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Writing a Literature Review

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A literature review is a document or section of a document that collects key sources on a topic and discusses those sources in conversation with each other (also called synthesis ). The lit review is an important genre in many disciplines, not just literature (i.e., the study of works of literature such as novels and plays). When we say “literature review” or refer to “the literature,” we are talking about the research ( scholarship ) in a given field. You will often see the terms “the research,” “the scholarship,” and “the literature” used mostly interchangeably.

Where, when, and why would I write a lit review?

There are a number of different situations where you might write a literature review, each with slightly different expectations; different disciplines, too, have field-specific expectations for what a literature review is and does. For instance, in the humanities, authors might include more overt argumentation and interpretation of source material in their literature reviews, whereas in the sciences, authors are more likely to report study designs and results in their literature reviews; these differences reflect these disciplines’ purposes and conventions in scholarship. You should always look at examples from your own discipline and talk to professors or mentors in your field to be sure you understand your discipline’s conventions, for literature reviews as well as for any other genre.

A literature review can be a part of a research paper or scholarly article, usually falling after the introduction and before the research methods sections. In these cases, the lit review just needs to cover scholarship that is important to the issue you are writing about; sometimes it will also cover key sources that informed your research methodology.

Lit reviews can also be standalone pieces, either as assignments in a class or as publications. In a class, a lit review may be assigned to help students familiarize themselves with a topic and with scholarship in their field, get an idea of the other researchers working on the topic they’re interested in, find gaps in existing research in order to propose new projects, and/or develop a theoretical framework and methodology for later research. As a publication, a lit review usually is meant to help make other scholars’ lives easier by collecting and summarizing, synthesizing, and analyzing existing research on a topic. This can be especially helpful for students or scholars getting into a new research area, or for directing an entire community of scholars toward questions that have not yet been answered.

What are the parts of a lit review?

Most lit reviews use a basic introduction-body-conclusion structure; if your lit review is part of a larger paper, the introduction and conclusion pieces may be just a few sentences while you focus most of your attention on the body. If your lit review is a standalone piece, the introduction and conclusion take up more space and give you a place to discuss your goals, research methods, and conclusions separately from where you discuss the literature itself.

Introduction:

• An introductory paragraph that explains what your working topic and thesis is
• A forecast of key topics or texts that will appear in the review
• Potentially, a description of how you found sources and how you analyzed them for inclusion and discussion in the review (more often found in published, standalone literature reviews than in lit review sections in an article or research paper)
• Summarize and synthesize: Give an overview of the main points of each source and combine them into a coherent whole
• Analyze and interpret: Don’t just paraphrase other researchers – add your own interpretations where possible, discussing the significance of findings in relation to the literature as a whole
• Critically Evaluate: Mention the strengths and weaknesses of your sources
• Write in well-structured paragraphs: Use transition words and topic sentence to draw connections, comparisons, and contrasts.

Conclusion:

• Summarize the key findings you have taken from the literature and emphasize their significance
• Connect it back to your primary research question

How should I organize my lit review?

Lit reviews can take many different organizational patterns depending on what you are trying to accomplish with the review. Here are some examples:

• Chronological : The simplest approach is to trace the development of the topic over time, which helps familiarize the audience with the topic (for instance if you are introducing something that is not commonly known in your field). If you choose this strategy, be careful to avoid simply listing and summarizing sources in order. Try to analyze the patterns, turning points, and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred (as mentioned previously, this may not be appropriate in your discipline — check with a teacher or mentor if you’re unsure).
• Thematic : If you have found some recurring central themes that you will continue working with throughout your piece, you can organize your literature review into subsections that address different aspects of the topic. For example, if you are reviewing literature about women and religion, key themes can include the role of women in churches and the religious attitude towards women.
• Qualitative versus quantitative research
• Empirical versus theoretical scholarship
• Divide the research by sociological, historical, or cultural sources
• Theoretical : In many humanities articles, the literature review is the foundation for the theoretical framework. You can use it to discuss various theories, models, and definitions of key concepts. You can argue for the relevance of a specific theoretical approach or combine various theorical concepts to create a framework for your research.

What are some strategies or tips I can use while writing my lit review?

Any lit review is only as good as the research it discusses; make sure your sources are well-chosen and your research is thorough. Don’t be afraid to do more research if you discover a new thread as you’re writing. More info on the research process is available in our "Conducting Research" resources .

As you’re doing your research, create an annotated bibliography ( see our page on the this type of document ). Much of the information used in an annotated bibliography can be used also in a literature review, so you’ll be not only partially drafting your lit review as you research, but also developing your sense of the larger conversation going on among scholars, professionals, and any other stakeholders in your topic.

Usually you will need to synthesize research rather than just summarizing it. This means drawing connections between sources to create a picture of the scholarly conversation on a topic over time. Many student writers struggle to synthesize because they feel they don’t have anything to add to the scholars they are citing; here are some strategies to help you:

• It often helps to remember that the point of these kinds of syntheses is to show your readers how you understand your research, to help them read the rest of your paper.
• Writing teachers often say synthesis is like hosting a dinner party: imagine all your sources are together in a room, discussing your topic. What are they saying to each other?
• Look at the in-text citations in each paragraph. Are you citing just one source for each paragraph? This usually indicates summary only. When you have multiple sources cited in a paragraph, you are more likely to be synthesizing them (not always, but often
• Read more about synthesis here.

The most interesting literature reviews are often written as arguments (again, as mentioned at the beginning of the page, this is discipline-specific and doesn’t work for all situations). Often, the literature review is where you can establish your research as filling a particular gap or as relevant in a particular way. You have some chance to do this in your introduction in an article, but the literature review section gives a more extended opportunity to establish the conversation in the way you would like your readers to see it. You can choose the intellectual lineage you would like to be part of and whose definitions matter most to your thinking (mostly humanities-specific, but this goes for sciences as well). In addressing these points, you argue for your place in the conversation, which tends to make the lit review more compelling than a simple reporting of other sources.

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• Knowledge Base
• Dissertation
• What is a Literature Review? | Guide, Template, & Examples

What is a Literature Review? | Guide, Template, & Examples

Published on 22 February 2022 by Shona McCombes . Revised on 7 June 2022.

What is a literature review? A literature review is a survey of scholarly sources on a specific topic. It provides an overview of current knowledge, allowing you to identify relevant theories, methods, and gaps in the existing research.

There are five key steps to writing a literature review:

• Search for relevant literature
• Evaluate sources
• Identify themes, debates and gaps
• Outline the structure
• Write your literature review

A good literature review doesn’t just summarise sources – it analyses, synthesises, and critically evaluates to give a clear picture of the state of knowledge on the subject.

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Table of contents

Why write a literature review, examples of literature reviews, step 1: search for relevant literature, step 2: evaluate and select sources, step 3: identify themes, debates and gaps, step 4: outline your literature review’s structure, step 5: write your literature review, frequently asked questions about literature reviews, introduction.

• Quick Run-through
• Step 1 & 2

When you write a dissertation or thesis, you will have to conduct a literature review to situate your research within existing knowledge. The literature review gives you a chance to:

• Demonstrate your familiarity with the topic and scholarly context
• Develop a theoretical framework and methodology for your research
• Position yourself in relation to other researchers and theorists
• Show how your dissertation addresses a gap or contributes to a debate

You might also have to write a literature review as a stand-alone assignment. In this case, the purpose is to evaluate the current state of research and demonstrate your knowledge of scholarly debates around a topic.

The content will look slightly different in each case, but the process of conducting a literature review follows the same steps. We’ve written a step-by-step guide that you can follow below.

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Writing literature reviews can be quite challenging! A good starting point could be to look at some examples, depending on what kind of literature review you’d like to write.

• Example literature review #1: “Why Do People Migrate? A Review of the Theoretical Literature” ( Theoretical literature review about the development of economic migration theory from the 1950s to today.)
• Example literature review #2: “Literature review as a research methodology: An overview and guidelines” ( Methodological literature review about interdisciplinary knowledge acquisition and production.)
• Example literature review #3: “The Use of Technology in English Language Learning: A Literature Review” ( Thematic literature review about the effects of technology on language acquisition.)
• Example literature review #4: “Learners’ Listening Comprehension Difficulties in English Language Learning: A Literature Review” ( Chronological literature review about how the concept of listening skills has changed over time.)

You can also check out our templates with literature review examples and sample outlines at the links below.

Download Word doc Download Google doc

Before you begin searching for literature, you need a clearly defined topic .

If you are writing the literature review section of a dissertation or research paper, you will search for literature related to your research objectives and questions .

If you are writing a literature review as a stand-alone assignment, you will have to choose a focus and develop a central question to direct your search. Unlike a dissertation research question, this question has to be answerable without collecting original data. You should be able to answer it based only on a review of existing publications.

Make a list of keywords

Start by creating a list of keywords related to your research topic. Include each of the key concepts or variables you’re interested in, and list any synonyms and related terms. You can add to this list if you discover new keywords in the process of your literature search.

• Social media, Facebook, Instagram, Twitter, Snapchat, TikTok
• Body image, self-perception, self-esteem, mental health
• Generation Z, teenagers, adolescents, youth

Search for relevant sources

Use your keywords to begin searching for sources. Some databases to search for journals and articles include:

• Your university’s library catalogue
• Google Scholar
• Project Muse (humanities and social sciences)
• Medline (life sciences and biomedicine)
• EconLit (economics)
• Inspec (physics, engineering and computer science)

You can use boolean operators to help narrow down your search:

Read the abstract to find out whether an article is relevant to your question. When you find a useful book or article, you can check the bibliography to find other relevant sources.

To identify the most important publications on your topic, take note of recurring citations. If the same authors, books or articles keep appearing in your reading, make sure to seek them out.

You probably won’t be able to read absolutely everything that has been written on the topic – you’ll have to evaluate which sources are most relevant to your questions.

For each publication, ask yourself:

• What question or problem is the author addressing?
• What are the key concepts and how are they defined?
• What are the key theories, models and methods? Does the research use established frameworks or take an innovative approach?
• What are the results and conclusions of the study?
• How does the publication relate to other literature in the field? Does it confirm, add to, or challenge established knowledge?
• How does the publication contribute to your understanding of the topic? What are its key insights and arguments?
• What are the strengths and weaknesses of the research?

Make sure the sources you use are credible, and make sure you read any landmark studies and major theories in your field of research.

You can find out how many times an article has been cited on Google Scholar – a high citation count means the article has been influential in the field, and should certainly be included in your literature review.

The scope of your review will depend on your topic and discipline: in the sciences you usually only review recent literature, but in the humanities you might take a long historical perspective (for example, to trace how a concept has changed in meaning over time).

Remember that you can use our template to summarise and evaluate sources you’re thinking about using!

Take notes and cite your sources

As you read, you should also begin the writing process. Take notes that you can later incorporate into the text of your literature review.

It’s important to keep track of your sources with references to avoid plagiarism . It can be helpful to make an annotated bibliography, where you compile full reference information and write a paragraph of summary and analysis for each source. This helps you remember what you read and saves time later in the process.

You can use our free APA Reference Generator for quick, correct, consistent citations.

To begin organising your literature review’s argument and structure, you need to understand the connections and relationships between the sources you’ve read. Based on your reading and notes, you can look for:

• Trends and patterns (in theory, method or results): do certain approaches become more or less popular over time?
• Themes: what questions or concepts recur across the literature?
• Debates, conflicts and contradictions: where do sources disagree?
• Pivotal publications: are there any influential theories or studies that changed the direction of the field?
• Gaps: what is missing from the literature? Are there weaknesses that need to be addressed?

This step will help you work out the structure of your literature review and (if applicable) show how your own research will contribute to existing knowledge.

• Most research has focused on young women.
• There is an increasing interest in the visual aspects of social media.
• But there is still a lack of robust research on highly-visual platforms like Instagram and Snapchat – this is a gap that you could address in your own research.

There are various approaches to organising the body of a literature review. You should have a rough idea of your strategy before you start writing.

Depending on the length of your literature review, you can combine several of these strategies (for example, your overall structure might be thematic, but each theme is discussed chronologically).

Chronological

The simplest approach is to trace the development of the topic over time. However, if you choose this strategy, be careful to avoid simply listing and summarising sources in order.

Try to analyse patterns, turning points and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred.

If you have found some recurring central themes, you can organise your literature review into subsections that address different aspects of the topic.

For example, if you are reviewing literature about inequalities in migrant health outcomes, key themes might include healthcare policy, language barriers, cultural attitudes, legal status, and economic access.

Methodological

If you draw your sources from different disciplines or fields that use a variety of research methods , you might want to compare the results and conclusions that emerge from different approaches. For example:

• Look at what results have emerged in qualitative versus quantitative research
• Discuss how the topic has been approached by empirical versus theoretical scholarship
• Divide the literature into sociological, historical, and cultural sources

Theoretical

A literature review is often the foundation for a theoretical framework . You can use it to discuss various theories, models, and definitions of key concepts.

You might argue for the relevance of a specific theoretical approach, or combine various theoretical concepts to create a framework for your research.

Like any other academic text, your literature review should have an introduction , a main body, and a conclusion . What you include in each depends on the objective of your literature review.

The introduction should clearly establish the focus and purpose of the literature review.

If you are writing the literature review as part of your dissertation or thesis, reiterate your central problem or research question and give a brief summary of the scholarly context. You can emphasise the timeliness of the topic (“many recent studies have focused on the problem of x”) or highlight a gap in the literature (“while there has been much research on x, few researchers have taken y into consideration”).

Depending on the length of your literature review, you might want to divide the body into subsections. You can use a subheading for each theme, time period, or methodological approach.

As you write, make sure to follow these tips:

• Summarise and synthesise: give an overview of the main points of each source and combine them into a coherent whole.
• Analyse and interpret: don’t just paraphrase other researchers – add your own interpretations, discussing the significance of findings in relation to the literature as a whole.
• Critically evaluate: mention the strengths and weaknesses of your sources.
• Write in well-structured paragraphs: use transitions and topic sentences to draw connections, comparisons and contrasts.

In the conclusion, you should summarise the key findings you have taken from the literature and emphasise their significance.

If the literature review is part of your dissertation or thesis, reiterate how your research addresses gaps and contributes new knowledge, or discuss how you have drawn on existing theories and methods to build a framework for your research. This can lead directly into your methodology section.

A literature review is a survey of scholarly sources (such as books, journal articles, and theses) related to a specific topic or research question .

It is often written as part of a dissertation , thesis, research paper , or proposal .

There are several reasons to conduct a literature review at the beginning of a research project:

• To familiarise yourself with the current state of knowledge on your topic
• To ensure that you’re not just repeating what others have already done
• To identify gaps in knowledge and unresolved problems that your research can address
• To develop your theoretical framework and methodology
• To provide an overview of the key findings and debates on the topic

Writing the literature review shows your reader how your work relates to existing research and what new insights it will contribute.

The literature review usually comes near the beginning of your  dissertation . After the introduction , it grounds your research in a scholarly field and leads directly to your theoretical framework or methodology .

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• UConn Library
• Literature Review: The What, Why and How-to Guide
• Introduction

Literature Review: The What, Why and How-to Guide — Introduction

• Getting Started
• How to Pick a Topic
• Strategies to Find Sources
• Evaluating Sources & Lit. Reviews
• Tips for Writing Literature Reviews
• Writing Literature Review: Useful Sites
• Citation Resources
• Other Academic Writings

What are Literature Reviews?

So, what is a literature review? "A literature review is an account of what has been published on a topic by accredited scholars and researchers. In writing the literature review, your purpose is to convey to your reader what knowledge and ideas have been established on a topic, and what their strengths and weaknesses are. As a piece of writing, the literature review must be defined by a guiding concept (e.g., your research objective, the problem or issue you are discussing, or your argumentative thesis). It is not just a descriptive list of the material available, or a set of summaries." Taylor, D.  The literature review: A few tips on conducting it . University of Toronto Health Sciences Writing Centre.

Goals of Literature Reviews

What are the goals of creating a Literature Review?  A literature could be written to accomplish different aims:

• To develop a theory or evaluate an existing theory
• To summarize the historical or existing state of a research topic
• Identify a problem in a field of research 

Baumeister, R. F., & Leary, M. R. (1997). Writing narrative literature reviews .  Review of General Psychology , 1 (3), 311-320.

What kinds of sources require a Literature Review?

• A research paper assigned in a course
• A thesis or dissertation
• A grant proposal
• An article intended for publication in a journal

All these instances require you to collect what has been written about your research topic so that you can demonstrate how your own research sheds new light on the topic.

Types of Literature Reviews

What kinds of literature reviews are written?

Narrative review: The purpose of this type of review is to describe the current state of the research on a specific topic/research and to offer a critical analysis of the literature reviewed. Studies are grouped by research/theoretical categories, and themes and trends, strengths and weakness, and gaps are identified. The review ends with a conclusion section which summarizes the findings regarding the state of the research of the specific study, the gaps identify and if applicable, explains how the author's research will address gaps identify in the review and expand the knowledge on the topic reviewed.

• Example : Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework:  10.1177/08948453211037398  

Systematic review : "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139). Nelson, L. K. (2013). Research in Communication Sciences and Disorders . Plural Publishing.

• Example : The effect of leave policies on increasing fertility: a systematic review:  10.1057/s41599-022-01270-w

Meta-analysis : "Meta-analysis is a method of reviewing research findings in a quantitative fashion by transforming the data from individual studies into what is called an effect size and then pooling and analyzing this information. The basic goal in meta-analysis is to explain why different outcomes have occurred in different studies." (p. 197). Roberts, M. C., & Ilardi, S. S. (2003). Handbook of Research Methods in Clinical Psychology . Blackwell Publishing.

• Example : Employment Instability and Fertility in Europe: A Meta-Analysis:  10.1215/00703370-9164737

Meta-synthesis : "Qualitative meta-synthesis is a type of qualitative study that uses as data the findings from other qualitative studies linked by the same or related topic." (p.312). Zimmer, L. (2006). Qualitative meta-synthesis: A question of dialoguing with texts .  Journal of Advanced Nursing , 53 (3), 311-318.

• Example : Women’s perspectives on career successes and barriers: A qualitative meta-synthesis:  10.1177/05390184221113735

Literature Reviews in the Health Sciences

• UConn Health subject guide on systematic reviews Explanation of the different review types used in health sciences literature as well as tools to help you find the right review type
• << Previous: Getting Started
• Next: How to Pick a Topic >>
• Last Updated: Sep 21, 2022 2:16 PM
• URL: https://guides.lib.uconn.edu/literaturereview

• Methodology
• Open access
• Published: 11 October 2016

Reviewing the research methods literature: principles and strategies illustrated by a systematic overview of sampling in qualitative research

• Stephen J. Gentles 1 , 4 ,
• Cathy Charles 1 ,
• David B. Nicholas 2 ,
• Jenny Ploeg 3 &
• K. Ann McKibbon 1  

Systematic Reviews volume  5 , Article number:  172 ( 2016 ) Cite this article

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Overviews of methods are potentially useful means to increase clarity and enhance collective understanding of specific methods topics that may be characterized by ambiguity, inconsistency, or a lack of comprehensiveness. This type of review represents a distinct literature synthesis method, although to date, its methodology remains relatively undeveloped despite several aspects that demand unique review procedures. The purpose of this paper is to initiate discussion about what a rigorous systematic approach to reviews of methods, referred to here as systematic methods overviews , might look like by providing tentative suggestions for approaching specific challenges likely to be encountered. The guidance offered here was derived from experience conducting a systematic methods overview on the topic of sampling in qualitative research.

The guidance is organized into several principles that highlight specific objectives for this type of review given the common challenges that must be overcome to achieve them. Optional strategies for achieving each principle are also proposed, along with discussion of how they were successfully implemented in the overview on sampling. We describe seven paired principles and strategies that address the following aspects: delimiting the initial set of publications to consider, searching beyond standard bibliographic databases, searching without the availability of relevant metadata, selecting publications on purposeful conceptual grounds, defining concepts and other information to abstract iteratively, accounting for inconsistent terminology used to describe specific methods topics, and generating rigorous verifiable analytic interpretations. Since a broad aim in systematic methods overviews is to describe and interpret the relevant literature in qualitative terms, we suggest that iterative decision making at various stages of the review process, and a rigorous qualitative approach to analysis are necessary features of this review type.

Conclusions

We believe that the principles and strategies provided here will be useful to anyone choosing to undertake a systematic methods overview. This paper represents an initial effort to promote high quality critical evaluations of the literature regarding problematic methods topics, which have the potential to promote clearer, shared understandings, and accelerate advances in research methods. Further work is warranted to develop more definitive guidance.

Peer Review reports

While reviews of methods are not new, they represent a distinct review type whose methodology remains relatively under-addressed in the literature despite the clear implications for unique review procedures. One of few examples to describe it is a chapter containing reflections of two contributing authors in a book of 21 reviews on methodological topics compiled for the British National Health Service, Health Technology Assessment Program [ 1 ]. Notable is their observation of how the differences between the methods reviews and conventional quantitative systematic reviews, specifically attributable to their varying content and purpose, have implications for defining what qualifies as systematic. While the authors describe general aspects of “systematicity” (including rigorous application of a methodical search, abstraction, and analysis), they also describe a high degree of variation within the category of methods reviews itself and so offer little in the way of concrete guidance. In this paper, we present tentative concrete guidance, in the form of a preliminary set of proposed principles and optional strategies, for a rigorous systematic approach to reviewing and evaluating the literature on quantitative or qualitative methods topics. For purposes of this article, we have used the term systematic methods overview to emphasize the notion of a systematic approach to such reviews.

The conventional focus of rigorous literature reviews (i.e., review types for which systematic methods have been codified, including the various approaches to quantitative systematic reviews [ 2 – 4 ], and the numerous forms of qualitative and mixed methods literature synthesis [ 5 – 10 ]) is to synthesize empirical research findings from multiple studies. By contrast, the focus of overviews of methods, including the systematic approach we advocate, is to synthesize guidance on methods topics. The literature consulted for such reviews may include the methods literature, methods-relevant sections of empirical research reports, or both. Thus, this paper adds to previous work published in this journal—namely, recent preliminary guidance for conducting reviews of theory [ 11 ]—that has extended the application of systematic review methods to novel review types that are concerned with subject matter other than empirical research findings.

Published examples of methods overviews illustrate the varying objectives they can have. One objective is to establish methodological standards for appraisal purposes. For example, reviews of existing quality appraisal standards have been used to propose universal standards for appraising the quality of primary qualitative research [ 12 ] or evaluating qualitative research reports [ 13 ]. A second objective is to survey the methods-relevant sections of empirical research reports to establish current practices on methods use and reporting practices, which Moher and colleagues [ 14 ] recommend as a means for establishing the needs to be addressed in reporting guidelines (see, for example [ 15 , 16 ]). A third objective for a methods review is to offer clarity and enhance collective understanding regarding a specific methods topic that may be characterized by ambiguity, inconsistency, or a lack of comprehensiveness within the available methods literature. An example of this is a overview whose objective was to review the inconsistent definitions of intention-to-treat analysis (the methodologically preferred approach to analyze randomized controlled trial data) that have been offered in the methods literature and propose a solution for improving conceptual clarity [ 17 ]. Such reviews are warranted because students and researchers who must learn or apply research methods typically lack the time to systematically search, retrieve, review, and compare the available literature to develop a thorough and critical sense of the varied approaches regarding certain controversial or ambiguous methods topics.

While systematic methods overviews , as a review type, include both reviews of the methods literature and reviews of methods-relevant sections from empirical study reports, the guidance provided here is primarily applicable to reviews of the methods literature since it was derived from the experience of conducting such a review [ 18 ], described below. To our knowledge, there are no well-developed proposals on how to rigorously conduct such reviews. Such guidance would have the potential to improve the thoroughness and credibility of critical evaluations of the methods literature, which could increase their utility as a tool for generating understandings that advance research methods, both qualitative and quantitative. Our aim in this paper is thus to initiate discussion about what might constitute a rigorous approach to systematic methods overviews. While we hope to promote rigor in the conduct of systematic methods overviews wherever possible, we do not wish to suggest that all methods overviews need be conducted to the same standard. Rather, we believe that the level of rigor may need to be tailored pragmatically to the specific review objectives, which may not always justify the resource requirements of an intensive review process.

The example systematic methods overview on sampling in qualitative research

The principles and strategies we propose in this paper are derived from experience conducting a systematic methods overview on the topic of sampling in qualitative research [ 18 ]. The main objective of that methods overview was to bring clarity and deeper understanding of the prominent concepts related to sampling in qualitative research (purposeful sampling strategies, saturation, etc.). Specifically, we interpreted the available guidance, commenting on areas lacking clarity, consistency, or comprehensiveness (without proposing any recommendations on how to do sampling). This was achieved by a comparative and critical analysis of publications representing the most influential (i.e., highly cited) guidance across several methodological traditions in qualitative research.

The specific methods and procedures for the overview on sampling [ 18 ] from which our proposals are derived were developed both after soliciting initial input from local experts in qualitative research and an expert health librarian (KAM) and through ongoing careful deliberation throughout the review process. To summarize, in that review, we employed a transparent and rigorous approach to search the methods literature, selected publications for inclusion according to a purposeful and iterative process, abstracted textual data using structured abstraction forms, and analyzed (synthesized) the data using a systematic multi-step approach featuring abstraction of text, summary of information in matrices, and analytic comparisons.

For this article, we reflected on both the problems and challenges encountered at different stages of the review and our means for selecting justifiable procedures to deal with them. Several principles were then derived by considering the generic nature of these problems, while the generalizable aspects of the procedures used to address them formed the basis of optional strategies. Further details of the specific methods and procedures used in the overview on qualitative sampling are provided below to illustrate both the types of objectives and challenges that reviewers will likely need to consider and our approach to implementing each of the principles and strategies.

Organization of the guidance into principles and strategies

For the purposes of this article, principles are general statements outlining what we propose are important aims or considerations within a particular review process, given the unique objectives or challenges to be overcome with this type of review. These statements follow the general format, “considering the objective or challenge of X, we propose Y to be an important aim or consideration.” Strategies are optional and flexible approaches for implementing the previous principle outlined. Thus, generic challenges give rise to principles, which in turn give rise to strategies.

We organize the principles and strategies below into three sections corresponding to processes characteristic of most systematic literature synthesis approaches: literature identification and selection ; data abstraction from the publications selected for inclusion; and analysis , including critical appraisal and synthesis of the abstracted data. Within each section, we also describe the specific methodological decisions and procedures used in the overview on sampling in qualitative research [ 18 ] to illustrate how the principles and strategies for each review process were applied and implemented in a specific case. We expect this guidance and accompanying illustrations will be useful for anyone considering engaging in a methods overview, particularly those who may be familiar with conventional systematic review methods but may not yet appreciate some of the challenges specific to reviewing the methods literature.

Results and discussion

Literature identification and selection.

The identification and selection process includes search and retrieval of publications and the development and application of inclusion and exclusion criteria to select the publications that will be abstracted and analyzed in the final review. Literature identification and selection for overviews of the methods literature is challenging and potentially more resource-intensive than for most reviews of empirical research. This is true for several reasons that we describe below, alongside discussion of the potential solutions. Additionally, we suggest in this section how the selection procedures can be chosen to match the specific analytic approach used in methods overviews.

Delimiting a manageable set of publications

One aspect of methods overviews that can make identification and selection challenging is the fact that the universe of literature containing potentially relevant information regarding most methods-related topics is expansive and often unmanageably so. Reviewers are faced with two large categories of literature: the methods literature , where the possible publication types include journal articles, books, and book chapters; and the methods-relevant sections of empirical study reports , where the possible publication types include journal articles, monographs, books, theses, and conference proceedings. In our systematic overview of sampling in qualitative research, exhaustively searching (including retrieval and first-pass screening) all publication types across both categories of literature for information on a single methods-related topic was too burdensome to be feasible. The following proposed principle follows from the need to delimit a manageable set of literature for the review.

Principle #1:

Considering the broad universe of potentially relevant literature, we propose that an important objective early in the identification and selection stage is to delimit a manageable set of methods-relevant publications in accordance with the objectives of the methods overview.

Strategy #1:

To limit the set of methods-relevant publications that must be managed in the selection process, reviewers have the option to initially review only the methods literature, and exclude the methods-relevant sections of empirical study reports, provided this aligns with the review’s particular objectives.

We propose that reviewers are justified in choosing to select only the methods literature when the objective is to map out the range of recognized concepts relevant to a methods topic, to summarize the most authoritative or influential definitions or meanings for methods-related concepts, or to demonstrate a problematic lack of clarity regarding a widely established methods-related concept and potentially make recommendations for a preferred approach to the methods topic in question. For example, in the case of the methods overview on sampling [ 18 ], the primary aim was to define areas lacking in clarity for multiple widely established sampling-related topics. In the review on intention-to-treat in the context of missing outcome data [ 17 ], the authors identified a lack of clarity based on multiple inconsistent definitions in the literature and went on to recommend separating the issue of how to handle missing outcome data from the issue of whether an intention-to-treat analysis can be claimed.

In contrast to strategy #1, it may be appropriate to select the methods-relevant sections of empirical study reports when the objective is to illustrate how a methods concept is operationalized in research practice or reported by authors. For example, one could review all the publications in 2 years’ worth of issues of five high-impact field-related journals to answer questions about how researchers describe implementing a particular method or approach, or to quantify how consistently they define or report using it. Such reviews are often used to highlight gaps in the reporting practices regarding specific methods, which may be used to justify items to address in reporting guidelines (for example, [ 14 – 16 ]).

It is worth recognizing that other authors have advocated broader positions regarding the scope of literature to be considered in a review, expanding on our perspective. Suri [ 10 ] (who, like us, emphasizes how different sampling strategies are suitable for different literature synthesis objectives) has, for example, described a two-stage literature sampling procedure (pp. 96–97). First, reviewers use an initial approach to conduct a broad overview of the field—for reviews of methods topics, this would entail an initial review of the research methods literature. This is followed by a second more focused stage in which practical examples are purposefully selected—for methods reviews, this would involve sampling the empirical literature to illustrate key themes and variations. While this approach is seductive in its capacity to generate more in depth and interpretive analytic findings, some reviewers may consider it too resource-intensive to include the second step no matter how selective the purposeful sampling. In the overview on sampling where we stopped after the first stage [ 18 ], we discussed our selective focus on the methods literature as a limitation that left opportunities for further analysis of the literature. We explicitly recommended, for example, that theoretical sampling was a topic for which a future review of the methods sections of empirical reports was justified to answer specific questions identified in the primary review.

Ultimately, reviewers must make pragmatic decisions that balance resource considerations, combined with informed predictions about the depth and complexity of literature available on their topic, with the stated objectives of their review. The remaining principles and strategies apply primarily to overviews that include the methods literature, although some aspects may be relevant to reviews that include empirical study reports.

Searching beyond standard bibliographic databases

An important reality affecting identification and selection in overviews of the methods literature is the increased likelihood for relevant publications to be located in sources other than journal articles (which is usually not the case for overviews of empirical research, where journal articles generally represent the primary publication type). In the overview on sampling [ 18 ], out of 41 full-text publications retrieved and reviewed, only 4 were journal articles, while 37 were books or book chapters. Since many books and book chapters did not exist electronically, their full text had to be physically retrieved in hardcopy, while 11 publications were retrievable only through interlibrary loan or purchase request. The tasks associated with such retrieval are substantially more time-consuming than electronic retrieval. Since a substantial proportion of methods-related guidance may be located in publication types that are less comprehensively indexed in standard bibliographic databases, identification and retrieval thus become complicated processes.

Principle #2:

Considering that important sources of methods guidance can be located in non-journal publication types (e.g., books, book chapters) that tend to be poorly indexed in standard bibliographic databases, it is important to consider alternative search methods for identifying relevant publications to be further screened for inclusion.

Strategy #2:

To identify books, book chapters, and other non-journal publication types not thoroughly indexed in standard bibliographic databases, reviewers may choose to consult one or more of the following less standard sources: Google Scholar, publisher web sites, or expert opinion.

