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Peer Review: An Introduction: Where to Find Peer Reviewed Sources

• Why not just use Google or Wikipedia?
• Where to Find Peer Reviewed Sources
• Where to Get More Help

Need More Help?

Have more questions? Contact Scholarly Communication and Publishing at [email protected]   for more information and guidance.

Ask a Librarian

The Ask a Librarian service for general reference is available during all of the hours when the Main Library is open. Visit the  Ask a Librarian  page to chat with a librarian.

Why is it so hard to find Peer-Reviewed Sources?

It isn't hard to find peer-reviewed sources: you just need to know where to look!  If you start in the right place, you can usually find a relevant, peer-reviewed source for your research in as few clicks as a Google search, and you can even use many of the search techniques you use in Google and Wikipedia.

The easiest way to find a peer-reviewed article is by using one of the Library's numerous databases. All of the Library's databases are listed in the Online Journals and Databases index. The databases are divided by name and discipline.

Departmental libraries and library subject guides have created subject-focused lists of electronic and print research resources that are useful for their disciplines. You can search the library directory  for links to the departmental libraries at the University of Illinois Library, or search library websites by college  if you're not sure which departmental library serves your subject.

Peer-Reviewed Resources for Disciplinary Topics

There are numerous print and digital resources for specific disciplines, areas of study, and specialist fields.  To find research resources and databases for your area, consult the comprehensive directory of LibGuides , the websites of specialist libraries, and above all, contact a librarian for help !

Here are a few major databases for finding peer-reviewed research sources in the humanities, social sciences, and sciences:

• MLA International Bibliography This link opens in a new window Indexes critical materials on literature, languages, linguistics, and folklore. Proved access to citations from worldwide publications, including periodicals, books, essay collections, working papers, proceedings, dissertations and bibliographies. more... less... Alternate Access Link
• Web of Science (Core Collection) This link opens in a new window Web of Science indexes core journal articles, conference proceedings, data sets, and other resources in the sciences, social sciences, arts, and humanities.
• Academic Search Ultimate This link opens in a new window A scholarly, multidisciplinary database providing indexing and abstracts for over 10,000 publications, including monographs, reports, conference proceedings, and others. Also includes full-text access to over 5,000 journals. Offers coverage of many areas of academic study including: archaeology, area studies, astronomy, biology, chemistry, civil engineering, electrical engineering, ethnic & multicultural studies, food science & technology, general science, geography, geology, law, mathematics, mechanical engineering, music, physics, psychology, religion & theology, women's studies, and other fields. more... less... Alternate Access Link
• IEEE Xplore This link opens in a new window Provides full-text access to IEEE transactions, IEEE and IEE journals, magazines, and conference proceedings published since 1988, and all current IEEE standards; brings additional search and access features to IEEE/IEE digital library users. Browsable by books & e-books, conference publications, education and learning, journals and magazines, standards and by topic. Also provides links to IEEE standards, IEEE spectrum and other sites.
• Scopus This link opens in a new window Scopus is the largest abstract and citation database including peer-reviewed titles from international publishers, Open Access journals, conference proceedings, trade publications and quality web sources. Subject coverage includes: Chemistry, Physics, Mathematics and Engineering; Life and Health Sciences; Social Sciences, Psychology and Economics; Biological, Agricultural and Environmental Sciences.
• Business Source Ultimate This link opens in a new window Provides bibliographic and full text content, including indexing and abstracts for scholarly business journals back as far as 1886 and full text journal articles in all disciplines of business, including marketing, management, MIS, POM, accounting, finance and economics. The database full text content includes financial data, books, monographs, major reference works, book digests, conference proceedings, case studies, investment research reports, industry reports, market research reports, country reports, company profiles, SWOT analyses and more. more... less... Alternate Access Link
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• Last Updated: Nov 9, 2023 11:15 AM
• URL: https://guides.library.illinois.edu/peerreview

Where to find peer reviewed articles for research

This is our ultimate guide to helping you get familiar with your research field and find peer reviewed articles in the Web of Science™. It forms part of our Research Smarter series. 

Finding relevant research and journal articles in your field is critical to a successful research project. Unfortunately, it can be one of the hardest, most time-consuming challenges for academics.

This blog outlines how you can leverage the Web of Science citation network to complete an in-depth, comprehensive search for literature. We share insights about how you can find a research paper and quickly assess its impact. We also explain how to create alerts to keep track of new papers in your field – whether you’re new to the topic or about to embark on a literature review.

• Choosing research databases for your search
• Where to find peer reviewed articles? Master the keyword search
• Filter your results and analyze for trends
• Explore the citation network
• Save your searches and set up alerts for new journal articles

1. Choosing research databases for your search

The myriad search engines, research databases and data repositories all differ in reliability, relevancy and organization of data. This can make it tricky to navigate and assess what’s best for your research at hand.

The Web of Science stands out the most powerful and trusted citation database. It helps you connect ideas and advance scientific research across all fields and disciplines. This is made possible with best-in-class publication and citation data for confident discovery and assessment of journal articles. The Web of Science is also publisher-neutral, carefully-curated by a team of expert editors and consists of 19 different research databases.

The Web of Science Core Collection™ is the single most authoritative source for how to find research articles, discover top authors , and relevant journals . It only includes journals that have met rigorous quality and impact criteria, and it captures billions of cited references from globally significant journals, books and proceedings ( check out its coverage ). Researchers and organizations use this research database regularly to track ideas across disciplines and time.

