a literature review of biology

Research in the Biological and Life Sciences: A Guide for Cornell Researchers: Literature Reviews

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What is a Literature Review?

A literature review is a body of text that aims to review the critical points of current knowledge on a particular topic. Most often associated with science-oriented literature, such as a thesis, the literature review usually proceeds a research proposal, methodology and results section. Its ultimate goals is to bring the reader up to date with current literature on a topic and forms that basis for another goal, such as the justification for future research in the area. (retrieved from http://en.wikipedia.org/wiki/Literature_review )

Writing a Literature Review

The literature review is the section of your paper in which you cite and briefly review the related research studies that have been conducted. In this space, you will describe the foundation on which your research will be/is built. You will:

discuss the work of others
evaluate their methods and findings
identify any gaps in their research
state how your research is different

The literature review should be selective and should group the cited studies in some logical fashion.

If you need some additional assistance writing your literature review, the Knight Institute for Writing in the Disciplines offers a Graduate Writing Service .

Demystifying the Literature Review

For more information, visit our guide devoted to " Demystifying the Literature Review " which includes:

guide to conducting a literature review,
a recorded 1.5 hour workshop covering the steps of a literature review, a checklist for drafting your topic and search terms, citation management software for organizing your results, and database searching.

Online Resources

A Guide to Library Research at Cornell University
Literature Reviews: An Overview for Graduate Students North Carolina State University
The Literature Review: A Few Tips on Conducting Written by Dena Taylor, Director, Health Sciences Writing Centre, and Margaret Procter, Coordinator, Writing Support, University of Toronto
How to Write a Literature Review University Library, University of California, Santa Cruz
Review of Literature The Writing Center, University of Wisconsin-Madison

Print Resources

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Last Updated: Oct 25, 2023 11:28 AM
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What is a Literature Review?

What is a literature review?

A literature review surveys scholarly articles, books and other sources relevant to a particular issue, area of research, or theory. The purpose is to offer an overview of significant literature published on a topic.

A literature review may constitute an essential chapter of a thesis or dissertation, or may be a self-contained review of writings on a subject. In either case, its purpose is to:

Place each work in the context of its contribution to the understanding of the subject under review
Describe the relationship of each work to the others under consideration
Identify new ways to interpret, and shed light on any gaps in, previous research
Resolve conflicts amongst seemingly contradictory previous studies
Identify areas of prior scholarship to prevent duplication of effort
Point the way forward for further research
Place one's original work (in the case of theses or dissertations) in the context of existing literature

A literature review can be just a simple summary of the sources, but it usually has an organizational pattern and combines both summary and synthesis. 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. It might give a new interpretation of old material or combine new with old interpretations. Or it might trace the intellectual progression of the field, including major debates. And depending on the situation, the literature review may evaluate the sources and advise the reader on the most pertinent or relevant.

Similar to primary research, development of the literature review requires four stages:

Problem formulation—which topic or field is being examined and what are its component issues?
Literature search—finding materials relevant to the subject being explored
Data evaluation—determining which literature makes a significant contribution to the understanding of the topic
Analysis and interpretation—discussing the findings and conclusions of pertinent literature

Remember, this is a process and not necessarily a linear one. As you search and evaluate the literature, you may refine your topic or head in a different direction which will take you back to the search stage. In fact, it is useful to evaluate as you go along so you don't spend hours researching one aspect of your topic only to find yourself more interested in another.

The main focus of an academic research paper is to develop a new argument, and a research paper will contain a literature review as one of its parts. In a research paper, you use the literature as a foundation and as support for a new insight that you contribute. The focus of a literature review, however, is to summarize and synthesize the arguments and ideas of others without adding new contributions.

For additional information, including suggestions for the structure of your literature review, see this guide from the University of North Carolina's Writing Center: https://writingcenter.unc.edu/handouts/literature-reviews/

This <10 minute tutorial from North Carolina State University also provides a good overview of the literature review: https://www.lib.ncsu.edu/tutorials/lit-review/

Finding Examples

While we don't have any examples of an EEB JP literature review, it may be useful to look at other reviews to learn how researchers in the field "summarize and synthesize" the literature. Any research article or dissertation in the sciences will include a section which reviews the literature. Though the section may not be labeled as such, you will quickly recognize it by the number of citations and the discussion of the literature. Another option is to look for Review Articles, which are literature reviews as a stand alone article. Here are some resources where you can find Research Articles, Review Articles and Dissertations:

Web of Science - If you'd like to limit your results to Review Articles, look to the left side of your results page. There you will see many options to refine your search including the section labeled Document Types. Select "Review" as the document type and click on Refine.
Scopus - Similar to WoS, you can use the options on the left side of your results page if you'd like to limit the document type. Here you will again choose "Review" and then click on the Limit To button.
Annual Reviews - All articles in this database are review articles. You can search for your topic or browse in a related subject area.
Dissertations @ Princeton - Provides access to many Princeton dissertations, full text is available for most published after 1996.

*** Note about using Review Articles in your research - while they are useful in helping you to locate articles on your topic, remember that you must go to and use the original source if you intend to include a study mentioned in the review. The only time you would cite a review article is if they have made an original insight in their work that you talk about in your paper. Going to the original research paper allows you to verify the information about that study and determine whether the points made in the review are valid and accurate.

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Last Updated: Apr 16, 2024 11:35 AM
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04 December 2020
Correction 09 December 2020

How to write a superb literature review

Andy Tay is a freelance writer based in Singapore.

You can also search for this author in PubMed Google Scholar

Literature reviews are important resources for scientists. They provide historical context for a field while offering opinions on its future trajectory. Creating them can provide inspiration for one’s own research, as well as some practice in writing. But few scientists are trained in how to write a review — or in what constitutes an excellent one. Even picking the appropriate software to use can be an involved decision (see ‘Tools and techniques’). So Nature asked editors and working scientists with well-cited reviews for their tips.

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doi: https://doi.org/10.1038/d41586-020-03422-x

Interviews have been edited for length and clarity.

Updates & Corrections

Correction 09 December 2020 : An earlier version of the tables in this article included some incorrect details about the programs Zotero, Endnote and Manubot. These have now been corrected.

Hsing, I.-M., Xu, Y. & Zhao, W. Electroanalysis 19 , 755–768 (2007).

Article Google Scholar

Ledesma, H. A. et al. Nature Nanotechnol. 14 , 645–657 (2019).

Article PubMed Google Scholar

Brahlek, M., Koirala, N., Bansal, N. & Oh, S. Solid State Commun. 215–216 , 54–62 (2015).

Choi, Y. & Lee, S. Y. Nature Rev. Chem . https://doi.org/10.1038/s41570-020-00221-w (2020).

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Literature Review Basics

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This video will provide a short introduction to literature reviews.

Steps For Writing a Literature Review

Recommended steps for writing a literature review:

Review what a literature review is, and is not
Review your assignment and seek clarification from your instructor if needed
Narrow your topic
Search and gather literature resources.
Read and analyze literature resources
Write the literature review
Review appropriate Citation and Documentation Style for your assignment and literature review

Common Questions

What is a literature review?

A literature review is a type of scholarly, researched writing that discusses the already published information on a narrow topic .

What is the purpose of a writing literature review?

Writing a literature review improves your personal understanding of a topic, and demonstrates your knowledge and ability to make connections between concepts and ideas. The literature review is a service to your reader, summarizing past ideas about a topic, bringing them up to date on the latest research, and making sure they have all any background information they need to understand the topic.

What is "the literature"?

This already published information- called the literature- can be from primary information sources such as speeches, interviews, and reports, or from secondary information sources such as peer-reviewed journal articles, dissertations, and books. These type of sources are probably familiar to you from previous research projects you’ve done in your classes.

Is a literature review it's own paper?

You can write a literature review as a standalone paper , or as part of a larger research paper . When a standalone paper, the literature review acts as a summary, or snapshot, of what has been said and done about a topic in the field so far. When part of the a larger paper, a literature review still acts as a snapshot, but the prior information it provides can also support the new information, research, or arguments presented later in the paper.

Does a literature review contain an argument?

No, a literature review does NOT present an argument or new information. The literature review is a foundation that summarizes and synthesizes the existing literature in order for you and your readers to understand what has already been said and done about your topic.

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Last Updated: Sep 5, 2024 9:53 AM
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Research Guides

BIO 3800: Biological Research

Literature Review
Biological Research
Writing A Scientific Paper
Effective Presentations
How to Prepare an Annotation
Ethics in Research
RefWorks & Zotero This link opens in a new window

Need Assistance?

Find your librarian, schedule a research appointment, today's hours : , what is a literature review.

A literature review ought to be a clear, concise synthesis of relevant information. A literature review should introduce the study it precedes and show how that study fits into topically related studies that already exist. Structurally, a literature review ought to be something like a funnel: start by addressing the topic broadly and gradually narrow as the review progresses.

from Literature Reviews by CU Writing Center

Why review the literature?

Reference to prior literature is a defining feature of academic and research writing. Why review the literature?

To help you understand a research topic
To establish the importance of a topic
To help develop your own ideas
To make sure you are not simply replicating research that others have already successfully completed
To demonstrate knowledge and show how your current work is situated within, builds on, or departs from earlier publications

from Literature Review Basics from University of La Verne

Literature Review Writing Tips

Synthesize your findings . Your findings are your evaluation of the literature reviewed: what you consider the strengths and weakness of the studies reviewed; the comparison you did between studies; research trends and gaps in the research that you found while researching your topic, etc...

Across the articles that you read, pay attention to what are the:

Common/contested findings
Important trends
Influential theories

Lectures & Slides

Literature Reviews | CU Writing Center
Writing a Literature Review | CU Writing Center
Revising a Literature Review | CU Writing Center

How-To Guides

Literature Reviews | Purdue OWL A how-to guide from Purdue OWL
Literature Reviews | University of North Carolina
Literature Reviews (University of Wisconsin-Madison)
Literature Review: The What, Why and How-to Guide | University of Connecticut
Literature Reviews | Florida A & M
Conduct a Literature Review | SUNY
Literature Review Basics | University of LaVerne

Organizing a Literature Review

Your literature review should have the following components:

Introduction : Provide an overview of your topic, including the major problems and issues that have been studied.
Thematic : You may have noticed specific themes emerge as you did your reading; if so, this may be a good way to organize your literature review.
Chronological : To use the example above, you may have observed that the way principals deal with behavioral problems has changed over time. If that's the case, perhaps you want to give a historical overview of the literature.
Methodological : There are a number of different types of methodologies used in research.
Conclusion/Discussion : Summarize what you've found in your review of literature, and identify areas in need of further research. Make sure to mention any gaps in the literature - things you think should have been researched, but were not.

Sample Literature Reviews

Sample Literature Reviews | University of West Florida
Sample APA Papers: Literature Review | Purdue OWL

Other Libguides

Literature Reviews | Webster University
Write a Literature Review | UC Santa Cruz
Literature Reviews | California State University

A literature review may exist as:

part of a larger whole like a section of a journal article or dissertation, or chapter of a book
a self-contained entity, like an entire journal article
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What are Articles?
What Makes a Source Credible?

What is a Literature Review?

Literature review video.

Where to Search for Articles?
Books and E-books
APA Citation
Biology Associations
Book a Librarian This link opens in a new window

In Research Articles

What is a literature review? Rather than describing original research results, literature reviews summarize the research on a particular topic by synthesizing information from many primary sources.

Why should I read literature reviews? Review articles can be helpful for gathering background information and identifying key articles in a particular field.

How can I find a literature review? Many library databases, including Scopus, Web of Science, and PubMed, allow you to filter search results to include only "review articles" or "literature reviews."

For Class Assignments

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.

Source: The Writing Lab & The OWL at Purdue. (n/a). What is a literature review? Purdue University. Writing a Literature Review // Purdue Writing Lab

Writing a Literature Review - Purdue OWL A great place to learn more about Literature Reviews to help you write a literature. Consult Purdue OWL.

To better understand what is a literature review, watch the video from the NC State University Libraries.

Watch Literature Reviews: An Overview for Graduate Students 00:09:37

Source: NC State University Libraries(n.a.) Literature Reviews: An Overview for Graduate Students . Retrieved from https://www.lib.ncsu.edu/tutorials/lit-review

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Last Updated: Sep 11, 2024 9:51 AM
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Queen's University Library
Research Guides
Writing a Literature Review
Search Strategies
Evaluating Information
Finding Articles
Finding Books
Reference Materials
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How to Read an Article and Take Notes
Concept Mapping and the Synthesis Matrix
Writing the Review
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Scope Notes and Credits

Scope Notes

The purpose of this page is to provide information about writing literature reviews in STEM fields.

Maggie Gordon, MLIS

Literature Reviews

Literature reviews are an important step in the research process and are commonly assigned in upper-year and graduate level courses. Alternatively, you may need to include one at the beginning of a research paper or as a chapter in a dissertation or thesis. No matter your reason for conducting one, a literature review should show the reader that you have a comprehensive understanding of the published research on a particular topic . The literature review should identify what has already been done and what is still left to be explored in your topic area, which prevents duplication of research efforts. Finally, it should show that you can position your own informed perspective into the scholarly conversation as you make connections between studies and situate them within the broader context. The literature review should not be a summary of what you have found - it should be a critical evaluation .

The three goals of a literature review are to:

Summarize and analyze previous research and theories
Identify trends, important questions, common methodology, controversy, and contested claims
Highlight any gaps that may exist in the research to date

Depending on the purpose of your literature review, you may also need to situate your own research into the scholarly conversation and justify its value.

Getting Started

It's important to be well organized before you start working on your lit review. It might be helpful to have the following in place:

A plan to keep track of where you search and what you search. This can be as simple as a Word or Excel file where you list the databases that you search in and the search strings, parameters, and other filters that you've used.
A citation management tool such as Zotero, Mendeley, or EndNote. This will help you keep track of your references and auto-populate citations as you write your review. It can also be a great place to store PDFs of articles or book chapters that you read. For more information, see the tab on Citing & Citation Management

A sample search log:

Database	Search string	# of results	Notes/Thoughts	# of Articles Selected	Articles Selected
Scopus	(pollution AND environmental impacts AND Canadian lakes)	343	Too broad, retrieved too many articles and not all were relevant	2	Smith, 2021 Jin, 2018

Database

Search string

# of results

Notes/Thoughts

# of Articles Selected

Articles Selected

Scopus

(pollution AND environmental impacts AND Canadian lakes)

343

Too broad, retrieved too many articles and not all were relevant

Smith, 2021

Jin, 2018

This can be adapted to suit your needs, for a literature review that is part of a course assignment, you likely will not need the last two columns.

<< Previous: Citing & Citation Management
Next: How to Read an Article and Take Notes >>

What about Systematic Reviews?

