for policy success and failure, and the unintended consequences of implementing these policies?

How has evaluation of these policies been approached in the literature?

What are the methods or study designs used?

What are the outcomes?

What are the opportunities and challenges for evaluation?

Stage 2: identifying relevant studies

We systematically searched four electronic databases (Medline, Scopus, Web of Science, Global Health) in May 2021. The search strategy was organized by the main concepts in our research question: the spillover pathway; public policy; prevention; and zoonotic pathogens. The search strategy was developed iteratively, informed by existing systematic reviews focused on related concepts [ 28 , 45 , 46 , 47 , 48 , 49 ] and known indicator papers meeting inclusion criteria. We also searched the websites of 18 organisations involved in the prevention of zoonotic spillover to identify relevant grey literature. The choice of organisations was informed by an actor mapping exercise in which we identified key international organisations working on the prevention of emerging zoonoses using network sampling [ 50 ]. We searched the websites of a subset of these organisations, focusing on inter-governmental organisations and organisations whose main focus was zoonotic disease. See Supplementary File 1 for details of academic database and grey literature search strategies.

Stage 3: study selection

Studies were included if they met the following criteria:

Primary empirical study with an English-language abstract from any country or region (reviews were excluded);

Study reporting empirical findings from an evaluation of any sort; and.

Study focused on a policy implemented by government that targets the determinants of zoonotic spillover.

Academic records identified through the searches were collated and double screened using the online platform Covidence [ 51 ]. Two researchers (CCA and KML) initially screened titles and abstracts. Title and abstract screening of an initial set of 100 papers was undertaken by both researchers independently. Results were compared to ensure consistency in decisions around study eligibility, and discrepancies were resolved through consensus. This process was repeated until an acceptable level of agreement (> 90%) was reached. The remaining papers were then screened by one of the two reviewers. Full-text screening was undertaken by two independent researchers and discrepancies were resolved by consensus. Studies with full-texts in any language were eligible for inclusion if they include an English-language abstract. Full-text studies published in French, Spanish or Chinese were single-screened by a member of the research team fluent in that language (CCA or AY). Studies published in other languages were translated as necessary.

Grey literature was screened by one researcher (CCA) to determine whether it met the inclusion criteria. Publications were initially screened by looking at titles, tables of contents and executive summaries. Where these indicated that the publication might be eligible, documents were read in full to determine if inclusion criteria were met.

In line with published guidelines, the approach to study selection was refined iteratively when reviewing articles for inclusion [ 42 , 43 , 44 ].

Stage 4: charting the data

Data charting was conducted using a form designed to identify the information required to answer the research question and sub-research questions (see Supplementary File 2). Data charting focused on characteristics of the study, the policy, and the evaluation. For each policy, this included identifying which determinant of zoonotic spillover situated along the spillover pathway was being targeted. For the purpose of this study, we used a model of the spillover pathway adapted from Plowright et al.’s work [ 12 , 13 ], in which we differentiated between wildlife and domesticated animals (Fig. 1 ). This differentiation is important in the policy context, as the wildlife-domesticated animal interface is an important site for intervention, as well as the human-animal interface.

The data charting form was piloted with ten records to ensure that it was consistent with the research question, and revised iteratively [ 42 , 43 , 44 ]. Data charting was conducted by one researcher (CCA, RM, JC, AD or PS) and checked by a second researcher (CCA or KML). Discrepancies were resolved by consensus.

Stage 5: collating, summarising and reporting the results

Our protocol stated that we would use the Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project [ 52 ] to assess study quality [ 40 ]. However, on reviewing the included studies we selected two tools that were more appropriate to their characteristics: (1) ROBINS-I [ 53 ] for quantitative outcome evaluations and (2) a tool developed by the authors of a previous review [ 54 ] – based on Dixon-Woods et al.’s approach to assessing study credibility and contribution [ 55 ] – for all other study types. Two researchers (CCA and KML) assessed study quality independently for an initial set of 10 studies, before comparing assessments and reaching agreement where discrepancies occurred. This process was repeated until an adequate level of agreement was reached (> 90%). The remaining studies were assessed by a single researcher (CCA or KML). Records were not excluded based on quality assessment. Instead, assessments were primarily used to help synthesize the literature on how policies were evaluated. Quality assessment was not performed on grey literature due to the wide variability in the format and comprehensiveness of included publications.