Explore the Web of Science Core Collection

We recommend spending time exploring the Core Collection specifically because its advanced citation network features are unparalleled. If you are looking to do an exhaustive search of a specific field, you might want to switch to one of the field-specific databases like MEDLINE and INSPEC. You can also select “All databases” from the drop-down box on the main search page. This will cover all research databases your institution subscribes to. IF you are still unsure about where to find scholarly journal articles, you can learn more in our Quick Reference Guide, here, or try it out today.

“We recommend spending time exploring the Core Collection specifically because its advanced citation network features are unparalleled.”

2. Where to find peer reviewed articles? Master the keyword search

A great deal of care and consideration is needed to find peer review articles for research. It starts with your keyword search.

Your chosen keywords or search phrases cannot be too inclusive or limiting. They also require constant iteration as you become more familiar with your research field. Watch this video on search tips to learn more:

It’s worth noting that a repeated keyword search in the same Web of Science database will retrieve almost identical results every time, save for newly-indexed research. Not all research databases do this. If you are conducting a literature review and require a reproducible keyword search, it is best to steer clear of certain databases. For example, a research database that lacks overall transparency or frequently changes its search algorithm may be detrimental to your research.

3. Filter your search results and analyze trends

Group, rank and analyze the research articles in your search results to optimize the relevancy and efficiency of your efforts. In the Web of Science, researchers can cut through the data in a number of creative ways. This will help you when you’re stuck wondering where to find peer reviewed articles, journals and authors. The filter and refine tools , as well as the Analyze Results feature, are all at your disposal for this.

“Group, rank and analyze the research papers in your search results to optimize the relevancy and efficiency of your efforts.”

Filter and Refine tools in the Web of Science

You can opt for basic filter and refine tools in the Web of Science. These include subject category, publication date and open access within your search results. You can also filter by highly-cited research and hot research papers. A hot paper is a journal article that has accumulated rapid and significant numbers of citations over a short period of time.

The Analyze Results tool does much of this and more. It provides an interactive visualization of your results by the most prolific author, institution and funding agency, for example. This, combined, will help you understand trends across your field.

4. Explore the citation network

Keyword searches are essentially an a priori view of the literature. Citation-based searching, on the other hand, leads to “systematic serendipity”. This term was used by Eugene Garfield, the founder of Web of Science. New scientific developments are linked to the global sphere of human knowledge through the citation network. The constantly evolving connections link ideas and lead to systematic serendipity, allowing for all sorts of surprising discoveries.

Exploring the citation network helps you to:

• Identify a seminal research paper in any field. Pay attention to the number of times a journal article is cited to achieve this.
• Track the advancement of research as it progresses over time by analyzing the research papers that cite the original source. This will also help you catch retractions and corrections to research.
• Track the evolution of a research paper backward in time by tracking the work that a particular journal article cites.
• View related references. A research paper may share citations with another piece of work (calculated from bibliographic coupling). That means it’s likely discussing a similar topic.

Visualizing the history discoveries in the citation network

The Web of Science Core Collection indexes every piece of content cover-to-cover. This creates a complete and certain view of more than 115 years of the highest-quality journal articles. The depth of coverage enables you to uncover the historical trail of a research paper in your field. By doing so, it helps you visualize how discoveries unfold through time. You can also learn where they might branch off into new areas of research.  Achieve this in your search by ordering your result set by date of publication.

As PhD student Rachel Ragnhild Carlson (Stanford University) recently wrote in a column for Nature: [1]

”As a PhD student, I’ve learnt to rely not just on my Web of Science research but on numerous conversations with seasoned experts. And I make sure that my reading includes literature from previous decades, which often doesn’t rise to the top of a web search. This practice is reinforced by mentors in my lab, who often find research gems by filtering explicitly for studies greater than ten years old.”

5. Save your search and set up alerts for new journal articles

Save time and keep abreast of new journal articles in your field by saving your searches and setting up email alerts . This means you can return to your search at any time. You can also stay up-to-date about a new research paper included in your search result. This will help you find an article more easily in the future. Head over to Web of Science to try it out today.

“Everyone should set up email alerts with keywords for PubMed, Web of Science, etc. Those keyword lists will evolve and be fine-tuned over time. However, it really helps to get an idea of recent publications.” Thorbjörn Sievert , PhD student, University of Jyväskylä

[1] Ragnhild Carlson, R. 2020 ‘How Trump’s embattled environment agency prepared me for a PhD’, Nature 579, 458

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Finding Scholarly Articles: Home

What's a Scholarly Article?

Your professor has specified that you are to use scholarly (or primary research or peer-reviewed or refereed or academic) articles only in your paper. What does that mean?

Scholarly or primary research articles are peer-reviewed , which means that they have gone through the process of being read by reviewers or referees  before being accepted for publication. When a scholar submits an article to a scholarly journal, the manuscript is sent to experts in that field to read and decide if the research is valid and the article should be published. Typically the reviewers indicate to the journal editors whether they think the article should be accepted, sent back for revisions, or rejected.