Systematic Reviews are another type of knowledge synthesis that people might refer to when talking about a literature reviews; however, they are quite different! A true systematic review must follow a rigorous methodological process and requires at least two people. Other common types of evidence synthesis include Narrative Reviews, Rapid Reviews, and Scoping Reviews. To learn more, visit our Guide to Systematic Reviews & Other Synthesis .

Last Updated: Sep 13, 2024 2:51 PM
Subjects: Biology

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How to Write a Literature Review | Guide, Examples, & Templates

How to Write a Literature Review | Guide, Examples, & Templates

Published on January 2, 2023 by Shona McCombes . Revised on September 11, 2023.

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 that you can later apply to your paper, thesis, or dissertation topic .

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 summarize sources—it analyzes, synthesizes , and critically evaluates to give a clear picture of the state of knowledge on the subject.

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What is the purpose of 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, free lecture slides, other interesting articles, frequently asked questions, introduction.

Quick Run-through
Step 1 & 2

When you write a thesis , dissertation , or research paper , you will likely 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 its scholarly context
Develop a theoretical framework and methodology for your research
Position your work in relation to other researchers and theorists
Show how your research addresses a gap or contributes to a debate
Evaluate the current state of research and demonstrate your knowledge of the scholarly debates around your topic.

Writing literature reviews is a particularly important skill if you want to apply for graduate school or pursue a career in research. 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 problem and questions .

Make a list of keywords

Start by creating a list of keywords related to your research question. 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 as 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 useful 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 also use boolean operators to help narrow down your search.

Make sure to 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.

You likely won’t be able to read absolutely everything that has been written on your topic, so it will be necessary to evaluate which sources are most relevant to your research question.

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?
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 use our template to summarize and evaluate sources you’re thinking about using. Click on either button below to download.

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 is important to keep track of your sources with citations to avoid plagiarism . It can be helpful to make an annotated bibliography , where you compile full citation 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.

To begin organizing your literature review’s argument and structure, be sure you 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 organizing the body of a literature review. 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 summarizing sources in order.

Try to analyze 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 organize 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.

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, you can follow these tips:

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 sentences to draw connections, comparisons and contrasts

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

When you’ve finished writing and revising your literature review, don’t forget to proofread thoroughly before submitting. Not a language expert? Check out Scribbr’s professional proofreading services !

This article has been adapted into lecture slides that you can use to teach your students about writing a literature review.

Scribbr slides are free to use, customize, and distribute for educational purposes.

Open Google Slides Download PowerPoint

If you want to know more about the research process , methodology , research bias , or statistics , make sure to check out some of our other articles with explanations and examples.

Sampling methods
Simple random sampling
Stratified sampling
Cluster sampling
Likert scales
Reproducibility

Statistics

Null hypothesis
Statistical power
Probability distribution
Effect size
Poisson distribution

Research bias

Optimism bias
Cognitive bias
Implicit bias
Hawthorne effect
Anchoring bias
Explicit bias

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 thesis, dissertation , or research paper , in order to situate your work in relation to existing knowledge.

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

To familiarize 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 thesis or dissertation . After the introduction , it grounds your research in a scholarly field and leads directly to your theoretical framework or methodology .

A literature review is a survey of credible sources on a topic, often used in dissertations , theses, and research papers . Literature reviews give an overview of knowledge on a subject, helping you identify relevant theories and methods, as well as gaps in existing research. Literature reviews are set up similarly to other academic texts , with an introduction , a main body, and a conclusion .

An annotated bibliography is a list of source references that has a short description (called an annotation ) for each of the sources. It is often assigned as part of the research process for a paper .

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Structure of an Evidence Matrix

The purpose of a literature review is to demonstrate your familiarity with existing research and how your proposed research fits within it. It should consist of at least 4-5 peer-reviewed articles and provide an integration of ideas, concepts, theories and findings.

Constructing an Evidence Matrix will assist in the dissection of the articles being reviewed and provide a system that easily organizes common themes for later discussion.

Create a spreadsheet with the following fields:

Source	Research Questions	Methods	Major Findings
Article 1	Why was the article written?	Sampling strategies? Samples?	Conclusions? Errors?
Article 2
Article 3
Article 4

Themes are items of interest to you found within the article and are points of comparison between articles.

Has the subject or style of research evolved over time?
Are there any approaches or variables that have been consistently examined? Do the articles ask the same questions? Can you identify any gaps in research or inquiry?
Are you aware of any specific common theoretical models used?

NOTE: It is crucial that when summarizing any content that you appropriate paraphrase the text entered into your matrix. If not, use quotation marks for any words that are not your own and provide page numbers for your quotes. This will help avoid plagiarism.

Writing a Literature Review

In a full-length paper or thesis the literature review tends to be 4-5 paragraphs long and explains how your original research topic fits into the existing body of scholarship on the topic.

A basic format is as follows:

Paragraph #1. Introduction of the research topic. "The purpose of the study is to...".

Paragraph #2. Describe how others have studied the subjects (Methods column). Include any sampling techniques, strategies and limitations to research processes.

Paragraph #3. Discuss a common theme from two or more articles (identified in evidence matrix).

Paragraph #4. Discuss a common theme from two or more articles (identified in evidence matrix).

Paragraph #5. Discuss the existing research identified in previous paragraphs, then your research topic and why it is important. Give strong examples why your research is relevant and necessary to build a stronger understanding of the subject.

TIPS:

Do not summarize each article read in a separate paragraph. The purpose here is to critically analyze them as a whole and reflect.
When referencing an article in the literature, do not refer to it by its title. Instead relate the article to the author and date.

Source: https://libguides.sonoma.edu/c.php?g=202672&p=1354272 (Downloaded 17AUG2022)

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What is a Literature Review?

A literature review is a comprehensive and up-to-date overview of the principal research about the topic being studied.

The aim of a literature review is to show "that the writer has studied existing work in the field with insight" (Haywood and Wragg, 1982). It is not enough merely to show what others in your field have discovered. You need to view the work of others with insight to review critically. An effective review analyses and synthesizes material, and it should meet the following requirements: (Caulley, 1992)

Compare and contrast different authors' views on an issue
Group authors who draw similar conclusions,
Criticise aspects of methodology,
Note areas in which authors are in disagreement,
Highlight exemplary studies,
Identify patterns or trends in the literature
Highlight gaps in and omissions in previous research or questions left unanswered
Show how your study relates to previous studies,
Show how your study relates to the literature in general,
Conclude by summarising what the literature says.

A literature review has a number of purposes. It enables you to:

Set the background on what has been researched on a topic.
Show why a topic is significant to a subject area.
Discover relationships between ideas.
Identify major themes & concepts.
Identify critical gaps & points of disagreement.
Help the researcher turn a network of articles into a coherent view of the literature.

Source: University of Melbourne's Literature Review Libguide

Organizing the Review

Categorizing the Literature

When categorizing the writings in the review, the researcher might consider

the methodology employed;
the quality of the findings or conclusions;
the document’s major strengths and weaknesses;
any other pivotal information.

He/She might consider such questions as:

what beliefs are expressed?
Is there an ideological stance?
What is being described? Is it comprehensive or narrow?
Are the results generalizable?

Remember that you are relating other studies to your study. How do the studies in your lit. review relate to your thesis? How are the other studies related to each other?

From http://libguides.redlands.edu/content.php?pid=32380&sid=239161

Literature Review Samples

Otterbein's Institutional Repository You can browse by collection and then department and student scholarship. Look up samples of literature reviews in theses and dissertations.
OhioLink's ETD Browse by institution and look up samples of literature review in the students' theses and dissertations

Planning your Literature Review

While planning your review, in addition to finding and analyzing the reviews in dissertations, you might ask yourself questions such as the following:

What is my central question or issue that the literature can help define?

What is already known about the topic?

Is the scope of the literature being reviewed wide or narrow enough?

Is there a conflict or debate in the literature?

What connections can be made between the texts being reviewed?

What sort of literature should be reviewed? Historical? Theoretical? Methodological? Quantitative? Qualitative?

What criteria should be used to evaluate the literature being reviewed?

How will reviewing the literature justify the topic I plan to investigate?

From: Writing the successful thesis and dissertation: entering the conversation, by Irene L. Clark

source: Kent State University's Literature Reviews Libguide

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What is a Literature Review?

What is a literature review: a tutorial, literature reviews: an overview for graduate students.

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A Literature Review Is Not:

just a summary of sources
a grouping of broad, unrelated sources
a compilation of everything that has been written on a particular topic
literature criticism (think English) or a book review

So, what is it then?

A literature review is an integrated analysis-- not just a summary-- of scholarly writings that are related directly to your research question. That is, it represents the literature that provides background information on your topic and shows a correspondence between those writings and your research question.

A literature review may be a stand alone work or the introduction to a larger research paper, depending on the assignment. Rely heavily on the guidelines your instructor has given you.

Why is it important?

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.
Discovers relationships between research studies/ideas.
Identifies major themes, concepts, and researchers on a topic.
Identifies critical gaps and points of disagreement.
Discusses further research questions that logically come out of the previous studies.

Literature Reviews: An Overview for Graduate Students (by North Caroline State University Libraries)

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Steps involved in completing a literature review

Collecting information, further reading.

Writing Guides and Style Manuals
Related Research Guides

Adapted from NCSU Libraries - Literature Reviews: An Overview for Graduate Students

Formulate a winning search strategy:

Once you have identified your research topic or question:

Identify your key concepts and some keywords;
Essentially it’s a formula you develop to conduct your search.
Sample search strategy:

(coast* OR shoreline) AND (evolution OR change)

"sea level" AND (rise OR change)

“climate change”

Test your search string in a few databases and modify if necessary;
Run your final search.

Remember that the research process is iterative.

Research tips:

Choose the right database.

Identify the broad subject area of your topic.
Determine the type of information source you need (articles, books, statistics, etc.)
Select the relevant search tool(s) in order to be thorough

Ensure your database searches will be reproducible:

Any additional screening criteria such as a language, date range, etc.
Note any problematic terms.
Though this does not seem essential at the time, you may need to redo some of your searches at a later date. Having a detailed record will ensure consistency and will save time.

Online Resources

Literature Reviews: An Overview for Graduate Students (video)
The Literature Review: A Few Tips On Conducting It (University of Toronto)
Write a Literature Review (University of California Santa Cruz)

Guidelines and Standards for Evidence Synthesis in Environmental Management (Collaboration for Environmental Evidence)

Journal Articles

Bolderston, A. (2008). Writing an Effective Literature Review. Journal of Medical Imaging and Radiation Sciences , 39 (2), 86-92. http://dx.doi.org/10.1016/j.jmir.2008.04.009

Pautasso, M. (2013). Ten Simple Rules for Writing a Literature Review. PLOS Computational Biology , 9(7). Retrieved from http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003149 .

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What is a Literature Review?

Why write a literature review.

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A literature review is an explanation of what has been published on a subject. Occasionally you will be asked to write one as a separate assignment (sometimes in the form of an annotated bibliography), but more often it is part of the introduction to a research report, essay, thesis, or dissertation. It's not just a summary of sources. You should provide a new interpretation of old material. It should:

Connect your references
Synthesize what you've read
Evaluate your resources.

A literature review should do these things:

Be organized around and related directly to the thesis or research question you are developing
Synthesize results into a summary of what is and is not known
Identify areas of controversy in the literature
Formulate questions that need further research
To trace the progression of a field
To evaluate your sources. Does one article have different conclusions or results from your other resources?
To develop a better understanding of the field. It can be very helpful if you want to do your own research in the field.
To give a new interpretation to previous research.
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What is a Literature Review?

What is a literature review?

Before you start your research paper you need to find out what other research has been done on the topic. A literature review will include the works you consulted in order to understand and investigate your research problem. A good literature review is not simply a summary of other research articles. The sources listed should be organized logically with the sources dealing with the same aspects of the topic grouped together. You should also evaluate the sources, show the relationships among them and explain why they are important (or not) for your own research.

Literature reviews analyze critically this segment of a published body of knowledge through summary, classification, and comparison of prior research studies, reviews of literature, and theoretical articles.

A literature review is an overview of the previously published works on a specific topic. The term can refer to a full scholarly paper or a section of a scholarly work such as a book, or an article. Either way, a literature review is supposed to provide the researcher/author and the audiences with a general image of the existing knowledge on the topic under question. A good literature review can ensure that a proper research question has been asked and a proper theoretical framework and/or research methodology have been chosen. To be precise, a literature review serves to situate the current study within the body of the relevant literature and to provide context for the reader. In such case, the review usually precedes the methodology and results sections of the work.

Literature Reviews - Handout

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.

Questions to Ask

Some questions to think about as you develop your literature review:

What is known about the subject?
Are there any gaps in the knowledge of the subject?
Have areas of further study been identified by other researchers that you may want to consider?
Who are the significant research personalities in this area?
Is there consensus about the topic?
What aspects have generated significant debate on the topic?
What methods or problems were identified by others studying in the field and how might they impact your research?
What is the most productive methodology for your research based on the literature you have reviewed?
What is the current status of research in this area?
What sources of information or data were identified that might be useful to you?
How detailed? Will it be a review of ALL relevant material or will the scope be limited to more recent material, e.g., the last five years.
Are you focusing on methodological approaches; on theoretical issues; on qualitative or quantitative research?

Additional Help:

“Literature Reviews", The Writing Center at University of North Carolina at Chapel Hill

The Literature Review: A Few Tips On Conducting It

Patricia Cronin, Frances Ryan, and Michael Coughlan, “Undertaking a Literature Review: A Step-by-Step Approach,” British Journal of Nursing, 17, no 1 (2008), 38-43.

A Literature Review is NOT

Keep in mind that a literature review defines and sets the stage for your later research. While you may take the same steps in researching your literature review, your literature review is not:

Not an annotated bibliography in which you summarize each article that you have reviewed. A lit 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.

flow diagram of the steps to consider when developing a search strategy

Steps to Conduct a Literature Review

Finding the literature.

What Literature?
Grey Literature
Conference Papers

When someone talks about “the literature” they are referring to the body of research, scholarly articles, books and other sources (e.g. dissertations, conference proceedings) relevant to a particular issue, area of research, or theory. A literature review is a descriptive summary of research on a topic that has previously been studied. The purpose of a literature review is to inform readers of the significant knowledge and ideas that have been established on a topic. Its purpose is to compare, contrast and/or connect findings that were identified when reviewing researchers' work.

The word literature (in 'literature review') broadly refers to the scholarly or scientific writing on a topic.

Common sources of written works include:

peer-reviewed journal articles
books and book chapters
conference papers and government reports
theses / dissertations

A good quality literature review involves searching a number of databases individually.

The Library databases are an excellent resource for finding peer-reviewed journal articles (and also book chapters and conference papers).

Databases may be multidisciplinary or discipline-specific. The best way to find the relevant databases for your review is to consult a list of databases such as the ones found in:

The Databases by Subject library guide
Relevant subject-based library guides within your faculty area

Books are often useful for background information when learning about a topic. They may be general, such as textbooks, or specialised.