We analysed the charted data, presenting a numerical summary of the included studies in table form, allowing us to describe the range of policy interventions that have been evaluated, aspects of policy implementation and approaches to evaluation. Based on the charted data, we inductively grouped evaluated policies with similar characteristics into policy types and assigned a policy instrument to each policy type: communication/marketing, guidelines, fiscal, regulation, legislation, environmental/social planning or service provision. We mapped policy types onto the spillover pathway shown in Fig. 1 to outline the policies that have been used to target each of these determinants. Thematic analysis was conducted using the approach described by Braun and Clarke where the focus is guided by the researcher’s analytic interests [ 56 ], with five overarching themes chosen as an a priori coding framework: (1) reasons for policy success; (2) reasons for policy failure; (3) unintended consequences of policy implementation; (4) opportunities for policy evaluation; and (5) challenges for policy evaluation. We selected these themes based on our research questions and previous familiarisation with the included articles during the process of article selection, data extraction and quality assessment. Sub-themes were subsequently identified through close reading and coding of the included articles. Thematic analysis was conducted by one researcher (RM) using the qualitative data analysis software Dedoose [ 57 ] and reviewed by the lead author (CCA).

Study characteristics

After removing duplicates, our searches identified a total of 5064 academic records. After screening titles and abstracts, we considered 330 records for full-text review. We also identified 11 relevant publications through our grey literature search. Grey literature reports were published by five organisations: four organisations focused on health and disease, including an intergovernmental organisation (the World Organisation for Animal Health) and three non-governmental organisations (the One Health Commission, the Global Alliance for Rabies Control and EcoHealth Alliance); and one non-governmental organisation focused on wildlife trade (TRAFFIC). In total, we included 95 publications in this review (PRISMA diagram in Fig. 2 ) [ 58 ].

We excluded studies which assessed the unintended consequences of policies to prevent zoonotic spillover without evaluating their effectiveness. This included studies that looked exclusively at the mental health impacts of mandatory livestock culls on farm workers [ 59 ]; studies which focused on potentially relevant factors, such as the wildlife trade, but with no consideration of outcomes situated on the spillover pathway [ 60 ]; and studies which assessed the detection power of surveillance systems without assessing the impact of associated policy interventions [ 61 , 62 , 63 ].

Policy characteristics

The characteristics of the policies evaluated in the included studies are presented in Supplementary File 3 and summarised in Table 1 . Some studies evaluated more than one policy, particularly modelling studies which compared the impacts of several policy options and process evaluations focused on a range of activities undertaken by a single government. Therefore, the number of evaluated policies (n = 111) is greater than the number of included studies (n = 95).

Most policies were evaluated for their impact on human exposure (21%), pathogen prevalence in domesticated animals (18%), barriers within domesticated animals (15%), and pathogen survival and spread in domesticated animals (9%). There were also a number of multi-component policies studies across multiple stages of the spillover pathway (18%). Fewer studies focused on wildlife health and populations, and none of the included studies evaluated policies for their impact on infection intensity and pathogen release in either domesticated animals or wildlife.

Where the government department responsible for implementing a policy was identified in the paper, most policies were implemented by a single department (35%), although there were a number of multi-sectoral efforts (24%). The range of government sectors responsible for implementing policies to prevent zoonotic spillover included human health, animal health, food safety, agriculture, conservation, national parks, forestry, fisheries, environmental protection, border control and foreign affairs. Policies were predominantly intended to be implemented by private sector actors, including individuals and organisations working in trade, retail, hunting and animal agriculture. However, some policies were also implemented by public sector actors working in public health, veterinary public health and environmental conservation.

Most policies were situated in high-income (49%) and upper middle-income (28%) countries, with studies from East Asia and the Pacific (43%) and Europe and Central Asia (19%) dominating. Publications focused on policies targeting various zoonotic diseases, with the most common being avian influenza (50%), rabies (19%), brucellosis (11%) and Hendra virus (4%).