To decide whether an article is a primary research article, look for the following:

• The author’s (or authors') credentials and academic affiliation(s) should be given;
• There should be an abstract summarizing the research;
• The methods and materials used should be given, often in a separate section;
• There are citations within the text or footnotes referencing sources used;
• Results of the research are given;
• There should be discussion   and  conclusion ;
• With a bibliography or list of references at the end.

Caution: even though a journal may be peer-reviewed, not all the items in it will be. For instance, there might be editorials, book reviews, news reports, etc. Check for the parts of the article to be sure.   

You can limit your search results to primary research, peer-reviewed or refereed articles in many databases. To search for scholarly articles in  HOLLIS , type your keywords in the box at the top, and select  Catalog&Articles  from the choices that appear next.   On the search results screen, look for the  Show Only section on the right and click on  Peer-reviewed articles . (Make sure to  login in with your HarvardKey to get full-text of the articles that Harvard has purchased.)

Many of the databases that Harvard offers have similar features to limit to peer-reviewed or scholarly articles.  For example in Academic Search Premier , click on the box for Scholarly (Peer Reviewed) Journals  on the search screen.

Review articles are another great way to find scholarly primary research articles.   Review articles are not considered "primary research", but they pull together primary research articles on a topic, summarize and analyze them.  In Google Scholar , click on Review Articles  at the left of the search results screen. Ask your professor whether review articles can be cited for an assignment.

A note about Google searching.  A regular Google search turns up a broad variety of results, which can include scholarly articles but Google results also contain commercial and popular sources which may be misleading, outdated, etc.  Use Google Scholar  through the Harvard Library instead.

About Wikipedia .  W ikipedia is not considered scholarly, and should not be cited, but it frequently includes references to scholarly articles. Before using those references for an assignment, double check by finding them in Hollis or a more specific subject  database .

Still not sure about a source? Consult the course syllabus for guidance, contact your professor or teaching fellow, or use the Ask A Librarian service.

• Last Updated: Oct 3, 2023 3:37 PM
• URL: https://guides.library.harvard.edu/FindingScholarlyArticles

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Tips for Finding Peer Reviewed Articles

What is a peer reviewed article, example of a peer reviewed article, gale academic onefile.

Because of this more rigorous process, a peer reviewed article is considered to have the most value, even more than other scholarly articles.

Extracted from   Alexander Hamilton and the Sedition Act: A Founder's Ambivalence on Freedom of the Press . (Must be on campus or have a COM account to view the entire article).

Get peer reviewed articles in Gale ​Academic OneFile. Here's how:

• Perform a search on your topic. 
• Under Filter Your Results , select Peer-Reviewed Journals .
• All your results will now be peer reviewed.

All the articles in JSTOR are not only scholarly, but peer reviewed so you can search as you normally would. JSTOR does include content other than articles, such as primary sources, images reports and open content in the results, however, that are not peer reviewed. To take these out your results: 

• Under  Refine Results , find  Academic Content
• Select Journals 
• You should be left with peer reviewed content. 

Get peer reviewed articles in ProQuest. Here's how:

• Select the Peer Reviewed option directly under the search box, or in the Narrow results column.
• Last Updated: May 13, 2024 4:39 PM
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Finding Peer-Reviewed Articles: Google Scholar

• Introduction
• Using Databases
• Searching for Specific Journals
• Google Scholar
• Inter-Library Loan

Google Scholar Search

Advanced Scholar Search Tips

About Google Scholar

Google Scholar provides a simple way to broadly search for scholarly literature.  You can search across many disciplines and sources for:  articles, theses, books, abstracts and court opinions, from academic publishers, professional societies, online repositories, universities and other web sites. 

Features of Google Scholar:

• Search diverse sources from one convenient place
• Find articles, theses, books, abstracts or court opinions
• Locate the complete document through your library or on the web
• Learn about key scholarly literature in any area of research

With Google Scholar, you can search by scholar preferences, easily navigate to related articles, and see how many times an article has been cited.  Use search criteria to locate peer-reviewed articles.

Search with Google Scholar

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• Last Updated: Sep 14, 2022 4:20 PM
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Articles: Finding (and Identifying) Peer-Reviewed Articles: What is Peer Review?

• What is Peer Review?
• Finding Peer Reviewed Articles
• Databases That Can Determine Peer Review

Peer Review in 3 Minutes

What is "Peer-Review"?

What are they.

Scholarly articles are papers that describe a research study. 

Why are scholarly articles useful?

They report original research projects that have been reviewed by other experts before they are accepted for publication, so you can reasonably be assured that they contain valid information. 

How do you identify scholarly or peer-reviewed articles?

• They are usually fairly lengthy - most likely at least 7-10 pages
• The authors and their credentials should be identified, at least the company or university where the author is employed
• There is usually a list of References or Works Cited at the end of the paper, listing the sources that the authors used in their research

How do you find them? 

Some of the library's databases contain scholarly articles, either exclusively or in combination with other types of articles. 

Google Scholar is another option for searching for scholarly articles. 

Know the Difference Between Scholarly and Popular Journals/Magazines

Peer reviewed articles are found in scholarly journals.  The checklist below can help you determine if what you are looking at is peer reviewed or scholarly.

• Both kinds of journals and magazines can be useful sources of information.
• Popular magazines and newspapers are good for overviews, recent news, first-person accounts, and opinions about a topic.
• Scholarly journals, often called scientific or peer-reviewed journals, are good sources of actual studies or research conducted about a particular topic. They go through a process of review by experts, so the information is usually highly reliable.