In the case of the overview on sampling in qualitative research [ 18 ], Google Scholar had two advantages over other standard bibliographic databases: it indexes and returns records of books and book chapters likely to contain guidance on qualitative research methods topics; and it has been validated as providing higher citation counts than ISI Web of Science (a producer of numerous bibliographic databases accessible through institutional subscription) for several non-biomedical disciplines including the social sciences where qualitative research methods are prominently used [ 19 – 21 ]. While we identified numerous useful publications by consulting experts, the author publication lists generated through Google Scholar searches were uniquely useful to identify more recent editions of methods books identified by experts.

Searching without relevant metadata

Determining what publications to select for inclusion in the overview on sampling [ 18 ] could only rarely be accomplished by reviewing the publication’s metadata. This was because for the many books and other non-journal type publications we identified as possibly relevant, the potential content of interest would be located in only a subsection of the publication. In this common scenario for reviews of the methods literature (as opposed to methods overviews that include empirical study reports), reviewers will often be unable to employ standard title, abstract, and keyword database searching or screening as a means for selecting publications.

Principle #3:

Considering that the presence of information about the topic of interest may not be indicated in the metadata for books and similar publication types, it is important to consider other means of identifying potentially useful publications for further screening.

Strategy #3:

One approach to identifying potentially useful books and similar publication types is to consider what classes of such publications (e.g., all methods manuals for a certain research approach) are likely to contain relevant content, then identify, retrieve, and review the full text of corresponding publications to determine whether they contain information on the topic of interest.

In the example of the overview on sampling in qualitative research [ 18 ], the topic of interest (sampling) was one of numerous topics covered in the general qualitative research methods manuals. Consequently, examples from this class of publications first had to be identified for retrieval according to non-keyword-dependent criteria. Thus, all methods manuals within the three research traditions reviewed (grounded theory, phenomenology, and case study) that might contain discussion of sampling were sought through Google Scholar and expert opinion, their full text obtained, and hand-searched for relevant content to determine eligibility. We used tables of contents and index sections of books to aid this hand searching.

Purposefully selecting literature on conceptual grounds

A final consideration in methods overviews relates to the type of analysis used to generate the review findings. Unlike quantitative systematic reviews where reviewers aim for accurate or unbiased quantitative estimates—something that requires identifying and selecting the literature exhaustively to obtain all relevant data available (i.e., a complete sample)—in methods overviews, reviewers must describe and interpret the relevant literature in qualitative terms to achieve review objectives. In other words, the aim in methods overviews is to seek coverage of the qualitative concepts relevant to the methods topic at hand. For example, in the overview of sampling in qualitative research [ 18 ], achieving review objectives entailed providing conceptual coverage of eight sampling-related topics that emerged as key domains. The following principle recognizes that literature sampling should therefore support generating qualitative conceptual data as the input to analysis.

Principle #4:

Since the analytic findings of a systematic methods overview are generated through qualitative description and interpretation of the literature on a specified topic, selection of the literature should be guided by a purposeful strategy designed to achieve adequate conceptual coverage (i.e., representing an appropriate degree of variation in relevant ideas) of the topic according to objectives of the review.

Strategy #4:

One strategy for choosing the purposeful approach to use in selecting the literature according to the review objectives is to consider whether those objectives imply exploring concepts either at a broad overview level, in which case combining maximum variation selection with a strategy that limits yield (e.g., critical case, politically important, or sampling for influence—described below) may be appropriate; or in depth, in which case purposeful approaches aimed at revealing innovative cases will likely be necessary.

In the methods overview on sampling, the implied scope was broad since we set out to review publications on sampling across three divergent qualitative research traditions—grounded theory, phenomenology, and case study—to facilitate making informative conceptual comparisons. Such an approach would be analogous to maximum variation sampling.

At the same time, the purpose of that review was to critically interrogate the clarity, consistency, and comprehensiveness of literature from these traditions that was “most likely to have widely influenced students’ and researchers’ ideas about sampling” (p. 1774) [ 18 ]. In other words, we explicitly set out to review and critique the most established and influential (and therefore dominant) literature, since this represents a common basis of knowledge among students and researchers seeking understanding or practical guidance on sampling in qualitative research. To achieve this objective, we purposefully sampled publications according to the criterion of influence , which we operationalized as how often an author or publication has been referenced in print or informal discourse. This second sampling approach also limited the literature we needed to consider within our broad scope review to a manageable amount.

To operationalize this strategy of sampling for influence , we sought to identify both the most influential authors within a qualitative research tradition (all of whose citations were subsequently screened) and the most influential publications on the topic of interest by non-influential authors. This involved a flexible approach that combined multiple indicators of influence to avoid the dilemma that any single indicator might provide inadequate coverage. These indicators included bibliometric data (h-index for author influence [ 22 ]; number of cites for publication influence), expert opinion, and cross-references in the literature (i.e., snowball sampling). As a final selection criterion, a publication was included only if it made an original contribution in terms of novel guidance regarding sampling or a related concept; thus, purely secondary sources were excluded. Publish or Perish software (Anne-Wil Harzing; available at http://www.harzing.com/resources/publish-or-perish ) was used to generate bibliometric data via the Google Scholar database. Figure  1 illustrates how identification and selection in the methods overview on sampling was a multi-faceted and iterative process. The authors selected as influential, and the publications selected for inclusion or exclusion are listed in Additional file 1 (Matrices 1, 2a, 2b).

Literature identification and selection process used in the methods overview on sampling [ 18 ]

In summary, the strategies of seeking maximum variation and sampling for influence were employed in the sampling overview to meet the specific review objectives described. Reviewers will need to consider the full range of purposeful literature sampling approaches at their disposal in deciding what best matches the specific aims of their own reviews. Suri [ 10 ] has recently retooled Patton’s well-known typology of purposeful sampling strategies (originally intended for primary research) for application to literature synthesis, providing a useful resource in this respect.

Data abstraction

The purpose of data abstraction in rigorous literature reviews is to locate and record all data relevant to the topic of interest from the full text of included publications, making them available for subsequent analysis. Conventionally, a data abstraction form—consisting of numerous distinct conceptually defined fields to which corresponding information from the source publication is recorded—is developed and employed. There are several challenges, however, to the processes of developing the abstraction form and abstracting the data itself when conducting methods overviews, which we address here. Some of these problems and their solutions may be familiar to those who have conducted qualitative literature syntheses, which are similarly conceptual.

Iteratively defining conceptual information to abstract

In the overview on sampling [ 18 ], while we surveyed multiple sources beforehand to develop a list of concepts relevant for abstraction (e.g., purposeful sampling strategies, saturation, sample size), there was no way for us to anticipate some concepts prior to encountering them in the review process. Indeed, in many cases, reviewers are unable to determine the complete set of methods-related concepts that will be the focus of the final review a priori without having systematically reviewed the publications to be included. Thus, defining what information to abstract beforehand may not be feasible.

Principle #5:

Considering the potential impracticality of defining a complete set of relevant methods-related concepts from a body of literature one has not yet systematically read, selecting and defining fields for data abstraction must often be undertaken iteratively. Thus, concepts to be abstracted can be expected to grow and change as data abstraction proceeds.

Strategy #5:

Reviewers can develop an initial form or set of concepts for abstraction purposes according to standard methods (e.g., incorporating expert feedback, pilot testing) and remain attentive to the need to iteratively revise it as concepts are added or modified during the review. Reviewers should document revisions and return to re-abstract data from previously abstracted publications as the new data requirements are determined.

In the sampling overview [ 18 ], we developed and maintained the abstraction form in Microsoft Word. We derived the initial set of abstraction fields from our own knowledge of relevant sampling-related concepts, consultation with local experts, and reviewing a pilot sample of publications. Since the publications in this review included a large proportion of books, the abstraction process often began by flagging the broad sections within a publication containing topic-relevant information for detailed review to identify text to abstract. When reviewing flagged text, the reviewer occasionally encountered an unanticipated concept significant enough to warrant being added as a new field to the abstraction form. For example, a field was added to capture how authors described the timing of sampling decisions, whether before (a priori) or after (ongoing) starting data collection, or whether this was unclear. In these cases, we systematically documented the modification to the form and returned to previously abstracted publications to abstract any information that might be relevant to the new field.

The logic of this strategy is analogous to the logic used in a form of research synthesis called best fit framework synthesis (BFFS) [ 23 – 25 ]. In that method, reviewers initially code evidence using an a priori framework they have selected. When evidence cannot be accommodated by the selected framework, reviewers then develop new themes or concepts from which they construct a new expanded framework. Both the strategy proposed and the BFFS approach to research synthesis are notable for their rigorous and transparent means to adapt a final set of concepts to the content under review.

Accounting for inconsistent terminology

An important complication affecting the abstraction process in methods overviews is that the language used by authors to describe methods-related concepts can easily vary across publications. For example, authors from different qualitative research traditions often use different terms for similar methods-related concepts. Furthermore, as we found in the sampling overview [ 18 ], there may be cases where no identifiable term, phrase, or label for a methods-related concept is used at all, and a description of it is given instead. This can make searching the text for relevant concepts based on keywords unreliable.

Principle #6:

Since accepted terms may not be used consistently to refer to methods concepts, it is necessary to rely on the definitions for concepts, rather than keywords, to identify relevant information in the publication to abstract.

Strategy #6:

An effective means to systematically identify relevant information is to develop and iteratively adjust written definitions for key concepts (corresponding to abstraction fields) that are consistent with and as inclusive of as much of the literature reviewed as possible. Reviewers then seek information that matches these definitions (rather than keywords) when scanning a publication for relevant data to abstract.

In the abstraction process for the sampling overview [ 18 ], we noted the several concepts of interest to the review for which abstraction by keyword was particularly problematic due to inconsistent terminology across publications: sampling , purposeful sampling , sampling strategy , and saturation (for examples, see Additional file 1 , Matrices 3a, 3b, 4). We iteratively developed definitions for these concepts by abstracting text from publications that either provided an explicit definition or from which an implicit definition could be derived, which was recorded in fields dedicated to the concept’s definition. Using a method of constant comparison, we used text from definition fields to inform and modify a centrally maintained definition of the corresponding concept to optimize its fit and inclusiveness with the literature reviewed. Table  1 shows, as an example, the final definition constructed in this way for one of the central concepts of the review, qualitative sampling .

We applied iteratively developed definitions when making decisions about what specific text to abstract for an existing field, which allowed us to abstract concept-relevant data even if no recognized keyword was used. For example, this was the case for the sampling-related concept, saturation , where the relevant text available for abstraction in one publication [ 26 ]—“to continue to collect data until nothing new was being observed or recorded, no matter how long that takes”—was not accompanied by any term or label whatsoever.

This comparative analytic strategy (and our approach to analysis more broadly as described in strategy #7, below) is analogous to the process of reciprocal translation —a technique first introduced for meta-ethnography by Noblit and Hare [ 27 ] that has since been recognized as a common element in a variety of qualitative metasynthesis approaches [ 28 ]. Reciprocal translation, taken broadly, involves making sense of a study’s findings in terms of the findings of the other studies included in the review. In practice, it has been operationalized in different ways. Melendez-Torres and colleagues developed a typology from their review of the metasynthesis literature, describing four overlapping categories of specific operations undertaken in reciprocal translation: visual representation, key paper integration, data reduction and thematic extraction, and line-by-line coding [ 28 ]. The approaches suggested in both strategies #6 and #7, with their emphasis on constant comparison, appear to fall within the line-by-line coding category.

Generating credible and verifiable analytic interpretations

The analysis in a systematic methods overview must support its more general objective, which we suggested above is often to offer clarity and enhance collective understanding regarding a chosen methods topic. In our experience, this involves describing and interpreting the relevant literature in qualitative terms. Furthermore, any interpretative analysis required may entail reaching different levels of abstraction, depending on the more specific objectives of the review. For example, in the overview on sampling [ 18 ], we aimed to produce a comparative analysis of how multiple sampling-related topics were treated differently within and among different qualitative research traditions. To promote credibility of the review, however, not only should one seek a qualitative analytic approach that facilitates reaching varying levels of abstraction but that approach must also ensure that abstract interpretations are supported and justified by the source data and not solely the product of the analyst’s speculative thinking.

Principle #7:

Considering the qualitative nature of the analysis required in systematic methods overviews, it is important to select an analytic method whose interpretations can be verified as being consistent with the literature selected, regardless of the level of abstraction reached.

Strategy #7:

We suggest employing the constant comparative method of analysis [ 29 ] because it supports developing and verifying analytic links to the source data throughout progressively interpretive or abstract levels. In applying this approach, we advise a rigorous approach, documenting how supportive quotes or references to the original texts are carried forward in the successive steps of analysis to allow for easy verification.

The analytic approach used in the methods overview on sampling [ 18 ] comprised four explicit steps, progressing in level of abstraction—data abstraction, matrices, narrative summaries, and final analytic conclusions (Fig.  2 ). While we have positioned data abstraction as the second stage of the generic review process (prior to Analysis), above, we also considered it as an initial step of analysis in the sampling overview for several reasons. First, it involved a process of constant comparisons and iterative decision-making about the fields to add or define during development and modification of the abstraction form, through which we established the range of concepts to be addressed in the review. At the same time, abstraction involved continuous analytic decisions about what textual quotes (ranging in size from short phrases to numerous paragraphs) to record in the fields thus created. This constant comparative process was analogous to open coding in which textual data from publications was compared to conceptual fields (equivalent to codes) or to other instances of data previously abstracted when constructing definitions to optimize their fit with the overall literature as described in strategy #6. Finally, in the data abstraction step, we also recorded our first interpretive thoughts in dedicated fields, providing initial material for the more abstract analytic steps.

Summary of progressive steps of analysis used in the methods overview on sampling [ 18 ]

In the second step of the analysis, we constructed topic-specific matrices , or tables, by copying relevant quotes from abstraction forms into the appropriate cells of matrices (for the complete set of analytic matrices developed in the sampling review, see Additional file 1 (matrices 3 to 10)). Each matrix ranged from one to five pages; row headings, nested three-deep, identified the methodological tradition, author, and publication, respectively; and column headings identified the concepts, which corresponded to abstraction fields. Matrices thus allowed us to make further comparisons across methodological traditions, and between authors within a tradition. In the third step of analysis, we recorded our comparative observations as narrative summaries , in which we used illustrative quotes more sparingly. In the final step, we developed analytic conclusions based on the narrative summaries about the sampling-related concepts within each methodological tradition for which clarity, consistency, or comprehensiveness of the available guidance appeared to be lacking. Higher levels of analysis thus built logically from the lower levels, enabling us to easily verify analytic conclusions by tracing the support for claims by comparing the original text of publications reviewed.

Integrative versus interpretive methods overviews

The analytic product of systematic methods overviews is comparable to qualitative evidence syntheses, since both involve describing and interpreting the relevant literature in qualitative terms. Most qualitative synthesis approaches strive to produce new conceptual understandings that vary in level of interpretation. Dixon-Woods and colleagues [ 30 ] elaborate on a useful distinction, originating from Noblit and Hare [ 27 ], between integrative and interpretive reviews. Integrative reviews focus on summarizing available primary data and involve using largely secure and well defined concepts to do so; definitions are used from an early stage to specify categories for abstraction (or coding) of data, which in turn supports their aggregation; they do not seek as their primary focus to develop or specify new concepts, although they may achieve some theoretical or interpretive functions. For interpretive reviews, meanwhile, the main focus is to develop new concepts and theories that integrate them, with the implication that the concepts developed become fully defined towards the end of the analysis. These two forms are not completely distinct, and “every integrative synthesis will include elements of interpretation, and every interpretive synthesis will include elements of aggregation of data” [ 30 ].

The example methods overview on sampling [ 18 ] could be classified as predominantly integrative because its primary goal was to aggregate influential authors’ ideas on sampling-related concepts; there were also, however, elements of interpretive synthesis since it aimed to develop new ideas about where clarity in guidance on certain sampling-related topics is lacking, and definitions for some concepts were flexible and not fixed until late in the review. We suggest that most systematic methods overviews will be classifiable as predominantly integrative (aggregative). Nevertheless, more highly interpretive methods overviews are also quite possible—for example, when the review objective is to provide a highly critical analysis for the purpose of generating new methodological guidance. In such cases, reviewers may need to sample more deeply (see strategy #4), specifically by selecting empirical research reports (i.e., to go beyond dominant or influential ideas in the methods literature) that are likely to feature innovations or instructive lessons in employing a given method.

In this paper, we have outlined tentative guidance in the form of seven principles and strategies on how to conduct systematic methods overviews, a review type in which methods-relevant literature is systematically analyzed with the aim of offering clarity and enhancing collective understanding regarding a specific methods topic. Our proposals include strategies for delimiting the set of publications to consider, searching beyond standard bibliographic databases, searching without the availability of relevant metadata, selecting publications on purposeful conceptual grounds, defining concepts and other information to abstract iteratively, accounting for inconsistent terminology, and generating credible and verifiable analytic interpretations. We hope the suggestions proposed will be useful to others undertaking reviews on methods topics in future.

As far as we are aware, this is the first published source of concrete guidance for conducting this type of review. It is important to note that our primary objective was to initiate methodological discussion by stimulating reflection on what rigorous methods for this type of review should look like, leaving the development of more complete guidance to future work. While derived from the experience of reviewing a single qualitative methods topic, we believe the principles and strategies provided are generalizable to overviews of both qualitative and quantitative methods topics alike. However, it is expected that additional challenges and insights for conducting such reviews have yet to be defined. Thus, we propose that next steps for developing more definitive guidance should involve an attempt to collect and integrate other reviewers’ perspectives and experiences in conducting systematic methods overviews on a broad range of qualitative and quantitative methods topics. Formalized guidance and standards would improve the quality of future methods overviews, something we believe has important implications for advancing qualitative and quantitative methodology. When undertaken to a high standard, rigorous critical evaluations of the available methods guidance have significant potential to make implicit controversies explicit, and improve the clarity and precision of our understandings of problematic qualitative or quantitative methods issues.

A review process central to most types of rigorous reviews of empirical studies, which we did not explicitly address in a separate review step above, is quality appraisal . The reason we have not treated this as a separate step stems from the different objectives of the primary publications included in overviews of the methods literature (i.e., providing methodological guidance) compared to the primary publications included in the other established review types (i.e., reporting findings from single empirical studies). This is not to say that appraising quality of the methods literature is not an important concern for systematic methods overviews. Rather, appraisal is much more integral to (and difficult to separate from) the analysis step, in which we advocate appraising clarity, consistency, and comprehensiveness—the quality appraisal criteria that we suggest are appropriate for the methods literature. As a second important difference regarding appraisal, we currently advocate appraising the aforementioned aspects at the level of the literature in aggregate rather than at the level of individual publications. One reason for this is that methods guidance from individual publications generally builds on previous literature, and thus we feel that ahistorical judgments about comprehensiveness of single publications lack relevance and utility. Additionally, while different methods authors may express themselves less clearly than others, their guidance can nonetheless be highly influential and useful, and should therefore not be downgraded or ignored based on considerations of clarity—which raises questions about the alternative uses that quality appraisals of individual publications might have. Finally, legitimate variability in the perspectives that methods authors wish to emphasize, and the levels of generality at which they write about methods, makes critiquing individual publications based on the criterion of clarity a complex and potentially problematic endeavor that is beyond the scope of this paper to address. By appraising the current state of the literature at a holistic level, reviewers stand to identify important gaps in understanding that represent valuable opportunities for further methodological development.

To summarize, the principles and strategies provided here may be useful to those seeking to undertake their own systematic methods overview. Additional work is needed, however, to establish guidance that is comprehensive by comparing the experiences from conducting a variety of methods overviews on a range of methods topics. Efforts that further advance standards for systematic methods overviews have the potential to promote high-quality critical evaluations that produce conceptually clear and unified understandings of problematic methods topics, thereby accelerating the advance of research methodology.

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Acknowledgements

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There was no funding for this work.

Availability of data and materials

The systematic methods overview used as a worked example in this article (Gentles SJ, Charles C, Ploeg J, McKibbon KA: Sampling in qualitative research: insights from an overview of the methods literature. The Qual Rep 2015, 20(11):1772-1789) is available from http://nsuworks.nova.edu/tqr/vol20/iss11/5 .

Authors’ contributions

SJG wrote the first draft of this article, with CC contributing to drafting. All authors contributed to revising the manuscript. All authors except CC (deceased) approved the final draft. SJG, CC, KAB, and JP were involved in developing methods for the systematic methods overview on sampling.

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Competing interests.

The authors declare that they have no competing interests.

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Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

Stephen J. Gentles, Cathy Charles & K. Ann McKibbon

Faculty of Social Work, University of Calgary, Alberta, Canada

David B. Nicholas

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Gentles, S.J., Charles, C., Nicholas, D.B. et al. Reviewing the research methods literature: principles and strategies illustrated by a systematic overview of sampling in qualitative research. Syst Rev 5 , 172 (2016). https://doi.org/10.1186/s13643-016-0343-0

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• Systematic review
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Research Methods

• Getting Started
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Literature Review

• What is a Literature Review?
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• Purposes of a Literature Review
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• Literature Reviews vs. Systematic Reviews
• Systematic vs. Meta-Analysis

Literature Review  is a comprehensive survey of the works published in a particular field of study or line of research, usually over a specific period of time, in the form of an in-depth, critical bibliographic essay or annotated list in which attention is drawn to the most significant works.

Also, we can define a literature review as the collected body of scholarly works related to a topic:

• Summarizes and analyzes previous research relevant to a topic
• Includes scholarly books and articles published in academic journals
• Can be an specific scholarly paper or a section in a research paper

The objective of a Literature Review is to find previous published scholarly works relevant to an specific topic

• Help gather ideas or information
• Keep up to date in current trends and findings
• Help develop new questions

A literature review is important because it:

• Explains the background of research on a topic.
• Demonstrates why a topic is significant to a subject area.
• Helps focus your own research questions or problems
• Discovers relationships between research studies/ideas.
• Suggests unexplored ideas or populations
• Identifies major themes, concepts, and researchers on a topic.
• Tests assumptions; may help counter preconceived ideas and remove unconscious bias.
• Identifies critical gaps, points of disagreement, or potentially flawed methodology or theoretical approaches.
• Indicates potential directions for future research.

All content in this section is from Literature Review Research from Old Dominion University 

Keep in mind the following, a literature review is NOT:

Not an essay 

Not an annotated bibliography  in which you summarize each article that you have reviewed.  A literature review goes beyond basic summarizing to focus on the critical analysis of the reviewed works and their relationship to your research question.

Not a research paper   where you select resources to support one side of an issue versus another.  A lit review should explain and consider all sides of an argument in order to avoid bias, and areas of agreement and disagreement should be highlighted.

A literature review serves several purposes. For example, it

• provides thorough knowledge of previous studies; introduces seminal works.
• helps focus one’s own research topic.
• identifies a conceptual framework for one’s own research questions or problems; indicates potential directions for future research.
• suggests previously unused or underused methodologies, designs, quantitative and qualitative strategies.
• identifies gaps in previous studies; identifies flawed methodologies and/or theoretical approaches; avoids replication of mistakes.
• helps the researcher avoid repetition of earlier research.
• suggests unexplored populations.
• determines whether past studies agree or disagree; identifies controversy in the literature.
• tests assumptions; may help counter preconceived ideas and remove unconscious bias.

As Kennedy (2007) notes*, it is important to think of knowledge in a given field as consisting of three layers. First, there are the primary studies that researchers conduct and publish. Second are the reviews of those studies that summarize and offer new interpretations built from and often extending beyond the original studies. Third, there are the perceptions, conclusions, opinion, and interpretations that are shared informally that become part of the lore of field. In composing a literature review, it is important to note that it is often this third layer of knowledge that is cited as "true" even though it often has only a loose relationship to the primary studies and secondary literature reviews.

Given this, while literature reviews are designed to provide an overview and synthesis of pertinent sources you have explored, there are several approaches to how they can be done, depending upon the type of analysis underpinning your study. Listed below are definitions of types of literature reviews:

Argumentative Review      This form examines literature selectively in order to support or refute an argument, deeply imbedded assumption, or philosophical problem already established in the literature. The purpose is to develop a body of literature that establishes a contrarian viewpoint. Given the value-laden nature of some social science research [e.g., educational reform; immigration control], argumentative approaches to analyzing the literature can be a legitimate and important form of discourse. However, note that they can also introduce problems of bias when they are used to to make summary claims of the sort found in systematic reviews.

Integrative Review      Considered a form of research that reviews, critiques, and synthesizes representative literature on a topic in an integrated way such that new frameworks and perspectives on the topic are generated. The body of literature includes all studies that address related or identical hypotheses. A well-done integrative review meets the same standards as primary research in regard to clarity, rigor, and replication.

Historical Review      Few things rest in isolation from historical precedent. Historical reviews are focused on examining research throughout a period of time, often starting with the first time an issue, concept, theory, phenomena emerged in the literature, then tracing its evolution within the scholarship of a discipline. The purpose is to place research in a historical context to show familiarity with state-of-the-art developments and to identify the likely directions for future research.

Methodological Review      A review does not always focus on what someone said [content], but how they said it [method of analysis]. This approach provides a framework of understanding at different levels (i.e. those of theory, substantive fields, research approaches and data collection and analysis techniques), enables researchers to draw on a wide variety of knowledge ranging from the conceptual level to practical documents for use in fieldwork in the areas of ontological and epistemological consideration, quantitative and qualitative integration, sampling, interviewing, data collection and data analysis, and helps highlight many ethical issues which we should be aware of and consider as we go through our study.

Systematic Review      This form consists of an overview of existing evidence pertinent to a clearly formulated research question, which uses pre-specified and standardized methods to identify and critically appraise relevant research, and to collect, report, and analyse data from the studies that are included in the review. Typically it focuses on a very specific empirical question, often posed in a cause-and-effect form, such as "To what extent does A contribute to B?"

Theoretical Review      The purpose of this form is to concretely examine the corpus of theory that has accumulated in regard to an issue, concept, theory, phenomena. The theoretical literature review help establish what theories already exist, the relationships between them, to what degree the existing theories have been investigated, and to develop new hypotheses to be tested. Often this form is used to help establish a lack of appropriate theories or reveal that current theories are inadequate for explaining new or emerging research problems. The unit of analysis can focus on a theoretical concept or a whole theory or framework.

* Kennedy, Mary M. "Defining a Literature."  Educational Researcher  36 (April 2007): 139-147.

All content in this section is from The Literature Review created by Dr. Robert Larabee USC

Robinson, P. and Lowe, J. (2015),  Literature reviews vs systematic reviews.  Australian and New Zealand Journal of Public Health, 39: 103-103. doi: 10.1111/1753-6405.12393

What's in the name? The difference between a Systematic Review and a Literature Review, and why it matters . By Lynn Kysh from University of Southern California

Systematic review or meta-analysis?

A  systematic review  answers a defined research question by collecting and summarizing all empirical evidence that fits pre-specified eligibility criteria.

A  meta-analysis  is the use of statistical methods to summarize the results of these studies.

Systematic reviews, just like other research articles, can be of varying quality. They are a significant piece of work (the Centre for Reviews and Dissemination at York estimates that a team will take 9-24 months), and to be useful to other researchers and practitioners they should have:

• clearly stated objectives with pre-defined eligibility criteria for studies
• explicit, reproducible methodology
• a systematic search that attempts to identify all studies
• assessment of the validity of the findings of the included studies (e.g. risk of bias)
• systematic presentation, and synthesis, of the characteristics and findings of the included studies

Not all systematic reviews contain meta-analysis. 

Meta-analysis is the use of statistical methods to summarize the results of independent studies. By combining information from all relevant studies, meta-analysis can provide more precise estimates of the effects of health care than those derived from the individual studies included within a review.  More information on meta-analyses can be found in  Cochrane Handbook, Chapter 9 .

A meta-analysis goes beyond critique and integration and conducts secondary statistical analysis on the outcomes of similar studies.  It is a systematic review that uses quantitative methods to synthesize and summarize the results.

An advantage of a meta-analysis is the ability to be completely objective in evaluating research findings.  Not all topics, however, have sufficient research evidence to allow a meta-analysis to be conducted.  In that case, an integrative review is an appropriate strategy. 

Some of the content in this section is from Systematic reviews and meta-analyses: step by step guide created by Kate McAllister.

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A literature review surveys prior research published in books, scholarly articles, and any other sources relevant to a particular issue, area of research, or theory, and by so doing, provides a description, summary, and critical evaluation of these works in relation to the research problem being investigated. Literature reviews are designed to provide an overview of sources you have used in researching a particular topic and to demonstrate to your readers how your research fits within existing scholarship about the topic.

Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper . Fourth edition. Thousand Oaks, CA: SAGE, 2014.

Importance of a Good Literature Review

A literature review may consist of simply a summary of key sources, but in the social sciences, a literature review usually has an organizational pattern and combines both summary and synthesis, often within specific conceptual categories . A summary is a recap of the important information of the source, but a synthesis is a re-organization, or a reshuffling, of that information in a way that informs how you are planning to investigate a research problem. The analytical features of a literature review might:

• Give a new interpretation of old material or combine new with old interpretations,
• Trace the intellectual progression of the field, including major debates,
• Depending on the situation, evaluate the sources and advise the reader on the most pertinent or relevant research, or
• Usually in the conclusion of a literature review, identify where gaps exist in how a problem has been researched to date.

Given this, the purpose of a literature review is to:

• Place each work in the context of its contribution to understanding the research problem being studied.
• Describe the relationship of each work to the others under consideration.
• Identify new ways to interpret prior research.
• Reveal any gaps that exist in the literature.
• Resolve conflicts amongst seemingly contradictory previous studies.
• Identify areas of prior scholarship to prevent duplication of effort.
• Point the way in fulfilling a need for additional research.
• Locate your own research within the context of existing literature [very important].

Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper. 2nd ed. Thousand Oaks, CA: Sage, 2005; Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1998; Jesson, Jill. Doing Your Literature Review: Traditional and Systematic Techniques . Los Angeles, CA: SAGE, 2011; Knopf, Jeffrey W. "Doing a Literature Review." PS: Political Science and Politics 39 (January 2006): 127-132; Ridley, Diana. The Literature Review: A Step-by-Step Guide for Students . 2nd ed. Los Angeles, CA: SAGE, 2012.

Types of Literature Reviews

It is important to think of knowledge in a given field as consisting of three layers. First, there are the primary studies that researchers conduct and publish. Second are the reviews of those studies that summarize and offer new interpretations built from and often extending beyond the primary studies. Third, there are the perceptions, conclusions, opinion, and interpretations that are shared informally among scholars that become part of the body of epistemological traditions within the field.

In composing a literature review, it is important to note that it is often this third layer of knowledge that is cited as "true" even though it often has only a loose relationship to the primary studies and secondary literature reviews. Given this, while literature reviews are designed to provide an overview and synthesis of pertinent sources you have explored, there are a number of approaches you could adopt depending upon the type of analysis underpinning your study.

Argumentative Review This form examines literature selectively in order to support or refute an argument, deeply embedded assumption, or philosophical problem already established in the literature. The purpose is to develop a body of literature that establishes a contrarian viewpoint. Given the value-laden nature of some social science research [e.g., educational reform; immigration control], argumentative approaches to analyzing the literature can be a legitimate and important form of discourse. However, note that they can also introduce problems of bias when they are used to make summary claims of the sort found in systematic reviews [see below].

Integrative Review Considered a form of research that reviews, critiques, and synthesizes representative literature on a topic in an integrated way such that new frameworks and perspectives on the topic are generated. The body of literature includes all studies that address related or identical hypotheses or research problems. A well-done integrative review meets the same standards as primary research in regard to clarity, rigor, and replication. This is the most common form of review in the social sciences.

Historical Review Few things rest in isolation from historical precedent. Historical literature reviews focus on examining research throughout a period of time, often starting with the first time an issue, concept, theory, phenomena emerged in the literature, then tracing its evolution within the scholarship of a discipline. The purpose is to place research in a historical context to show familiarity with state-of-the-art developments and to identify the likely directions for future research.

Methodological Review A review does not always focus on what someone said [findings], but how they came about saying what they say [method of analysis]. Reviewing methods of analysis provides a framework of understanding at different levels [i.e. those of theory, substantive fields, research approaches, and data collection and analysis techniques], how researchers draw upon a wide variety of knowledge ranging from the conceptual level to practical documents for use in fieldwork in the areas of ontological and epistemological consideration, quantitative and qualitative integration, sampling, interviewing, data collection, and data analysis. This approach helps highlight ethical issues which you should be aware of and consider as you go through your own study.