Most policies were evaluated using process (38%) or outcome (31%) evaluation. The most frequently used policy instrument was legislation (59%), particularly for managing pathogen spread in domesticated animals through measures such as mandatory vaccination, culls or disinfection protocols. Meanwhile, communication and marketing or service provision was more typically used to reduce risk in wildlife and human populations, for example by providing guidance around recommended hygiene protocol, by distributing oral vaccination in wildlife habitat or by offering vaccination to human populations.

PRISMA 2020 diagram [ 58 ]

What policies aimed at preventing zoonotic spillover have been evaluated?

Policy types targeted different determinants across the pathway to zoonotic spillover and used various approaches with different evidence of success (Table 2 ). We identified policy options including culling – both general and targeted – of wild and domesticated animals; habitat protection (limiting activities such as agriculture and animal husbandry in wildlife habitats); supplemental feeding to control wildlife movements; vaccination of both wildlife, domesticated animals and human populations with occupational exposure to animals; policies to improve biosecurity in sites where animals are kept, slaughtered and sold, including mandates and information campaigns; live animal market closures; and bans on hunting and selling wildlife. Where outcomes or impacts were evaluated, most policies saw some level of success (i.e., outcome measures were found to vary in a direction that indicated policy success), though relative effectiveness was not assessed due to variation in study design and outcome measure. Policies with consistent evidence of effectiveness – where outcome measures varied in a direction that indicated policy success in all studies included in the review – included culling and sterilisation of wildlife populations, habitat protection, vaccination in wildlife and domesticated animal populations and mandated disinfection protocols. Policies with equivocal evidence of success (i.e., outcome measures varied in different directions or studies had different findings, some indicating success and some indicating failure) included supplemental feeding of wildlife, pre-emptive livestock culls, live animal market closures and bans on wildlife hunting, trade and consumption. For many policies, there were no impact or outcome evaluations identified in this review.

What are the reasons for policy success?

The evidence from the identified impact and outcome evaluations suggests that most of the policies succeeded to some extent. A range of factors contributed to policy success. First, studies emphasized the importance of effective collaboration and coordination between various agencies, disciplines, and levels of government in the execution of policy directives [ 114 , 115 ], in line with a One Health approach to policy and governance. Policy success was attributed, in part, to strong working relationships that encouraged effective communication between various government agencies, and facilitated timely and appropriate policy responses [ 115 ]. Synergy between agencies responsible for surveillance and the execution of control strategies was also reported to be beneficial. For example, prompt communication and effective collaboration between laboratories testing samples and agencies implementing culls in the field was seen as important in the control of highly pathogenic avian influenza in Nigeria [ 116 ]. Similarly, authors also identified the importance of private-public relations and private sector contributions to implementing policies to prevent zoonotic spillover [ 112 ]. This included stronger government engagement with private veterinarians as a factor for success in reducing the spillover of Hendra virus in Queensland [ 109 ], and with farmers, poultry companies and national farming and poultry processing associations in Ghana as part of a successful campaign to reduce risk from highly pathogenic avian influenza [ 112 ]. Studies suggest that the inclusion of private sector stakeholders in the policy process has the potential to improve compliance through transparent dialogue around disease ecology, risk and risk mitigation [ 90 , 91 , 103 , 117 ]; and highlight the utility of participatory approaches in prompting behaviour changes [ 91 ].

Second, authors emphasised the significance of economic incentives, suggesting that policy impact is dependent on private actors’ appraisal of costs and benefits. Studies illustrated how incentives, including compensation, subsidies, rebates, and fines, have had varying degrees of success [ 91 , 97 , 112 , 115 ]. Compensation levels [ 104 , 114 ] and enforcement practices [ 92 ] were identified as salient factors for compliance and adherence. For example, fear of sanctions for bushmeat hunting while a ban was in place in some parts of West Africa were identified as a stronger incentive to avoid bushmeat hunting than the fear of contracting Ebola virus [ 97 ]. Culls were seen as particularly challenging in this regard: while the long-term benefits for farmers may outweigh the financial loss [ 104 ], authorities need to be conscientious of the substantial economic impacts when considering policies that mandate culling or safe disposal [ 95 ]. The direct losses related to compliance (time, labour and expenses) and indirect losses due to price fluctuations and decreases in trade volume, as well as losses to associated industries, are substantial [ 88 , 96 , 113 , 118 ].