• Next: Finding Peer Reviewed Articles >>
• Last Updated: Feb 28, 2023 10:46 AM
• URL: https://libguides.usu.edu/peer-review

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Which Source Should I Use?

• The Right Source For Your Need-Authority
• Finding Subject Specific Sources: Research Guides
• Understanding Peer Reviewed Articles
• Understanding Peer Reviewed Articles- Arts & Humanities
• How to Read a Journal Article
• Locating Journals
• How to Find Streaming Media

The Peer Review Process

So you need to use scholarly, peer-reviewed articles for an assignment...what does that mean? 

Peer review  is a process for evaluating research studies before they are published by an academic journal. These studies typically communicate  original research  or analysis for other researchers. 

The Peer Review Process at a Glance:

Looking for peer-reviewed articles?  Try searching in OneSearch or a library database  and look for options to limit your results to scholarly/peer-reviewed or academic journals. Check out this brief tutorial to show you how:   How to Locate a Scholarly (Peer Reviewed) Article

Part 1: Watch the Video

Part 1: watch the video all about peer review (3 min.) and reflect on discussion questions..

Discussion Questions

After watching the video, reflect on the following questions:

• According to the video, what are some of the pros and cons of the peer review process?
• Why is the peer review process important to scholarship?
• Do you think peer reviewers should be paid for their work? Why or why not?

Part 2: Practice

Part 2: take an interactive tutorial on reading a research article for your major..

Includes a certification of completion to download and upload to Canvas.

Social Sciences

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(e.g. Health Science, Biology)

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(e.g. Visual & Media Arts, Cultural Studies, Literature, History)

Click on the handout to view in a new tab, download, or print.

For Instructors

• Teaching Peer Review for Instructors

In class or for homework, watch the video “All About Peer Review” (3 min.) .

Video discussion questions:

• According to the video, what are some of the pros and cons of the peer review process

Assignment Ideas

• Ask students to conduct their own peer review of an important journal article in your field. Ask them to reflect on the process. What was hard to critique?
• Have students examine a journals’ web page with information for authors. What information is given to the author about the peer review process for this journal?
• Assign this reading by CSUDH faculty member Terry McGlynn, "Should journals pay for manuscript reviews?" What is the author's argument? Who profits the most from published research? You could also hold a debate with one side for paying reviewers and the other side against.
• Search a database like Cabell’s for information on the journal submission process for a particular title or subject. How long does peer review take for a particular title? Is it is a blind review? How many reviewers are solicited? What is their acceptance rate?
• Assign short readings that address peer review models. We recommend this issue of Nature on peer review debate and open review and this Chronicle of Higher Education article on open review in Shakespeare Quarterly .

Proof of Completion

Mix and match this suite of instructional materials for your course needs!

Questions about integrating a graded online component into your class, contact the Online Learning Librarian, Rebecca Nowicki ( [email protected] ).

Example of a certificate of completion:

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Finding Journal Articles 101

Peer-reviewed or refereed.

• Research Article
• Review Article
• By Journal Title

What Does "Peer-reviewed" or "Refereed" Mean?

Peer review is a process that journals use to ensure the articles they publish represent the best scholarship currently available. When an article is submitted to a peer reviewed journal, the editors send it out to other scholars in the same field (the author's peers) to get their opinion on the quality of the scholarship, its relevance to the field, its appropriateness for the journal, etc.

Publications that don't use peer review (Time, Cosmo, Salon) just rely on the judgment of the editors whether an article is up to snuff or not. That's why you can't count on them for solid, scientific scholarship.

Note:This is an entirely different concept from " Review Articles ."

How do I know if a journal publishes peer-reviewed articles?

Usually, you can tell just by looking. A scholarly journal is visibly different from other magazines, but occasionally it can be hard to tell, or you just want to be extra-certain. In that case, you turn to Ulrich's Periodical Directory Online . Just type the journal's title into the text box, hit "submit," and you'll get back a report that will tell you (among other things) whether the journal contains articles that are peer reviewed, or, as Ulrich's calls it, Refereed.

Remember, even journals that use peer review may have some content that does not undergo peer review. The ultimate determination must be made on an article-by-article basis.

For example, the journal  Science  publishes  a mix  of peer-reviewed and non-peer-reviewed content. Here are two articles from the same issue of  Science . 

This one is not peer-reviewed:  https://science-sciencemag-org.ezproxy.lib.utexas.edu/content/303/5655/154.1  This one is a peer-reviewed research article:  https://science-sciencemag-org.ezproxy.lib.utexas.edu/content/303/5655/226

That is consistent with the Ulrichsweb  description of  Science , which states, "Provides news of recent international developments and research in all fields of science. Publishes original research results, reviews and short features."

Test these periodicals in Ulrichs :

• Advances in Dental Research
• Clinical Anatomy
• Molecular Cancer Research
• Journal of Clinical Electrophysiology
• Last Updated: Aug 28, 2023 9:25 AM
• URL: https://guides.lib.utexas.edu/journalarticles101

Peer-reviewed journal articles

• Overview of peer review
• Scholarly and academic - good enough?
• Find peer-reviewed articles

Using Library Search

Is a journal peer reviewed, check the journal.

Resources listed in  Library Search that are peer reviewed will include the Peer Reviewed icon.