A good way to find books is to use an online catalog such as the Felician University Library catalog.

More recent editions may include information not found in previous editions
Authors may discuss different aspects of a topic or present the information in different ways - reading widely can help understanding
Once you have a basic understanding of the topic, searching for journal articles may help you to learn more and access the most current information.

Grey literature is information which has been published informally or non-commercially (where the main purpose of the producing body is not commercial publishing) or remains unpublished.

It can include a range of material, such as government reports, policy documents, statistics, discussion papers, dissertations, conference proceedings and unpublished trial data. The quality of grey literature can vary greatly - some may be peer-reviewed whereas some may not have been through a traditional editorial process.

Grey literature may be included in a literature review to minimize publication bias .

Key ways of finding grey literature include using search engines, databases, government or organization websites and grey literature directories. For example:

Analysis and Policy Observatory
OpenGrey (European)
New York Academy of Medicine grey literature report (US)
The Global Science Gateway

Additional statistics are available from many government websites. Try limiting by site or domain in Google Advanced Search and using the keyword Statistics.

Data Sources (includes Biological Sciences Data/Sets)

re3data.org (Registry of Research Data Repositories)

Dryad Digital Repository

U.S. Government Open Data

NIH Data Sharing Repositories

DataONE (Earth and environmental data)

EPA Environmental dataset gateway

OpenDOAR : Directory of Open Access Repositories is a browsable directory of open access repositories. Search by subject, country of origin and content type.

Health Statistics

CDC SNAPS (county and state level)

Centers for Disease Control and Prevention (CDC)

Community Health Status Indicators Report

County Health Rankings (Robert Wood Johnson Foundation)

National Center for Health Statistics (NCHS)

Partners in Information Access for the Public Health Workforce

State Health Facts Online (Kaiser Family Foundation)

Dissertation Databases

PQDT Open (ProQuest)

Open Access Theses and Dissertations

OpenDissertations (EBSCO)

Dissertation Search

Limit to Thesis/Dissertation under Content

Conference papers are typically published in conference proceedings (the collection of papers presented at a conference), and may be found on an organization or Society's website, as a journal, or as a special issue of journal.

In some disciplinary areas (such as computer science), conference papers may be a particularly well regarded as a form of scholarly communication; the conferences are highly selective, the papers are generally peer-reviewed, and papers are published in proceedings affiliated with high-quality publishing houses.

Tips for finding conference papers:

The year of publication may be different to the year the conference was held. If applying a date limit to your search, try a range of years.
Try searching for the conference title rather than the title or author of the paper. The entire conference proceedings may be cited under a special title. You can also try searching for the conference location or sponsoring organization.

When you are writing your own primary literature review you must:

(a) use recent articles that report research tightly connected to the same specific current research problem (not simply any primary articles somehow related to the same general topic), and;

(b) write paragraphs that explicitly compare the objectives, methods, and findings of the articles with each other and with your proposed research project or findings*

*A literature review is not simply summarizing each article separately one after the other -- that would be more like an annotated bibliography and does not connect the details to your own methods/findings in your research proposal (BIO 450) or discussion/conclusion (BIO 451).

Write about how the specific research objectives, methods, and findings of the articles are similar and how are they different from each other as well as yours.

Literature Review vs. Systematic Review

It is common to confuse systematic and literature reviews as both are used to provide a summary of the existent literature or research on a specific topic. Even with this common ground, both types vary significantly. Please review the following chart (and its corresponding poster linked below) for a detailed explanation of each as well as the differences between each type of review.

What's in a name? The difference between a Systematic Review and a Literature Review, and why it matters by Lynn Kysh, MLIS, University of Southern California - Norris Medical Library

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BIOL 356: Microbiology: Literature Review

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Writing a Literature Review by Conrad Woxland Last Updated Jun 17, 2024 136 views this year
Lit Review Guide--University of Pittsburgh

What is a Literature Review?

A literature review is a comprehensive and up-to-date overview of the principal research about the topic being studied.
The review helps form the intellectual framework for the study.
The review need not be exhaustive; the objective is not to list as many relevant books, articles, reports as possible.
However, the review should contain the most pertinent studies and point to important past and current research and practices in the field.

Purpose of a Literature Review

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.

What is "the literature"?

You'll often hear "explore the literature" or "what does the literature say?" So, what is "the literature?"

Most simply put, "the literature" is a collection of scholarly writings on a topic. This includes:

peer-reviewed journal articles
conference proceedings
dissertations

How do you know when you are done researching?

Are you seeing the same articles over and over?

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Literature Reviews, Theoretical Frameworks, and Conceptual Frameworks: An Introduction for New Biology Education Researchers

Affiliations.

1 Department of Mathematics, Social Studies, and Science Education, Mary Frances Early College of Education, University of Georgia, Athens, GA 30602-7124.
2 Department of Teaching & Learning, College of Education & Human Ecology, Ohio State University, Columbus, OH 43210.
3 Department of Biology, Eastern Washington University, Cheney, WA 99004.
4 Department of Biology, Middle Tennessee State University, Murfreesboro, TN 37132.
PMID: 35759629
PMCID: PMC9582830
DOI: 10.1187/cbe.21-05-0134

To frame their work, biology education researchers need to consider the role of literature reviews, theoretical frameworks, and conceptual frameworks as critical elements of the research and writing process. However, these elements can be confusing for scholars new to education research. This Research Methods article is designed to provide an overview of each of these elements and delineate the purpose of each in the educational research process. We describe what biology education researchers should consider as they conduct literature reviews, identify theoretical frameworks, and construct conceptual frameworks. Clarifying these different components of educational research studies can be helpful to new biology education researchers and the biology education research community at large in situating their work in the broader scholarly literature.

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Conceptual framework from Sabel et…

Conceptual framework from Sabel et al. (2017).

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Reviewing the Literature: Why do it?

Personal: To familiarize yourself with a new area of research, to get an overview of a topic, so you don't want to miss something important, etc.
Required writing for a journal article, thesis or dissertation, grant application, etc.

Literature reviews vary; there are many ways to write a literature review based on discipline, material type, and other factors.

Background:

Literature Reviews - UNC Writing Center
Literature Reviews: An Overview for Graduate Students - What is a literature review? What purpose does it serve in research? What should you expect when writing one? - NCSU Video

Where to get help (there are lots of websites, blogs , articles, and books on this topic) :

The Center for writing and Communicating Ideas (CWCI)
(these are non-STEM examples: dissertation guidance , journal guidelines )
How to prepare a scientific doctoral dissertation based on research articles (2012)
Writing a graduate thesis or dissertation (2016)
The good paper : a handbook for writing papers in higher education (2015)
Proposals that work : a guide for planning dissertations and grant proposals (2014)
Theses and dissertations : a guide to planning, research, and writing (2008)
Talk to your professors, advisors, mentors, peers, etc. for advice

READ related material and pay attention to how others write their literature reviews:

Dissertations
Journal articles
Grant proposals
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Ten Simple Rules for Writing a Literature Review

* E-mail: [email protected]

Affiliations Centre for Functional and Evolutionary Ecology (CEFE), CNRS, Montpellier, France, Centre for Biodiversity Synthesis and Analysis (CESAB), FRB, Aix-en-Provence, France

Marco Pautasso

Published: July 18, 2013

https://doi.org/10.1371/journal.pcbi.1003149
Reader Comments

Citation: Pautasso M (2013) Ten Simple Rules for Writing a Literature Review. PLoS Comput Biol 9(7): e1003149. https://doi.org/10.1371/journal.pcbi.1003149

Editor: Philip E. Bourne, University of California San Diego, United States of America

Copyright: © 2013 Marco Pautasso. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was funded by the French Foundation for Research on Biodiversity (FRB) through its Centre for Synthesis and Analysis of Biodiversity data (CESAB), as part of the NETSEED research project. The funders had no role in the preparation of the manuscript.

Competing interests: The author has declared that no competing interests exist.

Literature reviews are in great demand in most scientific fields. Their need stems from the ever-increasing output of scientific publications [1] . For example, compared to 1991, in 2008 three, eight, and forty times more papers were indexed in Web of Science on malaria, obesity, and biodiversity, respectively [2] . Given such mountains of papers, scientists cannot be expected to examine in detail every single new paper relevant to their interests [3] . Thus, it is both advantageous and necessary to rely on regular summaries of the recent literature. Although recognition for scientists mainly comes from primary research, timely literature reviews can lead to new synthetic insights and are often widely read [4] . For such summaries to be useful, however, they need to be compiled in a professional way [5] .

When starting from scratch, reviewing the literature can require a titanic amount of work. That is why researchers who have spent their career working on a certain research issue are in a perfect position to review that literature. Some graduate schools are now offering courses in reviewing the literature, given that most research students start their project by producing an overview of what has already been done on their research issue [6] . However, it is likely that most scientists have not thought in detail about how to approach and carry out a literature review.

Reviewing the literature requires the ability to juggle multiple tasks, from finding and evaluating relevant material to synthesising information from various sources, from critical thinking to paraphrasing, evaluating, and citation skills [7] . In this contribution, I share ten simple rules I learned working on about 25 literature reviews as a PhD and postdoctoral student. Ideas and insights also come from discussions with coauthors and colleagues, as well as feedback from reviewers and editors.

Rule 1: Define a Topic and Audience

How to choose which topic to review? There are so many issues in contemporary science that you could spend a lifetime of attending conferences and reading the literature just pondering what to review. On the one hand, if you take several years to choose, several other people may have had the same idea in the meantime. On the other hand, only a well-considered topic is likely to lead to a brilliant literature review [8] . The topic must at least be:

interesting to you (ideally, you should have come across a series of recent papers related to your line of work that call for a critical summary),
an important aspect of the field (so that many readers will be interested in the review and there will be enough material to write it), and
a well-defined issue (otherwise you could potentially include thousands of publications, which would make the review unhelpful).

Ideas for potential reviews may come from papers providing lists of key research questions to be answered [9] , but also from serendipitous moments during desultory reading and discussions. In addition to choosing your topic, you should also select a target audience. In many cases, the topic (e.g., web services in computational biology) will automatically define an audience (e.g., computational biologists), but that same topic may also be of interest to neighbouring fields (e.g., computer science, biology, etc.).

Rule 2: Search and Re-search the Literature

After having chosen your topic and audience, start by checking the literature and downloading relevant papers. Five pieces of advice here:

keep track of the search items you use (so that your search can be replicated [10] ),
keep a list of papers whose pdfs you cannot access immediately (so as to retrieve them later with alternative strategies),
use a paper management system (e.g., Mendeley, Papers, Qiqqa, Sente),
define early in the process some criteria for exclusion of irrelevant papers (these criteria can then be described in the review to help define its scope), and
do not just look for research papers in the area you wish to review, but also seek previous reviews.

The chances are high that someone will already have published a literature review ( Figure 1 ), if not exactly on the issue you are planning to tackle, at least on a related topic. If there are already a few or several reviews of the literature on your issue, my advice is not to give up, but to carry on with your own literature review,

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The bottom-right situation (many literature reviews but few research papers) is not just a theoretical situation; it applies, for example, to the study of the impacts of climate change on plant diseases, where there appear to be more literature reviews than research studies [33] .

https://doi.org/10.1371/journal.pcbi.1003149.g001

discussing in your review the approaches, limitations, and conclusions of past reviews,
trying to find a new angle that has not been covered adequately in the previous reviews, and
incorporating new material that has inevitably accumulated since their appearance.

When searching the literature for pertinent papers and reviews, the usual rules apply:

be thorough,
use different keywords and database sources (e.g., DBLP, Google Scholar, ISI Proceedings, JSTOR Search, Medline, Scopus, Web of Science), and
look at who has cited past relevant papers and book chapters.

Rule 3: Take Notes While Reading

If you read the papers first, and only afterwards start writing the review, you will need a very good memory to remember who wrote what, and what your impressions and associations were while reading each single paper. My advice is, while reading, to start writing down interesting pieces of information, insights about how to organize the review, and thoughts on what to write. This way, by the time you have read the literature you selected, you will already have a rough draft of the review.

Of course, this draft will still need much rewriting, restructuring, and rethinking to obtain a text with a coherent argument [11] , but you will have avoided the danger posed by staring at a blank document. Be careful when taking notes to use quotation marks if you are provisionally copying verbatim from the literature. It is advisable then to reformulate such quotes with your own words in the final draft. It is important to be careful in noting the references already at this stage, so as to avoid misattributions. Using referencing software from the very beginning of your endeavour will save you time.

Rule 4: Choose the Type of Review You Wish to Write

After having taken notes while reading the literature, you will have a rough idea of the amount of material available for the review. This is probably a good time to decide whether to go for a mini- or a full review. Some journals are now favouring the publication of rather short reviews focusing on the last few years, with a limit on the number of words and citations. A mini-review is not necessarily a minor review: it may well attract more attention from busy readers, although it will inevitably simplify some issues and leave out some relevant material due to space limitations. A full review will have the advantage of more freedom to cover in detail the complexities of a particular scientific development, but may then be left in the pile of the very important papers “to be read” by readers with little time to spare for major monographs.

There is probably a continuum between mini- and full reviews. The same point applies to the dichotomy of descriptive vs. integrative reviews. While descriptive reviews focus on the methodology, findings, and interpretation of each reviewed study, integrative reviews attempt to find common ideas and concepts from the reviewed material [12] . A similar distinction exists between narrative and systematic reviews: while narrative reviews are qualitative, systematic reviews attempt to test a hypothesis based on the published evidence, which is gathered using a predefined protocol to reduce bias [13] , [14] . When systematic reviews analyse quantitative results in a quantitative way, they become meta-analyses. The choice between different review types will have to be made on a case-by-case basis, depending not just on the nature of the material found and the preferences of the target journal(s), but also on the time available to write the review and the number of coauthors [15] .

Rule 5: Keep the Review Focused, but Make It of Broad Interest

Whether your plan is to write a mini- or a full review, it is good advice to keep it focused 16 , 17 . Including material just for the sake of it can easily lead to reviews that are trying to do too many things at once. The need to keep a review focused can be problematic for interdisciplinary reviews, where the aim is to bridge the gap between fields [18] . If you are writing a review on, for example, how epidemiological approaches are used in modelling the spread of ideas, you may be inclined to include material from both parent fields, epidemiology and the study of cultural diffusion. This may be necessary to some extent, but in this case a focused review would only deal in detail with those studies at the interface between epidemiology and the spread of ideas.

While focus is an important feature of a successful review, this requirement has to be balanced with the need to make the review relevant to a broad audience. This square may be circled by discussing the wider implications of the reviewed topic for other disciplines.