Third, trust in government and public support for implemented policy were specified as critical factors influencing the effectiveness of disease control strategies, and research suggests that strategic engagement to facilitate compliance is a necessary step in the policy process [ 97 ]. Participatory approaches that attempt to identify and understand factors influencing compliance have been consistently used to overcome resistance to policy, as insights from engagement and consultation can lead to solutions that facilitate behaviour change at the population level [ 91 , 103 ]. For example, a World Health Organization initiative to reduce avian influenza transmission in poultry markets in Indonesia worked alongside market vendors to achieve its aims, carrying out repeated consultations with the vendors and implementing market infrastructure (such as energy and running water in the market) in collaboration with local authorities to support vendor behaviour change [ 91 ].

Fourth, studies also demonstrated the importance of public communication. The quality of information, as well as the volume, complexity and delivery of public health messages, were key factors [ 75 , 114 ]. Authors contend that communication strategies must understand the target audience and how they interpret and engage with messages [ 97 ], for example by building on relationships where there is exiting trust, such as between veterinarians advising animal vaccination and animal owners [ 117 ]. Homogenously delivered communication strategies were ineffectual: they limited opportunities for open discourse; discounted contradictory lived experiences and expressions of uncertainty; and ultimately contributed to scepticism surrounding implemented policies [ 97 , 117 ].

Finally, studies underscored the importance of surveillance infrastructure to inform intervention strategies. Surveillance programs with the ability to collect and operationalize relevant data were essential to the development of appropriate interventions that are responsive to each unique context [ 115 , 119 ]. Implementing effective surveillance programmes requires the appropriate evaluation tools [ 120 ] and trained personnel [ 81 ].

What are the reasons for policy failure?

Studies showed that perceptions of acceptability and appropriateness were crucial to the effectiveness of implemented policies [ 101 , 104 ]. Several factors were identified that negatively affected acceptability and appropriateness, including: additional expenses for private sector actors without sufficient support [ 75 , 100 , 104 , 112 , 114 ], particularly were culls were demanded but reimbursement for farmers was slow and inadequate, as in a brucellosis eradication campaign in Macedonia [ 81 ]; lack of affordable alternatives [ 97 ]; impracticality of implemented strategies [ 75 , 101 ]; lack of cultural understanding in designing policy interventions [ 97 , 100 ], for example the distribution of footwear to pig farmers in a Polynesian context where footwear was not traditionally worn [ 100 ]; lack of understanding of viral ecology [ 100 ]; as well as public scepticism and distrust [ 97 , 114 ].

Additionally, policy ineffectiveness was associated with poor planning and execution of intervention strategies, including lack of clear direction [ 114 ]; incomplete or inconsistent implementation of control measures (17); limited scope of intervention [ 114 ]; and poor enforcement [ 92 ]. A lack of adequate resources to implement strategies also contributed to policy failure [ 81 ]. Adequate financial resources were necessary to hire and train staff to run surveillance and control operations [ 81 ]. Financial resources were also necessary to fund compensation mechanisms that facilitate compliance. Willingness to adopt policy-prescribed disposal practices was found to be associated with compensation levels (incentives) as a proportion of production price, dependency on income from activities driving zoonotic risk, and contact with prevention staff [ 92 ].

What are the unintended consequences of implementing policies to prevent zoonotic spillover?

A small number of the included studies collected data on the unintended consequences of policies to prevent zoonotic spillover (n = 18). In some instances, unintended consequences were due to disease ecology or human behaviour as a result of policy failure. For example, a study assessing the impacts of the closure of a live poultry market found that, following the closure, vendors travelled to neighbouring markets to sell their animals [ 94 ]. As a result, while cases of avian influenza decreased in the area surrounding the closed market, cases increased in these neighbouring markets, leading to the wider geographic spread of the disease. In another study, elk were provided with supplementary feeding grounds to discourage them from coming into contact with the livestock who shared their range [ 65 ]. While this intervention had the intended consequence of reducing the transmission of brucellosis between elk and livestock, the spread of brucellosis between the elk using the supplementary feeding grounds – who were gathering in larger, tighter groups for longer periods, resulting in higher within-herd transmission – and other elk populations in the area increased. This resulted in an increasing prevalence of brucellosis among the elk, potentially increasing the risk of spillover to livestock. These examples illustrate the complexity of the social and ecological systems in which these policies are implemented, further suggesting the need for a One Health approach to policies to prevent zoonotic spillover.