Systematic Review This form consists of an overview of existing evidence pertinent to a clearly formulated research question, which uses pre-specified and standardized methods to identify and critically appraise relevant research, and to collect, report, and analyze data from the studies that are included in the review. The goal is to deliberately document, critically evaluate, and summarize scientifically all of the research about a clearly defined research problem . Typically it focuses on a very specific empirical question, often posed in a cause-and-effect form, such as "To what extent does A contribute to B?" This type of literature review is primarily applied to examining prior research studies in clinical medicine and allied health fields, but it is increasingly being used in the social sciences.

Theoretical Review The purpose of this form is to examine the corpus of theory that has accumulated in regard to an issue, concept, theory, phenomena. The theoretical literature review helps to establish what theories already exist, the relationships between them, to what degree the existing theories have been investigated, and to develop new hypotheses to be tested. Often this form is used to help establish a lack of appropriate theories or reveal that current theories are inadequate for explaining new or emerging research problems. The unit of analysis can focus on a theoretical concept or a whole theory or framework.

NOTE : Most often the literature review will incorporate some combination of types. For example, a review that examines literature supporting or refuting an argument, assumption, or philosophical problem related to the research problem will also need to include writing supported by sources that establish the history of these arguments in the literature.

Baumeister, Roy F. and Mark R. Leary. "Writing Narrative Literature Reviews."  Review of General Psychology 1 (September 1997): 311-320; Mark R. Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper . 2nd ed. Thousand Oaks, CA: Sage, 2005; Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1998; Kennedy, Mary M. "Defining a Literature." Educational Researcher 36 (April 2007): 139-147; Petticrew, Mark and Helen Roberts. Systematic Reviews in the Social Sciences: A Practical Guide . Malden, MA: Blackwell Publishers, 2006; Torracro, Richard. "Writing Integrative Literature Reviews: Guidelines and Examples." Human Resource Development Review 4 (September 2005): 356-367; Rocco, Tonette S. and Maria S. Plakhotnik. "Literature Reviews, Conceptual Frameworks, and Theoretical Frameworks: Terms, Functions, and Distinctions." Human Ressource Development Review 8 (March 2008): 120-130; Sutton, Anthea. Systematic Approaches to a Successful Literature Review . Los Angeles, CA: Sage Publications, 2016.

Structure and Writing Style

I.  Thinking About Your Literature Review

The structure of a literature review should include the following in support of understanding the research problem :

• An overview of the subject, issue, or theory under consideration, along with the objectives of the literature review,
• Division of works under review into themes or categories [e.g. works that support a particular position, those against, and those offering alternative approaches entirely],
• An explanation of how each work is similar to and how it varies from the others,
• Conclusions as to which pieces are best considered in their argument, are most convincing of their opinions, and make the greatest contribution to the understanding and development of their area of research.

The critical evaluation of each work should consider :

• Provenance -- what are the author's credentials? Are the author's arguments supported by evidence [e.g. primary historical material, case studies, narratives, statistics, recent scientific findings]?
• Methodology -- were the techniques used to identify, gather, and analyze the data appropriate to addressing the research problem? Was the sample size appropriate? Were the results effectively interpreted and reported?
• Objectivity -- is the author's perspective even-handed or prejudicial? Is contrary data considered or is certain pertinent information ignored to prove the author's point?
• Persuasiveness -- which of the author's theses are most convincing or least convincing?
• Validity -- are the author's arguments and conclusions convincing? Does the work ultimately contribute in any significant way to an understanding of the subject?

II.  Development of the Literature Review

Four Basic Stages of Writing 1.  Problem formulation -- which topic or field is being examined and what are its component issues? 2.  Literature search -- finding materials relevant to the subject being explored. 3.  Data evaluation -- determining which literature makes a significant contribution to the understanding of the topic. 4.  Analysis and interpretation -- discussing the findings and conclusions of pertinent literature.

Consider the following issues before writing the literature review: Clarify If your assignment is not specific about what form your literature review should take, seek clarification from your professor by asking these questions: 1.  Roughly how many sources would be appropriate to include? 2.  What types of sources should I review (books, journal articles, websites; scholarly versus popular sources)? 3.  Should I summarize, synthesize, or critique sources by discussing a common theme or issue? 4.  Should I evaluate the sources in any way beyond evaluating how they relate to understanding the research problem? 5.  Should I provide subheadings and other background information, such as definitions and/or a history? Find Models Use the exercise of reviewing the literature to examine how authors in your discipline or area of interest have composed their literature review sections. Read them to get a sense of the types of themes you might want to look for in your own research or to identify ways to organize your final review. The bibliography or reference section of sources you've already read, such as required readings in the course syllabus, are also excellent entry points into your own research. Narrow the Topic The narrower your topic, the easier it will be to limit the number of sources you need to read in order to obtain a good survey of relevant resources. Your professor will probably not expect you to read everything that's available about the topic, but you'll make the act of reviewing easier if you first limit scope of the research problem. A good strategy is to begin by searching the USC Libraries Catalog for recent books about the topic and review the table of contents for chapters that focuses on specific issues. You can also review the indexes of books to find references to specific issues that can serve as the focus of your research. For example, a book surveying the history of the Israeli-Palestinian conflict may include a chapter on the role Egypt has played in mediating the conflict, or look in the index for the pages where Egypt is mentioned in the text. Consider Whether Your Sources are Current Some disciplines require that you use information that is as current as possible. This is particularly true in disciplines in medicine and the sciences where research conducted becomes obsolete very quickly as new discoveries are made. However, when writing a review in the social sciences, a survey of the history of the literature may be required. In other words, a complete understanding the research problem requires you to deliberately examine how knowledge and perspectives have changed over time. Sort through other current bibliographies or literature reviews in the field to get a sense of what your discipline expects. You can also use this method to explore what is considered by scholars to be a "hot topic" and what is not.

III.  Ways to Organize Your Literature Review

Chronology of Events If your review follows the chronological method, you could write about the materials according to when they were published. This approach should only be followed if a clear path of research building on previous research can be identified and that these trends follow a clear chronological order of development. For example, a literature review that focuses on continuing research about the emergence of German economic power after the fall of the Soviet Union. By Publication Order your sources by publication chronology, then, only if the order demonstrates a more important trend. For instance, you could order a review of literature on environmental studies of brown fields if the progression revealed, for example, a change in the soil collection practices of the researchers who wrote and/or conducted the studies. Thematic [“conceptual categories”] A thematic literature review is the most common approach to summarizing prior research in the social and behavioral sciences. Thematic reviews are organized around a topic or issue, rather than the progression of time, although the progression of time may still be incorporated into a thematic review. For example, a review of the Internet’s impact on American presidential politics could focus on the development of online political satire. While the study focuses on one topic, the Internet’s impact on American presidential politics, it would still be organized chronologically reflecting technological developments in media. The difference in this example between a "chronological" and a "thematic" approach is what is emphasized the most: themes related to the role of the Internet in presidential politics. Note that more authentic thematic reviews tend to break away from chronological order. A review organized in this manner would shift between time periods within each section according to the point being made. Methodological A methodological approach focuses on the methods utilized by the researcher. For the Internet in American presidential politics project, one methodological approach would be to look at cultural differences between the portrayal of American presidents on American, British, and French websites. Or the review might focus on the fundraising impact of the Internet on a particular political party. A methodological scope will influence either the types of documents in the review or the way in which these documents are discussed.

Other Sections of Your Literature Review Once you've decided on the organizational method for your literature review, the sections you need to include in the paper should be easy to figure out because they arise from your organizational strategy. In other words, a chronological review would have subsections for each vital time period; a thematic review would have subtopics based upon factors that relate to the theme or issue. However, sometimes you may need to add additional sections that are necessary for your study, but do not fit in the organizational strategy of the body. What other sections you include in the body is up to you. However, only include what is necessary for the reader to locate your study within the larger scholarship about the research problem.

Here are examples of other sections, usually in the form of a single paragraph, you may need to include depending on the type of review you write:

• Current Situation : Information necessary to understand the current topic or focus of the literature review.
• Sources Used : Describes the methods and resources [e.g., databases] you used to identify the literature you reviewed.
• History : The chronological progression of the field, the research literature, or an idea that is necessary to understand the literature review, if the body of the literature review is not already a chronology.
• Selection Methods : Criteria you used to select (and perhaps exclude) sources in your literature review. For instance, you might explain that your review includes only peer-reviewed [i.e., scholarly] sources.
• Standards : Description of the way in which you present your information.
• Questions for Further Research : What questions about the field has the review sparked? How will you further your research as a result of the review?

IV.  Writing Your Literature Review

Once you've settled on how to organize your literature review, you're ready to write each section. When writing your review, keep in mind these issues.

Use Evidence A literature review section is, in this sense, just like any other academic research paper. Your interpretation of the available sources must be backed up with evidence [citations] that demonstrates that what you are saying is valid. Be Selective Select only the most important points in each source to highlight in the review. The type of information you choose to mention should relate directly to the research problem, whether it is thematic, methodological, or chronological. Related items that provide additional information, but that are not key to understanding the research problem, can be included in a list of further readings . Use Quotes Sparingly Some short quotes are appropriate if you want to emphasize a point, or if what an author stated cannot be easily paraphrased. Sometimes you may need to quote certain terminology that was coined by the author, is not common knowledge, or taken directly from the study. Do not use extensive quotes as a substitute for using your own words in reviewing the literature. Summarize and Synthesize Remember to summarize and synthesize your sources within each thematic paragraph as well as throughout the review. Recapitulate important features of a research study, but then synthesize it by rephrasing the study's significance and relating it to your own work and the work of others. Keep Your Own Voice While the literature review presents others' ideas, your voice [the writer's] should remain front and center. For example, weave references to other sources into what you are writing but maintain your own voice by starting and ending the paragraph with your own ideas and wording. Use Caution When Paraphrasing When paraphrasing a source that is not your own, be sure to represent the author's information or opinions accurately and in your own words. Even when paraphrasing an author’s work, you still must provide a citation to that work.

V.  Common Mistakes to Avoid

These are the most common mistakes made in reviewing social science research literature.

• Sources in your literature review do not clearly relate to the research problem;
• You do not take sufficient time to define and identify the most relevant sources to use in the literature review related to the research problem;
• Relies exclusively on secondary analytical sources rather than including relevant primary research studies or data;
• Uncritically accepts another researcher's findings and interpretations as valid, rather than examining critically all aspects of the research design and analysis;
• Does not describe the search procedures that were used in identifying the literature to review;
• Reports isolated statistical results rather than synthesizing them in chi-squared or meta-analytic methods; and,
• Only includes research that validates assumptions and does not consider contrary findings and alternative interpretations found in the literature.

Cook, Kathleen E. and Elise Murowchick. “Do Literature Review Skills Transfer from One Course to Another?” Psychology Learning and Teaching 13 (March 2014): 3-11; Fink, Arlene. Conducting Research Literature Reviews: From the Internet to Paper . 2nd ed. Thousand Oaks, CA: Sage, 2005; Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1998; Jesson, Jill. Doing Your Literature Review: Traditional and Systematic Techniques . London: SAGE, 2011; Literature Review Handout. Online Writing Center. Liberty University; Literature Reviews. The Writing Center. University of North Carolina; Onwuegbuzie, Anthony J. and Rebecca Frels. Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach . Los Angeles, CA: SAGE, 2016; Ridley, Diana. The Literature Review: A Step-by-Step Guide for Students . 2nd ed. Los Angeles, CA: SAGE, 2012; Randolph, Justus J. “A Guide to Writing the Dissertation Literature Review." Practical Assessment, Research, and Evaluation. vol. 14, June 2009; Sutton, Anthea. Systematic Approaches to a Successful Literature Review . Los Angeles, CA: Sage Publications, 2016; Taylor, Dena. The Literature Review: A Few Tips On Conducting It. University College Writing Centre. University of Toronto; Writing a Literature Review. Academic Skills Centre. University of Canberra.

Writing Tip

Break Out of Your Disciplinary Box!

Thinking interdisciplinarily about a research problem can be a rewarding exercise in applying new ideas, theories, or concepts to an old problem. For example, what might cultural anthropologists say about the continuing conflict in the Middle East? In what ways might geographers view the need for better distribution of social service agencies in large cities than how social workers might study the issue? You don’t want to substitute a thorough review of core research literature in your discipline for studies conducted in other fields of study. However, particularly in the social sciences, thinking about research problems from multiple vectors is a key strategy for finding new solutions to a problem or gaining a new perspective. Consult with a librarian about identifying research databases in other disciplines; almost every field of study has at least one comprehensive database devoted to indexing its research literature.

Frodeman, Robert. The Oxford Handbook of Interdisciplinarity . New York: Oxford University Press, 2010.

Another Writing Tip

Don't Just Review for Content!

While conducting a review of the literature, maximize the time you devote to writing this part of your paper by thinking broadly about what you should be looking for and evaluating. Review not just what scholars are saying, but how are they saying it. Some questions to ask:

• How are they organizing their ideas?
• What methods have they used to study the problem?
• What theories have been used to explain, predict, or understand their research problem?
• What sources have they cited to support their conclusions?
• How have they used non-textual elements [e.g., charts, graphs, figures, etc.] to illustrate key points?

When you begin to write your literature review section, you'll be glad you dug deeper into how the research was designed and constructed because it establishes a means for developing more substantial analysis and interpretation of the research problem.

Hart, Chris. Doing a Literature Review: Releasing the Social Science Research Imagination . Thousand Oaks, CA: Sage Publications, 1 998.

Yet Another Writing Tip

When Do I Know I Can Stop Looking and Move On?

Here are several strategies you can utilize to assess whether you've thoroughly reviewed the literature:

• Look for repeating patterns in the research findings . If the same thing is being said, just by different people, then this likely demonstrates that the research problem has hit a conceptual dead end. At this point consider: Does your study extend current research?  Does it forge a new path? Or, does is merely add more of the same thing being said?
• Look at sources the authors cite to in their work . If you begin to see the same researchers cited again and again, then this is often an indication that no new ideas have been generated to address the research problem.
• Search Google Scholar to identify who has subsequently cited leading scholars already identified in your literature review [see next sub-tab]. This is called citation tracking and there are a number of sources that can help you identify who has cited whom, particularly scholars from outside of your discipline. Here again, if the same authors are being cited again and again, this may indicate no new literature has been written on the topic.

Onwuegbuzie, Anthony J. and Rebecca Frels. Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach . Los Angeles, CA: Sage, 2016; Sutton, Anthea. Systematic Approaches to a Successful Literature Review . Los Angeles, CA: Sage Publications, 2016.

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A literature review is a review and synthesis of existing research on a topic or research question. A literature review is meant to analyze the scholarly literature, make connections across writings and identify strengths, weaknesses, trends, and missing conversations. A literature review should address different aspects of a topic as it relates to your research question. A literature review goes beyond a description or summary of the literature you have read. 

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Writing a Scientific Review Article: Comprehensive Insights for Beginners

Ayodeji amobonye.

1 Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, P.O. Box 1334, KwaZulu-Natal, Durban 4000, South Africa

2 Writing Centre, Durban University of Technology, P.O. Box 1334 KwaZulu-Natal, Durban 4000, South Africa

Japareng Lalung

3 School of Industrial Technology, Universiti Sains Malaysia, Gelugor 11800, Pulau Pinang, Malaysia

Santhosh Pillai

Associated data.

The data and materials that support the findings of this study are available from the corresponding author upon reasonable request.

Review articles present comprehensive overview of relevant literature on specific themes and synthesise the studies related to these themes, with the aim of strengthening the foundation of knowledge and facilitating theory development. The significance of review articles in science is immeasurable as both students and researchers rely on these articles as the starting point for their research. Interestingly, many postgraduate students are expected to write review articles for journal publications as a way of demonstrating their ability to contribute to new knowledge in their respective fields. However, there is no comprehensive instructional framework to guide them on how to analyse and synthesise the literature in their niches into publishable review articles. The dearth of ample guidance or explicit training results in students having to learn all by themselves, usually by trial and error, which often leads to high rejection rates from publishing houses. Therefore, this article seeks to identify these challenges from a beginner's perspective and strives to plug the identified gaps and discrepancies. Thus, the purpose of this paper is to serve as a systematic guide for emerging scientists and to summarise the most important information on how to write and structure a publishable review article.

1. Introduction

Early scientists, spanning from the Ancient Egyptian civilization to the Scientific Revolution of the 16 th /17 th century, based their research on intuitions, personal observations, and personal insights. Thus, less time was spent on background reading as there was not much literature to refer to. This is well illustrated in the case of Sir Isaac Newton's apple tree and the theory of gravity, as well as Gregor Mendel's pea plants and the theory of inheritance. However, with the astronomical expansion in scientific knowledge and the emergence of the information age in the last century, new ideas are now being built on previously published works, thus the periodic need to appraise the huge amount of already published literature [ 1 ]. According to Birkle et al. [ 2 ], the Web of Science—an authoritative database of research publications and citations—covered more than 80 million scholarly materials. Hence, a critical review of prior and relevant literature is indispensable for any research endeavour as it provides the necessary framework needed for synthesising new knowledge and for highlighting new insights and perspectives [ 3 ].

Review papers are generally considered secondary research publications that sum up already existing works on a particular research topic or question and relate them to the current status of the topic. This makes review articles distinctly different from scientific research papers. While the primary aim of the latter is to develop new arguments by reporting original research, the former is focused on summarising and synthesising previous ideas, studies, and arguments, without adding new experimental contributions. Review articles basically describe the content and quality of knowledge that are currently available, with a special focus on the significance of the previous works. To this end, a review article cannot simply reiterate a subject matter, but it must contribute to the field of knowledge by synthesising available materials and offering a scholarly critique of theory [ 4 ]. Typically, these articles critically analyse both quantitative and qualitative studies by scrutinising experimental results, the discussion of the experimental data, and in some instances, previous review articles to propose new working theories. Thus, a review article is more than a mere exhaustive compilation of all that has been published on a topic; it must be a balanced, informative, perspective, and unbiased compendium of previous studies which may also include contrasting findings, inconsistencies, and conventional and current views on the subject [ 5 ].

Hence, the essence of a review article is measured by what is achieved, what is discovered, and how information is communicated to the reader [ 6 ]. According to Steward [ 7 ], a good literature review should be analytical, critical, comprehensive, selective, relevant, synthetic, and fully referenced. On the other hand, a review article is considered to be inadequate if it is lacking in focus or outcome, overgeneralised, opinionated, unbalanced, and uncritical [ 7 ]. Most review papers fail to meet these standards and thus can be viewed as mere summaries of previous works in a particular field of study. In one of the few studies that assessed the quality of review articles, none of the 50 papers that were analysed met the predefined criteria for a good review [ 8 ]. However, beginners must also realise that there is no bad writing in the true sense; there is only writing in evolution and under refinement. Literally, every piece of writing can be improved upon, right from the first draft until the final published manuscript. Hence, a paper can only be referred to as bad and unfixable when the author is not open to corrections or when the writer gives up on it.

According to Peat et al. [ 9 ], “everything is easy when you know how,” a maxim which applies to scientific writing in general and review writing in particular. In this regard, the authors emphasized that the writer should be open to learning and should also follow established rules instead of following a blind trial-and-error approach. In contrast to the popular belief that review articles should only be written by experienced scientists and researchers, recent trends have shown that many early-career scientists, especially postgraduate students, are currently expected to write review articles during the course of their studies. However, these scholars have little or no access to formal training on how to analyse and synthesise the research literature in their respective fields [ 10 ]. Consequently, students seeking guidance on how to write or improve their literature reviews are less likely to find published works on the subject, particularly in the science fields. Although various publications have dealt with the challenges of searching for literature, or writing literature reviews for dissertation/thesis purposes, there is little or no information on how to write a comprehensive review article for publication. In addition to the paucity of published information to guide the potential author, the lack of understanding of what constitutes a review paper compounds their challenges. Thus, the purpose of this paper is to serve as a guide for writing review papers for journal publishing. This work draws on the experience of the authors to assist early-career scientists/researchers in the “hard skill” of authoring review articles. Even though there is no single path to writing scientifically, or to writing reviews in particular, this paper attempts to simplify the process by looking at this subject from a beginner's perspective. Hence, this paper highlights the differences between the types of review articles in the sciences while also explaining the needs and purpose of writing review articles. Furthermore, it presents details on how to search for the literature as well as how to structure the manuscript to produce logical and coherent outputs. It is hoped that this work will ease prospective scientific writers into the challenging but rewarding art of writing review articles.

2. Benefits of Review Articles to the Author

Analysing literature gives an overview of the “WHs”: WHat has been reported in a particular field or topic, WHo the key writers are, WHat are the prevailing theories and hypotheses, WHat questions are being asked (and answered), and WHat methods and methodologies are appropriate and useful [ 11 ]. For new or aspiring researchers in a particular field, it can be quite challenging to get a comprehensive overview of their respective fields, especially the historical trends and what has been studied previously. As such, the importance of review articles to knowledge appraisal and contribution cannot be overemphasised, which is reflected in the constant demand for such articles in the research community. However, it is also important for the author, especially the first-time author, to recognise the importance of his/her investing time and effort into writing a quality review article.

Generally, literature reviews are undertaken for many reasons, mainly for publication and for dissertation purposes. The major purpose of literature reviews is to provide direction and information for the improvement of scientific knowledge. They also form a significant component in the research process and in academic assessment [ 12 ]. There may be, however, a thin line between a dissertation literature review and a published review article, given that with some modifications, a literature review can be transformed into a legitimate and publishable scholarly document. According to Gülpınar and Güçlü [ 6 ], the basic motivation for writing a review article is to make a comprehensive synthesis of the most appropriate literature on a specific research inquiry or topic. Thus, conducting a literature review assists in demonstrating the author's knowledge about a particular field of study, which may include but not be limited to its history, theories, key variables, vocabulary, phenomena, and methodologies [ 10 ]. Furthermore, publishing reviews is beneficial as it permits the researchers to examine different questions and, as a result, enhances the depth and diversity of their scientific reasoning [ 1 ]. In addition, writing review articles allows researchers to share insights with the scientific community while identifying knowledge gaps to be addressed in future research. The review writing process can also be a useful tool in training early-career scientists in leadership, coordination, project management, and other important soft skills necessary for success in the research world [ 13 ]. Another important reason for authoring reviews is that such publications have been observed to be remarkably influential, extending the reach of an author in multiple folds of what can be achieved by primary research papers [ 1 ]. The trend in science is for authors to receive more citations from their review articles than from their original research articles. According to Miranda and Garcia-Carpintero [ 14 ], review articles are, on average, three times more frequently cited than original research articles; they also asserted that a 20% increase in review authorship could result in a 40–80% increase in citations of the author. As a result, writing reviews can significantly impact a researcher's citation output and serve as a valuable channel to reach a wider scientific audience. In addition, the references cited in a review article also provide the reader with an opportunity to dig deeper into the topic of interest. Thus, review articles can serve as a valuable repository for consultation, increasing the visibility of the authors and resulting in more citations.

3. Types of Review Articles

The first step in writing a good literature review is to decide on the particular type of review to be written; hence, it is important to distinguish and understand the various types of review articles. Although scientific review articles have been classified according to various schemes, however, they are broadly categorised into narrative reviews, systematic reviews, and meta-analyses [ 15 ]. It was observed that more authors—as well as publishers—were leaning towards systematic reviews and meta-analysis while downplaying narrative reviews; however, the three serve different aims and should all be considered equally important in science [ 1 ]. Bibliometric reviews and patent reviews, which are closely related to meta-analysis, have also gained significant attention recently. However, from another angle, a review could also be of two types. In the first class, authors could deal with a widely studied topic where there is already an accumulated body of knowledge that requires analysis and synthesis [ 3 ]. At the other end of the spectrum, the authors may have to address an emerging issue that would benefit from exposure to potential theoretical foundations; hence, their contribution would arise from the fresh theoretical foundations proposed in developing a conceptual model [ 3 ].

3.1. Narrative Reviews

Narrative reviewers are mainly focused on providing clarification and critical analysis on a particular topic or body of literature through interpretative synthesis, creativity, and expert judgement. According to Green et al. [ 16 ], a narrative review can be in the form of editorials, commentaries, and narrative overviews. However, editorials and commentaries are usually expert opinions; hence, a beginner is more likely to write a narrative overview, which is more general and is also referred to as an unsystematic narrative review. Similarly, the literature review section of most dissertations and empirical papers is typically narrative in nature. Typically, narrative reviews combine results from studies that may have different methodologies to address different questions or to formulate a broad theoretical formulation [ 1 ]. They are largely integrative as strong focus is placed on the assimilation and synthesis of various aspects in the review, which may involve comparing and contrasting research findings or deriving structured implications [ 17 ]. In addition, they are also qualitative studies because they do not follow strict selection processes; hence, choosing publications is relatively more subjective and unsystematic [ 18 ]. However, despite their popularity, there are concerns about their inherent subjectivity. In many instances, when the supporting data for narrative reviews are examined more closely, the evaluations provided by the author(s) become quite questionable [ 19 ]. Nevertheless, if the goal of the author is to formulate a new theory that connects diverse strands of research, a narrative method is most appropriate.

3.2. Systematic Reviews

In contrast to narrative reviews, which are generally descriptive, systematic reviews employ a systematic approach to summarise evidence on research questions. Hence, systematic reviews make use of precise and rigorous criteria to identify, evaluate, and subsequently synthesise all relevant literature on a particular topic [ 12 , 20 ]. As a result, systematic reviews are more likely to inspire research ideas by identifying knowledge gaps or inconsistencies, thus helping the researcher to clearly define the research hypotheses or questions [ 21 ]. Furthermore, systematic reviews may serve as independent research projects in their own right, as they follow a defined methodology to search and combine reliable results to synthesise a new database that can be used for a variety of purposes [ 22 ]. Typically, the peculiarities of the individual reviewer, different search engines, and information databases used all ensure that no two searches will yield the same systematic results even if the searches are conducted simultaneously and under identical criteria [ 11 ]. Hence, attempts are made at standardising the exercise via specific methods that would limit bias and chance effects, prevent duplications, and provide more accurate results upon which conclusions and decisions can be made.

The most established of these methods is the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines which objectively defined statements, guidelines, reporting checklists, and flowcharts for undertaking systematic reviews as well as meta-analysis [ 23 ]. Though mainly designed for research in medical sciences, the PRISMA approach has gained wide acceptance in other fields of science and is based on eight fundamental propositions. These include the explicit definition of the review question, an unambiguous outline of the study protocol, an objective and exhaustive systematic review of reputable literature, and an unambiguous identification of included literature based on defined selection criteria [ 24 ]. Other considerations include an unbiased appraisal of the quality of the selected studies (literature), organic synthesis of the evidence of the study, preparation of the manuscript based on the reporting guidelines, and periodic update of the review as new data emerge [ 24 ]. Other methods such as PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols), MOOSE (Meta-analysis Of Observational Studies in Epidemiology), and ROSES (Reporting Standards for Systematic Evidence Syntheses) have since been developed for systematic reviews (and meta-analysis), with most of them being derived from PRISMA.

Consequently, systematic reviews—unlike narrative reviews—must contain a methodology section which in addition to all that was highlighted above must fully describe the precise criteria used in formulating the research question and setting the inclusion or exclusion criteria used in selecting/accessing the literature. Similarly, the criteria for evaluating the quality of the literature included in the review as well as for analysing, synthesising, and disseminating the findings must be fully described in the methodology section.

3.3. Meta-Analysis

Meta-analyses are considered as more specialised forms of systematic reviews. Generally, they combine the results of many studies that use similar or closely related methods to address the same question or share a common quantitative evaluation method [ 25 ]. However, meta-analyses are also a step higher than other systematic reviews as they are focused on numerical data and involve the use of statistics in evaluating different studies and synthesising new knowledge. The major advantage of this type of review is the increased statistical power leading to more reliable results for inferring modest associations and a more comprehensive understanding of the true impact of a research study [ 26 ]. Unlike in traditional systematic reviews, research topics covered in meta-analyses must be mature enough to allow the inclusion of sufficient homogeneous empirical research in terms of subjects, interventions, and outcomes [ 27 , 28 ].

Being an advanced form of systematic review, meta-analyses must also have a distinct methodology section; hence, the standard procedures involved in the traditional systematic review (especially PRISMA) also apply in meta-analyses [ 23 ]. In addition to the common steps in formulating systematic reviews, meta-analyses are required to describe how nested and missing data are handled, the effect observed in each study, the confidence interval associated with each synthesised effect, and any potential for bias presented within the sample(s) [ 17 ]. According to Paul and Barari [ 28 ], a meta-analysis must also detail the final sample, the meta-analytic model, and the overall analysis, moderator analysis, and software employed. While the overall analysis involves the statistical characterization of the relationships between variables in the meta-analytic framework and their significance, the moderator analysis defines the different variables that may affect variations in the original studies [ 28 , 29 ]. It must also be noted that the accuracy and reliability of meta-analyses have both been significantly enhanced by the incorporation of statistical approaches such as Bayesian analysis [ 30 ], network analysis [ 31 ], and more recently, machine learning [ 32 ].

3.4. Bibliometric Review

A bibliometric review, commonly referred to as bibliometric analysis, is a systematic evaluation of published works within a specific field or discipline [ 33 ]. This bibliometric methodology involves the use of quantitative methods to analyse bibliometric data such as the characteristics and numbers of publications, units of citations, authorship, co-authorship, and journal impact factors [ 34 ]. Academics use bibliometric analysis with different objectives in mind, which includes uncovering emerging trends in article and journal performance, elaborating collaboration patterns and research constituents, evaluating the impact and influence of particular authors, publications, or research groups, and highlighting the intellectual framework of a certain field [ 35 ]. It is also used to inform policy and decision-making. Similarly to meta-analysis, bibliometric reviews rely upon quantitative techniques, thus avoiding the interpretation bias that could arise from the qualitative techniques of other types of reviews [ 36 ]. However, while bibliometric analysis synthesises the bibliometric and intellectual structure of a field by examining the social and structural linkages between various research parts, meta-analysis focuses on summarising empirical evidence by probing the direction and strength of effects and relationships among variables, especially in open research questions [ 37 , 38 ]. However, similarly to systematic review and meta-analysis, a bibliometric review also requires a well-detailed methodology section. The amount of data to be analysed in bibliometric analysis is quite massive, running to hundreds and tens of thousands in some cases. Although the data are objective in nature (e.g., number of citations and publications and occurrences of keywords and topics), the interpretation is usually carried out through both objective (e.g., performance analysis) and subjective (e.g., thematic analysis) evaluations [ 35 ]. However, the invention and availability of bibliometric software such as BibExcel, Gephi, Leximancer, and VOSviewer and scientific databases such as Dimensions, Web of Science, and Scopus have made this type of analysis more feasible.

3.5. Patent Review

Patent reviews provide a comprehensive analysis and critique of a specific patent or a group of related patents, thus presenting a concise understanding of the technology or innovation that is covered by the patent [ 39 ]. This type of article is useful for researchers as it also enhances their understanding of the legal, technical, and commercial aspects of an intellectual property/innovation; in addition, it is also important for stakeholders outside the research community including IP (intellectual property) specialists, legal professionals, and technology-transfer officers [ 40 ]. Typically, patent reviews encompass the scope, background, claims, legal implications, technical specifications, and potential commercial applications of the patent(s). The article may also include a discussion of the patent's strengths and weaknesses, as well as its potential impact on the industry or field in which it operates. Most times, reviews are time specified, they may be regionalised, and the data are usually retrieved via patent searches on databases such as that of the European Patent Office ( https://www.epo.org/searching.html ), United States Patent and Trademark Office ( https://patft.uspto.gov/ ), the World Intellectual Property Organization's PATENTSCOPE ( https://patentscope.wipo.int/search/en/structuredSearch.jsf ), Google Patent ( https://www.google.com/?tbm=pts ), and China National Intellectual Property Administration ( https://pss-system.cponline.cnipa.gov.cn/conventionalSearch ). According to Cerimi et al. [ 41 ], the retrieved data and analysed may include the patent number, patent status, filing date, application date, grant dates, inventor, assignee, and pending applications. While data analysis is usually carried out by general data software such as Microsoft Excel, an intelligence software solely dedicated to patent research and analysis, Orbit Intelligence has been found to be more efficient [ 39 ]. It is also mandatory to include a methodology section in a patent review, and this should be explicit, thorough, and precise to allow a clear understanding of how the analysis was carried out and how the conclusions were arrived at.