Rule 6: Be Critical and Consistent

Reviewing the literature is not stamp collecting. A good review does not just summarize the literature, but discusses it critically, identifies methodological problems, and points out research gaps [19] . After having read a review of the literature, a reader should have a rough idea of:

the major achievements in the reviewed field,
the main areas of debate, and
the outstanding research questions.

It is challenging to achieve a successful review on all these fronts. A solution can be to involve a set of complementary coauthors: some people are excellent at mapping what has been achieved, some others are very good at identifying dark clouds on the horizon, and some have instead a knack at predicting where solutions are going to come from. If your journal club has exactly this sort of team, then you should definitely write a review of the literature! In addition to critical thinking, a literature review needs consistency, for example in the choice of passive vs. active voice and present vs. past tense.

Rule 7: Find a Logical Structure

Like a well-baked cake, a good review has a number of telling features: it is worth the reader's time, timely, systematic, well written, focused, and critical. It also needs a good structure. With reviews, the usual subdivision of research papers into introduction, methods, results, and discussion does not work or is rarely used. However, a general introduction of the context and, toward the end, a recapitulation of the main points covered and take-home messages make sense also in the case of reviews. For systematic reviews, there is a trend towards including information about how the literature was searched (database, keywords, time limits) [20] .

How can you organize the flow of the main body of the review so that the reader will be drawn into and guided through it? It is generally helpful to draw a conceptual scheme of the review, e.g., with mind-mapping techniques. Such diagrams can help recognize a logical way to order and link the various sections of a review [21] . This is the case not just at the writing stage, but also for readers if the diagram is included in the review as a figure. A careful selection of diagrams and figures relevant to the reviewed topic can be very helpful to structure the text too [22] .

Rule 8: Make Use of Feedback

Reviews of the literature are normally peer-reviewed in the same way as research papers, and rightly so [23] . As a rule, incorporating feedback from reviewers greatly helps improve a review draft. Having read the review with a fresh mind, reviewers may spot inaccuracies, inconsistencies, and ambiguities that had not been noticed by the writers due to rereading the typescript too many times. It is however advisable to reread the draft one more time before submission, as a last-minute correction of typos, leaps, and muddled sentences may enable the reviewers to focus on providing advice on the content rather than the form.

Feedback is vital to writing a good review, and should be sought from a variety of colleagues, so as to obtain a diversity of views on the draft. This may lead in some cases to conflicting views on the merits of the paper, and on how to improve it, but such a situation is better than the absence of feedback. A diversity of feedback perspectives on a literature review can help identify where the consensus view stands in the landscape of the current scientific understanding of an issue [24] .

Rule 9: Include Your Own Relevant Research, but Be Objective

In many cases, reviewers of the literature will have published studies relevant to the review they are writing. This could create a conflict of interest: how can reviewers report objectively on their own work [25] ? Some scientists may be overly enthusiastic about what they have published, and thus risk giving too much importance to their own findings in the review. However, bias could also occur in the other direction: some scientists may be unduly dismissive of their own achievements, so that they will tend to downplay their contribution (if any) to a field when reviewing it.

In general, a review of the literature should neither be a public relations brochure nor an exercise in competitive self-denial. If a reviewer is up to the job of producing a well-organized and methodical review, which flows well and provides a service to the readership, then it should be possible to be objective in reviewing one's own relevant findings. In reviews written by multiple authors, this may be achieved by assigning the review of the results of a coauthor to different coauthors.

Rule 10: Be Up-to-Date, but Do Not Forget Older Studies

Given the progressive acceleration in the publication of scientific papers, today's reviews of the literature need awareness not just of the overall direction and achievements of a field of inquiry, but also of the latest studies, so as not to become out-of-date before they have been published. Ideally, a literature review should not identify as a major research gap an issue that has just been addressed in a series of papers in press (the same applies, of course, to older, overlooked studies (“sleeping beauties” [26] )). This implies that literature reviewers would do well to keep an eye on electronic lists of papers in press, given that it can take months before these appear in scientific databases. Some reviews declare that they have scanned the literature up to a certain point in time, but given that peer review can be a rather lengthy process, a full search for newly appeared literature at the revision stage may be worthwhile. Assessing the contribution of papers that have just appeared is particularly challenging, because there is little perspective with which to gauge their significance and impact on further research and society.

Inevitably, new papers on the reviewed topic (including independently written literature reviews) will appear from all quarters after the review has been published, so that there may soon be the need for an updated review. But this is the nature of science [27] – [32] . I wish everybody good luck with writing a review of the literature.

Acknowledgments

Many thanks to M. Barbosa, K. Dehnen-Schmutz, T. Döring, D. Fontaneto, M. Garbelotto, O. Holdenrieder, M. Jeger, D. Lonsdale, A. MacLeod, P. Mills, M. Moslonka-Lefebvre, G. Stancanelli, P. Weisberg, and X. Xu for insights and discussions, and to P. Bourne, T. Matoni, and D. Smith for helpful comments on a previous draft.

1. Rapple C (2011) The role of the critical review article in alleviating information overload. Annual Reviews White Paper. Available: http://www.annualreviews.org/userimages/ContentEditor/1300384004941/Annual_Reviews_WhitePaper_Web_2011.pdf . Accessed May 2013.
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7. Budgen D, Brereton P (2006) Performing systematic literature reviews in software engineering. Proc 28th Int Conf Software Engineering, ACM New York, NY, USA, pp. 1051–1052. doi: https://doi.org/10.1145/1134285.1134500 .
16. Eco U (1977) Come si fa una tesi di laurea. Milan: Bompiani.
17. Hart C (1998) Doing a literature review: releasing the social science research imagination. London: SAGE.
21. Ridley D (2008) The literature review: a step-by-step guide for students. London: SAGE.

Human Biology: Literature Review

Searching & reviewing the literature.

Literature Review
Search Strategy
Database search tips

A literature review is an evaluation of relevant literature on a topic and is usually the starting point for any undergraduate essay or postgraduate thesis. The focus for a literature review is on scholarly published materials such as books, journal articles and reports.

A search and review of relevant sources may be extensive and form part of a thesis or research project. Postgraduate researchers will normally focus on primary sources such as research studies in journals.

A literature review also provides evidence for an undergraduate assignment. Students new to a discipline may find that starting with an overview or review of relevant research in books and journals, the easiest way to begin researching a topic and obtaining the necessary background information.

Source materials can be categorised as:

Primary source : Original research from journals articles or conference papers, original materials such as historical documents, or creative works.

Secondary source : Evaluations, reviews or syntheses of original work. e.g. review articles in journals.

Tertiary source : Broadly scoped material put together usually from secondary sources to provide an overview, e.g. a book.

The Literature Review Structure : Like a standard academic essay, a literature review is made up of three key components: an introduction, a body and a conclusion. Most literature reviews can follow the following format: • Introduction: Introduce the topic/problem and the context within which it is found. • Body: Examine past research in the area highlighting methodological and/or theoretical developments, areas of agreement, contentious areas, important studies and so forth. Keep the focus on your area of interest and identify gaps in the research that your research/investigation will attempt to fill. State clearly how your work builds on or responds to earlier work. • Conclusion: Summarise what has emerged from the review of literature and reiterate conclusions.

This information has been adapted from the Edith Cowan University Literature review: Academic tip sheet .

Steps in searching and reviewing the literature:

Define the topic and scope of the assignment. Ensure you understand the question and expectations of the assignment. It's useful to develop a plan and outline, headings, etc.
Check terminology. e.g. dictionaries, encyclopedias, thesauruses
Identify keywords for searching (include English and American spelling and terminology)
Identify types of publications. e.g. books, journal articles, reports.
Search relevant databases (refer to the relevant subject guide for key databases and sources)
Select and evaluate relevant sources
Synthesise the information
Write the review following the structure outlined.
Save references used. e.g. from the databases save, email, print or download references to EndNote.
Reference sources (APA 7th) (see Referencing Library Guide )

When you are writing for an academic purpose such as an essay for an assignment, you need to find evidence to support your ideas. The library is a good place to begin your search for the evidence, as it acquires books and journals to support the disciplines within the University. The following outlines a list of steps to follow when starting to write an academic assignment:

Define your topic and scope of the search

This will provide the search terms when gathering evidence from the literature to support your arguments.
Sometimes it is a good idea to concept map key themes.

The scope will advise you:

How much information is required, often identified by the number of words ie 500 or 3000 words
What sort of writing you are to do eg essay, report, annotated bibliography
How many marks are assigned. This may indicate the amount of time to allocate to the task.

Gather the information - Before writing about your topic, you will need to find evidence to support your ideas.

Books provide a useful starting point for an introduction to the subject. Books also provide an in-depth coverage of a topic.

Journal Articles: For current research or information on a very specific topic, journal articles may be the most useful, as they are published on a regular basis. It is normally expected that you will use some journal articles in your assignment. When using journal articles, check whether they are from a magazine or scholalry publication. Scholarly publications are often peer reviewed, which means that the articles are reviewed by expert/s before being accepted for publication.

Reports : useful information can also be found in free web publications from government or research organizations (e.g. reports). Any web publications should be carefully evaluated. You are also required to view the whole publication, not just the abstract, if using the information in your assignment.

Remember to ensure that you note the citation details for references that you collect, at the time of locating the items. It is often time consuming and impossible to track the required data later.

Analyse the information collected

Have I collected enough information on the topic?

Synthesise your information

Write the report or essay

Check the ECU Academic tip sheet: the Academic Essay for some useful pointers
Remember, in most cases you will need an introduction, body and conclusion
Record details of references used for referencing. Information on referencing can be located on the ECU Referencing Guide.

Database search tips:

1. Identify main concepts and keywords . Search the main concepts first, then limit further as necessary.

2. Find Synonyms (Boolean OR broadens the search to include alternative keywords or subject thesaurus terms):

pediatrics OR children
teenagers OR adolescents

3. AND (Boolean AND joins concepts and narrows the search):

occupational therapy AND children
stress AND (occupation OR job)

4. Be aware of differences in American and English spelling and terminology. Most databases use American spelling and terminology as preferred subject terms.

5. Use Truncation (putting * at the end of a word stem will search all forms of the word):

disab * (disability, disabilities, disabled)
child * (child, children, childhood, children's)

6. "...." (inverted commas) use for a phrase

"mental health"
"occupational therapy"

7. Wildcard ? will search for any single letter in the space. e.g. wom?n will search women, woman, organi?ation will search organisation, organization.

8. Wildcard * can also be used where alternate spelling may contain an extra character. e.g. p*ediatric, will search paediatric or pediatric, behavio*r, will search behaviour or behavior.

Search strategy planner
MEDLINE database guide
CINAHL database guide
SPORTDiscus database guide
Web of Science database guide

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Molecular and Cellular Biology: Literature Review

Literature Review
Protocols and Methods
3-D Visualizations

Recommended Databases

PubMed This link opens in a new window The most comprehensive medical database. This resource covers medicine, dentistry, nursing, physical therapy, biomedical research, clinical practice, administration, policy issues, and health care services. It also includes extra life sciences journals and ebooks in addition to MEDLINE.
ScienceDirect This link opens in a new window Excellent place to start a literature review. Get peer-reviewed journals, articles, book chapters on a wide variety of scientific topics, including the life sciences and health topics, as well as engineering content related to biology, including chemical engineering.
Academic Search Complete This link opens in a new window Offers coverage of many areas of academic study including: biology, chemistry, food science & technology, general science, psychology, etc. Useful for building contextual knowledge of your research topic.
Web of Science This link opens in a new window Covers topics in the sciences, social sciences, and humanities.
American Society for Microbiology This link opens in a new window Full-text of the Society's 11 journals, from molecular and cellular biology to biomedical research and technology.
SciFinder This link opens in a new window Indexes the literature of chemistry, including journal articles, patents, substance data, chemical reactions, chemical regulatory data, and chemical suppliers. Registration is required. Note: Access to SciFinder includes access to ChemZent and PatentPak.
Dissertations & Theses This link opens in a new window Graduate dissertations from over 1,000 North American graduate schools and selected European universities, dating from 1861- present.

Journal Search

Journal Search Use this search to find a journal in our library. You can search by name or ISSN. You can also use the "search by citation" tab for more searching options, including by an article's DOI. The majority of our journals are accessible online.

Recommended Journals

Cell Biology
Cellular and Molecular Immunology
Nature Reviews: Cancer
Nature Reviews: Molecular Cell Biology

Article Pre-prints

Cell: new articles Access articles published just ahead of final publication in an issue. The articles have been copyedited and incorporate the authors' final corrections.
bioRxiv Pre-print server for the biological sciences, including cellular biology and related fields. Hosted at the Cold Spring Harbor Laboratory.
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20 Topics For A Biology Literature Review

Advanced Stem Cell And Developmental Biology – Experimental Design

Finding Articles And Books Using Database For Your Discipline

The literature review writing service helps the researchers to complte their medical researches. In most research areas literature reviews are in high demand. A need stems from the ever-increasing output of scientific publications .
Although recognition for scientists mainly comes from primary research, timely literature reviews and the topic selected can lead to new synthetic insights and are often widely read.

The building block of all academic research activities , regardless of discipline, is to base the work on existing knowledge and link it up. Hence, doing so correctly should be a priority for all academics. However, the task has got more and more complicated. Development of knowledge within the field of business research is growing at a tremendous pace while remaining fragmented and interdisciplinary at the same time. This makes it difficult to keep up with state of the art studies and be at the forefront, as well as analyse the accumulated evidence in a specific area of research. Therefore, the literature review as a method of research is more relevant than ever. A review of literature can be generally defined as a more or less systematic way of collecting and synthesizing prior research.

A successful and well-done analysis as a research method provides a firm foundation for the advancement of knowledge and the growth of theory. Scientific research support service offer the medical analysis data that are related to research work. Through combining observations and insights from many scientific studies, a review of the literature will answer research questions with a strength that no single study has (Boyd & Solarino , 2016).

Literature Search, Topics, Journals, Coronavirus, Biology

The Process of Conducting a Literature Review

There are a number of steps that need to be taken and decisions are taken to produce a study that satisfies the publication criteria. The basic steps and essential choices involved in conducting a literature review will be suggested and addressed in four phases; (1) Planning of the review, (2) Conducting of the review, (3) Analyses and (4) Writing the review (Palmatier et al., 2018).

Interesting topics to Choose in Biology

Here we have discussed 20 topics to choose in biology, which can be quite interesting. The first 10 topics are explained to the point where we can work and the remaining 10 articles are stated on general themes.

1.Obesity related to Genetic Phenomenon

Obesity is a heterogeneous disease whose biological causes are complex. The increasing frequency of obesity over the last few decades is attributed to environmental factors such as sedentary lifestyles and overnutrition, but that is obese at an individual level is determined by genetic susceptibility (Venkatesan & Mohan, 2016).