For example:

If you have not used Library Search to find the article, which may indicate if it's peer reviewed, you can use Ulrichsweb to check.

• Go to Ulrichsweb

Screenshot of search box in UlrichsWeb  © Proquest

•  Enter the journal title in the search box.

Screenshot of results list in UlrichsWeb  © Proquest

•  If there are no results, do a search in Ulrichsweb to find journals in your field that are peer reviewed.

Be aware that not all articles in peer reviewed journals are refereed or peer reviewed, for example, editorials and book reviews.

If the journal is not listed in Ulrichsweb :

• Go to the journal's website
• Check for information on a peer review process for the journal. Try the Author guidelines , Instructions for authors  or About this journal sections.

If you can find no evidence that a journal is peer reviewed, but you are required to have a refereed article, you may need to choose a different article.

• << Previous: Find peer-reviewed articles
• Last Updated: Dec 6, 2023 2:42 PM
• URL: https://guides.library.uq.edu.au/how-to-find/peer-reviewed-articles

Reference management. Clean and simple.

How to know if an article is peer reviewed [6 key features]

Features of a peer reviewed article

How to find peer reviewed articles, frequently asked questions about peer reviewed articles, related articles.

A peer reviewed article refers to a work that has been thoroughly assessed, and based on its quality, has been accepted for publication in a scholarly journal. The aim of peer reviewing is to publish articles that meet the standards established in each field. This way, peer reviewed articles that are published can be taken as models of research practices.

A peer reviewed article can be recognized by the following features:

• It is published in a scholarly journal.
• It has a serious, and academic tone.
• It features an abstract at the beginning.
• It is divided by headings into introduction, literature review or background, discussion, and conclusion.
• It includes in-text citations, and a bibliography listing accurately all references.
• Its authors are affiliated with a research institute or university.

There are many ways in which you can find peer reviewed articles, for instance:

• Check the journal's features and 'About' section. This part should state if the articles published in the journal are peer reviewed, and the type of reviewing they perform.
• Consult a database with peer reviewed journals, such as Web of Science Master Journal List , PubMed , Scopus , Google Scholar , etc. Specify in the advanced search settings that you are looking for peer reviewed journals only.
• Consult your library's database, and specify in the search settings that you are looking for peer reviewed journals only.

➡️ Want to know if a source is scholarly? Check out our guide on scholarly sources.

➡️ Want to know if a source is credible? Find out in our guide on credible sources (+ how to find them).

A peer reviewed article refers to a work that has been thoroughly assessed, and based on its quality has been accepted to be published in a scholarly journal.

Once an article has been submitted for publication to a peer reviewed journal, the journal assigns the article to an expert in the field, who is considered the “peer”.

The easiest way to find a peer reviewed article is to narrow down the search in the "Advanced search" option. Then, mark the box that says "peer reviewed".

Consult a database with peer reviewed journals, such as Web of Science Master Journal List , PubMed , Scopus , etc.

There are many views on peer reviewed articles. Take a look at Peer Review in Scientific Publications: Benefits, Critiques, & A Survival Guide for more insight on this topic.

Finding scholarly, peer reviewed articles

Learn how to search for only scholarly and peer-reviewed journal articles.

Scholarly articles are written by researchers and intended for an audience of other researchers. Scholarly writers may assume that the reader already has some understanding of the topic and its vocabulary. Peer-reviewed articles are evaluated by other scholars or experts within the same field as the author before they are published, to help ensure the validity of the research being done. Learn more about the peer review process .

Many scholarly articles are peer-reviewed and vice versa, but this may not always be the case. In addition, an article can be from a peer-reviewed journal and not actually be peer reviewed. Components such as editorials, news items, and book reviews do not go through the same review process.

Many professors will require that you use only scholarly, peer-reviewed journal articles in your research papers and assignments. To simplify the research process, you can limit your search to only see peer-reviewed articles in Library Search and many library databases.

Limiting to peer-reviewed articles in Library Search

In Library Search, you can refine your results to peer-reviewed articles by selecting two filters. Under “Availability,” choose “Peer-reviewed Journals.” Under “Resource Type,” choose “Articles.” If you plan to do multiple searches, be sure to click the lock icon that says “Remember all filters” underneath “Active Filters” at the top. This will ensure your results continue to show only peer-reviewed articles even if you try different keywords. Peer-reviewed articles will display a purple icon of a book with an eye over it under their title and citation information.

Filter options in Library Search. The "Peer-reviewed Journals" and "Articles" options have filled checkboxes next to their names, which indicates these options have been selected.

Limiting to peer-reviewed articles in databases

Many databases have an option to limit your search results to peer-reviewed articles. This will usually appear either in advanced search options or in a bank of filters in the search results screen.

Search options for a database hosted in EBSCO. Under the subheading “Limit your results,” a checkbox with the words “Peer Reviewed” above it is enclosed in a red square to indicate its position on the screen.

Checking the status of your article

If you need further confirmation of whether an article comes from a peer-reviewed journal, you can follow one of the procedures below.

Search for a journal title in the library’s Journals search list. Titles that are peer reviewed will have a small purple icon of an eye above an open book with the words “Peer-Reviewed” next to it.

A small purple icon of an eye above an open book, and the words "Peer-Reviewed" are enclosed in a red rectangle.