4. Searching Literature

One of the most challenging tasks in writing a review article on a subject is the search for relevant literature to populate the manuscript as the author is required to garner information from an endless number of sources. This is even more challenging as research outputs have been increasing astronomically, especially in the last decade, with thousands of new articles published annually in various fields. It is therefore imperative that the author must not only be aware of the overall trajectory in a field of investigation but must also be cognizant of recent studies so as not to publish outdated research or review articles. Basically, the search for the literature involves a coherent conceptual structuring of the topic itself and a thorough collation of evidence under the common themes which might reflect the histories, conflicts, standoffs, revolutions, and/or evolutions in the field [ 7 ]. To start the search process, the author must carefully identify and select broad keywords relevant to the subject; subsequently, the keywords should be developed to refine the search into specific subheadings that would facilitate the structure of the review.

Two main tactics have been identified for searching the literature, namely, systematic and snowballing [ 42 ]. The systematic approach involves searching literature with specific keywords (for example, cancer, antioxidant, and nanoparticles), which leads to an almost unmanageable and overwhelming list of possible sources [ 43 ]. The snowballing approach, however, involves the identification of a particular publication, followed by the compilation of a bibliography of articles based on the reference list of the identified publication [ 44 ]. Many times, it might be necessary to combine both approaches, but irrespective, the author must keep an accurate track and record of papers cited in the search. A simple and efficient strategy for populating the bibliography of review articles is to go through the abstract (and sometimes the conclusion) of a paper; if the abstract is related to the topic of discourse, the author might go ahead and read the entire article; otherwise, he/she is advised to move on [ 45 ]. Winchester and Salji [ 5 ] noted that to learn the background of the subject/topic to be reviewed, starting literature searches with academic textbooks or published review articles is imperative, especially for beginners. Furthermore, it would also assist in compiling the list of keywords, identifying areas of further exploration, and providing a glimpse of the current state of the research. However, past reviews ideally are not to serve as the foundation of a new review as they are written from someone else's viewpoint, which might have been tainted with some bias. Fortunately, the accessibility and search for the literature have been made relatively easier than they were a few decades ago as the current information age has placed an enormous volume of knowledge right at our fingertips [ 46 ]. Nevertheless, when gathering the literature from the Internet, authors should exercise utmost caution as much of the information may not be verified or peer-reviewed and thus may be unregulated and unreliable. For instance, Wikipedia, despite being a large repository of information with more than 6.7 million articles in the English language alone, is considered unreliable for scientific literature reviews, due to its openness to public editing [ 47 ]. However, in addition to peer-reviewed journal publications—which are most ideal—reviews can also be drawn from a wide range of other sources such as technical documents, in-house reports, conference abstracts, and conference proceedings. Similarly, “Google Scholar”—as against “Google” and other general search engines—is more appropriate as its searches are restricted to only academic articles produced by scholarly societies or/and publishers [ 48 ]. Furthermore, the various electronic databases, such as ScienceDirect, Web of Science, PubMed, and MEDLINE, many of which focus on specific fields of research, are also ideal options [ 49 ]. Advancement in computer indexing has remarkably expanded the ease and ability to search large databases for every potentially relevant article. In addition to searching by topic, literature search can be modified by time; however, there must be a balance between old papers and recent ones. The general consensus in science is that publications less than five years old are considered recent.

It is important, especially in systematic reviews and meta-analyses, that the specific method of running the computer searches be properly documented as there is the need to include this in the method (methodology) section of such papers. Typically, the method details the keywords, databases explored, search terms used, and the inclusion/exclusion criteria applied in the selection of data and any other specific decision/criteria. All of these will ensure the reproducibility and thoroughness of the search and the selection procedure. However, Randolph [ 10 ] noted that Internet searches might not give the exhaustive list of articles needed for a review article; hence, it is advised that authors search through the reference lists of articles that were obtained initially from the Internet search. After determining the relevant articles from the list, the author should read through the references of these articles and repeat the cycle until saturation is reached [ 10 ]. After populating the articles needed for the literature review, the next step is to analyse them individually and in their whole entirety. A systematic approach to this is to identify the key information within the papers, examine them in depth, and synthesise original perspectives by integrating the information and making inferences based on the findings. In this regard, it is imperative to link one source to the other in a logical manner, for instance, taking note of studies with similar methodologies, papers that agree, or results that are contradictory [ 42 ].

5. Structuring the Review Article

The title and abstract are the main selling points of a review article, as most readers will only peruse these two elements and usually go on to read the full paper if they are drawn in by either or both of the two. Tullu [ 50 ] recommends that the title of a scientific paper “should be descriptive, direct, accurate, appropriate, interesting, concise, precise, unique, and not be misleading.” In addition to providing “just enough details” to entice the reader, words in the titles are also used by electronic databases, journal websites, and search engines to index and retrieve a particular paper during a search [ 51 ]. Titles are of different types and must be chosen according to the topic under review. They are generally classified as descriptive, declarative, or interrogative and can also be grouped into compound, nominal, or full-sentence titles [ 50 ]. The subject of these categorisations has been extensively discussed in many articles; however, the reader must also be aware of the compound titles, which usually contain a main title and a subtitle. Typically, subtitles provide additional context—to the main title—and they may specify the geographic scope of the research, research methodology, or sample size [ 52 ].

Just like primary research articles, there are many debates about the optimum length of a review article's title. However, the general consensus is to keep the title as brief as possible while not being too general. A title length between 10 and 15 words is recommended, since longer titles can be more challenging to comprehend. Paiva et al. [ 53 ] observed that articles which contain 95 characters or less get more views and citations. However, emphasis must be placed on conciseness as the audience will be more satisfied if they can understand what exactly the review has contributed to the field, rather than just a hint about the general topic area. Authors should also endeavour to stick to the journal's specific requirements, especially regarding the length of the title and what they should or should not contain [ 9 ]. Thus, avoidance of filler words such as “a review on/of,” “an observation of,” or “a study of” is a very simple way to limit title length. In addition, abbreviations or acronyms should be avoided in the title, except the standard or commonly interpreted ones such as AIDS, DNA, HIV, and RNA. In summary, to write an effective title, the authors should consider the following points. What is the paper about? What was the methodology used? What were the highlights and major conclusions? Subsequently, the author should list all the keywords from these answers, construct a sentence from these keywords, and finally delete all redundant words from the sentence title. It is also possible to gain some ideas by scanning indices and article titles in major journals in the field. It is important to emphasise that a title is not chosen and set in stone, and the title is most likely to be continually revised and adjusted until the end of the writing process.

5.2. Abstract

The abstract, also referred to as the synopsis, is a summary of the full research paper; it is typically independent and can stand alone. For most readers, a publication does not exist beyond the abstract, partly because abstracts are often the only section of a paper that is made available to the readers at no cost, whereas the full paper may attract a payment or subscription [ 54 ]. Thus, the abstract is supposed to set the tone for the few readers who wish to read the rest of the paper. It has also been noted that the abstract gives the first impression of a research work to journal editors, conference scientific committees, or referees, who might outright reject the paper if the abstract is poorly written or inadequate [ 50 ]. Hence, it is imperative that the abstract succinctly represents the entire paper and projects it positively. Just like the title, abstracts have to be balanced, comprehensive, concise, functional, independent, precise, scholarly, and unbiased and not be misleading [ 55 ]. Basically, the abstract should be formulated using keywords from all the sections of the main manuscript. Thus, it is pertinent that the abstract conveys the focus, key message, rationale, and novelty of the paper without any compromise or exaggeration. Furthermore, the abstract must be consistent with the rest of the paper; as basic as this instruction might sound, it is not to be taken for granted. For example, a study by Vrijhoef and Steuten [ 56 ] revealed that 18–68% of 264 abstracts from some scientific journals contained information that was inconsistent with the main body of the publications.

Abstracts can either be structured or unstructured; in addition, they can further be classified as either descriptive or informative. Unstructured abstracts, which are used by many scientific journals, are free flowing with no predefined subheadings, while structured abstracts have specific subheadings/subsections under which the abstract needs to be composed. Structured abstracts have been noted to be more informative and are usually divided into subsections which include the study background/introduction, objectives, methodology design, results, and conclusions [ 57 ]. No matter the style chosen, the author must carefully conform to the instructions provided by the potential journal of submission, which may include but are not limited to the format, font size/style, word limit, and subheadings [ 58 ]. The word limit for abstracts in most scientific journals is typically between 150 and 300 words. It is also a general rule that abstracts do not contain any references whatsoever.

Typically, an abstract should be written in the active voice, and there is no such thing as a perfect abstract as it could always be improved on. It is advised that the author first makes an initial draft which would contain all the essential parts of the paper, which could then be polished subsequently. The draft should begin with a brief background which would lead to the research questions. It might also include a general overview of the methodology used (if applicable) and importantly, the major results/observations/highlights of the review paper. The abstract should end with one or few sentences about any implications, perspectives, or future research that may be developed from the review exercise. Finally, the authors should eliminate redundant words and edit the abstract to the correct word count permitted by the journal [ 59 ]. It is always beneficial to read previous abstracts published in the intended journal, related topics/subjects from other journals, and other reputable sources. Furthermore, the author should endeavour to get feedback on the abstract especially from peers and co-authors. As the abstract is the face of the whole paper, it is best that it is the last section to be finalised, as by this time, the author would have developed a clearer understanding of the findings and conclusions of the entire paper.

5.3. Graphical Abstracts

Since the mid-2000s, an increasing number of journals now require authors to provide a graphical abstract (GA) in addition to the traditional written abstract, to increase the accessibility of scientific publications to readers [ 60 ]. A study showed that publications with GA performed better than those without it, when the abstract views, total citations, and downloads were compared [ 61 ]. However, the GA should provide “a single, concise pictorial, and visual summary of the main findings of an article” [ 62 ]. Although they are meant to be a stand-alone summary of the whole paper, it has been noted that they are not so easily comprehensible without having read through the traditionally written abstract [ 63 ]. It is important to note that, like traditional abstracts, many reputable journals require GAs to adhere to certain specifications such as colour, dimension, quality, file size, and file format (usually JPEG/JPG, PDF, PNG, or TIFF). In addition, it is imperative to use engaging and accurate figures, all of which must be synthesised in order to accurately reflect the key message of the paper. Currently, there are various online or downloadable graphical tools that can be used for creating GAs, such as Microsoft Paint or PowerPoint, Mindthegraph, ChemDraw, CorelDraw, and BioRender.

5.4. Keywords

As a standard practice, journals require authors to select 4–8 keywords (or phrases), which are typically listed below the abstract. A good set of keywords will enable indexers and search engines to find relevant papers more easily and can be considered as a very concise abstract [ 64 ]. According to Dewan and Gupta [ 51 ], the selection of appropriate keywords will significantly enhance the retrieval, accession, and consequently, the citation of the review paper. Ideally, keywords can be variants of the terms/phrases used in the title, the abstract, and the main text, but they should ideally not be the exact words in the main title. Choosing the most appropriate keywords for a review article involves listing down the key terms and phrases in the article, including abbreviations. Subsequently, a quick review of the glossary/vocabulary/term list or indexing standard in the specific discipline will assist in selecting the best and most precise keywords that match those used in the databases from the list drawn. In addition, the keywords should not be broad or general terms (e.g., DNA, biology, and enzymes) but must be specific to the field or subfield of study as well as to the particular paper [ 65 ].

5.5. Introduction

The introduction of an article is the first major section of the manuscript, and it presents basic information to the reader without compelling them to study past publications. In addition, the introduction directs the reader to the main arguments and points developed in the main body of the article while clarifying the current state of knowledge in that particular area of research [ 12 ]. The introduction part of a review article is usually sectionalised into background information, a description of the main topic and finally a statement of the main purpose of the review [ 66 ]. Authors may begin the introduction with brief general statements—which provide background knowledge on the subject matter—that lead to more specific ones [ 67 ]. It is at this point that the reader's attention must be caught as the background knowledge must highlight the importance and justification for the subject being discussed, while also identifying the major problem to be addressed [ 68 ]. In addition, the background should be broad enough to attract even nonspecialists in the field to maximise the impact and widen the reach of the article. All of these should be done in the light of current literature; however, old references may also be used for historical purposes. A very important aspect of the introduction is clearly stating and establishing the research problem(s) and how a review of the particular topic contributes to those problem(s). Thus, the research gap which the paper intends to fill, the limitations of previous works and past reviews, if available, and the new knowledge to be contributed must all be highlighted. Inadequate information and the inability to clarify the problem will keep readers (who have the desire to obtain new information) from reading beyond the introduction [ 69 ]. It is also pertinent that the author establishes the purpose of reviewing the literature and defines the scope as well as the major synthesised point of view. Furthermore, a brief insight into the criteria used to select, evaluate, and analyse the literature, as well as the outline or sequence of the review, should be provided in the introduction. Subsequently, the specific objectives of the review article must be presented. The last part of the “introduction” section should focus on the solution, the way forward, the recommendations, and the further areas of research as deduced from the whole review process. According to DeMaria [ 70 ], clearly expressed or recommended solutions to an explicitly revealed problem are very important for the wholesomeness of the “introduction” section. It is believed that following these steps will give readers the opportunity to track the problems and the corresponding solution from their own perspective in the light of current literature. As against some suggestions that the introduction should be written only in present tenses, it is also believed that it could be done with other tenses in addition to the present tense. In this regard, general facts should be written in the present tense, specific research/work should be in the past tense, while the concluding statement should be in the past perfect or simple past. Furthermore, many of the abbreviations to be used in the rest of the manuscript and their explanations should be defined in this section.

5.6. Methodology

Writing a review article is equivalent to conducting a research study, with the information gathered by the author (reviewer) representing the data. Like all major studies, it involves conceptualisation, planning, implementation, and dissemination [ 71 ], all of which may be detailed in a methodology section, if necessary. Hence, the methodological section of a review paper (which can also be referred to as the review protocol) details how the relevant literature was selected and how it was analysed as well as summarised. The selection details may include, but are not limited to, the database consulted and the specific search terms used together with the inclusion/exclusion criteria. As earlier highlighted in Section 3 , a description of the methodology is required for all types of reviews except for narrative reviews. This is partly because unlike narrative reviews, all other review articles follow systematic approaches which must ensure significant reproducibility [ 72 ]. Therefore, where necessary, the methods of data extraction from the literature and data synthesis must also be highlighted as well. In some cases, it is important to show how data were combined by highlighting the statistical methods used, measures of effect, and tests performed, as well as demonstrating heterogeneity and publication bias [ 73 ].

The methodology should also detail the major databases consulted during the literature search, e.g., Dimensions, ScienceDirect, Web of Science, MEDLINE, and PubMed. For meta-analysis, it is imperative to highlight the software and/or package used, which could include Comprehensive Meta-Analysis, OpenMEE, Review Manager (RevMan), Stata, SAS, and R Studio. It is also necessary to state the mathematical methods used for the analysis; examples of these include the Bayesian analysis, the Mantel–Haenszel method, and the inverse variance method. The methodology should also state the number of authors that carried out the initial review stage of the study, as it has been recommended that at least two reviews should be done blindly and in parallel, especially when it comes to the acquisition and synthesis of data [ 74 ]. Finally, the quality and validity assessment of the publication used in the review must be stated and well clarified [ 73 ].

5.7. Main Body of the Review

Ideally, the main body of a publishable review should answer these questions: What is new (contribution)? Why so (logic)? So what (impact)? How well it is done (thoroughness)? The flow of the main body of a review article must be well organised to adequately maintain the attention of the readers as well as guide them through the section. It is recommended that the author should consider drawing a conceptual scheme of the main body first, using methods such as mind-mapping. This will help create a logical flow of thought and presentation, while also linking the various sections of the manuscript together. According to Moreira [ 75 ], “reports do not simply yield their findings, rather reviewers make them yield,” and thus, it is the author's responsibility to transform “resistant” texts into “docile” texts. Hence, after the search for the literature, the essential themes and key concepts of the review paper must be identified and synthesised together. This synthesis primarily involves creating hypotheses about the relationships between the concepts with the aim of increasing the understanding of the topic being reviewed. The important information from the various sources should not only be summarised, but the significance of studies must be related back to the initial question(s) posed by the review article. Furthermore, MacLure [ 76 ] stated that data are not just to be plainly “extracted intact” and “used exactly as extracted,” but must be modified, reconfigured, transformed, transposed, converted, tabulated, graphed, or manipulated to enable synthesis, combination, and comparison. Therefore, different pieces of information must be extracted from the reports in which they were previously deposited and then refined into the body of the new article [ 75 ]. To this end, adequate comparison and combination might require that “qualitative data be quantified” or/and “quantitative data may be qualitized” [ 77 ]. In order to accomplish all of these goals, the author may have to transform, paraphrase, generalize, specify, and reorder the text [ 78 ]. For comprehensiveness, the body paragraphs should be arranged in a similar order as it was initially stated in the abstract or/and introduction. Thus, the main body could be divided into thematic areas, each of which could be independently comprehensive and treated as a mini review. Similarly, the sections can also be arranged chronologically depending on the focus of the review. Furthermore, the abstractions should proceed from a wider general view of the literature being reviewed and then be narrowed down to the specifics. In the process, deep insights should also be provided between the topic of the review and the wider subject area, e.g., fungal enzymes and enzymes in general. The abstractions must also be discussed in more detail by presenting more specific information from the identified sources (with proper citations of course!). For example, it is important to identify and highlight contrary findings and rival interpretations as well as to point out areas of agreement or debate among different bodies of literature. Often, there are previous reviews on the same topic/concept; however, this does not prevent a new author from writing one on the same topic, especially if the previous reviews were written many years ago. However, it is important that the body of the new manuscript be written from a new angle that was not adequately covered in the past reviews and should also incorporate new studies that have accumulated since the last review(s). In addition, the new review might also highlight the approaches, limitations, and conclusions of the past studies. But the authors must not be excessively critical of the past reviews as this is regarded by many authors as a sign of poor professionalism [ 3 , 79 ]. Daft [ 79 ] emphasized that it is more important for a reviewer to state how their research builds on previous work instead of outright claiming that previous works are incompetent and inadequate. However, if a series of related papers on one topic have a common error or research flaw that needs rectification, the reviewer must point this out with the aim of moving the field forward [ 3 ]. Like every other scientific paper, the main body of a review article also needs to be consistent in style, for example, in the choice of passive vs. active voice and present vs. past tense. It is also important to note that tables and figures can serve as a powerful tool for highlighting key points in the body of the review, and they are now considered core elements of reviews. For more guidance and insights into what should make up the contents of a good review article, readers are also advised to get familiarised with the Boote and Beile [ 80 ] literature review scoring rubric as well as the review article checklist of Short [ 81 ].

5.8. Tables and Figures

An ideal review article should be logically structured and efficiently utilise illustrations, in the form of tables and figures, to convey the key findings and relationships in the study. According to Tay [ 13 ], illustrations often take a secondary role in review papers when compared to primary research papers which are focused on illustrations. However, illustrations are very important in review articles as they can serve as succinct means of communicating major findings and insights. Franzblau and Chung [ 82 ] pointed out that illustrations serve three major purposes in a scientific article: they simplify complex data and relationships for better understanding, they minimise reading time by summarising and bringing to focus on the key findings (or trends), and last, they help to reduce the overall word count. Hence, inserting and constructing illustrations in a review article is as meticulous as it is important. However, important decisions should be made on whether the charts, figures, or tables to be potentially inserted in the manuscript are indeed needed and how best to design them [ 83 ]. Illustrations should enhance the text while providing necessary information; thus, the information described in illustrations should not contradict that in the main text and should also not be a repetition of texts [ 84 ]. Furthermore, illustrations must be autonomous, meaning they ought to be intelligible without having to read the text portion of the manuscript; thus, the reader does not have to flip back and forth between the illustration and the main text in order to understand it [ 85 ]. It should be noted that tables or figures that directly reiterate the main text or contain extraneous information will only make a mess of the manuscript and discourage readers [ 86 ].

Kotz and Cals [ 87 ] recommend that the layout of tables and figures should be carefully designed in a clear manner with suitable layouts, which will allow them to be referred to logically and chronologically in the text. In addition, illustrations should only contain simple text, as lengthy details would contradict their initial objective, which was to provide simple examples or an overview. Furthermore, the use of abbreviations in illustrations, especially tables, should be avoided if possible. If not, the abbreviations should be defined explicitly in the footnotes or legends of the illustration [ 88 ]. Similarly, numerical values in tables and graphs should also be correctly approximated [ 84 ]. It is recommended that the number of tables and figures in the manuscript should not exceed the target journal's specification. According to Saver [ 89 ], they ideally should not account for more than one-third of the manuscript. Finally, the author(s) must seek permission and give credits for using an already published illustration when necessary. However, none of these are needed if the graphic is originally created by the author, but if it is a reproduced or an adapted illustration, the author must obtain permission from the copyright owner and include the necessary credit. One of the very important tools for designing illustrations is Creative Commons, a platform that provides a wide range of creative works which are available to the public for use and modification.

5.9. Conclusion/Future Perspectives

It has been observed that many reviews end abruptly with a short conclusion; however, a lot more can be included in this section in addition to what has been said in the major sections of the paper. Basically, the conclusion section of a review article should provide a summary of key findings from the main body of the manuscript. In this section, the author needs to revisit the critical points of the paper as well as highlight the accuracy, validity, and relevance of the inferences drawn in the article review. A good conclusion should highlight the relationship between the major points and the author's hypothesis as well as the relationship between the hypothesis and the broader discussion to demonstrate the significance of the review article in a larger context. In addition to giving a concise summary of the important findings that describe current knowledge, the conclusion must also offer a rationale for conducting future research [ 12 ]. Knowledge gaps should be identified, and themes should be logically developed in order to construct conceptual frameworks as well as present a way forward for future research in the field of study [ 11 ].

Furthermore, the author may have to justify the propositions made earlier in the manuscript, demonstrate how the paper extends past research works, and also suggest ways that the expounded theories can be empirically examined [ 3 ]. Unlike experimental studies which can only draw either a positive conclusion or ambiguous failure to reject the null hypothesis, four possible conclusions can be drawn from review articles [ 1 ]. First, the theory/hypothesis propounded may be correct after being proven from current evidence; second, the hypothesis may not be explicitly proven but is most probably the best guess. The third conclusion is that the currently available evidence does not permit a confident conclusion or a best guess, while the last conclusion is that the theory or hypothesis is false [ 1 ]. It is important not to present new information in the conclusion section which has link whatsoever with the rest of the manuscript. According to Harris et al. [ 90 ], the conclusions should, in essence, answer the question: if a reader were to remember one thing about the review, what would it be?

5.10. References

As it has been noted in different parts of this paper, authors must give the required credit to any work or source(s) of information that was included in the review article. This must include the in-text citations in the main body of the paper and the corresponding entries in the reference list. Ideally, this full bibliographical list is the last part of the review article, and it should contain all the books, book chapters, journal articles, reports, and other media, which were utilised in the manuscript. It has been noted that most journals and publishers have their own specific referencing styles which are all derived from the more popular styles such as the American Psychological Association (APA), Chicago, Harvard, Modern Language Association (MLA), and Vancouver styles. However, all these styles may be categorised into either the parenthetical or numerical referencing style. Although a few journals do not have strict referencing rules, it is the responsibility of the author to reference according to the style and instructions of the journal. Omissions and errors must be avoided at all costs, and this can be easily achieved by going over the references many times for due diligence [ 11 ]. According to Cronin et al. [ 12 ], a separate file for references can be created, and any work used in the manuscript can be added to this list immediately after being cited in the text [ 12 ]. In recent times, the emergence of various referencing management software applications such as Endnote, RefWorks, Mendeley, and Zotero has even made referencing easier. The majority of these software applications require little technical expertise, and many of them are free to use, while others may require a subscription. It is imperative, however, that even after using these software packages, the author must manually curate the references during the final draft, in order to avoid any errors, since these programs are not impervious to errors, particularly formatting errors.

6. Concluding Remarks

Writing a review article is a skill that needs to be learned; it is a rigorous but rewarding endeavour as it can provide a useful platform to project the emerging researcher or postgraduate student into the gratifying world of publishing. Thus, the reviewer must develop the ability to think critically, spot patterns in a large volume of information, and must be invested in writing without tiring. The prospective author must also be inspired and dedicated to the successful completion of the article while also ensuring that the review article is not just a mere list or summary of previous research. It is also important that the review process must be focused on the literature and not on the authors; thus, overt criticism of existing research and personal aspersions must be avoided at all costs. All ideas, sentences, words, and illustrations should be constructed in a way to avoid plagiarism; basically, this can be achieved by paraphrasing, summarising, and giving the necessary acknowledgments. Currently, there are many tools to track and detect plagiarism in manuscripts, ensuring that they fall within a reasonable similarity index (which is typically 15% or lower for most journals). Although the more popular of these tools, such as Turnitin and iThenticate, are subscription-based, there are many freely available web-based options as well. An ideal review article is supposed to motivate the research topic and describe its key concepts while delineating the boundaries of research. In this regard, experience-based information on how to methodologically develop acceptable and impactful review articles has been detailed in this paper. Furthermore, for a beginner, this guide has detailed “the why” and “the how” of authoring a good scientific review article. However, the information in this paper may as a whole or in parts be also applicable to other fields of research and to other writing endeavours such as writing literature review in theses, dissertations, and primary research articles. Finally, the intending authors must put all the basic rules of scientific writing and writing in general into cognizance. A comprehensive study of the articles cited within this paper and other related articles focused on scientific writing will further enhance the ability of the motivated beginner to deliver a good review article.

Acknowledgments

This work was supported by the National Research Foundation of South Africa under grant number UID 138097. The authors would like to thank the Durban University of Technology for funding the postdoctoral fellowship of the first author, Dr. Ayodeji Amobonye.

Data Availability

Conflicts of interest.

The authors declare that they have no conflicts of interest.

A conceptual framework proposed through literature review to determine the dimensions of social transparency in global supply chains

• Published: 16 May 2024

Cite this article

• Preethi Raja 1 &
• Usha Mohan   ORCID: orcid.org/0000-0003-2161-7600 1  

The current focus in supply chain management (SCM) research revolves around the relationship between sustainability and supply chain transparency (SCT). Despite the three pillars of sustainability – environmental, social, and economic- the limited and scattered analysis is on the social part, and the least is on socially responsible supply chain management (SR-SCM). SCT plays a significant role in elevating the sustainability of the supply chain. This review paper emphasizes the integration of SCT and sustainable supply chain, especially the social aspect as SR-SCM, and coining the new term social transparency (ST). ST is openness to communicating details about the impact of business on people, their well-being, and compliance with social sustainability standards and policies. This paper establishes a conceptual framework using three research methods. systematic literature review, content analysis-based literature review, and framework development. By locating studies in databases like EBSCO, Scopus, and Web of Science, 273 peer-reviewed articles were identified in the intersection of social sustainability, supply chains, and transparency. Finally, the framework proposes five dimensions: tracking and tracing suppliers till provenance, product and process specifications, financial transaction information, social sustainability policies and compliance, and performance assessment to determine ST in global supply chains.

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Data availability

The data that supports the findings of this systematic literature review and content analysis are either included in this manuscript or are publicly available in the referenced sources. All included studies and their respective citations are provided in the reference section. Any additional data or materials used for this review can be obtained upon request from the corresponding author.

Abbreviations

Supply chain management

Socially responsible supply chain management

Supply Chain Transparency

Social Transparency

Multinational Corporations

Code of Conduct

Corporate Social Responsibility

Preferred Reporting Items for Systematic Reviews and Meta-analyses

Radio frequency Identification

Internet of Things

Sustainable Supply Chain Management

Supply Chain

Textile Standard Certification

Worldwide Responsible Accredited Production

Global Organic Textile Standard

Global Recycled Standard

Registration, Evaluation, Authorization and Restriction on the use of Chemicals

Social Accountability International Certification

Indian Standards Institution Mark

Bureau of Indian Standards

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Raja, P., Mohan, U. A conceptual framework proposed through literature review to determine the dimensions of social transparency in global supply chains. Manag Rev Q (2024). https://doi.org/10.1007/s11301-024-00440-1

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REVIEW article

Bioprospecting of aspergillus sp. as a promising repository for anti-cancer agents: a comprehensive bibliometric investigation.

• 1 School of Bioengineering and Biosciences, Lovely Professional University, Jalandhar, Punjab, India
• 2 Department of Biotechnology, Mahatma Jyoti Rao Phoole University, Jaipur, Rajasthan, India
• 3 School of Agriculture, Lovely Professional University, Jalandhar, Punjab, India
• 4 Department of Microbiology, National Medical College & Teaching Hospital, Birgunj, Nepal

Cancer remains a significant global health challenge, claiming nearly 10 million lives in 2020 according to the World Health Organization. In the quest for novel treatments, fungi, especially Aspergillus species, have emerged as a valuable source of bioactive compounds with promising anticancer properties. This study conducts a comprehensive bibliometric analysis to map the research landscape of Aspergillus in oncology, examining publications from 1982 to the present. We observed a marked increase in research activity starting in 2000, with a notable peak from 2005 onwards. The analysis identifies key contributors, including Mohamed GG, who has authored 15 papers with 322 citations, and El-Sayed Asa, with 14 papers and 264 citations. Leading countries in this research field include India, Egypt, and China, with King Saud University and Cairo University as the leading institutions. Prominent research themes identified are “endophyte,” “green synthesis,” “antimicrobial,” “anti-cancer,” and “biological activities,” indicating a shift towards environmentally sustainable drug development. Our findings highlight the considerable potential of Aspergillus for developing new anticancer therapies and underscore the necessity for further research to harness these natural compounds for clinical use.

1 Introduction

Cancer, often described as a modern-day scourge, is not a singular disease but rather a complex constellation of disorders that share a common hallmark: the uncontrolled proliferation of cells. This unregulated growth often leads to the formation of tumors, which can invade adjacent tissues and spread to other parts of the body, a process known as metastasis ( Baskar et al., 2014 ). The multifaceted nature of cancer, with its myriad types and subtypes, each with its unique genetic and environmental triggers, makes it a challenging disease to understand, diagnose, and treat. In the year 2018, around 18.1 million new instances of cancer and 9.6 million fatalities occurred on a global scale, underscoring the significant influence of cancer on global public health ( Sung et al., 2021 ) The rates of cancer incidence and mortality have displayed fluctuations over time. For instance, in 2020, there were approximately 19.3 million fresh cancer cases and nearly 10.0 million deaths, with female breast cancer emerging as the most frequently identified form of cancer ( Ferlay et al., 2021 ). Further Cancer statistics reveal that in 2022, approximately 1,918,030 new cancer cases and 609,360 deaths were projected, reflecting a continued decline in mortality due to advances in treatment, particularly for lung cancer ( Siegel et al., 2023 ). In 2023, it is estimated that there will be 1,958,310 new cases and 609,820 deaths, with significant declines in cervical cancer incidence among younger women attributed to the HPV vaccine, showcasing the impact of preventive healthcare ( Siegel et al., 2023 ).

These figures are not just numbers; they represent individuals, families, and communities affected by the disease, emphasizing the urgency to address this global health crisis. Over the decades, the scientific community has made remarkable strides in the field of oncology ( Kruk et al., 2018 ). From the advent of chemotherapy, and targeted therapies, to the recent breakthroughs in immunotherapy, the landscape of cancer treatment has transformed dramatically. Patients today have access to a broader spectrum of therapeutic options than ever before, leading to improved survival rates and quality of life for many cancer types. Many current therapeutic regimens come with a host of side effects, some of which can be severe and diminish the quality of life ( Meng et al., 2022 ). Resistance to treatment, either intrinsic or developed over time, is another significant hurdle. Furthermore, for some aggressive and rare cancers, effective treatments remain elusive. This backdrop underscores the continuous quest for novel anti-cancer agents. The ideal therapeutic would not only be effective in halting the progression of the disease but would also exhibit minimal toxicity, ensuring better patient compliance and outcomes ( Biswas et al., 2019 ). The exploration for such agents is expansive, spanning from synthetic compounds to natural products, with the latter holding significant promise due to their vast structural diversity and proven track record in drug discovery. While significant advancements have been made in the realm of cancer therapeutics, the quest for novel, effective, and less toxic anti-cancer agents continues ( Vora et al., 2023 ). Natural substances are essential in the field of cancer treatment, playing a crucial role in influencing various processes like cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. These mechanisms are vital for treating diverse cancer types, as highlighted by Singh et al. (2023) . Furthermore, these natural products exhibit the ability to regulate autophagy, providing novel possibilities for the development of mechanism-oriented anticancer medications by modulating this pivotal cellular homeostasis process ( Al-Bari et al., 2021 ).