2.Is Paleo diet the healthiest choice

Paleolithic diet has been gaining worldwide popularity due to its putative health benefits. “Paleo” was Google’s most wanted diet word in 2014. Nonetheless, a 2015 US News and World Report ranking of 35 diets with feedback from a panel of health experts ranked the Paleolithic diet dead last, citing a lack of evidence of clinical benefits from research (Manheimer et al., 2015).

3.Resistant to Antibiotics

Antibiotics are the’ wonder medicines’ used for battling microbes. Numerous types of antibiotics have been not only used for therapeutic purposes for decades but have been used prophylactically across other fields such as livestock and animal husbandry. Uncertainty has emerged as microbes have become immune to specific antibiotics while the host remains unaware of the development of antibiotic resistance (Zaman et al., 2017).

4.The Need of the Hour – Coronavirus

A cluster of identified-cause pneumonia patients was related to a wholesale market for seafood in Wuhan, China, in December 2019. A previously unknown betacoronavirus was discovered from patients with pneumonia by using objective sequencing in the samples .

5.Impact of Tobacco Use

Cigarettes smoked in the form of either smoke or smokeless is dangerous for the human body. Globally, the death toll from cigarettes has risen to around 6.4 million annually and is on a steady rise (Shah et al., 2018).

6.The need to review HIV

Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome (HIV / AIDS) is a global health problem: more than 70 million people were diagnosed with HIV, 35 million died, and 36.7 million people are currently living with the disease (Fajardo-Ortiz et al., 2017).

7.The Unsolved Leprosy

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has destroyed human societies for thousands of years. This ancestral pathogen causes cutaneous lesions to disfigure, peripheral nerve damage, ostearticular deformity, loss of limbs and weakness, blindness and stigma (Franco-Paredes & Rodriguez-Morales, 2016).

8.Tuberculosis – The Disease without Boundaries

An airborne disease of Tuberculosis (TB) is caused by Mycobacterium tuberculosis (MTB), which usually affects the lungs causing severe coughing, fever, and chest pain. While current research has provided valuable insight into the transmission, diagnosis, and treatment of TB over the past four years, much remains to be learned to effectively decrease the occurrence of and ultimately eliminate TB (Levine et al., 2015).

9.The Epidemic of the Century – Diabetes

It studies the epidemic essence of diabetes mellitus in various regions. The North Africa and the Middle East region has the lowest prevalence of diabetes in adults (10.9 percent), while the Western Pacific region has the highest number of diabetes-diagnosed adults and countries with the highest incidence of diabetes (37.5 per cent) (Kharroubi, 2015).

10.Parkinson’s Disease

The disease of Parkinson is a progressive neurodegenerative disease characterized by tremor and bradykinesia and is a common neurological disorder. Male sex and advancing age are independent risk factors, and rising productivity and medical resources are taking on increasing toll as the population ages (Hayes, 2019).

General Topics to Focus

Challenges faced in Research of Herbal Medicines.
The Global Burden of Periodontitis.
The new Addiction of the Era – Gaming.
The prevalence of Road Traffic Accidents among Food Delivery Workers.
Diet and Nutrition assessment among School Children
The Boon and Ban of self-medication in India.
Zombie – A Psychological concept of old tales.
Backpain among weavers and farmers in India.
Trends of Oral Cancer in India.
Self-examination for Breast Cancer among women

Future Scopes

A review of the literature may be thorough or limited, but it should discuss landmark or principal works and works that have been important in the field. The complexity of a review of the literature can vary according to assignment and discipline. The analysis of literature may be part of a larger piece of work or a stand-alone post, meaning it’s a paper entirely. Moreover, literature reviews can pave a way to numerous research questions and research ideas.

References:

Boyd, B. K., & Solarino, A. M. (2016). Ownership of Corporations. Journal of Management, 42(5), 1282–1314. https://doi.org/10.1177/0149206316633746
Fajardo-Ortiz, D., Lopez-Cervantes, M., Duran, L., Dumontier, M., Lara, M., Ochoa, H., & Castano, V. M. (2017). The emergence and evolution of the research fronts in HIV/AIDS research. PLOS ONE, 12(5), e0178293. https://doi.org/10.1371/journal.pone.0178293
Franco-Paredes, C., & Rodriguez-Morales, A. J. (2016). Unsolved matters in leprosy: a descriptive review and call for further research. Annals of Clinical Microbiology and Antimicrobials, 15(1), 33. https://doi.org/10.1186/s12941-016-0149-x
Hayes, M. T. (2019). Parkinson’s Disease and Parkinsonism. The American Journal of Medicine, 132(7), 802–807. https://doi.org/10.1016/j.amjmed.2019.03.001
Kharroubi, A. T. (2015). Diabetes mellitus: The epidemic of the century. World Journal of Diabetes, 6(6), 850. https://doi.org/10.4239/wjd.v6.i6.850
Levine, D. M., Dutta, N. K., Eckels, J., Scanga, C., Stein, C., Mehra, S., Kaushal, D., Karakousis, P. C., & Salamon, H. (2015). A tuberculosis ontology for host systems biology. Tuberculosis, 95(5), 570–574. https://www.sciencedirect.com/science/article/pii/S1472979214205890
Manheimer, E. W., van Zuuren, E. J., Fedorowicz, Z., & Pijl, H. (2015). Paleolithic nutrition for metabolic syndrome: systematic review and meta-analysis. The American Journal of Clinical Nutrition, 102(4), 922–932. https://doi.org/10.3945/ajcn.115.113613
Palmatier, R. W., Houston, M. B., & Hulland, J. (2018). Review articles: purpose, process, and structure. Journal of the Academy of Marketing Science, 46(1), 1–5. https://doi.org/10.1007/s11747-017-0563-4
Shah, S., Dave, B., Shah, R., Mehta, T., & Dave, R. (2018). Socioeconomic and cultural impact of tobacco in India. Journal of Family Medicine and Primary Care, 7(6), 1173. https://doi.org/10.4103/jfmpc.jfmpc_36_18
Venkatesan, R., & Mohan, V. (2016). Obesity – Are we continuing to play the genetic “blame game”? Advances in Genomics and Genetics, Volume 6, 11–23. https://doi.org/10.2147/AGG.S52018
Zaman, S. Bin, Hussain, M. A., Nye, R., Mehta, V., Mamun, K. T., & Hossain, N. (2017). A Review on Antibiotic Resistance: Alarm Bells are Ringing. Cureus. https://doi.org/10.7759/cureus.1403

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Cadmium Associated Preeclampsia: A Systematic Literature Review of Pregnancy and Birth Outcomes

Published: 10 September 2024

Cite this article

Fatima Sardar 1 ,
Yuhaniza Shafinie Kamsani 1 , 2 ,
Fathi Ramly 1 , 3 ,
Nor Ashikin Mohamed Noor Khan 1 , 2 ,
Razia Sardar 1 &
Anisa Aishah Aminuddin 1 , 3

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Preeclampsia (PE), caused by multiple factors, is one of the most serious complications of pregnancy. Cadmium (Cd) is a heavy metal environmental pollutant, reproductive toxicant, and endocrine disruptor, which can increase the risk of PE. Cd toxicity due to occupational, diet, and environmental factors has worsened the risk. Studies showed elevated Cd concentration in maternal blood and placenta of PE women. However, the implicit association between Cd associated PE is still not highlighted. We systematically reviewed Cd-associated PE and its effect on pregnancy and birth outcomes. Based on “Preferred reporting items for systematic reviews and meta-analyses (PRISMA)” guidelines, eighty-six studies were identified by PubMed, Web of Science (WOS), and Scopus databases. Publications were included until October 2023 and articles screened based on our inclusion criteria. Our study identified that the exposure of controlled and uncontrolled Cd induces PE, which negatively affects pregnancy and birth outcomes. Given the serious nature of this finding, Cd is a potential adverse agent that impacts pregnancy and future neonatal health. Further comprehensive studies covering the whole trimesters of pregnancy and neonatal developments are warranted. Data on the molecular mechanisms behind Cd-induced PE is also essential for potential preventive, diagnostic, or therapeutic targets.

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Advances in pathogenesis of preeclampsia

Cadmium exposure and the risk of GDM: evidence emerging from the systematic review and meta-analysis

Maternal Exposure to Cadmium and Fetal Growth: a Systematic Review and Meta-Analysis

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Acknowledgements

This study has been conducted in the framework of the research activities of the projects funded by University Technology Mara (UiTM) under grants: 600-UiTMSEL (PI.5/4) (023/2022) and 600-TNCPI 5/3/DDF (MEDIC) (004/2021). The authors are grateful to University Technology Mara (UiTM) for supporting this research. The authors also appreciate and acknowledge the valuable time of the Editor and the reviewers.

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Fatima Sardar, Yuhaniza Shafinie Kamsani, Fathi Ramly, Nor Ashikin Mohamed Noor Khan, Razia Sardar & Anisa Aishah Aminuddin

Maternofetal and Embryo (MatE) Research Group, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia

Yuhaniza Shafinie Kamsani & Nor Ashikin Mohamed Noor Khan

Department of Obstetrics & Gynaecology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia

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The authors FS and RS identified and evaluated each study separately. Based on seven domains (mentioned in Fig. 2 ), the studies were categorized into “low risk”, “unclear”, and “high risk” by FS and RS and then checked by YSK, FR, and AAA. The detailed review evaluation of the selected studies was made by FS and RS. The results were discussed with four other authors (YSK, FR, AAA, and NAMK). These four authors checked and verified the findings.

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Keyword combinations used for searching databases

No	Keywords combination
1	“cadmium” AND “preeclampsia” AND “pregnancy”
2	“cadmium” AND “preeclampsia” AND “pregnancy” AND “birth”
3	“cadmium” AND “preeclampsia” AND “pregnancy” AND “prenatal”
4	“cadmium” AND “preeclampsia” AND “pregnancy” AND “maternal”
5	“cadmium” AND “preeclampsia” AND “birth”
6	“cadmium” AND “preeclampsia” AND “birth” AND “prenatal”
7	“cadmium” AND “preeclampsia” AND “birth” AND “maternal”
8	“cadmium” AND “preeclampsia” AND “pregnancy” AND “birth” AND “prenatal”
9	“cadmium” AND “preeclampsia” AND “pregnancy” AND “birth” AND “maternal”
10	“cadmium” AND “preeclampsia” AND “pregnancy” AND “birth” AND “prenatal” AND “maternal”

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Sardar, F., Kamsani, Y.S., Ramly, F. et al. Cadmium Associated Preeclampsia: A Systematic Literature Review of Pregnancy and Birth Outcomes. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-024-04364-5

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DOI : https://doi.org/10.1007/s12011-024-04364-5

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Extracellular vesicles: diagnostic and therapeutic applications in cancer.

Simple Summary

Graphical Abstract

1. Introduction

EVs have an aqueous core enclosed by a membranous lipid bilayer which contains several biomolecules that can be delivered to nearby or distant target cells. Since EVs play crucial roles as messengers over long and short distances, they can influence the microenvironment through the direct and protected shuttling of bioactive molecules, such as receptors and effector molecules, that can be protective or pathogenic [ 12 , 13 , 14 ].
EVs are involved in various physiological processes (apoptosis, differentiation, and proliferation), but they can also affect different pathophysiological conditions in the body, including inflammation, infection, immune response, and cancer [ 15 , 16 , 17 , 18 ].
Of natural origin, EVs exhibit low toxicity, biocompatibility, and high stability in the blood, due to their ability of immune system escape. Another EV advantage is their target potential [ 19 ].
Apoptotic bodies (1–5 µm) released by cell membrane blebbing during apoptosis.
Microvesicles (150 nm–1 µm) shed directly by the plasma membrane with a mechanism of outward budding and fission.
Exosomes (EXOs) (30–150 nm) originating from late endosomal trafficking [ 15 , 20 , 21 , 22 ].