A key unintended consequence can be attributed to the loss of profits and livelihoods sometimes associated with policies to prevent zoonotic spillover, as described above. The losses incurred by complying with regulations made farmers, hunters and other private sector actors reluctant to report potential infections, contributing to increased unauthorized or illegal activity, and unrestrained spread of disease [ 90 , 92 , 94 , 98 , 112 , 114 ]. Studies investigated the creative ways policy enforcement was circumvented, including hiding hunting equipment on the outskirts of towns or developing informal trade markets and networks [ 97 , 98 ]. Unintended consequences identified in the included evaluations emphasize an opportunity for policymakers to improve sector compliance through public education, levying the influence of consumer attitudes on industry standards [ 104 , 113 ].

A range of study designs were used to evaluate policies. Outcome evaluations (n = 33) used time series or repeat cross-sectional data to conduct evaluations of natural experiments, though most studies did not include a control group for comparison. Outcome evaluations also used case-control and modelling approaches to assess policy impact on an outcome of interest. Process evaluations (n = 30) used cross-sectional and qualitative approaches, as well as study designs combining multiple sources of data, to understand aspects of policy implementation such as the extent to which the policy was being implemented as designed, and the responses and attitudes of stakeholders involved in policy implementation. Economic evaluations (n = 11) included cost-benefit analyses, risk-benefit analyses and modelling studies. Formative evaluations (n = 17) used modelling approaches to estimate what the impacts of a proposed policy option would be in a specific context.

Outcome variables interpreted as indicators of policy success were also numerous and represented determinants along the spillover pathway. As expected, many studies assessed impact on disease transmission, including disease prevalence and incidence, disease eradication, case numbers, and basic reproduction number in human and animal populations, as well as evidence of disease in environmental samples, such as in live animal markets or at carcass disposal sites. Studies also assessed impacts on intermediate factors indicative of successful implementation of specific policies, such as the availability of wild species in markets where a trade ban had been implemented, or knowledge and practices of stakeholders in response to an educational or information campaign.

While most studies found a reduced risk of zoonotic spillover following policy implementation, comparing the magnitude of these impacts was challenging due to the variety of study designs and outcome measures used in the included studies. However, we identified several studies which used modelling to directly compare the impacts of policy options. These studies evaluated various policy scenarios: different combinations within multi-component policy interventions [ 121 ]; culling versus vaccinating wildlife [ 122 ] and livestock [ 84 , 85 ] populations; targeting strategies to humans exclusively versus targeting humans and livestock [ 108 ]; and altering the parameters for culling and vaccination strategies, for example by modelling different ranges for culling and vaccination near infected farms [ 85 ]. These studies often highlighted trade-offs between the effectiveness of policy measures and their cost. For example, estimates of the number of infected flocks were lower when incorporating a ring cull (cull of animals on farms surrounding an outbreak) into a multi-component control strategy for highly pathogenic avian influenza [ 121 ]. However, livestock vaccination was estimated to be a highly effective strategy, with one study findings livestock vaccination to be as or more effective than a pre-emptive cull for outbreak control purposes (depending on the extent of vaccination coverage), while minimising the number of animals culled [ 85 ]. One study jointly modelled costs and benefits of strategies, and found that livestock vaccination had a higher cost-benefit ratio than a wildlife cull [ 122 ]. A final study highlighted the potential of holistic approaches, with drug administration in humans and livestock having a lower cost per disability-adjusted life year averted than intervention in humans alone [ 108 ].

Study authors noted a number of challenges encountered while evaluating policies to prevent zoonotic spillover. One study noted the difficulty of determining the impact of policies aiming to reduce spillover events between wildlife, livestock and humans, as the number of spillover events is often relatively small [ 65 ]. This highlights the importance of considering upstream determinants and risk factors as outcome measures in attempting to evaluate these policies, particularly where spillover events may happen infrequently or not at all during the period of observation. Studying changes in risk factors for spillover can provide insight on the effectiveness of different policies in tackling spillover risk.