In the vast realm of natural products, fungi have emerged as a prolific source of bioactive compounds with therapeutic potential. Among fungi, the genus Aspergillus holds a special place in bioprospecting endeavors. Aspergillus species have been recognized for their ability to produce a myriad of secondary metabolites, many of which exhibit potent biological activities ( Bok et al., 2006 ). These metabolites range from antibiotics, and immunosuppressants, to agents with anti-cancer properties. Aspergillus species produce a diverse array of compounds, such as alkaloids, butenolides, terpenoids, and polyketides, known for their anti-cancer activities. These secondary metabolites exhibit promising anti-cancer activity, with variable toxic potential and apoptotic potential, suggesting their potential use as supplementary agents in existing anti-cancer drug regimens ( Siddhardha et al., 2010 ). Further, specific strains like Aspergillus sp. strain F1544 have been identified to produce compounds with noteworthy antileishmanial and moderate anticancer activities ( Martínez-Luis et al., 2012 ). Bibliometric analysis of the research landscape in this field reveals a significant body of work focusing on various anticancer compounds produced by Aspergillus species. This analysis highlights the importance of genetic research in understanding the biosynthetic pathways of these metabolites. For instance, studies have provided comprehensive annotations of secondary metabolite biosynthetic genes and gene clusters in Aspergillus species, aiding in the discovery of novel secondary metabolites and potential anti-cancer drugs ( Inglis et al., 2013 ). Overall, the exploration of Aspergillus species in the search for anti-cancer agents, supported by a robust bibliometric analysis, represents a generative field of study. The Potential of bioactive compounds offers promising avenues for the development of new therapeutic strategies in oncology, highlighting the potential of this genus in bioprospecting endeavors.

2 Literature review

2.1 aspergillus species diversity and bioprospecting potential.

Aspergillus sp. a genus consisting of several hundred mold species, is found in various climates worldwide. This genus was first identified in 1729 by Pier Antonio Micheli. It includes notable species like A. flavus , a plant pathogen and common cause of aspergillosis; A. fumigatus , prevalent in immunocompromised individuals; A. nidulans , used in cell biology research; Aspergillus niger , in the chemical industry; and A. oryzae and Aspergillus sojae , used in East Asian cuisine ( Yadav et al., 2019 ). The genus is divided into six subgenera, further split into 27 sections. Aspergillus species are primarily conidial fungi, often in an asexual state, but some have a sexual state in Ascomycota. They thrive in high osmotic pressure environments and are highly aerobic, found in oxygen-rich settings, and grow on carbon-rich substrates like monosaccharides and polysaccharides. This makes them common contaminants of starchy foods and plants ( de Vries et al., 2017 ).

Ecologically, Aspergillus sp. species are significant mycotoxin producers. Their presence in ecosystems is controlled by factors such as microclimate, substrate availability, and water activity. They play crucial roles as decomposers of organic materials and have a substantial impact on ecosystems, agriculture, food production, biotechnology, and human health. The effects of climate change might lead to the emergence of new Aspergillus sp. species and increased mycotoxin contamination risks, as these species can adapt to nutritional and biophysical challenges ( Navale et al., 2021 ). With most of their gene clusters remaining silent, they are a potential source of underexplored bioactive compounds. In summary, Aspergillus sp. is important in both scientific research and industry, as well as in ecological contexts, due to its roles in decomposition, mycotoxin production, and its impact on agriculture and food safety ( Nji et al., 2023 ). The complexity of its interactions in various environments and the potential for discovering new bioactive compounds from its species underscore the importance of continued research in this area. One additional aspect to consider is the health implications of Aspergillus sp. While certain species are beneficial for industrial and culinary uses, others can pose health risks, particularly for people with weakened immune systems ( Vaou et al., 2021 ). For example, Aspergillus fumigatus is a common cause of aspergillosis, an infection that can be severe in immunocompromised individuals. Apart from Aspergillus fumigatus , a frequent cause of aspergillosis in immunocompromised individuals, Aspergillus terreus is also clinically important. This species is associated with several severe conditions such as allergic bronchopulmonary aspergillosis, Aspergillus bronchitis, and invasive aspergillosis, underscoring the importance of understanding and researching the pathogenic capabilities of different Aspergillus species.

Moreover, the production of mycotoxins by some Aspergillus species, notably A. flavus and A. parasiticus which produces aflatoxins, is a significant concern in food safety ( Latgé, 1999 ). Aflatoxins are potent carcinogens and pose a serious risk to both human and animal health, contaminating crops like grains, nuts, and spices. It’s also worth noting the adaptability and resilience of Aspergillus sp. ( Dhakal et al., 2023 ). Their ability to thrive in diverse and often harsh environments, such as high-sugar or high-salt conditions, highlights their evolutionary success. This resilience, however, also means that they can readily colonize and contaminate food and environments, posing ongoing challenges in food storage, agricultural practices, and indoor air quality. In conclusion, while Aspergillus sp. are ecologically and industrially important, their impact on human health and agriculture through disease and mycotoxin production is a critical area of ongoing research and monitoring ( Dhakal et al., 2023 ).

2.2 Genetic makeup of Aspergillus contributes to its potential in drug discovery

The genetic composition of Aspergillus , a group of filamentous fungi, is of great significance in drug discovery due to its capacity to produce a diverse array of secondary metabolites (SMs). These metabolites, such as mycotoxins, polyketides, and peptides, are well-known for their varied biological activities, making them promising candidates for pharmaceutical research and development. Aspergillus species can synthesize over 200 different secondary metabolites thanks to their intricate genetic structure, which includes unique enzymatic pathways. These pathways play a vital role in the fungus’s survival and adaptation to different environments, while also offering a valuable source of bioactive compounds for drug discovery ( Keller, 2019 ). Therefore, comprehending how metabolite production is genetically controlled in Aspergillus is crucial for leveraging its potential in creating innovative therapeutics.

2.2.1 Genome mining and secondary metabolites

Recent advancements in whole genome sequencing methods have greatly improved our comprehension of Aspergillus species, revealing a diverse genetic reservoir poised for the production of secondary metabolites (SMs). Detailed genetic investigations have identified numerous gene clusters responsible for SM biosynthesis, many of which remain inactive or express at low levels under standard laboratory conditions ( Romsdahl and Wang, 2019 ). This discovery suggests a potential treasure trove of new bioactive compounds suitable for pharmaceutical purposes. To unlock this potential, researchers have employed innovative techniques such as modifying growth conditions, using chemical triggers, and employing gene editing tools like CRISPR-Cas9 to activate these dormant gene clusters. For instance, specific adjustments to nutrient levels in growth media have induced the expression of previously inactive biosynthetic pathways, creating novel SMs ( Dzobo, 2022 ).

Additionally, the use of bioinformatics tools has enabled scientists to predict the structure of new compounds by analyzing the genetic sequences responsible for their formation. This method has facilitated the identification of promising drug candidates even before chemical synthesis, significantly expediting the discovery process ( Bayat, 2002 ). One notable breakthrough involved activating a previously unidentified gene cluster in Aspergillus nidulans, leading to the discovery of nidulanins A and B, compounds potentially possessing anti-inflammatory properties. This was achieved by overexpressing specific transcription factors that regulate SM biosynthesis, showcasing how genetic insights can guide the exploration and exploitation of fungal secondary metabolites ( Wang et al., 2021 ).

These initiatives in genome exploration and genetic manipulation not only deepen our understanding of fungal biology but also have the potential to transform drug discovery by presenting new blueprints for therapeutic agents. Through these comprehensive genomic investigations, Aspergillus remains a significant source of pharmacologically active compounds, aiding in the development of next-generation medications.

2.2.2 Biosynthetic gene clusters

The magnitude of BGCs in a single filamentous fungal genome suggests that the secondary metabolite wealth of filamentous fungi like Aspergillus is largely untapped. BGCs are chromosomal architectures encoding necessary synthetases and/or synthases in the fungal genome, controlling the production of fungal secondary metabolites ( Clevenger et al., 2017 ). Genome sequencing has shown diverse chemical applications of these metabolites. For instance, Aspergillus ficuum, a member of the Niger group of fungi, has been documented for its large number of secondary metabolites and mycotoxins, including ochratoxins, fumonisins, naphtha-pyrones, bicoumarins, malformins, asperazines, and alkaloids ( Nielsen et al., 2009 ). These compounds have various applications in pharmaceuticals, cosmetics, and other industries. Further Table 1 details the diversity of secondary metabolites produced by different species of Aspergillus and other fungi, highlighting the associated BGCs, their applications, and strategies employed for activating these gene clusters. The information underscores the immense potential of these organisms in the biotechnology and pharmaceutical industries.

Table 1 . Overview of biosynthetic gene clusters (BGCs) in Aspergillus species.

2.2.3 Pharmacological profiling

The pharmacological potential of Aspergillus species, such as A. ficuum, has been explored through techniques like Liquid Chromatography Quadruple Time-of-Flight Mass Spectrometry (LC-QToF-MS) and Gas Chromatography–Mass Spectrometry (GC–MS) ( Shah et al., 2022 ). These studies focus on uncovering untargeted metabolites biosynthesized in liquid culture. Investigations include assessing the anti-inflammatory, acute oral toxicity, antibacterial, and free radical scavenging potentials of these fungal metabolites. Molecular docking analysis has also been used to understand how these mycocompounds interact with specific enzymes like DNA-polymerase of Bacillus subtilis and the inflammation-supporting enzyme cyclooxygenase-2 ( Orozco-Cortés et al., 2023 ).

In summary, the genetic makeup of Aspergillus significantly contributes to its potential in drug discovery. Its genome harbors a plethora of biosynthetic genes that produce a diverse array of secondary metabolites, many of which have been identified as potential drug candidates. The ongoing exploration and understanding of these metabolites through advanced genomic and pharmacological techniques continue to open new avenues in the search for novel therapeutic agents.

2.3 Anti-cancer agents from Aspergillus species

Aspergillus species are emerging as promising candidates in the quest for innovative anti-cancer agents. Their distinctive metabolic capabilities allow for the synthesis of a wide range of bioactive compounds, demonstrating significant effectiveness against diverse cancer types ( Kalimuthu et al., 2022 ). For example, optimizing the fermentation of Aspergillus wentii EN-48 resulted in a substantial increase in the yield of asperolide A, a potent agent against lung cancer ( Teixeira et al., 2019 ). Similarly, Aspergillus ochraceus is recognized for producing nitrobenzoyl sesquiterpenoids with notable cytotoxicity against a variety of cancer cell lines, highlighting the adaptability of Aspergillus species in targeting different cancers ( Fang et al., 2014 ).

The anti-cancer properties of Aspergillus species are evident in their production of various compounds, including alkaloids, butenolides, terpenoids, and polyketides ( Figure 1 ). This structural diversity contributes to their multifaceted approach to combating cancer ( Bladt et al., 2013 ). Significantly, these species have been identified as prolific producers of anticancer compounds, effectively inhibiting cancer cell growth and inducing apoptosis ( Figure 2 ), a crucial mechanism in cancer therapy ( Greenwell and Rahman, 2015 ). Comparatively, while other fungi possess medicinal properties, the anti-cancer compounds of Aspergillus species appear to be more diverse and potent. For instance, Trichoderma species, known for their antifungal activities, lack the same breadth of anti-cancer potential as Aspergillus ( Noman et al., 2021 ). Furthermore, Aspergillus species’ secondary metabolites, such as terpenes, alkaloids, and polyketides, exhibit greater cytotoxic potency against specific cancer cell lines, such as colorectal cancer, than those from many other natural sources. These findings suggest a heightened potential for Aspergillus species in the development of new cancer treatments ( Shah et al., 2023 ). Additionally, these metabolites show promise as supplementary agents in existing anti-cancer drug regimens, potentially enhancing the efficacy of current treatments ( Chehelgerdi et al., 2023 ).

Figure 1 . Chemical structure of anticancer compound reported from Aspergillus sp.

Figure 2 . Various mode of action of anti-cancer agents produced from Aspergillus species (Adapted and modified from Bladt et al., 2013 ; Noman et al., 2021 ).

The anti-cancer potential of Aspergillus is further emphasized by its ability to produce a diverse array of bioactive metabolites, ranging from potential anti-cancer drugs to therapeutic antibiotics. This highlights the versatility and broad applicability of compounds derived from Aspergillus, positioning it as a significant and versatile contributor to drug discovery, particularly in the field of cancer research ( Dehelean et al., 2021 ). Subsequent Table 2 outlines some of these key classes of anti-cancer compounds along with their mechanism of action and known targets produced by Aspergillus species.

Table 2 . Various anti-cancer compounds reported from Aspergillus sp. and their mechanism of action.

Aspergillus species are a rich source of diverse and biologically active secondary metabolites, encompassing polyketides, terpenoids, peptides, and alkaloids, each with distinct anti-cancer properties. Investigating these compounds through structure–activity relationships (SAR) provides crucial insights for future oncological treatments ( Hu et al., 2020 ). Notably, polyketides like lovastatin from Aspergillus terreus and terpenoids such as Asperolide A exhibit significant anti-cancer potential. Lovastatin, a well-studied compound, exemplifies the importance of specific structural elements; its hydroxylated open-ring form inhibits HMG-CoA reductase, a key enzyme in the mevalonate pathway, disrupting tumor growth at a biochemical level ( Srinivasan et al., 2022 ).

Terpenoids, known for their rigid structure and functional diversity, interact with cellular targets intricately. For instance, asperolide A induces apoptosis and cell cycle arrest, possibly by interacting with regulatory proteins. Functional groups like epoxides within terpenoids enhance molecular reactivity and target specificity, highlighting the connection between chemical structure and biological activity ( Thoppil and Bishayee, 2011 ).

In developing anti-cancer agents from Aspergillus , advanced screening methods are crucial to identify compounds with novel structures and increased potency. Leveraging biosynthetic gene clusters (BGCs) through genomic tools can expedite the identification and modification of these metabolites, improving pharmacokinetics and therapeutic efficacy. Detailed mechanistic studies will refine these compounds’ applications against specific cancer types, enriching the pipeline of innovative therapies and maximizing the therapeutic potential of Aspergillus -derived compounds in oncology.

2.4 Bioprospecting approaches

2.4.1 isolating and characterizing aspergillus strains.

In the intricate field of mycology, sophisticated molecular techniques are employed for the isolation and characterization of Aspergillus strains, ensuring precise identification and detailed analysis. A key method involves ribosomal DNA (rDNA) analysis which is highly valuable due to the conserved nature of rDNA sequences across species, making it an excellent marker for fungal identification ( Diba et al., 2014 ). Additionally, microsatellite Single Nucleotide Polymorphisms (SNPs) enable high-resolution genetic profiling, allowing researchers to differentiate closely related strains and assess genetic diversity within populations. Another important technique is Restriction Fragment Length Polymorphism (RFLP), which examines the pattern of DNA fragments produced by restriction enzymes ( Cruz and Buttner, 2008 ). This method plays a crucial role in mapping genetic relationships and variations among Aspergillus strains, providing insights essential for both fundamental research and practical applications. Furthermore, Multilocus Sequence Typing (MLST) is used to gain a comprehensive view of the genetic landscape by analyzing multiple genetic loci, which is pivotal for understanding the evolutionary paths and relationships among different fungal strains ( Uran-Velasquez et al., 2022 ).

For rapid detection and quantification of specific strains like Aspergillus flavus, real-time Quantitative PCR (qPCR) has been developed. This technique not only detects minute amounts of DNA but also provides quantitative data crucial for pathogen monitoring and management in clinical and agricultural settings ( Mitema et al., 2019 ). Integrating these DNA-based techniques with physical methods such as Percoll density gradient centrifugation, which separates strains based on cell density, and isoenzyme analysis, which distinguishes strains by their metabolic enzyme profiles, offers a robust framework for comprehensive characterization of Aspergillus species ( Huang et al., 2015 ).

Moreover, the use of universal fungal barcodes and functional gene analysis enhances species-level identification precision, consolidating the role of genetic tools in studying fungal diversity and pathogenicity in depth. Collectively, these methods deepen our understanding of genetic and phenotypic diversity within the Aspergillus genus, paving the way for innovative applications in biotechnology and medicine ( Xu, 2016 ).

2.4.2 Screening and identification of bioactive compounds

Sophisticated approaches for the screening and recognition of bioactive compounds encompass a diverse set of methods. Crucial roles are played by biological screening techniques such as cell culture, dialysis, and various chromatographic methods ( Fu et al., 2019 ). Computational tools are employed in virtual screening and ligand-based target prediction methods to identify potential compounds ( Yang et al., 2021 ). Additionally, techniques like HPLC, when combined with biochemical assays, provide efficient screening capabilities without necessitating the purification of compounds ( Zhang et al., 2023 ). A detailed Flow Chart for the Screening and Identification of Bioactive Compounds is illustrated in Figure 3 .

Figure 3 . Detailed flow chart for the screening and identification of bioactive compounds adapted and modified from Zhang et al. (2023) and Yang et al. (2021) .

2.4.3 Integration of omics technologies

Significant progress has been made in the utilization of omics technologies in bioprospecting. Recent advancements involve the incorporation of genomics, transcriptomics, proteomics, and metabolomics, leading to improved biotechnological production of valuable natural products ( Dai and Shen, 2022 ). Additionally, omics technologies are increasingly paired with machine learning and artificial intelligence to further enhance bioprospecting objectives ( Cembrowska-Lech et al., 2023 ).

2.4.4 Role of synthetic biology

Synthetic biology plays a pivotal role in advancing compound production and refinement. Progress in synthetic biology has resulted in the creation of microbial strains equipped with optimized biosynthetic pathways, enhancing the synthesis of value-added compounds ( Chu et al., 2021 ). Additionally, synthetic biology tools aid in the exploration and optimization of gene clusters responsible for secondary metabolites, thereby significantly contributing to the development of new drugs derived from natural sources ( Breitling and Takano, 2016 ). These comprehensive approaches and methodologies in bioprospecting offer a detailed understanding of the processes involved in isolating, characterizing, screening, and producing bioactive compounds from diverse biological sources. The amalgamation of advanced molecular techniques, omics technologies, and synthetic biology has markedly increased the efficiency and effectiveness of bioprospecting endeavors ( Sekurova et al., 2019 ).

3 Methodology

3.1 research design.

This study employs a bibliometric analysis to comprehensively investigate the research landscape surrounding the bioprospecting of Aspergillus species for anti-cancer agents. Bibliometric analysis is a quantitative approach used to assess the impact and development of a field of research by analyzing patterns in academic literature ( Xu et al., 2023 ).

3.2 Data sources

The data for this bibliometric study were extracted from Scopus databases. This database was chosen due to its extensive coverage of life sciences, and biomedical research, and its robust bibliometric data ( Baas et al., 2020 ).

3.3 Search strategy

A systematic search was conducted using a combination of keywords and phrases related to “ Aspergillus species,” “Bioprospecting,” and “Anti-cancer.” Boolean operators (AND, OR) were used to refine the search. The search was limited to articles published in English ( Guo et al., 2023 ).

3.4 Inclusion and exclusion criteria

Articles were included if they were primary research articles, or meta-analyses focusing on the bioprospecting of Aspergillus species for anti-cancer agents. Excluded were non-English articles, Reviews, conference abstracts, books, book chapters, and articles unrelated to the specific focus of Aspergillus species as a source for anti-cancer compounds ( Bezerra et al., 2021 ).

3.5 Data extraction

For each article, the following information was extracted: title, author(s), year of publication, journal name, number of citations, and keywords. The bibliometric criteria chosen for this analysis were carefully selected to illuminate the diverse landscape of Aspergillus research and its evolution over time. The title of each publication offers fundamental insights into the central themes and scope of the research, indicating shifts in scientific focus and emerging areas of interest. The names of the author(s) highlight key contributors, aiding in the mapping of expert networks and identifying pivotal figures whose work has significantly advanced the field. Analysis based on the year of publication reveals the historical trajectory of research efforts, pinpointing temporal trends and periods of breakthroughs in Aspergillus -related studies. The journal name where each study is published serves as an indicator of the research’s reach and relevance, reflecting the community’s engagement with and acknowledgment of the work. The number of citations received by a paper acts as a measure of its influence and the resonance of its findings within the broader scientific discourse. Lastly, the keywords used in the studies provide a vocabulary of the field’s focal points, revealing prevalent topics, methodological approaches, and conceptual linkages that characterize the body of Aspergillus literature. Together, these six criteria form a robust framework for bibliometric investigation, facilitating a comprehensive analysis that captures both the breadth and depth of the research domain ( Kalantari et al., 2017 ).

3.6 Bibliometric analysis

• Publication Trend Analysis: To observe the growth or decline in research activity over time ( Nelis et al., 2022 ).

• Citation Analysis: To assess the impact of the research field ( Brown and Gardner, 1985 ).

• Co-occurrence Network Analysis: To identify the most frequent and influential keywords, indicating major research themes ( Zhang et al., 2019 ).

• Co-authorship Analysis: To examine collaboration patterns among authors and institutions ( Fonseca et al., 2016 ).

• Thematic Mapping: To analyze trends and research gaps ( Parlina et al., 2020 ).

3.7 Tools for analysis

Bibliometric data were analyzed using tools such as Vosviewer for mapping & visualizing bibliometric networks. Biblioshiny, based on the R language script uses analysis of scientific production ( Aria and Cuccurullo, 2017 ).

4 Results and discussion

Figure 4 offers a comprehensive overview of diverse bibliometric statistics related to the exploration of Aspergillus species as a promising reservoir for anti-cancer agents. Spanning from 1982 to 2023, the data encapsulates more than four decades of scholarly endeavors, encompassing 420 sources distributed across various journals, conference proceedings, and databases. The total of 868 documents, including research papers, reviews, and case studies, underscores the depth and breadth of exploration within this field. Demonstrating a robust and escalating interest, the field exhibits an annual growth rate in publications of 11.6%. The collaborative nature of this research is emphasized by the involvement of 3,955 authors in contributing to the body of work, with 12 instances of single-authored documents suggesting a prevalent collaborative norm. Noteworthy is the international co-authorship present in 31.91% of the documents, accentuating the global collaborative efforts, while an average of 5.46 co-authors per document further underscores the cooperative essence of the research community. The research’s diverse focus areas are evident in the 2,261 author’s keywords, reflecting a multifaceted exploration of Aspergillus species. With a total of 39,115 references cited, the research foundation is extensive, actively contributing to scholarly dialogue. The average document age of 5.55 years implies a recent emphasis or sustained relevance of older works, complemented by an impressive average of 21.22 citations per document, highlighting the research’s impact and significance in this field. In summary, this infographic provides a detailed glimpse into the dynamic landscape of Aspergillus -related anti-cancer research, revealing a substantial and expanding body of work. The collaborative, globally engaged, and impactful nature of the research community is apparent, affirming its considerable influence on the scientific literature.

Figure 4 . Overview of scientific data of anticancer studies on Aspergillus sp. collected from Scopus database on November 10, 2023.

4.1 Annual scientific production

Figure 5 is a line graph depicting the progression of annual publications on Aspergillus species as potential sources of anti-cancer agents. An analysis based on the graph’s elements is as follows:

• X-axis (Publications Year): This axis delineates a timeline from 1982 to 2022, indicating the years in which publications were released.

• Y-axis (Number of Publications): The vertical axis denotes the quantity of publications, ranging from 0 to 140.

• Trend Line: Represented by a blue line, it illustrates the annual count of publications, reflecting the research output over time.

Figure 5 . Annual publication data of scientific papers reported the anticancer studies on Aspergillus sp. collected from Scopus Database (between 1982 and 2023).

Observations from the graph include:

1. Gradual Increase: The number of publications exhibits a gradual rise over time, marked by intermittent fluctuations. This implies a growing scientific interest and exploration of Aspergillus species for their anti-cancer potential.

2. Uptrend Post-2000: Notably, an upward trend becomes apparent around the year 2000, with more pronounced growth post-2010.

3. Peak in 2020–2022: The highest concentration of publications occurs between 2020 and 2022, indicating a recent surge in research activity.

This graph effectively illustrates the expanding body of research into the medicinal properties of Aspergillus. It signifies the increased prominence of scientific exploration in this domain over the last two decades. Factors contributing to the rise in publications may include advancements in research methodologies, augmented funding, an influx of researchers into the field, or a combination of these influences.

Aspergillus species are recognized for producing diverse secondary metabolites, some possessing anti-cancer properties. The depicted trend underscores the significance of this genus in the quest for novel anti-cancer compounds, with the potential to advance drug and therapy development. Furthermore, it highlights the heightened awareness within the scientific community regarding the potential of natural products in drug discovery, emphasizing the ongoing necessity to explore and assess such biological resources ( Kousar et al., 2022 ).

4.2 Publication distribution based regions

Figure 6 shows the global distribution of scientific publications related to Aspergillus species as a source of anticancer agents. The color intensity represents the number of publications, with darker shades indicating higher publication counts. This suggests that the regions in darker red have higher research output in this field, while those in blue have relatively lower output.

Figure 6 . Countries scientific publication frequency of scientific papers reported the anticancer studies on Aspergillus sp. collected from Scopus database (between 1982 and 2023).

Global collaboration between countries in the field of research on Aspergillus species as anticancer agents is illustrated in Figure 7 . The thickness of the lines may represent the strength or number of collaborations, with the countries shown in darker shades possibly having more collaborations or a central role in the research network.

Figure 7 . Countries collaboration network data of scientific papers reported the anticancer studies on Aspergillus sp. collected from Scopus database (between 1982 and 2023).

4.3 Three field plot

Figure 8 depicts a Sankey diagram, a type of flow diagram where the arrow width represents the flow rate or quantity. In the given context, it illustrates the interrelation among author countries (AU_CO), individual authors (AU), and types of anti-cancer agents or activities studied in Aspergillus species (DE).

Figure 8 . Three field plot (Country, Author name, and Keyword) of the publications on the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

To interpret the diagram:

1. AU_CO (Author Country): This category displays countries likely representing the researchers’ origin or institutional affiliation, such as Egypt, USA, Malaysia, India, Saudi Arabia, and Korea. This indicates contributions from researchers in these nations.

2. AU (Author): This section presents the author’s initials and last names, likely of researchers who have published studies on Aspergillus species and their potential as sources of anti-cancer agents.

3. DE (Descriptors): This category lists various activities or properties researched in Aspergillus species, such as anti-cancer, antimicrobial, antifungal, and antioxidant activities.

Lines connecting countries to authors and authors to descriptors indicate which authors from which countries have contributed to researching specific aspects of Aspergillus species. For instance, an Egyptian author may have publications related to the anticancer and antimicrobial activities of Aspergillus species.

In the broader scientific research context, this diagram may be part of a bibliometric analysis, a method of quantitatively analyzing scientific literature. Such analyses unveil research patterns, identifying leading countries, prolific authors, and primary research focus areas. Here, the analysis centers around Aspergillus species’ potential as sources of anti-cancer compounds. Aspergillus , a fungi genus, produces various secondary metabolites, some with medicinal properties, including anti-cancer activities. This diagram underscores the global research effort exploring these properties for potential therapeutic applications.

4.4 Journal bibliometric analysis

Recognizing the trends in publications within a particular field holds significant importance for researchers aiming to find the most suitable platform to share their work or for those evaluating the overall advancement of the field. Utilizing bibliometric methods to conduct a thorough analysis of journals reveals valuable perspectives on the output of each journal. Such insights are indispensable for researchers deciding where to publish their research and for stakeholders keen on monitoring the progress of a specific research domain. Tables 3 , 4 show the most relevant journal & their impact on this research domain.

Table 3 . Top 10 journals with the highest publication output on the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

Table 4 . Top 10 journals with the highest impact output in the field of anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

Figure 9 illustrates the cumulative occurrences of publications across several scientific journals spanning from 1982 to 2021. The journals included in the graph are “Applied Organometallic Chemistry,” “European Journal of Medicinal Chemistry,” “Marine Drugs,” “Medicinal Chemistry Research,” and “Molecules.”

Figure 9 . Journal production over time based on the number of publications reported the anticancer studies on Aspergillus sp. collected from Scopus database (Between 1982–2023).

Here is a concise analysis of the graph:

• The initiation points of publication activity for each journal vary, reflecting either their respective founding years or the commencement of the time frame considered for this analysis.

• A discernible upward trend in cumulative occurrences is evident for all journals in the graph, indicating a progressive increase in research output over the years.

• Notably, “Molecules” exhibits a substantial spike in cumulative occurrences, especially prominent post the early 2000s, suggesting a significant surge in research publications within this journal during that period.

• The “European Journal of Medicinal Chemistry” also demonstrates a noticeable upswing, albeit commencing a bit earlier than “Molecules,” starting around the mid-1990s.

• In contrast, “Applied Organometallic Chemistry,” “Marine Drugs,” and “Medicinal Chemistry Research” display more modest growth patterns in comparison.

4.5 Bibliometric analysis of authorship

Table 5 lists authors who have contributed significantly to the field based on the number of articles published. The “Articles Fractionalized” column likely represents a fractional count of publications to account for co-authorship.

Table 5 . Most prolific author based on publication output in the field of anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

This part of the analysis focuses on the impact of authors’ publications within journals, measured by indices like the H-Index, G-Index, and M-Index, alongside total citations and the start year of publication (as shown in Table 6 ).

Table 6 . Top 10 authors with the highest impact output in the field of anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

In this examination, the H-Index serves as a metric assessing an author’s overall impact and productivity, while the G-Index enhances the H-Index by assigning greater significance to highly cited articles. The M-Index is calculated by dividing the H-Index by the number of years since the author’s initial publication. Total Citations represent the cumulative number of citations received by the author’s works, and the Number of Publications indicates the number of articles published by the author. The Publication Year Start indicates the commencement of the author’s contributions to the field based on the dataset. This information proves essential for comprehending the influence and productivity of individual researchers within their respective domains. Figure 10 presents a ranking of the top 10 institutions in the field of Aspergillus species research for anticancer agents.

Figure 10 . Top 10 institutions with the highest publication output on the anticancer properties of Aspergillus sp., Analyzed from Scopus database (1982–2023).

4.6 Author production analysis

Figure 11 depicts a bubble timeline chart that visually represents the publication output of various authors engaged in Aspergillus research for anticancer agents over time. An analysis of the elements in the graph reveals:

• Y-axis (Author): The vertical axis enumerates the names of authors actively involved in this research field.

• X-axis (Year): The horizontal axis spans from 2010 to 2022, representing the timeline.

• Bubbles: Each bubble corresponds to a publication by an author in a specific year. Bubble size likely correlates with the quantity or significance of publications, potentially reflecting factors like the number of papers or the impact factor of the respective journals.

Figure 11 . Author scientific production of publications overtime on the anticancer properties of Aspergillus sp., Analyzed from Scopus database (1982–2023).

From the chart, several observations can be drawn:

1. Multiple Authors: Notable researchers such as Mohamed GG, El-Sayed ASA, and others are listed, signifying key contributors in the field.

2. Distribution Patterns: The arrangement of bubbles along the timeline for each author indicates their publication frequency and potentially reflects their impact in the field.

3. Publication Patterns: Some authors exhibit a consistent spread of publications over the years, suggesting a sustained research effort. In contrast, others may display periods of heightened activity followed by intervals of reduced or no activity.

4. Recent Activity: The author with the largest bubble in the most recent year may suggest a noteworthy publication or an increase in research activity during that period.

This visual representation proves valuable for swiftly identifying leading authors, comprehending their publication trends, and analyzing shifts in research activity over time. It aids researchers and policymakers in recognizing key contributors, potential collaborators, and the field’s evolution in terms of research output.