2. Small EVs’ Characteristics and Biogenesis

History : EXOs were isolated for the first time in 1983 from a sheep reticulocyte culture supernatant. For many years, EXOs were considered as waste obtained from plasma membrane shedding. After several decades, this image of a bin to remove garbage from cells changed to that of a shuttle for bioactive particles. Later, the term “exosome” was coined to distinguish them from other types of EVs [ 20 , 37 , 38 , 39 ]. After these initial reports, the EXO research field has garnered much interest and has been enriched considerably, as documented by the exponential increase in publications that has occurred since 2010, according to PubMed.
Composition : Complex biological molecules of different kinds are found in EXOs; these bioactive molecules are selectively packaged on an EXO’s surface or inside the lumen. Omics approaches (proteomic, lipidomic, metabolomic, and deep sequencing technologies) allowed the discovery of the proteins, lipids, metabolites, and nucleic acids contained in EXOs. Based on specialized databases, such as EXOCARTA ( http://www.exocarta.org ), exoRBase ( http://www.exorbase.org ), EVpedia ( https://evpedia.info ), Vesiclepedia ( http://www.microvesicles.org ), EV-TRACK ( https://evtrack.org ), and ExoBCD ( https://exobcd.liumwei.org ), it is possible to collect information about EV cargos [ 40 , 41 , 42 , 43 , 44 ]. EXOCARTA (accessed on 1 June 2024) reports that EXOs contain 9769 proteins, 3408 mRNAs, 2838 microRNAs (miRNAs), and 1116 lipids [ 45 , 46 ]. Protein cargos are varied among EVs due to the specific features of the cell types, culture conditions, and isolation procedures. Some proteins are present mostly in EXOs, being specific to biogenesis and protein sorting; thus, they can be used as markers for EXO characterization [ 47 ]. Proteins include both membrane and cytosolic components, such as surface receptors, adhesion proteins, integrins, cytoskeletal proteins, membrane transport proteins, and fusion-related proteins. One of the reasons for EXO heterogeneity is the presence of specific proteins that mirror the status of the parental cell. For instance, EXOs released by T-lymphocytes have enzymes and perforin on their surface. Antigen-presenting cells (B-lymphocytes and dendritic cells), APC-derived EXOs, contain major histocompatibility antigen complexes (MHC, MHC-I, and MHC-II) [ 48 ]. The tetraspanin proteins (CD9, CD63, CD81, CD82, and CD86) are localized on EXO membranes and represent hallmarks of them. Alix, flotillin, and TSG101 are involved in their biogenesis [ 49 ]. EXO intravesicular proteins are heat shock proteins (Hsp20, Hsp27, Hsp60, Hsp70, and Hsp90), cytoskeletal proteins that are the most conserved molecules; transcription factors (Wnt, Notch, and hedgehog), transport and fusion proteins (GTPase), cell-surface peptidases (CD13 and CD26), and signaling receptors like EGFR are abundant in EXOs [ 17 , 50 ]. Nucleic acid cargos are very abundant in EXOs and are variably expressed in different disorders. They contain both DNA molecules, such as double-stranded (dsDNA), single-stranded (ssDNA), and mitochondrial DNA (mtDNA), and RNA [ 51 , 52 ]. EXOs are enriched with several different species of RNA, such as messenger RNA (mRNA), transfer RNA (tRNA), 18S and 28S ribosomal RNAs (rRNAs), microRNA (miRNA), Y-RNA, long non-coding RNA (lncRNA), circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNAs (snoRNAs), P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs), and viral RNA [ 53 ]. Hundreds of lipid species are found in EXO membranes; sphingomielyn, desaturated lipids, and cholesterol, abundantly present, are responsible for the stability of these vesicles [ 54 , 55 ]. Ceramide phosphates seem to be involved in the anti-inflammatory function of EXOs [ 56 , 57 ].
Formation: EXOs originate from the endo-lysosomal compartment. As a first step, plasma membrane invaginations generate early endosomes that mature to late endosomes, producing multivesicular bodies (MVBs). The latter contain intraluminal vesicles (ILVs) formed after invagination of the late endosomal membrane and enclosing cargo inside [ 58 ]. Subsequently, MVBs may bind to the plasma membrane, and EXOs are released into the extracellular space. To develop ILVs, ESCRTs (endosomal sorting complexes required for transport) are essential. Protein ESCRTs 0-III are involved in promoting MVB formation, vesicle budding, and sorting of protein cargo [ 59 ]. An alternative ESCRT-independent mechanism including roles for tetraspanins, and lipid rafts is also required.
Release: To release EXOs into the extracellular space, MVBs fuse with the plasma membrane. The process is coordinated by RAB proteins and their effectors, or Snap receptors. Without these interactions, MVBs will be degraded into lysosomes [ 59 ].
Uptake: EXOs released into the extracellular space deliver their cargo to the recipient cells or can be destroyed. The target cells may be in proximity to or distant from the parental cells. EXOs can travel over large distances via blood or lymphatic circulation; their lipidic membrane is a protection barrier for the cargo, and the signals travel protected from degradation, avoiding phagocytosis. Molecules such as nucleic acids that could be degraded in extracellular spaces are protected from enzymatic degradation (by RNAse, for example) [ 13 ]. The cargos enter through three major mechanisms: endocytosis uptake, direct fusion to target cell membranes, and receptor–ligand binding ( Figure 2 ). The recipient cells can internalize EXOs as whole vesicles that surf on filopodia to reach endocytic hot spots; then, they pass through endosomes and are finally targeted to the endoplasmic reticulum [ 60 , 61 , 62 , 63 ].
Function: EXO cargos, released inside target cells, can act in appropriate cellular compartments, performing various functions that, depending on the cellular origin, regulate a plethora of activities. EXOs may modulate gene expression, metabolism, and responses to microbial infection and enhance disease progression [ 23 ]. It has been demonstrated that EXOs may transfer nucleic acids, such as mRNA and miRNA, between cells and facilitate their translation in target cells [ 64 ]. EXOs generated from dendritic cells can alter the immune cell response of dendritic cells through the transfer of MHC classes I and II [ 65 ]. The amount of released EXOs depends on the parental cell’s physiological and/or pathological states. Cell stress and the activation of several pathways can regulate EXO production. According to several reports, cancer cells release more EXOs than normal cells. Specific tumor antigens and miRNAs found in EXOs can promote cancer progression by activating oncogenic and anti-apoptotic pathways, such as invasion, angiogenesis, and metastasis [ 66 ]. EXOs also promote tumor immune escape with T-cell apoptosis induction. They have important roles in epithelial–mesenchymal and mesenchymal–epithelial transition in different malignancies. Thus, it is crucial to know the biological conditions of parental cells to guarantee the safety of these vesicles in clinical applications [ 18 , 67 , 68 , 69 , 70 ] ( Figure 2 ).

3. EV Isolation and Storage Methods in Cancer Diagnostics

3.1. conventional ev isolation methods.

Ultrafiltration (UF): This technique is a passive isolation method that utilizes membranes such as polyether sulfone (PES) with predetermined, extremely small pores (100 nm diameter) to isolate vesicles based on their size and molecular weight [ 72 ]. The method involves the use of fluid pressure to drive the migration of a sample through a polymeric filter. EVs are isolated selectively from samples with simultaneous retention of larger particles. UF is a simple and fast method of low cost. However, the applied pressure in filtering the material can damage EVs via shear stress. The result is loss of vesicles; membrane pore blockage, due to the accumulation of particles with the interaction between vesicles and membranes, is also a noticeable problem, as it can reduce the lifetime of membranes and leads to lower EV purity and low efficiency. This reduces UF efficiency, and although UF might be sufficient for good EV isolation, better selectivity and purity can be achieved with a combination of UF and other techniques [ 73 , 74 ].
Immunoaffinity capture (IC): This technique is an isolation technique based on the specific recognition and binding between antibodies or affinity ligands (such as lectins and heparin) and EV marker components (antigens) that are ubiquitously exposed on vesicle surfaces. The approach is simple, as the antibodies or ligands are immobilized on solid substrates such as magnetic beads. A sample is incubated with these beads, and they are captured through specific antigen–antibody binding or ligand–receptor interactions. The magnetic beads are separated from the other molecules contained in the sample using a magnetic field. A washing step with buffers reduces the non-specific interactions, and after elution the vesicles can be used for further analysis [ 75 ]. EV surface markers, such as fusion proteins (flotillin and annexin) and transmembrane proteins (CD63, CD81, and CD82), can be recognized by antibodies that are applied to separate vesicles from various sources. Several commercial kits have been developed over the past decade for selectively isolating EV subpopulations. Using specific biomarkers such as EpCAM (epithelial cell adhesion molecule) overexpressed on tumor-derived EVs, researchers were able to isolate EVs from clinical samples and evaluate the presence of marker-related tumors [ 76 ]. The method based on magnetic beads can achieve strong specificity and good purity and yields; it can be used with small volumes of a sample; and it is useful for the separation of cell-type-specific EVs [ 77 ]. For instance, the isolation of CD9 + EVs can lead to the exclusion of CD9 EVs, which can be used for diagnostic purposes. A disadvantage associated with this methodology is the selection by the users of a subset of marker-specific vesicles that may not reflect all EVs. A limit on its large-scale use is the availability of specific and good antibodies and the high reagent cost. Indeed, immunoaffinity capture is one of the most expensive methods of EV isolation from a large sample volume, as it requires high amounts of antibody-conjugated beads. Therefore, it is only appropriate for small sample sizes, which presents a barrier to any potential therapeutic use. In the past few years, several isolation platforms based on aptamers have been developed [ 78 , 79 ]. Aptamers are short DNA or RNA oligonucleotides that can recognize and bind targets in a manner like antibodies. In comparison with antibodies, they can be produced by chemical synthesis in vitro, present low or no immunogenicity, and be low cost. Therefore, they can be used to detect EVs from cancer cells, as they bind with high affinity and specificity. Aptamers can bind EVs with high specificity; however, they have not been widely used for EV isolation, being used mainly for analysis and detection [ 80 ].
Ultracentrifugation (UC): Ultracentrifugation (100,000× g or greater) is currently used in about 80% of EV isolation methods. It is based on the principle of sedimentation and mainly depends on vesicle density, size/weight, and shape, as denser and/or larger particles tend to fall to the bottom first [ 81 , 82 ]. UC involves two steps with increasing centrifugal power after pelleting down cells: first a pre-cleaning and filtering of samples centrifuged at low and intermediate speed centrifugations (500–2000× g ) to remove dead cells and large debris; then, the pellet is resuspended in a suitable medium and centrifuged at 10,000–16,000× g to pellet apoptotic bodies [ 83 ]. After removing these large species, via ultracentrifugation at 20,000× g , a pellet enriched in MVs, a subset of large-sized extracellular vesicles, can be obtained. The supernatant is then filtered through a 0.45–0.22 μm filter (Millipore) to reduce potential MV contamination and centrifuged at high speed (40,000–100,000× g ) for several hours. EVs are separated from different components of the sample, pelleted at the bottom of the tube, and collected after removing the supernatant. The centrifugation is operated at 4 °C. UC presents several advantages: it requires little sample pre-treatment, and it is suitable for processing large samples (depending on the rotor utilized), such as cell culture media and easily accessible biofluids, and isolating large amounts of EVs [ 82 ]. Furthermore, UC has the characteristic of low contamination risk and is also inexpensive, apart from requiring access to expensive equipment (purchase of an ultracentrifuge). At the same time, however, there are several limitations because UC isolation is a time-consuming method (>4 h) and requires extra care to prevent damage from the centrifugal force. UC may result in partial vesicle aggregation and degradation and can also lead to the loss of some of the EVs’ original biomolecular contents [ 81 , 84 ]. In addition, the resulting supernatants obtained by ultracentrifugation at 100,000× g may contain non-vesicular extracellular nanoparticles, such as exomeres and supermeres, which were recently discovered and seem to contain and transfer functional cargos [ 85 ]. As regards human plasma, because of the considerable overlap in terms of both particle size and density between EVs and lipoprotein particles, such as low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), and chylomicrons, an unintentional coisolation of these two different entities may occur. Hence, ultracentrifugation is not widely recommended to purify EVs for therapeutic purposes, as it may coisolate protein aggregates [ 86 ].
Density-gradient centrifugation (DGC): To eliminate impurities, such as proteins, lipoproteins, and RNA, from biological fluid, high-speed centrifugation and density gradients are often combined. These procedures involve the use of centrifuge tubes filled with an inert medium such as sucrose or iodixanol (Opti Prep) that decreases in thickness from bottom to top [ 87 , 88 ]. DGC utilizes differences in densities between particles and media. The process starts by filtering or centrifuging a sample to remove debris and large particles. The sample is loaded on top of the density gradient and centrifuged at high speed for several hours [ 89 , 90 ]. EVs are separated according to their density, size, and mass. Each sample component migrates according to its density in the tube’s pre-loaded density gradient, causing separation to occur [ 91 ]. EVs are localized in a density range of 1.1 to 1.2 g/mL in sucrose density gradients. The EV aliquot is collected from the required density range; the sample is ultracentrifuged at 100,000× g , for a few minutes, to yield pure EV pellets. Depending on the acceleration, the type of rotor in which the samples are placed, the viscosity of the solution in question, and the time needed to obtain the pellets, preservation of vesicular structures with high purity is obtained. Compared to differential ultracentrifugation, density-gradient centrifugation gives a cleaner EV population. However, it has several limitations: DGC requires specialized equipment and can be expensive and time intensive. Moreover, some contaminants can persist because EVs cannot be isolated from vesicles with the same density but different sizes [ 92 ]. Because of the long time required, DGC is not applicable for use in clinical settings or efficient enough for biomarker discovery, but it is an important technique in EV research.
Polymer-based precipitation: The coprecipitation method is a simple, quick, and efficient way to isolate EVs. It uses hydrophilic polymers where the sample is incubated. Polymers at low-speed centrifugation sequester the water molecules so that the solubility of the soluble components decreases, and they are then forced to phase separate. EVs or biological material are excluded from the solvent regions and are concentrated until, their solubility being exceeded, they precipitate [ 93 ]. Currently, among hydrophilic polymers, polyethylene glycol (PEG), lectin, dextran, or salt solutions are used. After washing, and using a neutralizing agent, EVs are separated by low-speed centrifugation (1500× g ) [ 94 ]. This technique is used to separate EVs from biological fluids such as plasma, urine, and cerebrospinal fluid. PEG is used to process many samples simultaneously; it is easy to use, fast, does not require special equipment, is relatively low-cost, and does not cause deformation or damage to EVs. Commercial kits, such as Total Exosome Isolation, ExoSpin, and ExoQuick, are based on polymer precipitation and are available for scaling up. However, the low specificity and coprecipitation of different components like protein pollutants, polymeric materials, and lipoproteins may occur, which can lead to incorrect quantification of EVs, that is generally dependent on total proteins, which limits further analysis of EVs via omics-based assays. It is an attractive tool for rapid isolation, can be applied for preliminary analysis, and is efficient in clinical research settings, but it is not considered for functional analysis [ 95 ].
Size-exclusion chromatography (SEC): This technique, also referred to as gel filtration, has exploded in popularity in recent years. Using passive gravity flow, it can isolate solutes based on molecular size, shape, and density. The method includes the passage of an aqueous solution down a column filled with a porous unreactive stationary phase and a specific pre-size distribution to differentially enable elution of the material. When the sample, the initial biofluid, enters the gel, with the flow of the mobile phase, small particles or molecules with small hydrodynamic radii diffuse into the pores and are trapped in them for a long time, so they pass slowly through the column. Conversely, particles with large hydrodynamic radii are unable to access the pores, so they are eluted earlier from the column. Hence, the passage of proteins and other small contaminating particles is delayed, while larger particles or vesicles like EVs exit the column and are eluted earlier in the void volume [ 96 ]. The separated EVs are collected in fractions to be used for experiments. The porous stationary phase contained in the column can be a cross-linked dextran polymer (Sephadex), polyacrylamide (Sephacril), agarose beads (Sepharose), or allyldextrane (Sephacryl). In the last decade, many commercially available columns and SEC kits have been designed to simplify EV isolation: iZON Science produced the qEV Exosome isolation kit; the PURE-EVs kit (Hansa Biomed) has also been created. These systems allow rapid isolation with high precision in half an hour; the SEC methodology is relatively easy and fast [ 97 ]. SEC is useful to isolate EVs from a large variety of sample matrices from both prokaryotes and eukaryotes. This technique allows the isolation of high-purity EVs, preventing protein contamination, and the maintenance of the integrity of EV structures and biological activities, as this procedure relies on gravity rather than sheer force; it is suitable for use with small samples, efficient in terms of time (<0.5 h) and effort, and there is no or minimal sample loss. Therefore, SEC has potential for therapeutic applications and functional investigation [ 98 ]. The SEC approach requires dedicated equipment and has several limitations: (a) due to the possibility of contaminants gaining access to the chromatography columns, it is important to ensure aseptic working conditions, especially if the isolated EVs are destined for therapeutic use (to eliminate soluble contaminants, filtration-based techniques are used prior to injection into the column) [ 99 ]; (b) for the starting material, a medium sample volume is required; (c) the number of samples that can be processed simultaneously is another limitation associated with SEC; (d) low yield, due to the inability to separate EVs from other vesicles of the same size or protein aggregates or lipoproteins (including chylomicrons, VLDL, VLDL remnants (such as IDL) and LDL) in the same size range as EVs [ 100 ]. The identification of EV subtypes is important, and the combination of SEC and immunocapture methods is recommended. Research efforts have been made to overcome these challenges and enhance SEC efficacy and speed [ 82 , 96 ]. For instance, using a combination of UF/UC or PEG-based precipitation and SEC to remove pollutants makes it a powerful isolation technique for EV research, especially if subsequent downstream therapeutic and biomarker discovery applications are planned. SEC-coupled techniques generate a high yield of EVs that can be used for protein and RNA diagnostics, as well as potential drug or drug delivery systems. However, this combination target is not suitable for scaled-up production [ 97 , 101 ] ( Figure 3 ).