Lack of suitable data was a frequently cited barrier to policy evaluation. As policies to prevent zoonotic spillover are often reactive, being implemented in response to an outbreak in animal populations, accessing data from before a policy was implemented was challenging. Studies highlighted the value of routinely collected data, which was often the only data available and was frequently used for policy evaluation [ 65 , 66 , 94 , 115 , 119 , 123 ]. However, in many contexts routine data on animal health is not collected [ 80 ]. Routine testing data from livestock can sometimes be used for evaluation where it exists, but it does not always provide sufficient detail for examining the potential for a policy to prevent zoonotic spillover. For example, some tests do not differentiate between current and past infection, making it difficult to identify where and when spillover occurred [ 65 ], and animal health data may not be granular enough for policy evaluation, particularly in terms of evaluating local policies [ 94 ]. Studies also highlighted instances where the private sector may own data sets reporting disease prevalence and transmission, but may be reluctant to share the data for evaluation purposes [ 121 ]. In such instances, open communication and good relationships with the private sector may be facilitators to evaluation.

Beyond the lack of baseline data, studies highlighted the difficulty in collecting information about policy compliance. As failing to comply often puts farmers and hunters at risk of fines or imprisonment, they were reluctant to disclose information about non-compliance or participation in illegal trade and sale of animals [ 86 , 92 , 97 , 112 ]. This made it difficult to determine policy effectiveness.

Quality assessment

Of the 44 quantitative evaluations, 37 were evaluated as being at moderate or higher risk of bias (see Supplementary File 4), given the possibility of bias in the assessment of intervention impact due to the presence of confounding effects. A small number of studies were determined to be at serious (n = 6) or critical (n = 1) risk of bias, for two main reasons: only having data from after the intervention was implemented; or using a case-control study model without measuring and adjusting for important potential confounders, such as the prevalence of a targeted disease prior to policy implementation. These limitations may reflect the nature of zoonotic spillover events and policy responses, which can happen quickly and leave little time for baseline data collection. Many of the included studies relied on surveillance data, but where such data sets are not available, post-test and case-control study designs may be the only options.

The quality of studies assessed with the tool developed based on Dixon-Woods’ approach [ 55 ] was high overall (n = 41, see Supplementary file 5). Most studies were rated as high in terms of clearly and comprehensively presenting their results (n = 37), analysis (n = 34), research design (n = 33), aims (n = 32) and research process (n = 28). Most studies also had a high relevance to the research question (n = 31), indicating that the research was embedded in policy, being commissioned, co-designed or conducted in partnership with government stakeholders.

We identified a range of policies targeting different parts of the spillover pathway implemented by various policy and governance sectors, including some multi-sectoral initiatives. Policies tended to rely heavily on private sector actors (including actors ranging from small-scale farmers and hunters to larger commercial operations) for implementation, suggesting that open communication and collaboration with these actors was essential for successful policy implementation. Policy success was undermined by lack of collaboration between government agencies; lack of communication between surveillance and control operations; poor understanding of the context in which policies were implemented; and inadequate financial compensation for private sector actors who lost profits and incurred additional costs by complying with policies. Where policies were ineffective, this tended to be due to unintended consequences relating to complex dynamics within the social and ecological systems where policies were implemented. Lack of appropriate data was a key obstacle to policy evaluation, and studies emphasised the importance of robust surveillance infrastructure in evaluating policies that tended to be implemented reactively, in response to an outbreak of zoonotic disease in animal or human populations.

Implications for policy and practice

The key role that the private sector and industry actors play in implementing policies to prevent zoonotic spillover is an important consideration for policymakers. Our findings suggest that many of these policies must be complied with by farmers – from subsistence and smallholder farmers to large corporations – as well as by other actors, such as hunters. Lack of awareness as well as financial costs of compliance among these groups present key barriers to policy success in this area. This set of stakeholders is complex as some may make very marginal profits, if any, and may struggle to afford the additional costs of implementing preventive policies. However, powerful actors and profitable industries are also involved, including large-scale farms and primary resource extraction enterprises [ 22 ]. Acknowledging the differences across these stakeholder groups, and in particular assessing their capacity to bear some of the costs related to prevention, emerges as crucial in successful policy implementation.