4.7 Keyword analysis

In our study, we have conducted an in-depth analysis of the most frequently used keywords, which are pivotal for understanding the current trends in specific research domains. Table 7 lists the top 15 most frequently occurring author’s keywords based on total linkage strength.

Table 7 . Top 15 most frequently occurring keywords among the publications of the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

Vosviewer is employed for visualizing a network of keyword occurrences based on total linkage strength (as shown in Figure 12 ). Out of the initial pool of 2,263 keywords, a specific criterion was applied, selecting keywords with a minimum of 5 occurrences. Eighty-seven keywords met this criteria and were utilized for the network visualization, as illustrated in the figure.

Figure 12 . Network visualization of most occurring keyword among the publications of the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023) based on total linkage strength using Vosviewer.

4.8 Word cloud

Figure 13 is a word cloud, offering a visual representation of text data where the size of each word indicates its frequency or importance in the context of research on Aspergillus species as potential anti-cancer agents. A detailed analysis based on the words in the cloud is as follows:

1. “Article” and “Study”: Prominent in the cloud, these words suggest that the word cloud is derived from a body of literature, likely scholarly articles focused on studies in the field.

2. “ Aspergillus,” “Aspergillus niger,” and “Candida albicans ”: These words denote various species of fungi, with Aspergillus niger known for its biotechnological applications, including the production of anti-cancer compounds.

3. “Antineoplastic Agent” and “Anticancer”: Frequent inclusion of these terms indicates a primary focus on substances inhibiting or preventing tumor growth, underscoring the therapeutic aspect of the research.

4. “Antimicrobial,” “Antibacterial,” and “Antifungal Activity”: These terms imply a broad spectrum of bioactivity under investigation, extending beyond anti-cancer properties to antimicrobial effects.

5. “Nonhuman,” “Human,” “Controlled Study”: The presence of these terms suggests a comprehensive approach covering both nonhuman ( in vitro ) and human (clinical) research, possibly including controlled trials for rigorous scientific inquiry.

6. “IC50,” “Cytotoxicity,” “Cell Proliferation”: These terms, rooted in pharmacology and cellular biology, signify critical measures in cancer research. IC50 represents the concentration needed for 50% inhibition in vitro , while cytotoxicity and cell proliferation are pivotal in understanding the effects on cancer cells.

7. “ Staphylococcus aureus,” “Escherichia coli,” “Pseudomonas aeruginosa ”: Reference to these bacterial species commonly used in antimicrobial testing suggests a benchmark for evaluating potential anti-cancer drugs with antimicrobial properties.

8. “ In Vitro Study,” “Cell Line,” “MTT Assay”: These terms point towards laboratory methods and tools employed to study the impact of Aspergillus -derived compounds on cancer cells.

Figure 13 . Word cloud of most frequent occurring keyword among the publications of the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023) and prepared using R-Studio.

In essence, this word cloud visually summarizes the key concepts and methodologies prevalent in the research literature on Aspergillus species as sources of anti-cancer agents. It portrays a multidisciplinary approach, encompassing microbiology, pharmacology, molecular biology, and more, highlighting the diverse strategies employed to explore the therapeutic potential of fungal metabolites.

4.9 Word frequency over time

Figure 14 depicts a cumulative line graph that traces the frequency of specific terms over time in the research domain focused on Aspergillus as a potential source of anti-cancer agents. The X-axis, spanning from 1982 to 2021, represents the timeline for data collection, while the Y-axis quantifies cumulative occurrences, illustrating an increasing count over the years.

Figure 14 . Word frequency over time among the publications of the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023) and prepared using R-Studio.

Each line on the graph corresponds to distinct terms, including categories like “Antineoplastic Activity,” “Antineoplastic Agent,” “Article,” “ Aspergillus ,” “ Aspergillus niger ,” “Controlled Study,” “ E. coli ,” “Human,” “Nonhuman,” and “Unclassified Drug.”

Key observations reveal a general upward trend for all terms, particularly accelerating around the early 2000s, indicative of rising interest and an expanding body of research in these realms. The growth in both “Human” and “Nonhuman” terms suggests research conducted in clinical and preclinical settings.

Notably, terms related to anti-cancer efforts, such as “Antineoplastic Activity” and “Antineoplastic Agent,” exhibit a significant increase, signaling an intensified exploration of Aspergillus -derived compounds for cancer treatment and prevention. The ascending lines for “ Aspergillus ” and “ Aspergillus niger ” align with increased attention towards these fungi concerning their potential anti-cancer properties.

The sustained rise in the term “Controlled Study” indicates a growing application of rigorous scientific methodologies in this field over time. The inclusion of “ E. coli ,” although not directly tied to anti-cancer research, implies potential comparative studies on the antimicrobial properties of Aspergillus -derived compounds, given E. coli’s common use as a model organism.

Lastly, the presence of “Unclassified Drug” suggests an exploration of novel or not yet fully categorized compounds derived from Aspergillus, emphasizing the ongoing investigation into new therapeutic possibilities.

In summary, the graph visually summarizes the increasing prominence of specific research topics and methodologies over nearly four decades within the Aspergillus research field. It effectively conveys the cumulative interest and expanding research efforts into Aspergillus species and their potential applications in the realm of cancer treatment.

4.10 Thematic mapping

Figure 15 is commonly known as a “strategic quadrant” or “strategy canvas.” It finds application in diverse fields, including scientific research, to visually map themes or topics based on two axes: “Development Degree” and “Relevance Degree (Centrality).” In this context, these axes denote the maturity of the research and its centrality to the field, respectively.

Figure 15 . Thematic mapping of the publications on the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

Regarding Aspergillus species and their potential as reservoirs for anti-cancer agents, the figure illustrates the positioning of Aspergillus -related themes within various quadrants:

1. Basic Themes: These encompass well-established and central themes, denoted by terms such as “anticancer,” “antimicrobial activity,” “anti-inflammatory,” “antioxidant,” “antifungal activity,” and “metal complexes.” This positioning suggests widespread recognition of the role played by Aspergillus species in producing compounds with these activities, underscoring their fundamental importance in the field of study.

2. Niche Themes: Representing less developed and less central areas of research, these include “anti-microbial activity,” “hydrazone,” and “QSAR.” Such themes may signify emerging or specialized niches within the broader study of Aspergillus.

3. Motor Themes: These are highly developed and central themes, such as “Actinomycetes” and “ Streptomyces .” While not directly related to Aspergillus, these terms may indicate analogous or competing sources of anti-cancer agents in microbial bioprospecting.

4. Emerging or Declining Themes: Encompassing themes that lack both development and centrality, examples include “terrein.” These may signify either emerging areas of research or subjects losing focus.

The positioning of terms like “Aspergillus,” “ Fusarium, ” “phytochemicals,” “endophytes,” “fungi,” “marine-derived fungi,” and “ Aspergillus ” across the Motor and Basic Themes quadrants indicate a prominent and central role for Aspergillus species in producing biologically active compounds. Specifically, in the context of anti-cancer activity, it suggests that Aspergillus species are highly regarded as a source for discovering and developing new anti-cancer agents, given their involvement in generating diverse secondary metabolites with potential therapeutic effects.

4.11 Multi-correspondence analysis

The following Figure 16 is a biplot derived from a multi-correspondence analysis (MCA) analysis or a similar dimensionality reduction technique, which is often used in bioinformatics and data analysis to visualize the similarity of variables in a lower-dimensional space.

Figure 16 . Multi-correspondence analysis plot of the publications on the anticancer properties of Aspergillus sp., analyzed from Scopus database (1982–2023).

The image shows that the horizontal axis (Dim 1) captures 36.5% of the variance in the dataset, while the vertical axis (Dim 2) captures 11.23%. This indicates that Dim 1 is the most influential factor in this dataset, but together, these dimensions account for less than half of the total variance, suggesting that the underlying data is quite complex.

The terms plotted are likely keywords or terms extracted from scientific literature related to Aspergillus species and their potential biomedical applications. Here are some insights based on the grouping of terms:

1. Anticancer Potential : The terms “Anticancer,” “Antitumor,” “Cytotoxic,” and “Apoptosis” are clustered, suggesting a strong association between Aspergillus species and research into their anticancer properties. Apoptosis is the process of programmed cell death, and agents that can induce apoptosis are often explored for cancer therapy.

2. Antimicrobial Activity : The words “Antibacterial,” “Antifungal,” and “Antiviral” form another cluster, indicating that Aspergillus species may also be studied for their potential to fight various infections.

3. Synthesis Methods : “Green synthesis” is close to “Silver Nanoparticles” and “Gold Nanoparticles,” which might indicate investigations into environmentally friendly methods of synthesizing nanoparticles using Aspergillus species.

4. Bioinformatics Tools : The term “Molecular docking” is a bioinformatics method used to predict how a small molecule, such as a drug, interacts with a protein, suggesting that this technique is being used to study the interaction between Aspergillus -derived compounds and their potential targets in cancer cells.

5. Specific Species and Compounds : Specific Aspergillus species like “ Aspergillus terreus ” and “ Aspergillus flavus ” are mentioned alongside compounds like “Camptothecin” which is known for its anti-cancer properties, implying that these species may produce or be used to produce such compounds.

6. Secondary Metabolites : “Secondary Metabolites,” “Endophytes,” and “Phytochemicals” are also prominent, which points to the interest in the complex chemicals produced by Aspergillus that may have medicinal properties.

7. Cell Lines : The term “MCF 7” refers to a breast cancer cell line that is often used in cancer research, suggesting that studies are evaluating Aspergillus compounds against this particular type of cancer.

In summary, the visualization suggests a rich body of research focused on the bioactive potential of Aspergillus species, spanning anticancer activity, antimicrobial properties, and green synthesis methods. The analysis of such a biplot helps researchers identify trends, generate hypotheses, and select the most promising directions for further study.

5 Challenges and future perspective

5.1 challenges.

• The complexity of Aspergillus Metabolites: Unravelling the intricate biochemical pathways and the wide array of secondary metabolites generated by Aspergillus species ( Siddhardha et al., 2010 ).

• Drug Resistance: Confronting the evolving resistance to current anti-cancer agents and exploring how compounds derived from Aspergillus may offer solutions to overcome this challenge ( Sajna et al., 2020 ).

• Safety and Toxicity: Assessing the safety profile and potential toxicity of novel compounds sourced from Aspergillus species ( Barba-Ostria et al., 2022 ).

• Scalable Production: Formulating efficient and scalable techniques for producing bioactive compounds from Aspergillus ( Yuan et al., 2022 ).

• Regulatory Hurdles: Navigating the intricate regulatory landscape for the approval of new drugs derived from natural sources ( Atanasov et al., 2021 ).

5.2 Future perspective

• Genomic and Metabolomic Advancements: Employing genomic and metabolomic technologies to uncover and characterize novel compounds derived from Aspergillus ( Kalia et al., 2022 ).

• Targeted Drug Delivery: Examining Aspergillus metabolites for application in targeted drug delivery systems aimed at enhancing the effectiveness of cancer treatment ( Veselov et al., 2022 ).

• Combination Therapies: Assessing the potential of compounds sourced from Aspergillus in combination therapies with existing cancer treatments ( Mokhtari et al., 2017 ).

• Personalized Medicine: Employing Aspergillus compounds in personalized medicine approaches, tailoring treatments based on individual genetic profiles and specific cancer types ( Goetz and Schork, 2018 ).

• Sustainable Bioprospecting: Advocating for sustainable and ethical bioprospecting practices in exploring Aspergillus species, ensuring the investigation does not harm natural ecosystems ( Kuhad, 2012 ).

6 Conclusion

This research has emphasized the considerable promise of Aspergillus species in the development of anti-cancer agents, as indicated by our comprehensive bibliometric analysis. The varied bioactive compounds discovered in Aspergillus, including alkaloids, butenolides, terpenoids, and polyketides, exhibit significant effectiveness against diverse cancer types. The rising number of publications and international research collaborations in this realm reflects the increasing acknowledgment of natural products in cancer treatment and underscores the importance of sustaining this exploration.

Nevertheless, challenges persist in fully unlocking the potential of these compounds. There is a crucial need for a deeper understanding of their biosynthetic pathways, improved extraction and synthesis methods, and thorough clinical evaluations. This study highlights the essentiality of an integrative approach that combines traditional knowledge with modern scientific techniques to harness these natural resources more efficiently. The encouraging outcomes from research on Aspergillus species provide the impetus for ongoing and collaborative endeavors in the domain of natural product drug discovery, presenting new possibilities for safer and more efficacious cancer therapies.

Author contributions

HJ: Conceptualization, Writing – original draft. SG: Conceptualization, Writing – original draft. PK: Conceptualization, Writing – review & editing. AK: Conceptualization, Writing – review & editing. AS: Supervision, Writing – review & editing. GK: Conceptualization, Supervision, Writing – review & editing.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We would like to express our genuine appreciation to Lovely Professional University for creating an academic atmosphere and offering resources that greatly supported the successful culmination of this in-depth review paper.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: Aspergillus species, anti-cancer agents, bioprospecting, natural products, bibliometric analysis

Citation: Jangid H, Garg S, Kashyap P, Karnwal A, Shidiki A and Kumar G (2024) Bioprospecting of Aspergillus sp. as a promising repository for anti-cancer agents: a comprehensive bibliometric investigation. Front. Microbiol . 15:1379602. doi: 10.3389/fmicb.2024.1379602

Received: 31 January 2024; Accepted: 30 April 2024; Published: 15 May 2024.

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Copyright © 2024 Jangid, Garg, Kashyap, Karnwal, Shidiki and Kumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Amrullah Shidiki, [email protected] ; Gaurav Kumar, [email protected] ; [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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International Journal of Quality & Reliability Management

ISSN : 0265-671X

Article publication date: 17 May 2024

This study is intended to introduce and summarise Industry 4.0 practices in BRICS nations (the abbreviation “BRICS” is made up of the first letters of the member countries: Brazil, Russia, India, China and South Africa) and determine each nation’s current contribution to Industry 4.0 practice implementation based on past literature. As the BRICS countries continue to play an essential role in the global economy, it is significant to understand Industry 4.0, focussing on these emerging economies.

Design/methodology/approach

To assess the present research work on Industry 4.0 practices and research studies in BRICS nations, a systematic literature review (SLR) is performed using the articles available on the SCOPUS database. This study is a descriptive analysis based on the frequency and year of publications, the most influential universities, most influential journals and most influential articles. Similarly, this study consists of category analysis based on multi-criteria decision-making (MCDM) methods, research design used, research method utilised, different data analysis techniques and different Industry 4.0 technologies were used to solve different applications in the BRICS nations.

According to the analysis of past literature, the primary identified practices are centred on operations productivity, waste management, energy reduction and sustainable processes. It also found that despite the abundance of research on Industry 4.0, the major academic journal publications are restricted to a small number of industries and issues in which the manufacturing and automotive industries are front runners. The categorisation of selected papers based on the year of publication demonstrates that the number of publications has been rising. It is also found that China and India, out of the BRICS countries, have contributed significantly to Industry 4.0-related publications by contributing 61 percent of the total articles identified. Similarly, this study identified that qualitative research design is the most adopted framework for research, and empirical triangulation is the least adopted framework in this field. The categorisation of selected articles facilitates the identification of numerous gaps, such as that 67.14% of the literature research is qualitative.

Practical implications

Understanding Industry 4.0 in the BRICS nations helps to identify opportunities for international collaboration and future cooperation possibilities. This study helps to promote collaboration between BRICS countries and other nations, organisations or businesses interested in capitalising on these growing economies' assets and capabilities related to Industry 4.0 technologies. This study helps to provide essential insights into the economic, technological and societal impacts, allowing for effective decision-making and strategic planning for a sustainable and competitive future. So, this contribution links the entire world in terms of the better utilisation of resources, the reduction of downtime, improving product quality, personalised products and the development of human resource capabilities through the application of cutting-edge technologies for nearly half of the world’s population.

Originality/value

In this study, BRICS nations are selected due to their significant impact on the world regarding social, economic and environmental contributions. In the current review, 423 articles published up to August 2022 were selected from the SCOPUS database. The comparison analysis of each BRICS nation in the form of applications of Industry 4.0, the primary area of focus, leading industry working, industry involvement with universities and the area that needs attention are discussed. To the best of our knowledge, this is the most recent SLR and meta-analysis study about Industry 4.0 in BRICS nations, which analysed the past available literature in nine different descriptive and category-wise classifications, considering a total of 423 articles. Based on this SLR, this study makes some important recommendations and future directions that will help achieve social, economic and environmental sustainability in BRICS nations.

• Industry 4.0
• BRICS nations
• Emerging economies
• Competitive advantages
• Literature review
• Meta-analysis

Yadav, A. , Yadav, G. and Desai, T.N. (2024), "Unlocking the potential of Industry 4.0 in BRICS nations: a systematic literature review and meta-analysis", International Journal of Quality & Reliability Management , Vol. ahead-of-print No. ahead-of-print. https://doi.org/10.1108/IJQRM-06-2023-0180

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Copyright © 2024, Emerald Publishing Limited

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• Open access
• Published: 13 May 2024

Sexual and reproductive health implementation research in humanitarian contexts: a scoping review

• Alexandra Norton 1 &
• Hannah Tappis 2  

Reproductive Health volume  21 , Article number:  64 ( 2024 ) Cite this article

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Meeting the health needs of crisis-affected populations is a growing challenge, with 339 million people globally in need of humanitarian assistance in 2023. Given one in four people living in humanitarian contexts are women and girls of reproductive age, sexual and reproductive health care is considered as essential health service and minimum standard for humanitarian response. Despite growing calls for increased investment in implementation research in humanitarian settings, guidance on appropriate methods and analytical frameworks is limited.

A scoping review was conducted to examine the extent to which implementation research frameworks have been used to evaluate sexual and reproductive health interventions in humanitarian settings. Peer-reviewed papers published from 2013 to 2022 were identified through relevant systematic reviews and a literature search of Pubmed, Embase, PsycInfo, CINAHL and Global Health databases. Papers that presented primary quantitative or qualitative data pertaining to a sexual and reproductive health intervention in a humanitarian setting were included.

Seven thousand thirty-six unique records were screened for inclusion, and 69 papers met inclusion criteria. Of these, six papers explicitly described the use of an implementation research framework, three citing use of the Consolidated Framework for Implementation Research. Three additional papers referenced other types of frameworks used in their evaluation. Factors cited across all included studies as helping the intervention in their presence or hindering in their absence were synthesized into the following Consolidated Framework for Implementation Research domains: Characteristics of Systems, Outer Setting, Inner Setting, Characteristics of Individuals, Intervention Characteristics, and Process.

This review found a wide range of methodologies and only six of 69 studies using an implementation research framework, highlighting an opportunity for standardization to better inform the evidence for and delivery of sexual and reproductive health interventions in humanitarian settings. Increased use of implementation research frameworks such as a modified Consolidated Framework for Implementation Research could work toward both expanding the evidence base and increasing standardization.

Plain English summary

Three hundred thirty-nine million people globally were in need of humanitarian assistance in 2023, and meeting the health needs of crisis-affected populations is a growing challenge. One in four people living in humanitarian contexts are women and girls of reproductive age, and provision of sexual and reproductive health care is considered to be essential within a humanitarian response. Implementation research can help to better understand how real-world contexts affect health improvement efforts. Despite growing calls for increased investment in implementation research in humanitarian settings, guidance on how best to do so is limited. This scoping review was conducted to examine the extent to which implementation research frameworks have been used to evaluate sexual and reproductive health interventions in humanitarian settings. Of 69 papers that met inclusion criteria for the review, six of them explicitly described the use of an implementation research framework. Three used the Consolidated Framework for Implementation Research, a theory-based framework that can guide implementation research. Three additional papers referenced other types of frameworks used in their evaluation. This review summarizes how factors relevant to different aspects of implementation within the included papers could have been organized using the Consolidated Framework for Implementation Research. The findings from this review highlight an opportunity for standardization to better inform the evidence for and delivery of sexual and reproductive health interventions in humanitarian settings. Increased use of implementation research frameworks such as a modified Consolidated Framework for Implementation Research could work toward both expanding the evidence base and increasing standardization.

Peer Review reports

Over the past few decades, the field of public health implementation research (IR) has grown as a means by which the real-world conditions affecting health improvement efforts can be better understood. Peters et al. put forward the following broad definition of IR for health: “IR is the scientific inquiry into questions concerning implementation – the act of carrying an intention into effect, which in health research can be policies, programmes, or individual practices (collectively called interventions)” [ 1 ].

As IR emphasizes real-world circumstances, the context within which a health intervention is delivered is a core consideration. However, much IR implemented to date has focused on higher-resource settings, with many proposed frameworks developed with particular utility for a higher-income setting [ 2 ]. In recognition of IR’s potential to increase evidence across a range of settings, there have been numerous reviews of the use of IR in lower-resource settings as well as calls for broader use [ 3 , 4 ]. There have also been more focused efforts to modify various approaches and frameworks to strengthen the relevance of IR to low- and middle-income country settings (LMICs), such as the work by Means et al. to adapt a specific IR framework for increased utility in LMICs [ 2 ].

Within LMIC settings, the centrality of context to a health intervention’s impact is of particular relevance in humanitarian settings, which present a set of distinct implementation challenges [ 5 ]. Humanitarian responses to crisis situations operate with limited resources, under potential security concerns, and often under pressure to relieve acute suffering and need [ 6 ]. Given these factors, successful implementation of a particular health intervention may require different qualities than those that optimize intervention impact under more stable circumstances [ 7 ]. Despite increasing recognition of the need for expanded evidence of health interventions in humanitarian settings, the evidence base remains limited [ 8 ]. Furthermore, despite its potential utility, there is not standardized guidance on IR in humanitarian settings, nor are there widely endorsed recommendations for the frameworks best suited to analyze implementation in these settings.

Sexual and reproductive health (SRH) is a core aspect of the health sector response in humanitarian settings [ 9 ]. Yet, progress in addressing SRH needs has lagged far behind other services because of challenges related to culture and ideology, financing constraints, lack of data and competing priorities [ 10 ]. The Minimum Initial Service Package (MISP) for SRH in Crisis Situations is the international standard for the minimum set of SRH services that should be implemented in all crisis situations [ 11 ]. However, as in other areas of health, there is need for expanded evidence for planning and implementation of SRH interventions in humanitarian settings. Recent systematic reviews of SRH in humanitarian settings have focused on the effectiveness of interventions and service delivery strategies, as well as factors affecting utilization, but have not detailed whether IR frameworks were used [ 12 , 13 , 14 , 15 ]. There have also been recent reviews examining IR frameworks used in various settings and research areas, but none have explicitly focused on humanitarian settings [ 2 , 16 ].

Given the need for an expanded evidence base for SRH interventions in humanitarian settings and the potential for IR to be used to expand the available evidence, a scoping review was undertaken. This scoping review sought to identify IR approaches that have been used in the last ten years to evaluate SRH interventions in humanitarian settings.

This review also sought to shed light on whether there is a need for a common framework to guide research design, analysis, and reporting for SRH interventions in humanitarian settings and if so, if there are any established frameworks already in use that would be fit-for-purpose or could be tailored to meet this need.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews was utilized to guide the elements of this review [ 17 ]. The review protocol was retrospectively registered with the Open Science Framework ( https://osf.io/b5qtz ).

Search strategy

A two-fold search strategy was undertaken for this review, which covered the last 10 years (2013–2022). First, recent systematic reviews pertaining to research or evaluation of SRH interventions in humanitarian settings were identified through keyword searches on PubMed and Google Scholar. Four relevant systematic reviews were identified [ 12 , 13 , 14 , 15 ] Table 1 .

Second, a literature search mirroring these reviews was conducted to identify relevant papers published since the completion of searches for the most recent review (April 2017). Additional file 1 includes the search terms that were used in the literature search [see Additional file 1 ].

The literature search was conducted for papers published from April 2017 to December 2022 in the databases that were searched in one or more of the systematic reviews: PubMed, Embase, PsycInfo, CINAHL and Global Health. Searches were completed in January 2023 Table 2 .

Two reviewers screened each identified study for alignment with inclusion criteria. Studies in the four systematic reviews identified were considered potentially eligible if published during the last 10 years. These papers then underwent full-text review to confirm satisfaction of all inclusion criteria, as inclusion criteria were similar but not fully aligned across the four reviews.

Literature search results were exported into a citation manager (Covidence), duplicates were removed, and a step-wise screening process for inclusion was applied. First, all papers underwent title and abstract screening. The remaining papers after abstract screening then underwent full-text review to confirm satisfaction of all inclusion criteria. Title and abstract screening as well as full-text review was conducted independently by both authors; disagreements after full-text review were resolved by consensus.

Data extraction and synthesis

The following content areas were summarized in Microsoft Excel for each paper that met inclusion criteria: publication details including author, year, country, setting [rural, urban, camp, settlement], population [refugees, internally displaced persons, general crisis-affected], crisis type [armed conflict, natural disaster], crisis stage [acute, chronic], study design, research methods, SRH intervention, and intervention target population [specific beneficiaries of the intervention within the broader population]; the use of an IR framework; details regarding the IR framework, how it was used, and any rationale given for the framework used; factors cited as impacting SRH interventions, either positively or negatively; and other key findings deemed relevant to this review.

As the focus of this review was on the approach taken for SRH intervention research and evaluation, the quality of the studies themselves was not assessed.

Twenty papers underwent full-text review due to their inclusion in one or more of the four systematic reviews and meeting publication date inclusion criteria. The literature search identified 7,016 unique papers. After full-text screening, 69 met all inclusion criteria and were included in the review. Figure  1 illustrates the search strategy and screening process.

Flow chart of paper identification

Papers published in each of the 10 years of the review timeframe (2013–2022) were included. 29% of the papers originated from the first five years of the time frame considered for this review, with the remaining 71% papers coming from the second half. Characteristics of included publications, including geographic location, type of humanitarian crisis, and type of SRH intervention, are presented in Table  3 .

A wide range of study designs and methods were used across the papers, with both qualitative and quantitative studies well represented. Twenty-six papers were quantitative evaluations [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], 17 were qualitative [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], and 26 used mixed methods [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Within the quantitative evaluations, 15 were observational, while five were quasi-experimental, five were randomized controlled trials, and one was an economic evaluation. Study designs as classified by the authors of this review are summarized in Table  4 .

Six papers (9%) explicitly cited use of an IR framework. Three of these papers utilized the Consolidated Framework for Implementation Research (CFIR) [ 51 , 65 , 70 ]. The CFIR is a commonly used determinant framework that—in its originally proposed form in 2009—is comprised of five domains, each of which has constructs to further categorize factors that impact implementation. The CFIR domains were identified as core content areas influencing the effectiveness of implementation, and the constructs within each domain are intended to provide a range of options for researchers to select from to “guide diagnostic assessments of implementation context, evaluate implementation progress, and help explain findings.” [ 87 ] To allow for consistent terminology throughout this review, the original 2009 CFIR domains and constructs are used.

Guan et al. conducted a mixed methods study to assess the feasibility and effectiveness of a neonatal hepatitis B immunization program in a conflict-affected rural region of Myanmar. Guan et al. report mapping data onto the CFIR as a secondary analysis step. They describe that “CFIR was used as a comprehensive meta-theoretical framework to examine the implementation of the Hepatitis B Virus vaccination program,” and implementation themes from multiple study data sources (interviews, observations, examination of monitoring materials) were mapped onto CFIR constructs. They report their results in two phases – Pre-implementation training and community education, and Implementation – with both anchored in themes that they had mapped onto CFIR domains and constructs. All but six constructs were included in their analysis, with a majority summarized in a table and key themes explored further in the narrative text. They specify that most concerns were identified within the Outer Setting and Process domains, while elements identified within the Inner Setting domain provided strength to the intervention and helped mitigate against barriers [ 70 ].

Sarker et al. conducted a qualitative study to assess provision of maternal, newborn and child health services to Rohingya refugees residing in camps in Cox’s Bazar, Bangladesh. They cite using CFIR as a guide for thematic analysis, applying it after a process of inductive and deductive coding to index these codes into the CFIR domains. They utilized three of the five CFIR domains (Outer Setting, Inner Setting, and Process), stating that the remaining two domains (Intervention Characteristics and Characteristics of Individuals) were not relevant to their analysis. They then proposed two additional CFIR domains, Context and Security, for use in humanitarian contexts. In contrast to Guan et al., CFIR constructs are not used nor mentioned by Sarker et al., with content under each domain instead synthesized as challenges and potential solutions. Regarding the CFIR, Sarker et al. write, “The CFIR guided us for interpretative coding and creating the challenges and possible solutions into groups for further clarification of the issues related to program delivery in a humanitarian crisis setting.” [ 51 ]

Sami et al. conducted a mixed methods case study to assess the implementation of a package of neonatal interventions at health facilities within refugee and internally displaced persons camps in South Sudan. They reference use of the CFIR earlier in the study than Sarker et al., basing their guides for semi-structured focus group discussions on the CFIR framework. They similarly reference a general use of the CFIR framework as they conducted thematic analysis. Constructs are referenced once, but they do not specify whether their application of the CFIR framework included use of domains, constructs, or both. This may be in part because they then applied an additional framework, the World Health Organization (WHO) Health System Framework, to present their findings. They describe a nested approach to their use of these frameworks: “Exploring these [CFIR] constructs within the WHO Health Systems Framework can identify specific entry points to improve the implementation of newborn interventions at critical health system building blocks.” [ 65 ]

Three papers cite use of different IR frameworks. Bolan et al. utilized the Theoretical Domains Framework in their mixed methods feasibility study and pilot cluster randomized trial evaluating pilot use of the Safe Delivery App by maternal and newborn health workers providing basic emergency obstetric and newborn care in facilities in the conflict-affected Maniema province of the Democratic Republic of the Congo (DRC). They used the Theroetical Domains Framework in designing interview questions, and further used it as the coding framework for their analysis. Similar to the CFIR, the Theoretical Domains Framework is a determinant framework that consists of domains, each of which then includes constructs. Bolan et al. utilized the Theoretical Domains Framework at the construct level in interview question development and at the domain level in their analysis, mapping interview responses to eight of the 14 domains [ 83 ]. Berg et al. report using an “exploratory design guided by the principles of an evaluation framework” developed by the Medical Research Council to analyze the implementation process, mechanisms of impact, and outcomes of a three-pillar training intervention to improve maternal and neonatal healthcare in the conflict-affected South Kivu province of the DRC [ 67 , 88 ]. Select components of this evaluation framework were used to guide deductive analysis of focus group discussions and in-depth interviews [ 67 ]. In their study of health workers’ knowledge and attitudes toward newborn health interventions in South Sudan, before and after training and supply provision, Sami et al. report use of the Conceptual Framework of the Role of Attitudes in Evidence-Based Practice Implementation in their analysis process. The framework was used to group codes following initial inductive coding analysis of in-depth interviews [ 72 ].

Three other papers cite use of specific frameworks in their intervention evaluation [ 19 , 44 , 76 ]. As a characteristic of IR is the use of an explicit framework to guide the research, the use of the frameworks in these three papers meets the intention of IR and serves the purpose that an IR framework would have in strengthening the analytical rigor. Castle et al. cite use of their program’s theory of change as a framework for a mixed methods evaluation of the provision of family planning services and more specifically uptake of long-acting reversible contraception use in the DRC. They describe use of the theory of change to “enhance effectiveness of [long-acting reversible contraception] access and uptake.” [ 76 ] Thommesen et al. cite use of the AAAQ (Availability, Accessibility, Acceptability and Quality) framework in their qualitative study assessing midwifery services provided to pregnant women in Afghanistan. This framework is focused on the “underlying elements needed for attainment of optimum standard of health care,” but the authors used it in this paper to evaluate facilitators and barriers to women accessing midwifery services [ 44 ]. Jarrett et al. cite use of the Centers for Disease Control and Prevention’s (CDC) Guidelines for Evaluating Public Health Surveillance Systems to explore the characteristics of a population mobility, mortality and birth surveillance system in South Kivu, DRC. Use of these CDC guidelines is cited as one of four study objectives, and commentary is included in the Results section pertaining to each criteria within these guidelines, although more detail regarding use of these guidelines or the authors’ experience with their use in the study is not provided [ 19 ].