3.2. Advanced EV Isolation Techniques

Microfluidic-based platforms (MF): Microfluidic-based platforms are new isolation methods that are emerging due to their small size, automation, efficient and rapid enrichment, and isolation of particles of very similar shapes and sizes. They require only small volumes, but the devices are highly complex and expensive, although they are less expensive than those used for immunoaffinity capture. Microfluidics is a modern technology with promising prospects and has great potential in clinical applications, but it is not yet considered a standardized method of EV isolation. Different isolation principles have been designed: size-based, immune-affinity-based, and dynamic categories that make use of nanomaterials or polymethylmethacrylate (PMMA) [ 102 ].
Flow field-flow fractionation (FFF): This is an emerging passive size-based fractionation technique for EV separation based on the application of hydrodynamic forces. Asymmetrical flow field-flow fractionation (AsFlFFF or AF4) is the most popular FFF subtechnique used to fractionalize EVs from cell-line culture media and body fluids with high reproducibility and purity [ 118 ], although it is more expensive than the others.
Ion-exchange techniques: These allow the isolation of EVs, for instance, through chromatography- and metal-affinity-based systems that exploit the interactions between negatively charged EV membrane components whose charges have been determined by zeta potentials and an anion exchanger with positively charged functional groups or cations [ 119 ].

4. EV Characterization and Detection Techniques

4.1. commonly utilized ev characterization methods, 4.2. novel single-vesicle analysis methods.

Surface plasmon resonance (SPR) detection: SPR occurs when light incident at a certain angle through a glass prism strikes a metal sheet at the interface of two substances with different refractive indices. The resonance condition is strongly dependent on the refractive index of the media. This real-time analysis technique can thus detect molecular interaction on the surface of a gold layer by monitoring the changes in its refractive index [ 129 ]. Rapid real-time labelling detection can be achieved using plasmon resonance systems, which do not rely on secondary antibody labelling [ 130 ]. Plasmas can squeeze and enhance electromagnetic fields on the subwavelength scale, which is widely used in optoelectronics and quantum information, as well as biomedicine [ 131 ]. SPR may be used to detect and measure particle concentrations of EVs within 200 nm of the metal film. This technique provides various advantages, such as low cost, rapid detection, low sample consumption, specificity, and sensitivity. However, some limitations need to be overcome to make this method suitable for clinical application.
RAM surface-enhanced Raman spectroscopy (SERS) and Tip-enhanced Raman spectroscopy (TERS): These are powerful techniques to enhance the Raman scattering signals of the molecules adsorbed on or proximal to metal surfaces, semiconductors, and 2D nanomaterials. Particularly useful for studying complex biological systems, such as cells and extracellular vesicles, SERS and TERS are useful where traditional Raman spectroscopy may not provide sufficient sensitivity for identifying EV biochemical compositions and their membranes, allowing the detection of small molecules, lipids, and proteins. For instance, EVs contain helical fragments of proteins on their outer membranes. Upon EV interaction with gold nanoparticles or a gold-tip apex, they result in signal amplification, offering molecular specificity, high sensitivity, high spatial resolution, non-destructiveness, and versatility [ 132 ].
Single-particle interferometric reflectance imaging sensor (SP-IRIS) (Exo-View): This is a digital optical technology which enhances nanoparticle scatter signals by the application of extra layered substrates (silicon substrates). Based on this method, the Exo-View platform has been used to characterize different ratios of surface markers like tetraspanins, differentiating EV populations produced by cancer cells. It can detect EVs as small as 40 nm, and it can be used for the analysis of proteins of purified individual EVs [ 133 ].

5. The Role of EVs in Cancer Diagnosis: EVs as Biomarkers

6. the role of evs in cancer diagnosis: evs as new therapeutic options, 6.1. ev-based cancer immunotherapy, 6.2. drug delivery research.

Endogenous approach: Donor cells can be incubated with bioactive molecules of small molecular weight. Cargos, after passive diffusion across the plasma membrane, can concentrate in the cytoplasm; thus, the donor cell will utilize its natural mechanism to package drugs into vesicles, and, after appropriate stimulation, such as hypoxia or heat, EVs carrying these molecules are generated. Exogenous nucleic acids are usually loaded into donor cells using a gene transfection approach; the cells are transfected with DNA plasmid vectors, non-coding RNAs, etc., that are easily packaged within EVs by the natural processes of biomolecular synthesis. The approach is simple, but it can result in poor loading and is thus not suitable for wide application [ 178 ].
Exogenous approach: This is an alternative to encapsulation during vesicle biogenesis, as EVs previously isolated from donor cells are purified to obtain concentrated EVs. Then, vesicles are incubated with the drug of interest, which can easily penetrate inside and localize in the lumen. The loading strategy relies on a simple step of incubation (passive drug loading) or exposure of EVs to active stimuli (active drug loading), for example, electroporation, saponin permeabilization, freeze/thaw cycles, sonication, hypotonic dialysis, and/or extrusion. Currently, the principal method used for loading siRNA is EV electroporation. The application of high-voltage electricity to an EV suspension generates temporary pores in the membranes, through which therapeutic compounds can be internalized in EVs [ 177 ].
Inhalable dry powders of EVs
Three-Dimensional bioprinting of EVs

7. Considerations and Challenges in EV Research

The top priority is to use robust purification methods, as the extracellular environment in biofluids, such as plasma, urine, and saliva, used as non-invasive sources, is rich in proteins, lipoproteins, aggregates, cell debris, and other contaminants. It is necessary to consider the characteristic of the sample to be analyzed because each body fluid has its own composition and biophysical properties. The choice of isolation method for EVs can have an impact on the quantity as well as the cargo composition of the obtained EVs [ 209 ].
Moreover, some of these biomaterials contain EVs from all around the body, and it is extremely difficult to determine the origin of vesicles isolated from these biomaterials. Microvesicles in plasma are mainly from platelets, but other sources of EVs in blood plasma are endothelial cells, monocytes, lymphocytes, and erythrocytes [ 210 ], and less than 1% of EVs originate from tissues such as smooth muscle cells. EVs’ size heterogeneity and the diversity of their surface proteins, due to the wide range of producing cells, severely limits the purity of extracted EVs and their promising use.
Due to the biogenesis of these vesicles, there are still methodological difficulties in performing experiments to identify the tissue specificity of isolated EVs, nor it is possible to differentiate some membrane and cargo markers which are specific to EVs or which can be identified both in cells and in EVs from the parental cells.
The minimal relative abundance of EVs in body fluids makes their isolation and analysis more difficult.
Preservation of the structural integrity of EVs is necessary to allow proper characterization of them. EVs are sensitive to storage conditions, so the stability and integrity of biomarkers need to be preserved. EVs isolated from diverse sources may require different storage conditions. New appropriate storage conditions such as lyophilization methodologies and handling methods to maintain the stability and integrity of EVs need to be developed [ 211 , 212 , 213 ].

8. Conclusions and Outlooks

Author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Click here to enlarge figure

Principle	Purpose	Advantages	Disadvantages	Ref
EVs are challenged with laser beam, and scattered beam of light is captured at certain variable angle by detector. The size of the particles is determined by measuring the random changes (resulting from relative Brownian movements of particles) in the intensity of scattered light from sample suspension. Intensity of scattered light in function of time	Size distribution in the range of 1 to 6000 nm, for EVs concentrations from 106 to 109 particles/mL. After analysis sample recovery is possible.	Useful for qualitative anaysis No preparation steps	Not efficient with polydisperse samples Not suitable for measuring complex EVs samples with large size range. Non specificity Difficulty to distinguish contamination from EVs	[ ]
EVs are challenged with a beam of laser and forward scattered light which is captured (real time) by a microscope to calculate the sizes of particles based on their Brownian motion	Size detection in the range of 50 to 1000 nm, Measurement of distribution and concentration, NTA is compatible fluorescence detectors	Small amount of sample is required; possibility to get precise size distributions and their associated concentrations in 1-nm intervals. Detection speed is fast, and observation can be carried out in real time. analysis of EVs markers by fluorescent labeling.	Difficulty to distinguish contamination from EVs. Inaccurate if samples are aggregated and/or have different size distributions	[ ]
Imaging is performed using negative staining of EVs with heavy metals molecules. Immunogold labeling is used for staining specific structures. Cryo-TEM can be used for high resolution imaging. Scattered electron beam.	Direct visualization of EVs morphology, size measurement, and staining of specific structures	Requires a small sample amount. Semi-quantitative, can provide information of EVs distribution	Complicated operation and high requirements on sample preparation Sample preparation may lead to shape modifications	[ ]
Uses a cantilever with a free end that touches the sample surface. The interaction forces between the probing tip and the EVs surface allow to obtain topographical information	3-D topography and diameter of EVs. Resolution at nanometric level can be achieved. useful for analysis of both dry and liquid samples; can be integrated with microfluidic devices	Useful for size distribution profile determination. No fixation or staining steps. Requires a small sample amount	Does not provide direct imaging of the EVs samples. Sample dehydration may lead to topography modifications	[ ]
Based on the reaction between an antigen and an antibody	Detection of the marker proteins expression. WB involves lysis of vesicles and denaturation of proteins, so that both surface and internal proteins can be detected	Can qualitatively and quantitatively analyze marker proteins. Low sample volume, wide accessibility, ease of use	Time-consuming The Detection of marker proteins varies depending on the type of parental cells; not suitable for the detection of EVs markers in biological fluid	[ ]
Vesicles are swept along by a liquid stream to align the particles in single line at the center of the stream where they are excited by a beam of laser. The scattered light is collected by detectors situated 180° (size data) and 90° (morphology) to the laser beam. Fluorescent light	Analysis of EVs with a lower size limit of 250 to 500 nm; ability.to distinguish vesicles that differ 200 nm in size. New technological progress has reduced the limit of detection to ~100 nm and the discrimination power to 100 to 200 nm. It can be coupled with fluorescent latex beads for surface marker	Qualitative and quantitative. Analysis speed fast; simple, required low concentration of the sample	Time-consuming Particle size cannot be measured	[ ]

EV-Source	Bioactive Molecules	Ref
	miRNAs
plasma	let-7, miR-223, miR-383, miR-192, miR-30e-3p, miR-301, let-7f, miR-572, miR-20b, miR-345, miR-30b, miR-30c, miR-103, miR-195, miR-221, miR-222	[ , , ]
plasma	miR-1246, miR-21, miR-9, miR-16, mi-429, miR-338-3p, miR-340-5p, miR-124-3p, miR-29b-3p, miR-20b-5p, miR-17-5p, miR-130a-3p, miR-18a-5p, miR-195-5p, miR-486-5p, and miR-93-5p	[ , ]
plasma	miR-338-3p, miR-340-5p, miR-124-3p, miR-29b-3p, miR-20b-5p, miR-17-5p, miR-130a-3p, miR-18a-5p, miR-195-5p, miR-486-5p, and miR-93-5p	[ ]
serum, plasma	miR-92, miR-93, miR-126, miR-509-5p, miR-1270	[ ]
	Circular-RNAs
serum, plasma	CircRNA-051239, Cdr1as	[ ]
	Proteins
plasma	PD-L1	[ ]
urine	CD81, PSA	[ ]
tissue	CD24, EGFR	[ ]

urine	phosphatidylserine, galactosyl ceramide	[ ]
tissue, plasma	sphingolipid, phosphatidylcholine, phosphatidylethanolamine	[ ]

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Di Bella, M.A.; Taverna, S. Extracellular Vesicles: Diagnostic and Therapeutic Applications in Cancer. Biology 2024 , 13 , 716. https://doi.org/10.3390/biology13090716

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Eur J Case Rep Intern Med
v.11(9); 2024
PMC11379109

Legionella Pneumophila Presenting as a Rare Cause of Acute Thrombocytopenia: A Case Report and Review of Literature

Ryan berenji.

1 General Physician Cancer Care, Williamsville, USA

Sarah Faisal

2 Jinnah Sindh Medical University, Karachi, Pakistan

Syed Ather Hussain

3 Department of Hematology, Roswell Park Comprehensive Cancer Center, Buffalo, USA

Asma Faisal

4 Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan

Hafsa Faisal

5 Department of Pulmonary Critical Care Medicine, University at Buffalo, Buffalo, USA

Introduction

Legionella pneumophila can cause a wide spectrum of clinical manifestations, ranging from a mild flu-like illness to fulminant multi-organ involvement, characterised by severe pneumonia, diarrhoea, encephalopathy, shock, hepatic dysfunction and renal failure. Very rarely, it can be associated with haematologic conditions such as thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and immune thrombocytopenic purpura (ITP). We report a rare case of L. pneumophila causing ITP and review previously published cases of thrombocytopenia associated with Legionellosis in the literature.

Case description

A 53-year-old male presented with fevers, chills, a productive cough and severe haemoptysis. Blood work was remarkable for leukocytosis, severe thrombocytopenia and hyponatraemia. Computed tomography (CT) imaging showed left lower lobe lung consolidation, and a peripheral blood smear showed giant platelets consistent with ITP. Legionella urine antigen testing returned positive. He was treated with intravenous immunoglobin, steroid taper and a ten-day course of azithromycin, which led to normalisation of his platelet count and resolution of the pneumonia.

L. pneumophila can lead to complement-mediated destruction of platelets resulting in ITP. Antibodies against L. pneumophila can also cross-react with the enzyme ADAMTS13, inhibiting its function and resulting in TTP and HUS. Additionally, L. pneumophila can infect vascular endothelial cells causing their death and stimulating release of von Willebrand factor (vWF) multimers into the bloodstream, promoting thrombosis and platelet consumption.

It is important for internists to consider L. pneumophila in the differential for any patient presenting with pneumonia and severe thrombocytopenia. Earlier detection and intervention can lead to prevention of critical bleeding and better outcomes.

LEARNING POINTS

Legionella pneumophila is rarely associated with different haematologic disorders resulting in severe bleeding diathesis as well as thrombosis.
It is important for internists to consider Legionella pneumophila in the differential diagnosis for any patient presenting with pneumonia and severe thrombocytopenia.
Earlier detection and intervention can lead to prevention of critical bleeding and better outcomes.

INTRODUCTION

Legionella pneumophila , a Gram-negative intracellular aerobic bacillus, can cause a wide spectrum of clinical manifestations, ranging from a mild flu-like illness (Pontiac fever) to fulminant multi-organ involvement (Legionnaires disease), characterised by severe pneumonia, diarrhoea, encephalopathy, shock, hepatic dysfunction and renal failure [ 1 , 2 ] .