Finally, our findings highlight the importance of disease surveillance in efforts to reduce the risk of spillover events. As well as acting as an early warning system, surveillance provides a source of data to evaluate the impact of preventive policies. We found the availability of surveillance data to be a key enabling factor in evaluating policies. In addition, close collaboration between agencies responsible for disease surveillance and control efforts was key to policy success. National surveillance efforts, as well as cross-country collaboration to support global efforts, such as the United States Agency for International Development’s PREDICT program supporting surveillance in areas at high risk for zoonotic disease outbreaks [ 124 ], must be sustained and expanded. In complex areas such as the prevention of zoonotic spillover, approaches to surveillance which encompass risk factors and transmission pathways [ 125 ], as well as One Health surveillance systems which harmonise and integrate data collection and analysis from across human, animal and environmental sectors [ 126 ], are promising approaches to developing surveillance systems that support risk. This context also involves a need to strengthen surveillance capacity in remote and rural locations, as communities living in these contexts may have exposure to numerous pathogens of wildlife origin. This will require strengthening clinical and diagnostic capacity in these settings, as well as engaging with stakeholders such as community human and animal health workers and wildlife or national park rangers [ 127 ].

Comparison with existing literature

This review sought to map the range of policies implemented to reduce the risk of zoonotic spillover, and the various approaches taken to evaluation, and identify factors behind the success and failure of policy implementation and evaluation. Due to this broad scope, comparing relative effectiveness of policy interventions was challenging. Existing systematic reviews with a more specific focus could apply meta-analysis to determine which interventions were most effective. For example, a review of market-level biosecurity measures aiming to reduce the transmission of avian influenza found that reducing market size, separating poultry species, cleaning and disinfecting premises, closing markets and banning overnight storage were highly effective interventions [ 45 ]. However, our findings suggest that studies focused on the control of avian influenza dominate the literature in this space (55 out of 111 evaluated policies), and many of these are focused on market-level measures. Systematic reviews focused on other approaches to reduce spillover risk, such as on-farm biosecurity [ 47 ]; biosecurity for backyard poultry rearing [ 46 ]; and community-based interventions [ 28 ] comment on the paucity of high-quality evidence around the impacts of such approaches. By taking a broad perspective, we hope our findings will provide policy options for consideration in a number of contexts, and guide researchers in focusing their efforts on areas where evidence is lacking.

Strengths and weaknesses of the study

To our knowledge, this is the first attempt to systematically identify and document evaluations of policies aiming to prevent the spillover of zoonotic pathogens into human populations. However, because of the complex drivers of spillover events, some potentially relevant policy evaluations may be excluded where their outcome measures are too far removed from zoonotic spillover. While relevant, such evaluations will be difficult to systematically identify as they make no reference to zoonotic disease.

In addition, this review focused on policy evaluations that have been reported in the peer-reviewed literature and the grey literature published by international agencies and organisations working on these topics. Policies that have been implemented but not evaluated, or evaluated but not published in these literatures, will therefore be excluded from this review. As a result, potentially effective and important policies in the prevention of zoonotic spillover events may not have been identified. However, we hope that the findings from this review will highlight these gaps in the evaluative evidence. We also hope that this review, by extracting practical dimensions, such as study design, outcome measures and the challenges encountered in the evaluation process, will support policymakers and researchers in carrying out further policy evaluations in this space.

Unanswered questions and future research

Our findings highlight several important gaps in the evidence. First, while observational evidence emphasises the importance of upstream determinants such as environmental and ecosystem health in the increasing rate of zoonotic spillover [ 1 , 15 ], we only identified a single evaluation of a policy attempting to target one of these upstream determinants: an evaluation carried out in China to assess the impact of the Ramstar wetland protection program on avian influenza in migratory waterfowl [ 66 ]. This study found that proximity to protected wetlands reduced outbreak risk. Authors hypothesised that this effect was due to the separation of wild waterfowl and poultry populations and the diversion of wild waterfowl away from human-dominated landscapes and toward protected natural habitats. Our findings support existing calls for more quantitative and mechanistic studies of the impact of interventions supporting environmental and ecosystem health on zoonotic spillover risk [ 128 ], as well as calls for greater integration of the environment into One Health research, policy and practice [ 31 ]. Further evaluations of environment and habitat protection policies would strengthen our understanding of this area. In addition, the impact of policies to reduce deforestation or expand forest coverage, such as China’s Grain-to-Green program [ 129 ], on the spillover pathway could be evaluated. Such evaluations might consider potential unintended consequences, as these policies could promote healthier wildlife populations with better disease resistance, but may also facilitate wildlife population growth and higher rates of wildlife-human encounters [ 130 ].