Overall, 22 of the 69 papers either explicitly or implicitly identified IR as relevant to their work. Nineteen papers include a focus on feasibility (seven of which did not otherwise identify the importance of exploring questions concerning implementation), touching on a common outcome of interest in implementation research [ 89 ].

While a majority of papers did not explicitly or implicitly use an IR framework to evaluate their SRH intervention of focus, most identified factors that facilitated implementation when they were present or served as a barrier when absent. Sixty cite factors that served as facilitators and 49 cite factors that served as barriers, with just three not citing either. Fifty-nine distinct factors were identified across the papers.

Three of the six studies that explicitly used an IR framework used the CFIR, and the CFIR is the only IR framework that was used by multiple studies. As previously mentioned, Means et al. put forth an adaptation of the CFIR to increase its relevance in LMIC settings, proposing a sixth domain (Characteristics of Systems) and 11 additional constructs [ 2 ]. Using the expanded domains and constructs as proposed by Means et al., the 59 factors cited by papers in this review were thematically grouped into the six domains: Characteristics of Systems, Outer Setting, Inner Setting, Characteristics of Individuals, Intervention Characteristics, and Process. Within each domain, alignment with CFIR constructs was assessed for, and alignment was found with 29 constructs: eight of Means et al.’s 11 constructs, and 21 of the 39 standard CFIR constructs. Three factors did not align with any construct (all fitting within the Outer Setting domain), and 14 aligned with a construct label but not the associated definition. Table 5 synthesizes the mapping of factors affecting SRH intervention implementation to CFIR domains and constructs, with the construct appearing in italics if it is considered to align with that factor by label but not by definition.

Table 6 lists the CFIR constructs that were not found to have alignment with any factor cited by the papers in this review.

This scoping review sought to assess how IR frameworks have been used to bolster the evidence base for SRH interventions in humanitarian settings, and it revealed that IR frameworks, or an explicit IR approach, are rarely used. All four of the systematic reviews identified with a focus on SRH in humanitarian settings articulate the need for more research examining the effectiveness of SRH interventions in humanitarian settings, with two specifically citing a need for implementation research/science [ 12 , 13 ]. The distribution of papers across the timeframe included in this review does suggest that more research on SRH interventions for crisis-affected populations is taking place, as a majority of relevant papers were published in the second half of the review period. The papers included a wide range of methodologies, which reflect the differing research questions and contexts being evaluated. However, it also invites the question of whether there should be more standardization of outcomes measured or frameworks used to guide analysis and to facilitate increased comparison, synthesis and application across settings.

Three of the six papers that used an IR framework utilized the CFIR. Guan et al. used the CFIR at both a domain and construct level, Sarker et al. used the CFIR at the domain level, and Sami et al. did not specify which CFIR elements were used in informing the focus group discussion guide [ 51 , 65 , 70 ]. It is challenging to draw strong conclusions about the applicability of CFIR in humanitarian settings based on the minimal use of CFIR and IR frameworks within the papers reviewed, although Guan et al. provides a helpful model for how analysis can be structured around CFIR domains and constructs. It is worth considering that the minimal use of IR frameworks, and more specifically CFIR constructs, could be in part because that level of prescriptive categorization does not allow for enough fluidity in humanitarian settings. It also raises questions about the appropriate degree of standardization to pursue for research done in these settings.

The mapping of factors affecting SRH intervention implementation provides an example of how a modified CFIR framework could be used for IR in humanitarian contexts. This mapping exercise found factors that mapped to all five of the original CFIR domains as well as the sixth domain proposed by Means et al. All factors fit well within the definition for the selected domain, indicating an appropriate degree of fit between these existing domains and the factors identified as impacting SRH interventions in humanitarian settings. On a construct level, however, the findings were more variable, with one-quarter of factors not fully aligning with any construct. Furthermore, over 40% of the CFIR constructs (including the additional constructs from Means et al.) were not found to align with any factors cited by the papers in this review, also demonstrating some disconnect between the parameters posed by the CFIR constructs and the factors cited as relevant in a humanitarian context.

It is worth noting that while the CFIR as proposed in 2009 was used in this assessment, as well as in the included papers which used the CFIR, an update was published in 2022. Following a review of CFIR use since its publication, the authors provide updates to construct names and definitions to “make the framework more applicable across a range of innovations and settings.” New constructs and subconstructs were also added, for a total of 48 constructs and 19 subconstructs across the five domains [ 90 ]. A CFIR Outcomes Addendum was also published in 2022, based on recommendations for the CFIR to add outcomes and intended to be used as a complement to the CFIR determinants framework [ 91 ]. These expansions to the CFIR framework may improve applicability of the CFIR in humanitarian settings. Several constructs added to the Outer Setting domain could be of particular utility – critical incidents, local attitudes, and local conditions, each of which could help account for unique challenges faced in contexts of crisis. Sub-constructs added within the Inner Setting domain that seek to clarify structural characteristics and available resources would also be of high utility based on mapping of the factors identified in this review to the original CFIR constructs. As outcomes were not formally included in the CFIR until the 2022 addendum, a separate assessment of implementation outcomes was not undertaken in this review. However, analysis of the factors cited by papers in this review as affecting implementation was derived from the full text of the papers and thus captures content relevant to implementation determinants that is contained within the outcomes.

Given the demonstrated need for additional flexibility within an IR framework for humanitarian contexts, while not a focus of this review, it is worth considering whether a different framework could provide a better fit than the CFIR. Other frameworks have differing points of emphasis that would create different opportunities for flexibility but that do not seem to resolve the challenges experienced in applying the CFIR to a humanitarian context. As one example, the EPIS (Exploration, Preparation, Implementation, Sustainment) Framework considers the impact of inner and outer context on each of four implementation phases; while the constructs within this framework are broader than the CFIR, an emphasis on the intervention characteristics is missing, a domain where stronger alignment within the CFIR is also needed [ 92 ]. Alternatively, the PRISM (Practical, Robust Implementation and Sustainability Model) framework is a determinant and evaluation framework that adds consideration of context factors to the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) outcomes framework. It has a stronger emphasis on intervention aspects, with sub-domains to account for both organization and patient perspectives within the intervention. While PRISM does include aspects of context, external environment considerations are less robust and intentionally less comprehensive in scope, which would not provide the degree of alignment possible between the Characteristics of Systems and Outer Setting CFIR domains for the considerations unique to humanitarian environments [ 93 ].

Reflecting on their experience with the CFIR, Sarker et al. indicate that it can be a “great asset” in both evaluating current work and developing future interventions. They also encourage future research of humanitarian health interventions to utilize the CFIR [ 51 ]. The other papers that used the CFIR do not specifically reflect on their experience utilizing it, referring more generally to having felt that it was a useful tool [ 65 , 70 ]. On their use of an evaluation framework, Berg et al. reflected that it lent useful structure and helped to identify aspects affecting implementation that otherwise would have gone un-noticed [ 67 ]. The remaining studies that utilized an IR framework did not specifically comment on their experience with its use [ 72 , 83 ]. While a formal IR framework was not engaged by other studies, a number cite a desire for IR to contribute further detail to their findings [ 21 , 37 ].

In their recommendations for strengthening the evidence base for humanitarian health interventions, Ager et al. speak to the need for “methodologic innovation” to develop methodologies with particular applicability in humanitarian settings [ 7 ]. As IR is not yet routinized for SRH interventions, this could be opportune timing for the use of a standardized IR framework to gauge its utility. Using an IR framework to assess factors influencing implementation of the MISP in initial stages of a humanitarian response, and interventions to support more comprehensive SRH service delivery in protracted crises, could lend further rigor and standardization to SRH evaluations, as well as inform strategies to improve MISP implementation over time. Based on categorizing factors identified by these papers as relevant for intervention evaluation, there does seem to be utility to a modified CFIR approach. Given the paucity of formal IR framework use within SRH literature, it would be worth conducting similar scoping exercises to assess for explicit use of IR frameworks within the evidence base for other health service delivery areas in humanitarian settings. In the interim, the recommended approach from this review for future IR on humanitarian health interventions would be a modified CFIR approach with domain-level standardization and flexibility for constructs that may standardize over time with more use. This would enable use of a common analytical framework and vocabulary at the domain level for stakeholders to describe interventions and the factors influencing the effectiveness of implementation, with constructs available to use and customize as most appropriate for specific contexts and interventions.

This review had a number of limitations. As this was a scoping review and a two-part search strategy was used, the papers summarized here may not be comprehensive of those written pertaining to SRH interventions over the past 10 years. Papers from 2013 to 2017 that would have met this scoping review’s inclusion criteria may have been omitted due to being excluded from the systematic reviews. The review was limited to papers available in English. Furthermore, this review did not assess the quality of the papers included or seek to assess the methodology used beyond examination of the use of an IR framework. It does, however, serve as a first step in assessing the extent to which calls for implementation research have been addressed, and identify entry points for strengthening the science and practice of SRH research in humanitarian settings.

With one in 23 people worldwide in need of humanitarian assistance, and financing required for response plans at an all-time high, the need for evidence to guide resource allocation and programming for SRH in humanitarian settings is as important as ever [ 94 ]. Recent research agenda setting initiatives and strategies to advance health in humanitarian settings call for increased investment in implementation research—with priorities ranging from research on effective strategies for expanding access to a full range of contraceptive options to integrating mental health and psychosocial support into SRH programming to capturing accurate and actionable data on maternal and perinatal mortality in a wide range of acute and protracted emergency contexts [ 95 , 96 ]. To truly advance guidance in these areas, implementation research will need to be conducted across diverse humanitarian settings, with clear and consistent documentation of both intervention characteristics and outcomes, as well as contextual and programmatic factors affecting implementation.

Conclusions

Implementation research has potential to increase impact of health interventions particularly in crisis-affected settings where flexibility, adaptability and context-responsive approaches are highlighted as cornerstones of effective programming. There remains significant opportunity for standardization of research in the humanitarian space, with one such opportunity occurring through increased utilization of IR frameworks such as a modified CFIR approach. Investing in more robust sexual and reproductive health research in humanitarian contexts can enrich insights available to guide programming and increase transferability of learning across settings.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Availability, Accessibility, Acceptability and Quality

Centers for Disease Control and Prevention

Consolidated Framework for Implementation Research

Democratic Republic of the Congo

Exploration, Preparation, Implementation, Sustainment

• Implementation research

Low and middle income country

Minimum Initial Service Package

Practical, Robust Implementation and Sustainability Model

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Reach, Effectiveness, Adoption, Implementation, Maintenance

• Sexual and reproductive health

World Health Organization

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Effect of cytoplasmic fragmentation on embryo development, quality, and pregnancy outcome: a systematic review of the literature

• Ariella Yazdani 1 , 3 ,
• Iman Halvaei 2 ,
• Catherine Boniface 1 &
• Navid Esfandiari   ORCID: orcid.org/0000-0003-0979-5236 1 , 4  

Reproductive Biology and Endocrinology volume  22 , Article number:  55 ( 2024 ) Cite this article

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The role of cytoplasmic fragmentation in human embryo development and reproductive potential is widely recognized, albeit without standard definition nor agreed upon implication. While fragmentation is best understood to be a natural process across species, the origin of fragmentation remains incompletely understood and likely multifactorial. Several factors including embryo culture condition, gamete quality, aneuploidy, and abnormal cytokinesis seem to have important role in the etiology of cytoplasmic fragmentation. Fragmentation reduces the volume of cytoplasm and depletes embryo of essential organelles and regulatory proteins, compromising the developmental potential of the embryo. While it has been shown that degree of fragmentation and embryo implantation potential are inversely proportional, the degree, pattern, and distribution of fragmentation as it relates to pregnancy outcome is debated in the literature. This review highlights some of the challenges in analysis of fragmentation, while revealing trends in our evolving knowledge of how fragmentation may relate to functional development of the human embryos, implantation, and pregnancy outcome.

Introduction

Human preimplantation embryo scoring systems have been widely used to predict blastocyst development and implantation rate after in-vitro fertilization (IVF). The grading of embryos on day-2 and -3 after fertilization is largely subjective and interpretation varies across IVF laboratories, as it is commonly based on morphological appearance. Characteristics in early embryo grading schema include the amount of cytoplasmic fragmentation (CF) during early cleavage, speed of cellular division, number, size, and symmetry of cells (blastomeres). As defined by the Istanbul consensus workshop on embryo assessment, a fragment is “an extracellular membrane-bound cytoplasmic structure that is < 45 µm diameter in a day-2 embryo and < 40 µm diameter in a day-3 embryo” [ 1 ]. There are several different systems to evaluate embryo morphology including Hill’s scoring system [ 2 ] Cummins' grading system [ 3 ] ASEBIR grading system [ 1 ], the UK/ACE grading scheme [ 4 ]; each system has its own classification for degree of fragmentation as well as embryo grade. This heterogeneity further complicates analysis of fragmentation in relation to outcomes.

CF has been shown to occur early in embryonic division and is a common phenomenon seen in embryos cultured in vitro. CF has traditionally been used as a metric of embryo implantation potential [ 3 , 5 , 6 , 7 ]. The amount and pattern of fragments are analyzed in early development, incorporated into the embryo grade depending on grading system, and used to help select the most developmentally competent embryo to be transferred during an IVF cycle. This classification system is important as a proportion of embryos within a single cohort will not successfully develop to the blastocyst stage in vitro. Although there are various contributing factors to an embryo’s developmental capacity and viability, it is largely agreed upon that fragmentation plays an important role. It seems that the etiology of embryo fragmentation is not fully understood but it may be related to several factors like gamete quality, culture condition, and genetic abnormalities in the embryo [ 8 ]. It is difficult to directly compare and quantify relative degrees of fragmentation across studies. However, it has been repeatedly shown that the extent of fragmentation and implantation potential are inversely proportional [ 5 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. While a low degree of fragmentation does not seem to significantly impact embryo viability, severe fragmentation does [ 7 , 22 , 23 ]. Alongside the cell to cytoplasmic ratio, the pattern and distribution of fragmentation influence the developmental quality of the embryo [ 7 , 24 ]. There are two main patterns of embryo cytoplasmic fragments: scattered and concentrated. The former is characterized by fragment contact within several blastomeres and is related to aneuploidy [ 25 ]. Time-lapse studies have shown that fragmentation is thought to be a dynamic process, where some fragments can be expelled or reintroduced into the cells as the embryo continues to divide [ 25 , 26 ]. Fragments can also easily move or rotate around the associated blastomere and change their position in the embryo [ 27 ].

Current grading systems used to evaluate cleavage-stage embryos are largely based on day-2 or -3 morphology. This can be problematic, as developmental growth of an embryo is variable and the grade of a developing embryo at one point in time is not guaranteed to persist. For example, studies have suggested that embryo selection on day-2 or -3 based on morphological grade can be unreliable and lead to negative pregnancy outcomes [ 28 , 29 , 30 ]. Accordingly, new parameters for predicting implantation success have been proposed including extended embryo culture to the blastocyst stage to day-5, -6 or -7 [ 31 ]. Delaying embryo transfer to the blastocyst stage is advantageous as it can limit the number of unsuccessful embryo transfers and biochemical pregnancies or clinical pregnancy losses in IVF. While there are multiple reports on the impact of cleavage-stage embryo quality on blastocyst formation and blastocyst quality [ 32 , 33 ], few have specifically looked at the degree of fragmentation as a predictive variable.

In this systematic review, we comprehensively reviewed the available literature on the origin and characteristics of CF, factors affecting CF, and the effect of CF and fragment removal on embryo development and pregnancy rate.

Materials and methods

A search was conducted on October 10, 2023, using PubMed and Google Scholar databases in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines [ 34 ]. In PubMed, the search terms “embryo*[tw] OR cleavage stage [tw] OR "Embryonic Structures"[Mesh] OR "Embryonic Development"[Mesh] OR "Embryo, Mammalian"[Mesh] OR "Cleavage Stage, Ovum"[Mesh]” AND “cytoplasm*[tw] AND fragment*[tw] AND “(Blastocyst*[tw] OR "Blastocyst"[Mesh]) AND (form* OR develop* OR quality*)” were used. A title search in Google Scholar using search terms as above and “embryo cytoplasm fragmentation”, “blastocyst quality”, “blastocyst development” was performed. Only full-text publications in English were included. Full-text articles which did not have any mention of cytoplasmic or embryo fragmentation were excluded, however articles which mentioned both DNA fragmentation and CF were included. Since most of the studies discussing CF also discussed other morphologic features of the embryo, studies that mention embryo morphology, grade or quality were also included. Articles that looked at non-human embryo fragmentation, case reports, case series, book chapters and review papers were excluded. Titles and abstracts were screened, and study quality and bias were assessed. The primary outcomes of interest were embryo quality, blastocyst formation, and pregnancy outcome.

Figure 1 provides details of study screening and inclusion. There were 206 studies screened between the two search engines PubMed ( n =106) and Google Scholar ( n =100). There were 18 duplicates giving a total of 188 articles. Due to the small number of studies from the search criteria, no filter of time was placed. After removal of non-full text articles, articles that used non-human embryos, and articles not relevant to the topic, 20 articles were eligible for inclusion. Forty relevant references from the articles were also extracted, reviewed, and included in this review. These additional articles were reviewed with the same inclusion and exclusion criteria as mentioned above. A total of 60 articles were included in the qualitative synthesis of this review.

Article Identification and Screening

Origin and etiology of CF

The etiology of CF is not completely understood. There are several proposed theories as to why embryos display variable degrees of fragmentation. Fragmentation has been shown to be a natural, unpredictable process both in vitro and in vivo and is documented in various species [ 35 , 36 ]. This suggests that embryo fragmentation is neither species-specific nor solely a byproduct of in vitro culture. Assisted reproductive technology (ART) and IVF techniques, such as time-lapse microscopy (TLM) and transmission electron microscopic (TEM) analyses, have recently allowed for further understanding of embryo developmental potential and fragmentation (Figs.  2 and 3 ). Seven of the included studies in this review propose potential hypotheses as to the origin of CF (Table 1 ). Three of the articles evaluated gamete quality as related to fragmentation in a developing embryo [ 37 , 38 , 39 ].

Human cleavage stage embryos a) Day-2 embryo at 4-cell stage with no fragmentation, b) fragmented Day-2 embryo, c) Day-3 embryo at 8-cell stage with no fragmentation, d) fragmented Day-3 embryo, e) Day-5 cavitating Morula with no fragmentation, f) fragmented Day-5 cavitating Morula

Ultrastructure and organelle microtopography of an embryo fragment by transmission electron microscopy. Ly: primary lysosome, M: mitochondrion, rM: remnant of regressing mitochondrion, MV: mitochondria-vesicle complex, V: vesicle; scale bar: 1 µM

An early study showed that sperm DNA oxidation has been associated with embryo development and quality, and therefore linked to CF [ 37 ]. Nucleolar asynchrony in the zygote from sperm DNA fragmentation has previously been shown to predict future low-quality blastocyst development. A positive correlation has also been found between the percentage of sperm OxiDNA-stained cells with embryo fragmentation on day-2 and -3 of development. Sperm DNA oxidation may therefore be associated with fragmented, nonviable, poor-quality embryos [ 37 ] . A recent study also showed the negative correlation between sperm DNA fragmentation and blastomere DNA fragmentation and blastulation rate [ 40 ]. Further studies are needed to confirm the impact of sperm DNA oxidation on embryo fragmentation.

An observational study documented the degree of fragmentation of human embryos as they progressed through mitotic cell cycles [ 38 ]. In this study, the authors analyzed nearly 2,000 oocytes and 372 embryos, and found that increased embryo fragmentation (>50%) was associated with a specific pattern of development: delayed first division (oocyte spindle detected at 36.2 hours after hCG injection vs. 35.5 hours in low fragmentation), a significantly earlier start of the second mitosis (8.9 hours vs. 10.8 hours after the first mitosis), and a significant delay of the third mitosis after the second mitosis (2.2. hours vs. 0.6 hours). The authors did not comment on whether fragmentation could be a result of the cell dividing before proper chromosome alignment, or if existing aneuploidy resulted in erroneous cleavage patterns [ 38 ].

Polar body (PB) fragmentation has also been investigated in relation to cytoplasmic fragmentation. Ebner et al., in a prospective study analyzed the relationship between a fragmented first PB and embryo quality in patients undergoing ICSI. Two groups of oocytes were analyzed according to PB fragmentation: intact first PBs and those with fragmented PBs. Forty-two hours after ICSI, embryo morphology (i.e., number of blastomeres and degree of fragmentation) was recorded. Overall, a significantly higher percentage of cytoplasmic fragmentation was seen in day-2 embryos that originated from oocytes with fragmented first PBs than those with intact PBs ( P < 0.05). This study further supports the concept that oocyte quality contributes to overall embryo fragmentation and provides evidence that preselection of oocytes may contribute to the prognosis of embryo quality and blastocyst development [ 39 ]. The role of PB fragmentation on embryo quality was confirmed in other studies [ 41 , 42 ], however, a recent study has not recommended considering PB status as a tool for embryo selection [ 43 ].

Beyond analysis of gamete quality, other studies have shown a biochemical relationship between embryo competence and fragmentation. One study showed that disturbances in E-cadherin, a cell adhesion protein that plays a critical role in morphogenesis, occur in embryos with cleavage abnormalities and extensive cytoplasmic fragmentation, suggesting a possible mechanism to the loss of embryonic viability [ 44 ]. Further, by using mitochondrial fluorescence techniques, Van Blerkom et al., found that mitochondrial distribution at the pronuclear stage may be an epigenetic factor related to the organization of the embryo and further embryonic development [ 45 ]. Blastomeres that were deficient in mitochondria and thus ATP at the first or second cell division remained undivided and often died during subsequent culture. Although this study examined morphologically normal (unfragmented) cleavage-stage embryos, it may support the idea that perinuclear mitochondrial distribution and microtubular organization influence developmental capacity of early cleavage-stage embryos [ 45 ]. Higher numbers of mitochondria reported in fragmented compared to the normal blastomeres show the rapid depletion of ATP in the fragmented embryos [ 21 ]. There have also been reports of increased gene transcription of mitochondrial factors like OXPHOS complexes, ATP synthase, and mtDNA content in highly fragmented embryos compared to controls [ 46 ]. Mitochondrial activity is lower and more centralized in fragmented embryos compared to good quality embryos on day-3 [ 47 ]. Mitochondria are the main source of ATP for embryo mitosis, and their proper function is essential for embryo development. More research is needed to elucidate the morphology and role of mitochondria in embryo development, especially in relation to fragmentation.

A subsequent study by Van Blerkom et al., analyzed the temporal and spatial aspects of fragmentation through TLM and TEM analyses from the pronuclear to the 10-12-cell stage. Through TLM, the authors visualized the non-discrete, dynamic nature of fragments and noted that many were “bleb-elaborations” of the plasma membrane and cytoplasm. They characterized two patterns of fragmentation: definitive and pseudo-fragmentation. Definitive fragmentation was described as fragments detached from a blastomere, and pseudo-fragmentation was assigned when the fragments were no longer detectable during subsequent development. Often one developing embryo would show both fragmentation patterns at different stages of development, suggesting that these patterns may have different etiologies and effects on embryo development competence [ 47 ]. Hardarson et al., similarly used TLM to document that fragments are dynamic and can be internalized throughout cleavage during culture periods. The contents of the fragments were noted to be internalized and released into the cytoplasm of the blastomere and seen on multiple time-lapse photographs as a cytoplasmic turbulence. This is the first reported evidence that cellular fragments can “disappear” during the culture period in human IVF [ 26 ]. It seems that in mild to moderate CF, the timing of embryo evaluation and grading can affect the reported percent of fragmentation.

Lastly, we have included a preliminary study performed by Sermondade et al., that suggests a specific subgroup of patients who have had repeated IVF failures (presumably due to a recurring high rate of fragmented embryos) may benefit from early intrauterine embryo transfer at the zygote stage (2PN) [ 48 ]. Data showed a delivery rate per oocyte retrieval of 18.9%, which was significantly higher than the delivery rate of 7.5% in the matched control group. The results were encouraging and suggestive of a safe, non-invasive rescue strategy for patients who experience recurrent highly fragmented embryos and failed IVF attempts. The data further suggests that fertilized oocytes of this subgroup may have deficiencies in certain maternal factors (i.e., stress-response factors) that do not allow normal embryo development in culture environments [ 48 ]. Another study was also confirmed application of zygote transfer in patients with history of low-quality embryos [ 49 ]. However, further studies are required to verify the impact of this technique for patients with history of fragmented embryos.

Apoptosis is another proposed etiology of fragmentation. Apoptosis may occur in blastomeres with defective cytoplasm or abnormal chromosomes, leading to embryo fragmentation [ 50 ]. There are several studies reporting apoptosis in both fragments and neighboring blastomeres in a fragmented embryo [ 24 , 50 ]. Chi et al., showed that fragments are associated with both apoptosis and necrosis [ 21 ]. One of the factors that appears to induce apoptosis in blastomeres is suboptimal culture conditions such as hypoxia [ 51 ]. In addition, there are controversial reports on the role of reactive oxygen species (ROS) in embryo fragmentation [ 52 , 53 ]. It has been shown that ROS are present at high levels in the culture media of fragmented embryos [ 52 , 54 ]. Chen et al., recently showed that embryo culture in 5% oxygen, from days 1 to 3, is associated with higher embryo quality and live birth rate compared to 20% oxygen [ 55 ]. The effects of culture condition modifications, such as hypoxia and ROS, on embryo fragmentation need to be clarified to understand the importance of culture condition in this process.

Membrane compartmentalization of DNA, abnormal cytokinesis, and extra vesicular formation are other proposed theories for embryo fragmentation [ 8 ]. Defects or damages in mitochondria are associated with low ATP and high ROS production leading to a compromised cell division and cytokinesis [ 27 ]. In addition, there is a correlation between embryo fragmentation and ploidy status. Chavez et al., showed that CF was seen in a high proportion of aneuploid embryos, and that meiotic and mitotic errors may cause fragmentation in different cell development stages. Meiotic errors were associated with fragmentation at one-cell stage while mitotic errors were associated with fragmentation at interphase or after first cytokinesis [ 56 ]. Chromosomally abnormal embryos often have severe fragmentation, which may be another cause of CF [ 55 , 57 ].

Overall, the precise cause of CF has yet to be clearly defined. The above investigations have elucidated potential sources and associations of what is likely a complex and multifactorial process and represent our current understanding of CF origin.

What is contained in CF?

Four of the included studies used various technological advances to study the contents of CF in human embryos (Table 2 ). Two studies used TEM methods to evaluate fragment ultrastructure (Fig.  3 ) [ 21 , 58 ]. Fragments were extracted from embryos with 10-50% fragmentation and the ultrastructure evaluated by TEM. Micrographs showed that the fragments had a distinct membrane containing cytoplasmic organelles including mitochondria, mitochondria-vesicle complexes, Golgi apparatus, primary lysosomes, and vacuoles. Mitochondria were the most abundant structure.

In an additional evaluation of CF contents, Johansson et al., analyzed DNA content of fragments to define a cutoff diameter for an anucleate fragment or blastomere. Findings showed that 98% of fragments <45 µm on day-2 and 97% of those <40 µm on day-3 contained no DNA and, if not reabsorbed into a blastomere, showed a loss of cytoplasm. Presence of essential blastomere organelles such as mitochondria, mRNA, and proteins within cytoplasmic fragments were related to embryo development arrest [ 59 ]. Lastly, Chi et al., also used TEM to examine ultrastructure of the human fragmented embryos and found that blastomeres with anucleate fragments contained fewer mitochondria in their cytoplasm compared to normal blastomeres [ 21 ].

Cell death and CF

Eight of the included studies analyzed the relationship between cell death and embryo fragmentation (Table 3 ). Five studies analyzed the status of chromatin in arrested fragmented embryos through a combined technique for simultaneous nuclear and terminal transferase-mediated DNA end labelling (TUNEL) [ 24 , 60 , 61 , 62 , 63 ]. Two studies used a comet assay to analyze DNA fragmentation [ 21 , 63 ]. Four of the eight studies used Annexin V staining [ 21 , 61 , 62 , 63 ] with three including the presence of propidium iodide (PI) to compare apoptosis to necrosis [ 21 , 61 , 63 ].

Jurisicova et al., used a combined nuclear and fragmented DNA labeling approach which allowed distinction between chromatin status and DNA fragmentation, which serve as markers of apoptosis versus necrosis respectively [ 60 ]. After fertilization, embryos were stained with 4,6-diamidino-2-phenylindole (DAPI). In cases of compromised cell membrane integrity, DAPI stain was observed in the cytoplasm as a sign of necrosis. Concomitant use of TUNEL labeling reflected the integrity of the DNA and allowed distinction between necrotic and apoptotic cells. Through combined techniques of DAPI/TUNEL, TEM, scanning electron microscopy (SEM) and stereomicroscopic observations, 153 of 203 (75.4%) fragmented early cleavage-stage embryos displayed signs of apoptosis (i.e., chromatin condensation, cellular shrinkage, DNA fragmentation, presence of cell corpses) with or without normal nuclei [ 60 ].

Similarly, Levy et al., analyzed early arrested or fragmented preimplantation embryos and the pattern of DNA fragmentation using TUNEL assay and the presence of phosphatidylserine through Fluorescein isothiocyanate (FITC)-labelled Annexin V, a phosphatidylserine binding protein. The authors observed TUNEL staining in one or more nuclei of 15 out of 50 (30%) arrested embryos from the 2-cell stage to uncompacted morulae, all of which had high degrees of CF. Furthermore, embryos with regular-sized blastomeres without fragmentation were all TUNEL negative [ 50 ].

A separate prospective study by Antczak et al., explored the possible association between fragmentation and apoptosis using PI and Annexin V staining of plasma membrane phosphatidylserine and TUNEL analysis of blastomere DNA [ 24 ]. In contradistinction to prior studies, these authors found no direct correlation between fragmentation and apoptosis. Virtually all blastomeres that were PI negative, intact or fragmented, showed no TUNEL or annexin V fluorescence, suggesting no signs of apoptosis [ 24 ].

Liu et al., used a similar methodology of TUNEL labeling and Annexin V staining to detect markers of apoptosis in fragmented human embryos derived from IVF [ 61 ]. Overall, highly fragmented embryos had apoptotic features including bright fluorescence (positive TUNEL labeling signifying DNA fragmentation) on the cell corpses and in intact blastomeres [ 61 ]. By staining cells with both annexin V and PI, this study was able to demonstrate that apoptosis occurs frequently in fragmented human embryos and the coexistence of apoptotic, necrotic and viable sibling blastomeres can occur. Sibling blastomeres within an embryo often showed apoptotic features that led to secondary necrosis while others did not initiate apoptosis. The authors did not find a significant difference in the expression frequency of apoptotic genes between viable and nonviable or arrested embryos [ 61 ].

Chi et al., stained human embryos ( n =10) with annexin V and PI and found that human fragmented embryos exhibited characteristics of both necrosis and apoptosis [ 20 ]. Rather than TUNEL assay, these authors used a modified sperm comet assay to investigate DNA fragmentation of human fragmented embryos. They found that 6/7 human fragmented embryos (85.1%) stained positively for PI with the intensity of staining increasing with the degree of fragmentation. Of note, DNA fragmentation was observed in fragmented human embryos but not in the normal embryo [ 21 ].

Metcalfe et al., analyzed the expression of 11 BCL-2 family genes in normally developing embryos and in severely fragmented embryos [ 64 ]. They found that the expression of BCL-2 family genes was highest in the pronuclear stage and eight-cell stages, and lowest at the two-cell, four-cell, and blastocyst stages in developmentally intact embryos. Furthermore, the expression did not change in fragmented embryos, suggesting that embryo fragmentation does not likely compromise mRNA integrity and gene detection [ 64 ]. However, like Liu et al., [ 61 ] these authors did detect far fewer pro-apoptotic BCL-2 genes in fragmented embryos at the eight-cell stage. The authors noted that these findings do not distinguish between iatrogenic apoptosis from suboptimal in-vitro culture conditions [ 64 ]. A separate study by Jurisicova et al. similarly analyzed gene expression at the 2-, 4- and 8-cell stage of fragmented embryos. Embryos that had 30-50% fragmentation showed a significant increase in Hrk mRNA levels, a BCL-2 protein encoding gene ( P = 0.016). Further, these authors found an increase in Caspase-3 mRNA in fragmented embryos, as well as induction of Caspase-3-like enzyme activity in nucleated fragments, although this finding was not statistically significant [ 65 ].