If you don’t find a journal in the Journals’ list as described above, you can consult the UlrichsWeb database . It includes information on journals that are not owned by the University, so you might want to check a journal title there before you make an Interlibrary Loan request. When you search for a journal title in this database, you will see a small black and white referee icon. This indicates that the journal is peer reviewed. You can also check the journal publisher's website. It should indicate whether articles go through a peer-review process on a page that contains instructions for authors.

In this entry for the "Journal of Social Work," there is a small black and white "referee" icon, which indicates that the journal is peer reviewed. The "referee" icon is enclosed in a red square.

Library & Learning Commons

• Search for sources
• APA style guide

How to Find Scholarly, Peer-Reviewed Journal Articles

• Peer Review & Academic/Scholarly Journals
• How to Identify a Scholarly, Peer-Reviewed Journal Article
• Finding Academic/Scholarly Journal Articles in Library Databases

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Confused by scholarly, peer-reviewed sources?

This guide explains the peer review process, the identifying characteristics of a peer-reviewed article, and where you'll find scholarly, peer-reviewed journal articles in the RGO Library & Learning Commons databases.

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• What is Peer Review?
• What is an Academic/Scholarly Journal?
• What is a Peer-Reviewed Article?

Also called an academic or peer-reviewed journal, a scholarly journal:

       •  Is a type of periodical (a publication issued in regular periods, i.e. newspapers, magazines, etc.) that provides a forum for scholarly communication in a particular academic discipline,

       •  Publishes original, peer-reviewed research-based or theoretical articles are written by researchers and experts,

       •  Publishes additional forms of scholarly communication such as book reviews, editorials, conference proceedings, debate pieces, and interviews.

A scholarly, peer-reviewed journal article:

        •  Presents research studies and experiments or original theoretical analysis that advances what is understood or known in a specific subject area or discipline,

        •  Is written by the person(s) who conducted the research or analysis, who typically have advanced degrees, credentials, and/or academic positions,

        •  Often has a scientific format with sections and headings that follow the structure of a research study:

In addition to the scientific format described in the previous tab, there are several common types of scholarly, peer-reviewed journal articles.

Follow the links below to view examples of a systematic literature review , a case study , a theoretical research article, and a scientific research article from the library databases:

• Neighborhood safety factors associated with older adults' health-related outcomes: A systematic literature review. (2016) This is a sub-type of a LITERATURE REVIEW article that systematically and critically collects, describes and summarizes prior publications on a specific topic or subject, rather than reporting new original research. It features a substantial list of references that a reader may wish to consult when learning about or researching a topic.
• Chronic Schizophrenia and Cognitive Behaviour Therapy: Three Case Studies. (2015) Common in the social sciences and life sciences, a CASE STUDY provides an intensive analysis of an individual unit (such as a person, group, community or event) in order to illustrates a problem, present new variables, and provide possible solutions or questions for further research.
• Early childhood cognitive development and parental cognitive stimulation: Evidence for reciprocal gene-environment transactions (2012) This scientific RESEARCH STUDY presents original interpretation of data that was collected and analyzed by the authors. It uses technical and formal language with a logical structure that reflects the format of the study.
• The unifying function of affect: Founding a theory of psychocultural development in the epistemology of John Dewey and Carl Jung (2012) This example of a THEORETICAL RESEARCH article that presents an original argument or conclusion based on the interpretation of evidence. This type of article usually refers to or contains new or established abstract principles related to a very specific field of knowledge.

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• Next: How to Identify a Scholarly, Peer-Reviewed Journal Article >>
• Last Updated: Jan 25, 2024 10:44 AM
• URL: https://bowvalleycollege.libguides.com/scholarly-articles

7 Ways to Find Peer-Reviewed Articles on Google Scholar

Google Scholar is the professional place to find scholarly literature, peer-reviewed articles and high-quality, patented and unpatented research on a specialized Google platform. 

Google search is everything in 2021; one can search anything on the internet by Google search which provides nearly 99% accurate results. One can find products, literature, articles, information or any data from Google simply by telling “Hell Google” from your Phone. 

Say “Hello Google please suggest to me the best recipes for poached egg”

And that’s it! 

It will give you tons of results. 

But let me tell you that finding high-quality, peer-reviewed articles on Google isn’t that easy. The reason is that the Google search is meant for all people. Meaning, when searching anything directly from Google search, it will provide broad search results to cover all topics, products and results for all age groups. 

For example, 

When you search “Symptoms of H1N1 flu”; The results might show

• Some common symptoms
• Questions relevant to the topics  
• Products related to the H1N1 flu- medication, therapies and testing 
• Some good blog articles 
• Global News on H1N1 
• And like that… 

If you are a researcher, PhD scholar or scientist, these search results may not help you, I guess. You need more powerful, research-based, peer-reviewed and more scientific results. 

And for that my friends you have to go to Google Scholar. I know it isn’t that much hard to use Google Scholar but still, many research students still don’t know how to use it. 

I have conducted a small research study and asked my research students how they start searching the literature. 87% of them said, 

They go the Google, search their queries like 

• H1N1 Wikipedia 
• H1N1 articles PMC 
• H1N1 article PubMed 
• H1N1 article NCBI 

Like that, but mostly they avoid the very first segment suggested by Google itself, that’s our Google scholar,

When you click on it, you will get tons of high-quality research articles. Note that Google standard search and Google Scholar search have some substantial differences, take a look at the table,

Difference Between Google Search and Google Scholar search: 

There are several ways you can use this tool to find peer-reviewed articles, journal reviews and thesis. In this article, I will explain 7 ways to find peer-reviewed articles on Google Scholar. 