There is also a lack of evaluation of policies targeting infection intensity and pathogen release in either wildlife or domesticated animals. These could include approaches such as improving animal health and welfare to make these populations more resistant to disease [ 13 ]. While arguments have been made for strengthening legal structures supporting animal welfare in order to reduce the risk of zoonotic pathogen transmission [ 131 ], there is a need to evaluate policies that take this approach.

Our review found publications evaluating a wide range of policy interventions spanning the spillover pathway, including habitat protection; trade regulations; border control and quarantine procedures; farm and market biosecurity measures; public information campaigns; and vaccination programmes for wildlife and domesticated animals, as well as human populations with occupational exposure to animals. A wide range of governance sectors implemented these policies, highlighting the prevention of zoonotic spillover as a cross-sectoral issue, though most policies were implemented by a single sector. Our findings highlight the importance of industry and private actors in implementing policies to prevent zoonotic spillover, and the need for thoughtful and effective engagement with this wide range of actors, from subsistence hunters and farmers through to industrial animal agriculture operations to address their concerns through a range of incentives. We also identified the centrality of surveillance data in evaluating policies that are often implemented reactively, and effective collaboration between surveillance and control operations as a central factor in successful policy implementation.

Data Availability

All data generated or analysed during this study are included in this published article and its supplementary information files. Analysis code for descriptive characteristics of included policies is available on GitHub.

Abbreviations

Emerging infectious disease

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CCA, JC and TLP acknowledge internal research support from York University. MW and CCA acknowledge internal research support from the Dahdaleh Institute for Global Health Research. KML acknowledges funding from the Canadian Institutes of Health Research through a Health System Impact Fellowship. AY is funded by the BBSRC through the Mandala project (grant number BB/V004832/1). AMV acknowledges support from York University through a York Research Chair in Population Health Ethics & Law. This review was undertaken as part of a project funded by the Canadian Institutes of Health Research, Grant Reference Number VR5-172686. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Conception and design: CCA, KLM and TLP. Acquisition of data: CCA, KLM and AY. Analysis and interpretation of data: CCA, KML, RM, JC, AD and PS. Drafting of the manuscript: CCA and RM. Critical revision of the manuscript for important intellectual content: KML, RA, AA, MB, JC, AD, RL, AR, PS, KCT, AMV, MW, MKY, AY and TLP. Obtaining funding: TLP and MW.

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Clifford Astbury, C., Lee, K.M., Mcleod, R. et al. Policies to prevent zoonotic spillover: a systematic scoping review of evaluative evidence. Global Health 19 , 82 (2023). https://doi.org/10.1186/s12992-023-00986-x

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Literature Reviews by Lawrence A. Machi , Brenda T. McEvoy LAST REVIEWED: 27 October 2016 LAST MODIFIED: 27 October 2016 DOI: 10.1093/obo/9780199756810-0169

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Role of reactive oxygen species in myelodysplastic syndromes

Graphical Abstract

Introduction

Formation of ROS and OS

Source of ROS generation in hematopoietic cells

NADPH oxidase (NOX) family proteins

Metabolic pathways

Functions of ROS in the hematological niche

Fate of ROS and HSCs

Regulation of hematopoietic homeostasis

Pathophysiology of MDS

Molecular pathogenesis of MDS

Pathophysiology of MDS with isolated del(5q)

Mutation driver genes

Abnormality of RNA splicing and aberrant gene transcripts

ROS in the pathophysiology of MDS

Generation of ROS in MDS

Inevitable IOL and iron chelation therapy (ICT)

Is targeting ROS for MDS therapy feasible?

Is there a case for targeting ROS in MDS?

The prooxidant approach

The antioxidant approach

Other therapeutic approaches for MDS

Treatment options for LR-MDS patients

Treatment options for HR-MDS patients

Conclusions and future perspectives

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Cellular & Molecular Biology Letters

Policies to prevent zoonotic spillover: a systematic scoping review of evaluative evidence

Operationalising a One Health approach to policy

Aims and scope

Stage 1: identifying the research question

How has evaluation of these policies been approached in the literature?