It was first described in 1977 and is known to cause both community-acquired and nosocomial infections [ 3 ] . It has been estimated that between 2 and 15% of community-acquired Legionella infections result in hospitalisation [ 4 ] . Immunosuppression and exposure to contaminated water storage and distribution systems are major risk factors for developing Legionellosis [ 3 ] .

Very rarely, it has been associated with different haematologic conditions, resulting in thrombocytopenia and severe bleeding diathesis, including thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and immune thrombocytopenic purpura (ITP).

We report a rare case of L. pneumophila causing ITP, which resolved with treatment of the underlying infection and systemic steroids. We also review previously published cases of thrombocytopenia associated with L. pneumophila in the literature.

CASE DESCRIPTION

A 53-year-old male had a history of active tobacco and marijuana smoking as well as remote exposure to tuberculosis several decades ago, for which he completed six months of isoniazid. He presented to an outside hospital with three days of fevers, chills and productive cough associated with nausea and vomiting. His vitals revealed a temperature of 38°C, heart rate 107/min, blood pressure 121/82 mmHg, respiratory rate 24/min and oxygen saturation 96% on room air. A computed tomography (CT) angiogram showed no pulmonary embolism but demonstrated a left lower lobe consolidation consistent with pneumonia ( Fig. 1 ). A complete blood count showed a white blood cell count of 15,000/μl, neutrophilia 88%, bandemia 6%, haemoglobin 13.7 g/dl and a platelet count of 21,000/μl. Chemistry showed hyponatraemia with serum sodium 129 mEq/l, blood urea nitrogen 14 mg/dl, serum creatinine 0.8 mg/dl and total bilirubin of 0.8 mg/dl. Liver function tests, lactate dehydrogenase (LDH) and haptoglobin were noted to be within normal limits. Virology work-up was negative for influenza A/B, respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on polymerase chain reaction testing. Blood, sputum and urine cultures were negative. Urine antigen testing detected L. pneumophila serotype 1 antigen; broad spectrum antibiotics were switched to azithromycin. The patient was discharged home to complete a course of oral azithromycin.

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Computerised tomography (CT) scan of the chest obtained upon admission showing left lower lobe lung consolidation consistent with pneumonia in A) cross-sectional and B) coronal view.

The following day, he presented again to the same outside hospital reporting six episodes of large-volume haemoptysis, which led to readmission. A repeat complete blood count showed a white blood cell count of 7,800/μl, haemoglobin 13 g/dl and a worsened platelet count of 9,000/μl. Due to severe thrombocytopenia in combination with life-threatening haemoptysis, he was transferred to our hospital for haematology consultation. A peripheral blood smear showed severe thrombocytopenia with giant platelets consistent with ITP ( Fig. 2 ). Human immunodeficiency virus (HIV) 1/2, hepatitis B and C serology were negative. Serum vitamin B12 and folate were within normal limits. He was started on intravenous immunoglobin 1 g/kg and prednisone 60 mg daily for symptomatic ITP. His platelet count normalised to 204,000/μl on day four of therapy, with resolution of haemoptysis. After discharge, he completed a full ten-day course of azithromycin and continued to follow up with haematology for tapering of prednisone. He had a repeat CT chest four weeks after discharge, which showed resolution of left lobe pneumonia ( Fig. 3 ).

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Object name is 4817_Fig2.jpg

Peripheral blood smear obtained upon admission showing severe thrombocytopenia and giant platelet (red arrow) consistent with immune thrombocytopenic purpura (ITP). Normal platelet also seen for size comparison (black arrow).

An external file that holds a picture, illustration, etc.
Object name is 4817_Fig3.jpg

Repeat CT scan of the chest obtained four weeks after discharge showing improvement in left lower lobe lung consolidation in A) cross-sectional and B) coronal view.

We performed a comprehensive literature search on PubMed with keywords ‘ Legionella pneumophila ’ and ‘thrombocytopenia’. We screened the results by reviewing the abstract and the full manuscript to identify relevant articles which met our criteria. We retrieved seven articles and extracted data on eight patients. We cross-checked the references of the selected articles to identify any additional articles which met our criteria. We have summarised the clinical details of all patients with L. pneumophila and thrombocytopenia, including our own patient, in Table 1 .

Patient’s hypercoagulable test results.

Study	Age (years)	Gender	Comorbidities	Risk factor for	Initial presentation	Haematologic diagnosis	Platelet count (×10 /l)	White count (×10 /l)	Haemoglobin (g/dl)	Serum creatinine (mg/dl)	Coagulation profile	Peripheral smear	Bone marrow examination	testing	Treatment	Follow-up platelet count (×10 /l)	Outcome
Current study	53	M	-	Extensive smoking; works as a fuel attendant for refrigerated trailer trucks	Chills, productive cough, haemoptysis, nausea/vomiting	ITP	9	7.8	13.0	0.8	Normal	Giant platelets, severe thrombocytopenia	-	Positive serotype 1 urine antigen	Azithromycin, IVIG, prednisone	204	PC normalised 4 days after treatment; patient discharged home with haematology follow-up
Javed et al., 2022 ]	61	F	Asthma	Underlying lung disease	Epistaxis, fever, non-productive cough, SOB, haematochezia	ITP	2	20.69	10.2	-	Normal except elevated fibrinogen >700 mg/dl, D-dimer 947 ng/mlL	Giant platelets, anisocytosis, microcytosis	-	Positive for urine antigen	Levofloxacin, cefepime, IVIG, prednisone	293	PC normalised; patient discharged home one week later
Talebi et al., 2011 ]	65	M	HTN	Recent travel to the Bahamas	Epistaxis, fever, cough, headache, AMS	TTP	8	17.0	5.9	1.6	Normal	Multiple schistocytes, reticulocytes, severe thrombocytopenia	-	Positive IFA for at 1:256 Negative for urine antigen	Levofloxacin, methylprednisolone, plasma exchange	-	PC normalised; patient discharged home with haematology follow-up
Larsson et al., 1999 ]	73	M	Sinus thrombosis	-	Fever, cough, dyspnoea, renal insufficiency	Thrombocytopenia with acute renal failure	-	3.3	-	-	Elevated serum fibrinogen 730 mg/dl	-	-	Positive tracheal mucus culture Positive urine antigen	Intubation, NO, CVVH, LMWH, antibiotics	-	Passed away one week later from respiratory failure
Larsson et al., 1999 ]	49	M	Arteriosclerosis	-	Pneumonia, septic shock	Thrombocytopenia with acute renal failure	-	22.0	-	-	Elevated serum fibrinogen 890 mg/dl	-	-	Positive IFA for in tracheal mucus Positive tracheal mucus culture for serogroup 8	Intubation, NO, CVVH, heparin, antibiotics	-	Patient survived and was transferred to a regular ward
Canaud et al., 1989 ]	35	M	HTN	Swimming pool maintenance worker	Headache, productive cough, asthenia, myalgia, oliguria	HUS with malignant HTN	40	9	7.6	5	FDP > 40 mg/l	Schistocytes	-	Positive IFA for serotype 1–6 antibody at 1:512	Erythromycin, prostacyclin, epoprostenol	487	PC normalised six days after treatment
Barendregt et al., 1988 ]	53	F	Polycystic kidney disease, liver cysts, cadaveric renal transplant	Immunosuppression	Fever, pleuritic CP, bloody sputum	Thrombocytopenia with acute renal failure	5	-	-	8.5	Normal	-	-	Positive culture on a buffered charcoal yeast extract Positive indirect IFA for serotype 4 antibody at 1: >2048	Erythromycin, rifampicin, prednisone, RATG, haemodialysis	-	-
Riggs et al., 1982 ]	45	M	-	Recent travel to Los Angeles; a cluster of other cases reported in the area	Fever, chills, productive cough, arthralgia, watery diarrhoea	TTP	25	8.6	7.6	2.1	Elevated PT 16s, FDP 80–160 mg/l	Schistocytes, few spherocytes, several nucleated RBCs	Erythroid hyperplasia with adequate megakaryocytes	Positive Dieterle stain for GNRs on transbronchial biopsy Positive indirect IFA for antibody at 1:32	Erythromycin gluceptate, methylprednisolone sodium succinate, dipyridamole, cyproheptadine, haemodialysis, plasma exchange	55	Patient suffered a cardio-respiratory arrest on day 13 of hospitalisation despite haematologic improvement
Gasper et al., 1978 ]	22	M	Right calf DVT	-	Bronchospasm, epistaxis, diaphoresis malaise, pleuritic CP, slurred speech, unsteady gait	Thrombocytopenia	40	8.7	15.8	-	Normal except elevated FDP 40–80 mg/l	Toxic granulations, left shift, thrombocytopenia	Normal	Positive antibody titre at 1:>1020	Erythromycin, flucloxacillin	180	PC normalised five days after treatment

Abbreviations: AMS, altered mental status; CP, chest pain; CVVH, continuous veno-venous haemofiltration; F, female; FDP, fibrin degradation products; GNRs, Gram negative rods; HTN, hypertension; HUS, haemolytic uraemic syndrome; IFA, immunofluorescent assay; ITP, immune thrombocytopenic purpura; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin; M, male; NO, nitrous oxide; PKD, polycystic kidney disease; PT, prothrombin time; RATG, rabbit anti-thymocyte globulin; RBCs, red blood cells; SOB, shortness of breath; TTP, thrombotic thrombocytopenic purpura.

Of all the patients included in our literature review, one other patient had ITP, two had TTP, one had HUS, three had thrombocytopenia with acute renal failure and one had thrombocytopenia of unclear aetiology. Six patients had identifiable risk factors for contracting L. pneumophila , which included significant smoking, solid organ transplant, exposure to contaminated water or travel to an area with known outbreaks of L. pneumophila . Diagnostic work-up for L. pneumophila included urine antigen testing and direct/indirect immunofluorescent assay for antibodies or culture. One patient had a negative urine antigen but a positive immunofluorescent assay for antibodies against L. pneumophila . This could be because the urine antigen test is specific for L. pneumophila serotype 1 only, while most outbreaks of Legionnaires disease in the community are attributed to other serotypes [ 5 ] . All patients received treatment with either fluoroquinolone or macrolide. Treatment for thrombocytopenia varied based on the associated haematologic disease; two patients had a negative outcome despite treatment.

ITP is characterised by immune-mediated destruction of platelets. It is a diagnosis of exclusion but certain infections, medications, pregnancy and immune disorders have been associated with this condition [ 1 ] . Among infections, HIV, cytomegalovirus, streptococcus, mycoplasma, brucella, varicella zoster virus and Helicobacter pylori are the usual triggers [ 1 , 5 ] . Corticosteroids and intravenous immunoglobin are the standard initial therapy for patients with ITP who experience severe bleeding. L. pneumophila can activate the complement cascade by binding to the C1q component independently [ 6 ] . Platelets express C1q receptor on their surface; interaction between immune complexes containing C1q and the receptor result in platelet activation, aggregation and consumption, leading to thrombocytopenia [ 6 ] .

TTP and HUS are thought to be a continuum of the same disease process. It occurs due to a deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13, which leads to formation of large vWF multimers [ 5 ] . These multimers are not easily degraded: they bind to platelets and damage endothelial cells, forming extensive microthrombi throughout the circulation, resulting in consumption of platelets and destruction of red cells [ 5 ] . TTP can either be hereditary due to genetic mutations in the ADAMTS13 gene or acquired in the setting of a trigger, which over-activates the immune system [ 5 ] . Riggs et al. demonstrated the presence of L. pneumophila in the lung tissue autopsy specimen of a patient diagnosed with TTP [ 7 ] . Chiaraviglio et al. showed that L. pneumophila can directly infect endothelial cells causing their death, and stimulate the release of vWF multimers into the bloodstream [ 4 ] . It is hypothesised that antibodies against L. pneumophila cross-react and target ADAMTS13 , inhibiting its function, resulting in an acquired form of TTP [ 5 ] . Regardless of the aetiology, TTP is treated with steroids and plasmapheresis, which removes auto-antibodies as well as large vWF multimers from the circulation.

L. pneumophila is a rare cause of acute thrombocytopenia. It has been associated with life-threatening haematologic diseases such as ITP, TTP and HUS, which can result in major bleeding as well as thrombosis. It is important for internists to consider L. pneumophila in the differential for any patient presenting with pneumonia and severe thrombocytopenia. History of significant smoking, immunosuppression, exposure to contaminated water or travel to an area with known outbreaks of L. pneumophila are major risk factors for developing Legionellosis. Earlier detection and intervention can lead to prevention of critical bleeding and better outcomes.

Conflicts of Interests: The Authors declare that there are no competing interests.

Patient Consent: We obtained informed written/signed consent from the patient for publishing their clinical history.

COMMENTS

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The basic steps and essential choices involved in conducting a literature review will be suggested and addressed in four phases; (1) Planning of the review, (2) Conducting of the review, (3) Analyses and (4) Writing the review (Palmatier et al., 2018). Interesting topics to Choose in Biology
Transcranial Doppler With Microbubbles: Screening Test to Detect and
Contrast transcranial Doppler is a noninvasive, inexpensive, accurate tool for the detection of right-to-left shunt. We conducted a literature review on the use of contrast transcranial Doppler to detect and grade right-to-left shunt after an acute ischemic stroke and present a clinical workflow proposal for young and middle-aged patients.
Anguillids: widely studied yet poorly understood—a literature review of
Meaningful advances have been made in the understanding of the biology and behavior of temperate species, with focus shifting from basic biological questions in the 1980s and 1990s towards improving understanding of anthropogenic impacts and their mitigation. Our literature review identified several key gaps in the existing knowledge.
Cadmium Associated Preeclampsia: A Systematic Literature Review of
Preeclampsia (PE), caused by multiple factors, is one of the most serious complications of pregnancy. Cadmium (Cd) is a heavy metal environmental pollutant, reproductive toxicant, and endocrine disruptor, which can increase the risk of PE. Cd toxicity due to occupational, diet, and environmental factors has worsened the risk. Studies showed elevated Cd concentration in maternal blood and ...
Biology
This review reports the latest advances in EV studies, focusing on the nature and features of EVs and on conventional and emerging methodologies used for their separation, characterization, and visualization. By searching an extended portion of the relevant literature, this work aims to give a summary of advances in nanomedical applications of EVs.
Legionella Pneumophila Presenting as a Rare Cause of Acute
Very rarely, it can be associated with haematologic conditions such as thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and immune thrombocytopenic purpura (ITP). We report a rare case of L. pneumophila causing ITP and review previously published cases of thrombocytopenia associated with Legionellosis in the literature.
Data Envelopment Analysis and Higher Education: A Systematic Review of
The interest in Data Envelopment Analysis (DEA) has grown since its first put forward in 1978. In response to the overwhelming interest, systematic literature reviews, as well as bibliometric studies, have been performed in describing the state-of-the-art and offering quantitative outlines with regard to the high-impact papers on global applications of DEA and the higher education system (DEA-HE).

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