Search on Google: 

Directly go to google scholar: , write a topic name with +google scholar: , search peer-reviewed articles: , short by relevance: , search by author or authors name:,  search from the google scholar profile: .

• Wrapping up: 

7 Ways to find Peer-Reviewed articles on Google Scholar:

One of the easiest ways to find scholarly articles is by searching anything directly using Google search. 

Go to Google Search using this link > https://www.google.com/ .

Search in the search box, for example, “Articles on H1N1”. 

You will get various results, see the very first results (Image below)

Click on the “Scholarly articles for Articles on H1N1”

Now you will get so many articles that are well-cited, peer-reviewed and in-depth. 

Newbies usually don’t go directly to Google scholar, instead prefer to use Wiki or other resources. If you just have started your PhD and don’t know where to initiate, start reading articles only on Google Scholar. 

Go to the URL: https://scholar.google.com/

In the search box search only “H1N1” 

You will get various resources on H1N1 that help in your study. You will also get other relevant studies and articles, contact details, scientists, organizations or labs working in your research area, etc. 

In addition, you will get ideas for additional research queries relevant to your research. 

The easiest way to use the Google scholar database is to customize your research query. 

Go to Google >>  https://www.google.com/ .

Search “H1N1 articles on Google scholar” 

You will get a Google scholar list of articles as well as only high-quality articles related to the topic you searched.

Yet another easiest way to find the most outstanding peer-reviewed journal articles is by a consuming search query. 

Go to Google >> https://www.google.com/ .

Write Peer-reviewed articles on H1N1 

You will get the same list of scholarly articles on the present topic. 

Getting more relevant resources is yet another difficult task to complete. It’s practically not possible to go through all articles present in the Google Scholar library.  

One needs more precise, customized, appropriate and relevant results. 

Google Scholar provides a “Short By relevance” feature to find articles only what you want. 

For example, for H1N1 you will get tons of resources, some are useful and some are not!

Suppose you need review articles. 

Go to the sidebar and click on review articles. 

Suppose you need only articles published since 2020. 

On the sidebar, you can choose a year or from which year you want research articles. 

There are other options as well which you can use as per your requirement. 

Yet another interesting way to search scholarly research work is by searching articles by the name of the author; if his/her profile is there on Google scholar, it immediately shows you. 

Take look at the example, 

Influenza A H1N1 by Michaelis, you will get results like this, 

This is exactly the same results on Google Scholar, take a look, 

Note that this will be fine only if you know some of the renowned researchers and scientists working in your field. 

If you already have a Google Scholar account and some scholarly articles, you can search relevant resources from the profile of other researchers as well. 

For example,

Take a look at the profile of Elspeth M McLachlan. 

You can find all the publications and his collaboration on the Google Scholar profile. 

Read more: How to Generate a Bibliography using Citation Generator .

Wrapping up:  

Google Scholar is a significantly important sub-search engine for researchers, scientists and PhD students. If you have a Google Scholar profile, some Peer-reviewed articles, trust me you will get more citations, reads and rewards in your academic and research field. 

Use scholars and try to publish some good quality work as well. 

I hope this article will help you. 

Dr. Tushar Chauhan is a Scientist, Blogger and Scientific-writer. He has completed PhD in Genetics. Dr. Chauhan is a PhD coach and tutor.

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• Reumatologia
• v.59(1); 2021

Peer review guidance: a primer for researchers

Olena zimba.

1 Department of Internal Medicine No. 2, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

Armen Yuri Gasparyan

2 Departments of Rheumatology and Research and Development, Dudley Group NHS Foundation Trust (Teaching Trust of the University of Birmingham, UK), Russells Hall Hospital, Dudley, West Midlands, UK

The peer review process is essential for quality checks and validation of journal submissions. Although it has some limitations, including manipulations and biased and unfair evaluations, there is no other alternative to the system. Several peer review models are now practised, with public review being the most appropriate in view of the open science movement. Constructive reviewer comments are increasingly recognised as scholarly contributions which should meet certain ethics and reporting standards. The Publons platform, which is now part of the Web of Science Group (Clarivate Analytics), credits validated reviewer accomplishments and serves as an instrument for selecting and promoting the best reviewers. All authors with relevant profiles may act as reviewers. Adherence to research reporting standards and access to bibliographic databases are recommended to help reviewers draft evidence-based and detailed comments.

Introduction

The peer review process is essential for evaluating the quality of scholarly works, suggesting corrections, and learning from other authors’ mistakes. The principles of peer review are largely based on professionalism, eloquence, and collegiate attitude. As such, reviewing journal submissions is a privilege and responsibility for ‘elite’ research fellows who contribute to their professional societies and add value by voluntarily sharing their knowledge and experience.

Since the launch of the first academic periodicals back in 1665, the peer review has been mandatory for validating scientific facts, selecting influential works, and minimizing chances of publishing erroneous research reports [ 1 ]. Over the past centuries, peer review models have evolved from single-handed editorial evaluations to collegial discussions, with numerous strengths and inevitable limitations of each practised model [ 2 , 3 ]. With multiplication of periodicals and editorial management platforms, the reviewer pool has expanded and internationalized. Various sets of rules have been proposed to select skilled reviewers and employ globally acceptable tools and language styles [ 4 , 5 ].