Van Blerkom et al., also used TUNEL assay in conjunction with the comet assay as a method of identifying the specific pattern of cell death (necrosis, lysis or apoptosis) and the extent of DNA damage in developing embryos [ 47 ]. They analyzed the integrity of the plasma membrane through annexin V staining with PI. They examined both transient and persistent fragment clusters at day-3 and 3.5 embryos for evidence of programed cell death using time-lapse video and TEM. In contrast to previous studies, they found no indication of nuclear DNA damage or loss of membrane integrity. These results, led the authors to hypothesize that the fragmentation observed was not characteristic of programed cell death, but rather resembled features of oncosis. The culture in this study was not severely oxygen-deprived and thus the authors concluded that this oncosis-like process was potentially a result of disproportionate mitochondrial segregation during the first cleavage division. Without sufficient mitochondria, the early blastomeres did not maintain adequate ATP for normal cell function which may have precipitated an ATP-driven oncosis-like process [ 47 ].

Lastly, a study by Bencomo et al., found correlations between the degree of apoptosis in human granulosa-lutein (GL) cells, the outcome of IVF-ET cycle, the percentage of embryo fragmentation, and patient’s age [ 66 ]. Human GL cells were collected from follicular fluid, cultured for 48 hours, and marked with caspACE FITC-VAD-FMK, a fluorescent marker for activated caspases. Results showed that GL cells of older women (>38 years old) were significantly more susceptible to apoptosis at 43.2 ± 18.0% compared to the younger group (<38 years old) with a mean percentage of apoptotic cells 33 ± 17.2%. Women who had a positive pregnancy had a lower level of apoptosis in GL cultures than those who did not get pregnant (30.2 ± 14% vs. 40.4 ± 19.5%). There was a positive correlation between embryo fragmentation and GL cell apoptosis ( r = 0.214). Overall, the level of apoptosis of cultured GL cells was correlated with IVF outcome [ 66 ].

These studies demonstrate the diversity among techniques to evaluate cell death in the developing embryo. TUNEL labeling, sperm comet assay, annexin V staining or some combination of these techniques have been described. Furthermore, there are discrepancies between the stage at which apoptosis might occur, with majority of studies cited here suggesting that cell death occurs in early stages of development before blastocyst formation. While some studies suggest that fragmented embryos display signs of apoptosis, these findings are still disputed and the distinction between apoptosis and necrosis is not clearly defined in the literature.

Patient age and CF

There are inconsistencies within the literature regarding the relationship between maternal age and CF. A total of six studies in this review focused on this relationship (Table 4 ). Three of the studies found a positive correlation between patient age and degree of embryo fragmentation [ 67 , 68 , 69 ]. The other three studies found no age-related correlation between embryo fragmentation or quality [ 7 , 70 , 71 ].

A retrospective study by Ziebe et al., compared the relationship between age of women undergoing IVF and the proportion of anucleate fragmentation in cleavage-stage embryos. Using a logistic regression analysis, the authors compared the percentage of transfers using fragmented embryos with age; the odds of fragmentation increased by 3% per year (OR 1.033 [95% CI 0.996, 1.071]). There was a linear relationship between age and embryo fragmentation rate, with an increase in fragmentation of 0.76% per year (95% CI -0.09%, 1.61%) [ 68 ].

Keltz et al., assessed various predictors of embryo fragmentation in IVF and found that increased maternal age and lower number of oocytes and embryos were associated with increased embryo fragmentation. There was a significant difference between cycles with fragmented embryos ( n =74) at a mean age of 36.9 ± 4.24 years as compared to cycles with no fragmented embryos ( n =234) at a mean age of 35.4 ± 4.74 years. Overall, this retrospective analysis of fresh IVF cycles found that embryo fragmentation is indeed associated with older age and ultimately poor cycle outcome [ 67 ].

Contrary to these findings, an early study by Alikani et al., showed no relationship between maternal age and CF [ 7 ]. In a retrospective analysis of degree and pattern of embryo fragmentation on days 2 and 3, they defined five patterns of fragmentation. Both the degree and pattern of fragmentation impacted pregnancy and implantation rate, but the authors found no correlation between appearance of any CF pattern and maternal age. The average maternal age in their population was 35.7 ± 4.25 years [ 7 ]. Another study by Stensen et al., analyzed the effect of chronological age on oocyte quality (assessed by maturity) and embryo quality (assessed by cleavage-stage, blastomere size and embryo fragmentation). Women were divided into five age groups: ≤25, 26–30, 31–35, 36–40 and ≥41 years. The embryo morphological score was based on fragmentation and blastomere size with score of 0-4 where score of 4 being equally sized blastomeres and no fragmentation and score of 0 being cleavage arrest or morphologically abnormal embryo. The mean oocyte score and embryo morphology score were not found to be significantly different across the age groups [ 70 ]. Wu et al., also showed that age does not influence embryo fragmentation. Patient ages ranged from 20 to 44 years with a mean age of 30.6 ± 4.6 years and were divided into age groups of ≤29, 30–34, 35–37, 38–40, and ≥41 years of age. Analysis of embryos with similar degrees of fragmentation was used to assess whether maternal age was associated with embryo fragmentation and blastocyst development. There was no correlation between age and embryo fragmentation as a continuous variable ( r = 0.02; P = 0.25) nor was there a correlation when age was divided into the groups ( P = 0.2). They also found that neither age ( r = -0.08; P =0.16) nor degree of fragmentation ( r = -0.01; P = 0.81) had a significant impact on blastocyst development [ 71 ].

Recently, a retrospective time-lapse study evaluated the implantation rate of 379 fragmented embryos. The results showed that there was an association between advanced maternal age and fragmentation. Fragmentation rate was higher in patients ˃35 compared to patients ≤35 years old. It seems that the lower quality of oocytes in older patients results in increasing fragmentation [ 69 ]. Overall, the included studies have differing conclusions on the effect of maternal age and CF; varying definitions and analysis of CF remain a limitation.

IVF vs ICSI procedures and CF

Five of the included studies compared embryo quality between conventional IVF and intracytoplasmic sperm injection (ICSI) procedures (Table 5 ). Two of these studies found that ICSI was associated with impaired embryo morphology compared to IVF [ 72 , 73 ], while the other three showed no difference in embryo quality between the two fertilization modalities [ 74 , 75 , 76 ]. There were no studies within our search that identified embryos created by ICSI having greater morphology grade, or less embryo fragmentation, than IVF.

Frattarelli et al., directly examined the effect of ICSI on embryo fragmentation and implantation rate compared to IVF. There was a significant difference in mean embryo grade between IVF and ICSI. IVF patients had significantly more grade I, or non-fragmented, embryos compared to the ICSI group ( P < 0.01). However, there was no significant difference in mean number of embryos per embryo grade II – IV [ 72 ].

Similarly, Hsu et al., compared embryo quality, morphology, and cleavage after ICSI with standard IVF patients. They defined the grading system from 1 – 5, ranging from no fragments (grade 1) to severe or complete fragmentation (grade 5). They found that for the overall population, when comparing ICSI and IVF patients after matching for age and number of embryos transferred, the number of embryos with good morphology was significantly greater in the IVF group compared to ICSI ( P < 0.006). The average morphology scores, similar to the results of Frattarelli et al., were significantly different between the ICSI group and the IVF group. They also found IVF patients’ embryos to have significantly better cleavage rate than those from ICSI patients ( P < 0.001) [ 73 ].

Garello et al., evaluated if fertilization via ICSI influences pronuclear orientation, PB placement, and embryo quality when compared to IVF. Embryos were assessed using morphology, and grouped as good (grades 1-2), average (grades 3-4), or poor (grades 5-6). Embryos were also assessed for cleavage regularity and proportion of fragmentation (0, <20%, 20–50%, >50%). There was no statistically significant difference in mean morphology (good, average, poor) between the groups, although they did note an apparent increase in grade 4 versus grade 3 embryos after ICSI procedure. The two groups had similar proportions of fragmentation [ 74 ].

Two other studies took a unique approach in comparing embryo quality in ICSI and IVF patients by using randomized sibling oocytes [ 75 , 76 ]. Yoeli et al., studied oocytes retrieved from patients with a less than 40% fertilization rate in a previous standard IVF cycle and divided these oocytes into a conventional insemination group and an ICSI group. Each group had over 1400 oocytes. Overall, there was no significant difference between the IVF and ICSI groups in terms of cleavage rate or rate of high-quality embryos (both Grade A embryos with ≤10% fragmentation and embryos with ≤20% fragmentation) [ 75 ]. Ruiz et al., also analyzed sibling oocytes in patients who had failed intrauterine insemination attempts. The authors similarly found no significant difference in fertilization rates and degree of fragmentation between ICSI and standard IVF groups [ 76 ]. Most studies included in the search criteria showed that ART techniques such as ICSI do not significantly impact fragmentation rate in developing embryos, suggesting that ICSI is not a significant contributor to poorer outcomes by way of embryo fragmentation. Of note, the timing of cumulus cell denudation after conventional IVF is a matter of debate; none of the included studies in this review performed short-time insemination. In a meta-analysis reviewing denudation times, the number of good quality embryos produced after retaining cumulus cells was similar to those produced after early removal of these cells, suggesting that brief insemination has no impact on CF [ 77 ]. Liu et al. also showed that short insemination time is not associated with different outcomes in terms of embryo development [ 78 ].

Effect of CF on embryo development

It is commonly believed that CF has detrimental effects on embryo development. Thirteen of the included studies found a negative effect of CF on embryo development (Table 6 ). Various approaches have been used to propose a hypothesis as to how increased fragmentation impedes embryo development.

Van Blerkom et al., showed through time-lapse video and TEM that fragments physically impede cell-cell interactions, interfering with compaction, cavitation, and blastocyst formation [ 63 ]. In an ultrastructural observational study by Sathananthan et al., 15 embryos were cultured with human ampullary cell lines and TEM used to evaluate embryo development. They noted degeneration of blastomeres, including incomplete incorporation of chromatin into nuclei and formation of micronuclei, which was possibly a consequence of being adjacent to blastomere fragments [ 79 ]. A much larger prospective study by Antczak and Van Blerkom analyzed 2293 fertilized eggs from 257 IVF cycles to examine the effect of fragmentation on the distribution of eight regulatory proteins. Fragmentation reduced the volume of cytoplasm and depleted embryos of essential organelles or regulatory proteins, compromising the embryo developmental potential. They also found that specific fragmentation patterns during various stages of embryo development, i.e., 2- and 4-cell stages, were associated with embryo viability and therefore could have clinical application in the selection of embryos for transfer [ 24 ]. As previously mentioned, fragmentation may affect compacted/morula and blastocyst quality [ 80 ]. Cell exclusion at this stage is due to failure or abnormal expression of proteins involved in compaction [ 44 , 81 ]. Blastomeres may also irregularly divide, resulting in fragmentation and exclusion from compaction [ 82 ], and excluded cells have a high rate of aneuploidy [ 83 ]. Blastocyst quality from fully compacted embryos has been reported to be higher than blastocysts with partial compaction [ 84 ].

The hypothesis that fragmentation reflects inherent embryogenetic abnormalities, such as aneuploidy, increased mosaicism, or polyploidy, is supported by multiple studies in this review [ 55 , 57 , 85 ]. Morphologically poor-quality embryos, defined by amount of fragmentation, were often found to have concomitant chromosomal abnormalities [ 57 , 85 ]. Culture environment has also been implicated in presence and degree of fragmentation. For example, Morgan et al., using video-cinematography found that embryos cultured on a monolayer of feeder cells had fewer fragments than did embryos cultured alone [ 86 ]. In addition to aneuploidy and external environment, degree of fragmentation also appears to be related to embryo quality. Both Alikani et al., and Hardy et al., have shown that a small degree of fragmentation (<15%) on day-2 embryos did not affect blastocyst formation but increased (> 15%) fragmentation was associated with significantly reduced blastocyst development [ 23 , 87 ]. Similarly, a prospective study of over 4000 embryos by Guerif et al., showed that the rate of blastocyst formation increased significantly with decreased fragmentation (<20%) on day-2 embryos [ 32 ].

A separate study by Ivec et al., graded day-4 and -5 morulae based on the degree of fragmentation (<5%, 5%–20%, or >20%) and compared their blastocyst development rate. They found a negative correlation between degree of fragmentation and clinically usable blastocysts, optimal blastocysts, and those with a hatching zona pellucida. Through logistic regression analysis, they found that with each increase in percentage of fragmentation in morulae, there was a 4% decrease in the odds of hatching (OR: 0.96, 95% CI: 0.95–0.98;  P < 0.001) and optimal blastocyst formation (OR: 0.96, 95% CI: 0.94–0.97;  P < 0.001) [ 88 ]. It is important to point out that the degree of embryo fragmentation, no matter at what stage of development, is measured subjectively without standardized methods. One study from Hnida et al., included here recognized this limitation and used a computer-controlled system for multilevel embryo morphology analysis [ 89 ]. The degree of fragmentation was evaluated based on digital image sequences and correlated to the blastomere size. Fragments were defined to be anucleate with an average diameter of <40 µm. Not surprisingly, the mean blastomere volume decreased significantly with increasing degree of fragmentation ( P < 0.001). In addition, average blastomere size was significantly affected by the degree of fragmentation and multinuclearity which may function as a biomarker for embryo quality [ 89 ]. Furthermore, Sjöblom et al., analyzed the relationship of morphological characteristics to the developmental potential of embryos [ 90 ]. These authors, similar to Hnida et al., found that a large cytoplasmic deficit, i.e., blastomeres not filling the space under the zona, was detrimental to blastocyst development (P < 0.044). However, this is the only study in which the extent of CF observed was not significantly associated with blastocyst development [ 90 ]. Another study using time-lapse imaging showed an association between cytoplasmic fragments at the two-cell stage and perivitelline threads. Perivitelline threads can be observed as the cytoplasmic membrane withdraws from the zona pellucida during embryo cleavage. Ultimately, the presence of these threads, despite the level of fragmentation, did not affect embryo development [ 91 ]. As demonstrated by the studies described here, the degree of CF has a largely negative effect on embryo development.

Effect of CF on embryo implantation and pregnancy

In addition to evaluating the effect of CF on preimplantation embryo development, it is important to assess the effect of CF on implantation and pregnancy outcomes. Five of the included studies have shown a negative effect of CF on implantation or pregnancy outcome (Table 7 ). Assuming that increased fragmentation is detrimental to embryo development, implantation, and pregnancy outcome, it is important to understand the embryo scoring system that determines the best embryo for transfer. Giorgetti et al., used single embryo transfers to devise an embryo scoring pattern to best predict successful implantation. Not surprisingly, higher pregnancy rates were observed with embryos that displayed no fragmentation. The authors found that both pregnancy rate and live birth rate were significantly correlated with a 4-point score based on cleavage rate, fragmentation, irregularities displayed, and presence of a 4-cell embryo on day-2 [ 12 ].

Racowsky et al., assessed if multiple evaluations of an embryo improve selection quality and thus implantation and pregnancy success. They noted that an increased level of fragmentation on both day-2 and -3 was associated with a significant reduction in the number of fetuses that developed to 12 weeks. They also noted that severe fragmentation (>50%) impaired overall embryo viability and may be related to low pregnancy rates and high risk of congenital malformations. The authors ultimately concluded that single day morphological evaluation on day-2 or day-3 has the same predictive value to a multi-day scoring system [ 22 ].

Another retrospective analysis of 460 fresh embryo transfers by Ebner et al., sought to determine the impact of embryo fragmentation on not just pregnancy, but also obstetric and perinatal outcomes. There was a significant relationship between fragmentation and implantation and clinical pregnancy rate, but not with multiple pregnancy rate or ongoing pregnancy rate [ 10 ]. Alikani et al., also studied embryo fragmentation and its implications for implantation and pregnancy rate and included fragmentation pattern into their discussion. They too found a significant decrease in implantation and pregnancy rate as the degree of fragmentation increased. They identified an effect on pregnancy rate when the degree of fragmentation was greater than 35%. The authors went on to discuss that not all fragmentations are detrimental to the embryo development and that the pattern of fragmentation matters. They found that fragmentation pattern type IV, defined as having large fragments distributed randomly and associated with uneven cells, had significantly lower implantation and clinical pregnancy rates when compared to types I-III. They concluded that detaching blastomere cytoplasm as large fragments is most detrimental to embryo development and implantation rate. In contrast, small, scattered fragments (type III) did not seem to appreciably affect the cell number or pose a serious threat to further development [ 7 ].

Lastly, Paternot et al., used sequential imaging techniques and a computer-assisted scoring system to study blastocyst development and the effect of fragmentation on clinical pregnancy. The authors reviewed the volume reduction over time as a measure of embryo fragmentation. They analyzed volumes on day-1 to -3 and found a significant association between total embryo volume and pregnancy rate on both day-2 ( P = 0.003) and day-3 ( P = 0.0003), with the total volume measured on day-3 being the best predictor of pregnancy outcome [ 92 ]. In contrast, Lahav-Baratz recently showed that there was no association between fragmentation rate and abortion or live birth rate. It was concluded that fragmented embryos still have implantation potential and could be considered for transfer when applicable [ 69 ].

Effect of CF removal on embryo development

The effect of fragment removal on IVF outcomes has been controversial. Six of the studies included in this review discussed the impact of removing fragments on embryo development (Table 8 ) [ 7 , 67 , 93 , 94 , 95 , 96 ]. The literature is mixed, with some studies showing improvement in embryo development quality after fragmentation removal [ 7 , 93 ], and others showing no difference at all [ 70 , 94 , 95 ].

Alikani et al., were one of the first investigators to define various patterns of fragmentation and perform microsurgical fragment removal to improve implantation potential [ 7 ]. The authors found that the pattern and degree of fragmentation, and not merely the presence of fragmentation, was significant. When assisted hatching and microsurgical fragment removal was performed, there was an overall 4% increase in implantation rate. They concluded that the removal of the fragments possibly restored the spatial relationship of the cells and limited the interference of cell-cell contact. Further, their preliminary data showed that blastocysts formed after fragment removal were better organized than their unmanipulated counterparts [ 7 ].

Eftekhari-Yazdi et al., similarly studied the effect of fragment removal on blastocyst formation and quality of embryos [ 93 ]. They compared day-2 embryos without removal of fragments to those that fragments were microsurgically removed. There were significantly higher quality embryos in defragmented group compared to the control. Furthermore, fragment removal improved the blastocyst quality compared to the control group. There was also a reduction of apoptotic and necrotic cells in experimental group when compared with the control group [ 93 ].

Two separate studies by Keltz et al., assessed implantation, clinical pregnancy, and birth outcomes after defragmentation [ 67 ], as well as embryo development and fragmentation rate after day-3 embryo defragmentation [ 94 ]. The authors first compared cycle outcomes between low-grade embryos that underwent micromanipulation for fragment removal (>10% fragmentation) and high-grade embryos that did not undergo defragmentation but were hatched on day 3. When compared, the defragmented group showed no difference in rates of implantation, clinical pregnancy, live birth, spontaneous abortion, or fetal defects as compared to the cycles that included all top-grade embryos. Factors associated with poor IVF prognosis and formation of embryo fragments included advanced age, decreased number of oocytes and embryos, and embryo grade [ 67 ].

A separate prospective randomized study by Keltz et al., looked more specifically at day-5 fragmentation, compaction, morulation and blastulation rates after low grade day-3 embryo defragmentation [ 94 ]. Paired embryos from the same patient, not intended to be transferred, were randomly placed in either the experimental group, assisted hatching and embryo defragmentation, or control group (assisted hatching alone). Paired embryos had no difference in mean cell number, percent fragmentation, and grade before randomization. Results showed that on day-5, embryos in the defragmentation group had significantly diminished fragmentation when compared with controls; however, there was no difference in compaction rate, morula formation rate or blastocyst formation rate. Embryo grade generally improved in the treatment group, but this was not statistically significant. Overall, in both groups, improved embryo development was significantly associated with lower levels of fragmentation in the day-3 embryos, supporting the idea that defragmented embryos maintain their reduced fragmented state throughout preimplantation development. Of note, this study had 35 embryos in each group and was limited to lower grade embryos not intended for transfer [ 94 ].

Another, larger prospective randomized study by Halvaei et al., compared the effect of microsurgical removal of fragments on ART outcomes. The authors divided 150 embryos with 10-50% fragmentation into three groups, case ( n =50), sham ( n =50), and control ( n =50). They found no significant difference in rates of clinical pregnancy, miscarriage, live birth, multiple pregnancies, or congenital anomalies between these groups, ultimately showing that cosmetic microsurgery on preimplantation embryos to remove CFs had no beneficial effect [ 95 ].

Lastly, a pilot study by Yumoto et al., aimed to decrease CF in developing embryos by removing the zona pellucida of abnormally fertilized (3PN) donated oocytes [ 96 ]. Although they did not attempt to remove fragments themselves, this study is included as ZP-free oocytes are sometimes encountered in or because of ART procedures, i.e., ICSI. The results suggest that the rate of fragmentation is decreased after mechanical ZP removal. The authors concluded that ZP is not always necessary for normal embryo development since the ZP-free embryos developed normally, maintained their cell adhesions, and had a decreased rate of fragmentation [ 96 ]. It seems that defragmentation of an aneuploid or severely fragmented embryo, only improves the embryo morphology grade but the quality and fate of embryo is not changed [ 97 ].

CF and chromosomal abnormalities in embryo

Although the relationship between DNA fragmentation and chromosomal abnormalities has been more commonly explored in the literature, CF may also be related to intrinsic chromosomal abnormalities in developing embryos. Fourteen studies included in this review explored this relationship (Table 9 ) [ 55 , 56 , 85 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ].

CF was rarely seen in embryos with normal chromosomal content. Findikli et al., studied DNA fragmentation and aneuploidy in poor quality embryos by TUNEL and fluorescent in situ hybridization (FISH) techniques. Within seven chromosomally abnormal embryos, each had variable degrees of CF [ 98 ]. This study suggests that DNA fragmentation, being a sign of chromosomal abnormalities, may exist together with CF.

An earlier study by Munne et al., examined 524 embryos using FISH analysis for three to five chromosomes. While controlling for age, they divided the embryos into three groups: arrested, slow and/or fragmented, or morphologically and developmentally normal. They found that polyploidy was the most common chromosomal abnormality in the arrested embryo group and decreased with increasing embryonic competence, with 44.5% polyploidy in arrested compared to 2.1% in morphologically normal embryos. Maternal age was not associated with polyploidy rates, but aneuploidy significantly increased with maternal age in morphologically normal human embryos [ 57 ]. Another early study by Almeida and Bolton also examined the relationship between chromosomal abnormalities and embryonic developmental potential. They found that cleavage-stage embryos with poor morphology, defined as irregular shaped blastomeres with severe fragmentation, showed a higher incidence of chromosomal abnormalities than those with good morphology [ 100 ]. Magli et al., found a more direct relationship between chromosomal abnormalities and embryo fragmentation in a larger retrospective study of nearly 1600 embryos. There was a strong association between percentage of fragmentation and chromosomal abnormalities (monosomies and trisomies), where 90% of chromosomal abnormalities were found in embryos with greater than 40% fragmentation [ 101 ].

Another retrospective study comparing maternal age to embryo morphology and chromosomal abnormalities was conducted by Moayeri et al., By examining nine chromosomes in day-3 embryos, they found that morphology predicted chromosomal status in the advanced maternal age group (≥38 years old), but not in younger patients. Fragmentation alone predicted euploidy in both the advanced maternal age and younger groups. This suggests that cellular fragmentation may be a predictor of chromosomal competence and thus embryo developmental potential [ 102 ].

In contrast, Baltaci et al., examined 1,000 embryos and concluded that embryo morphology was not predictive of euploidy and that a considerable number of chromosomally abnormal embryos with good development potential may be selected for embryo transfer. They used FISH for five chromosomes and found that a large proportion of both normal and aneuploid embryos were evaluated as top quality (grade I). For example, 66% of chromosomally abnormal embryos were of good quality (grade I and II). They found no significant difference among aneuploid embryos when distributed by age. However, a higher embryo quality found in normal compared to aneuploid embryos [ 103 ].

In addition, Pellestor et al., compared the relationship between morphology and chromosomal abnormalities in two separate studies. The first study found that aneuploidy was the most frequently observed abnormality after cytogenetic analysis of preimplantation embryos [ 55 ]. They defined the quality of embryos as good (grade I and II) and poor (grades III and IV). There was an increased chromosomal abnormality in poor quality embryos (84.3%) when compared to embryos with good quality (33.9%). Both aneuploidy and fragmentation were shown to be predominant in poor quality embryos, whereas mosaicism and polyploidy were the most frequent abnormalities in good quality embryos [ 55 ]. Pellestor et al., also performed cytogenetic analysis on 411 poor-quality embryos (grade IV) [ 85 ]. Ninety percent of the successfully analyzed cases showed abnormal chromosome complements, with aneuploidy being the most frequently observed. These results further support that a large majority of poor grade embryos are chromosomally abnormal and ultimately offer low chance of reproductive success for either embryo transfer or cryopreservation [ 85 ].

A separate study by Chavez et al., combined time-lapse imaging with karyotypic status of blastomeres in the 4-cell embryo to test whether blastomere behavior may reflect chromosomal abnormalities, using array comparative genomic hybridization (aCGH), during early cleavage [ 56 ]. In time-lapse observations, a large proportion of aneuploid and triploid, but not euploid embryos, exhibited cellular fragmentation. They showed that the probability of aneuploidy increased with higher fragmentation and only 65% of the fragmented embryo would be expected to form blastocyst. Furthermore, all the aneuploid embryos with additional unbalanced sub-chromosomal errors exhibited CF. The authors concluded that although fragmentation alone at a single point in time does not predict embryo developmental potential, time-lapse imaging with dynamic fragmentation screening may help detect embryonic aneuploidy [ 56 ].

Two more recent studies also used aCGH to evaluate the association between embryo ploidy and fragmentation. Vera-Rodriguez et al., in a retrospective study, compared the rate of embryo aneuploidy between two groups of high (≥25%) and low (˂25%) fragmentation. They found that the rate of aneuploidy in high and low fragmentation was 62.5 and 46.3%, respectively. However, the difference was not statistically significant concluding that using degree of fragmentation alone is not suggested to predict the embryo ploidy status [ 107 ]. Minasi et al., in a case series evaluated 1730 blastocyst ploidy with aCGH. They showed that there is no significant difference between day-3 embryo morphology and embryo ploidy. However, the quality of blastocyst (inner cell mass grade, trophectoderm grade, degree of expansion) was associated with embryo ploidy [ 106 ].

In a recent meta-analysis, it was shown there is trend between degree of fragmentation and rate of aneuploidy [ 109 ]. A major source of controversy in both early and recent studies on aneuploidy and fragmentation is the variation in the methods and criteria used to evaluate these factors. One of the aspects that differ across studies include the technique for detecting aneuploidy; FISH vs aCGH. Recent studies have used aCGH to detect aneuploidy and found no clear relationship in this regard. Also, the quality of the matching between groups, the design of the study (retrospective vs prospective), the timing of the fragmentation assessment, the use of time-lapse imaging to monitor the fate of fragments are the other reasons for this discrepancy. There is still the lack of a clear cut-off point for the percentage of fragmentation to predict aneuploidy. Further powerful studies using new methods like next gene sequencing and tile-lapse systems are recommended to shed light on the relationship between fragmentation and aneuploidy.

The literature highlights that poor quality embryos have a higher incidence of chromosomal abnormalities. Notably, CF is rarely observed in embryos with normal chromosomal content. Technological advancements, such as TLM, offer promising avenues to enhance our understanding and detection of embryonic aneuploidy. Overall, these studies underscore the complexity of the relationship between fragmentation and chromosomal abnormalities, emphasizing the need for continued research to refine embryo selection strategies and improve reproductive outcomes.

Discussion and conclusion

The role of fragmentation in human embryo development and reproductive potential is widely recognized, albeit without standard definition nor agreed upon implication. While it has been shown that degree of fragmentation and embryo implantation potential are inversely proportional [ 5 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the degree, pattern, and distribution of fragmentation as it relates to pregnancy outcome is debated in the literature. Our qualitative synthesis of 60 articles related to the study of embryo fragmentation and reproductive outcomes highlighted some of the challenges in analysis of fragmentation, while revealing trends in our evolving knowledge of how fragmentation may relate to functional development of the human embryo.

While fragmentation is best understood to be a natural process across species, the origin of fragmentation remains incompletely understood and likely multifactorial. Degree of fragmentation has been plausibly correlated to sperm DNA oxidation [ 37 ], errors in division [ 37 ], mitochondrial distribution [ 45 ], and overall embryo quality [ 39 ]. However, some causes of fragmentation are based on outdated studies and require validation in future research with higher quality and more advanced techniques. While cause of fragmentation remains a focus of investigation, advances in technology have allowed for more detailed analysis of its effect on embryo development and reproductive outcome. At the cellular level, increased fragmentation has been shown to be associated with higher rates of apoptosis, necrosis, and programmed cell death of cleavage-stage embryos [ 60 , 61 , 62 ]. Given the recognized significance of fragmentation on embryo development, it follows that many studies have been focused on IVF and ART impacts on fragmentation, as well as determining quantitative reproductive outcomes. In terms of other influences on degree of fragmentation, patient age was not universally found to be significantly associated with fragmentation [ 7 , 70 , 71 ] although age is certainly known to influence embryo quality. Most studies included in the search criteria showed that ART such as ICSI do not significantly impact fragmentation rate in developing embryos [ 74 , 75 , 76 ]. Those studies that found significant differences in embryo grading either between conventional fertilization and ICSI either did not find a difference in implantation or pregnancy rate or did not study it, suggesting that ICSI is not a significant contributor to poorer ART outcomes by way of embryo fragmentation.

In synthesizing the available data on ART and pregnancy outcomes with varying degrees of embryo fragmentation, most included studies did find a negative impact of increasing fragmentation on reproductive success while severe fragmentation does appear to be associated with poorer implantation rate and clinical pregnancy rate. This association may be related to the observation that increased fragmentation at the cleavage-stage embryo is related to chromosomal abnormalities incompatible with ongoing development or pregnancy.

The reviewed studies have several limitations. There are different grading systems in use that may impact detecting and reporting the degree of CF. Different criteria and terminology used in different studies may in turn make the comparison of outcome measures difficult. Another factor is the distribution pattern of CF. There are two types of scattered and concentrated fragments with different prognoses that is not considered in grading systems. Therefore, due to the lack of a standard cleavage-stage embryo grading system, comparing different studies should be done with caution. In addition, evaluation of embryo fragmentation is mostly based on individual observation which is subjective and has inter- and intra-observer subjectivity leading to high variable results even if performed by an experienced embryologist [ 110 ]. TLM is considered as a non-invasive tool and evaluates the embryo quality continuously and without the need to remove the embryo from the incubator [ 111 ]. The use of this technology allows for the analysis of embryo morphokinetics and has advanced knowledge of the developing embryo. Recently, artificial intelligence (AI) including machine learning and neural network has gained popularity in various fields of medicine including IVF and embryology. Accuracy of AI in prediction of fragmentation has been studied with encouraging results [ 112 ]. Further advances in technology will promote the use of AI as a tool in defining the effect of fragmentation on human embryo development and reproductive potential.

Although the precise origin and the importance of external or iatrogenic factors on fragmentation of cleavage-stage embryos varies in the literature, there is more consensus regarding severe fragmentation worsening reproductive outcomes. Given this important pattern, and the availability of increasingly sophisticated embryologic technology, further research is warranted to characterize more completely preventative or rescue techniques to improve reproductive outcomes.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Yazdani, A., Halvaei, I., Boniface, C. et al. Effect of cytoplasmic fragmentation on embryo development, quality, and pregnancy outcome: a systematic review of the literature. Reprod Biol Endocrinol 22 , 55 (2024). https://doi.org/10.1186/s12958-024-01217-7

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