In the era of digitization, the ethical dimension of the peer review has emerged, necessitating involvement of peers with full understanding of research and publication ethics to exclude unethical articles from the pool of evidence-based research and reviews [ 6 ]. In the time of the COVID-19 pandemic, some, if not most, journals face the unavailability of skilled reviewers, resulting in an unprecedented increase of articles without a history of peer review or those with surprisingly short evaluation timelines [ 7 ].

Editorial recommendations and the best reviewers

Guidance on peer review and selection of reviewers is currently available in the recommendations of global editorial associations which can be consulted by journal editors for updating their ethics statements and by research managers for crediting the evaluators. The International Committee on Medical Journal Editors (ICMJE) qualifies peer review as a continuation of the scientific process that should involve experts who are able to timely respond to reviewer invitations, submitting unbiased and constructive comments, and keeping confidentiality [ 8 ].

The reviewer roles and responsibilities are listed in the updated recommendations of the Council of Science Editors (CSE) [ 9 ] where ethical conduct is viewed as a premise of the quality evaluations. The Committee on Publication Ethics (COPE) further emphasizes editorial strategies that ensure transparent and unbiased reviewer evaluations by trained professionals [ 10 ]. Finally, the World Association of Medical Editors (WAME) prioritizes selecting the best reviewers with validated profiles to avoid substandard or fraudulent reviewer comments [ 11 ]. Accordingly, the Sarajevo Declaration on Integrity and Visibility of Scholarly Publications encourages reviewers to register with the Open Researcher and Contributor ID (ORCID) platform to validate and publicize their scholarly activities [ 12 ].

Although the best reviewer criteria are not listed in the editorial recommendations, it is apparent that the manuscript evaluators should be active researchers with extensive experience in the subject matter and an impressive list of relevant and recent publications [ 13 ]. All authors embarking on an academic career and publishing articles with active contact details can be involved in the evaluation of others’ scholarly works [ 14 ]. Ideally, the reviewers should be peers of the manuscript authors with equal scholarly ranks and credentials.

However, journal editors may employ schemes that engage junior research fellows as co-reviewers along with their mentors and senior fellows [ 15 ]. Such a scheme is successfully practised within the framework of the Emerging EULAR (European League Against Rheumatism) Network (EMEUNET) where seasoned authors (mentors) train ongoing researchers (mentees) how to evaluate submissions to the top rheumatology journals and select the best evaluators for regular contributors to these journals [ 16 ].

The awareness of the EQUATOR Network reporting standards may help the reviewers to evaluate methodology and suggest related revisions. Statistical skills help the reviewers to detect basic mistakes and suggest additional analyses. For example, scanning data presentation and revealing mistakes in the presentation of means and standard deviations often prompt re-analyses of distributions and replacement of parametric tests with non-parametric ones [ 17 , 18 ].

Constructive reviewer comments

The main goal of the peer review is to support authors in their attempt to publish ethically sound and professionally validated works that may attract readers’ attention and positively influence healthcare research and practice. As such, an optimal reviewer comment has to comprehensively examine all parts of the research and review work ( Table I ). The best reviewers are viewed as contributors who guide authors on how to correct mistakes, discuss study limitations, and highlight its strengths [ 19 ].

Structure of a reviewer comment to be forwarded to authors

Some of the currently practised review models are well positioned to help authors reveal and correct their mistakes at pre- or post-publication stages ( Table II ). The global move toward open science is particularly instrumental for increasing the quality and transparency of reviewer contributions.

Advantages and disadvantages of common manuscript evaluation models

Since there are no universally acceptable criteria for selecting reviewers and structuring their comments, instructions of all peer-reviewed journal should specify priorities, models, and expected review outcomes [ 20 ]. Monitoring and reporting average peer review timelines is also required to encourage timely evaluations and avoid delays. Depending on journal policies and article types, the first round of peer review may last from a few days to a few weeks. The fast-track review (up to 3 days) is practised by some top journals which process clinical trial reports and other priority items.

In exceptional cases, reviewer contributions may result in substantive changes, appreciated by authors in the official acknowledgments. In most cases, however, reviewers should avoid engaging in the authors’ research and writing. They should refrain from instructing the authors on additional tests and data collection as these may delay publication of original submissions with conclusive results.

Established publishers often employ advanced editorial management systems that support reviewers by providing instantaneous access to the review instructions, online structured forms, and some bibliographic databases. Such support enables drafting of evidence-based comments that examine the novelty, ethical soundness, and implications of the reviewed manuscripts [ 21 ].

Encouraging reviewers to submit their recommendations on manuscript acceptance/rejection and related editorial tasks is now a common practice. Skilled reviewers may prompt the editors to reject or transfer manuscripts which fall outside the journal scope, perform additional ethics checks, and minimize chances of publishing erroneous and unethical articles. They may also raise concerns over the editorial strategies in their comments to the editors.

Since reviewer and editor roles are distinct, reviewer recommendations are aimed at helping editors, but not at replacing their decision-making functions. The final decisions rest with handling editors. Handling editors weigh not only reviewer comments, but also priorities related to article types and geographic origins, space limitations in certain periods, and envisaged influence in terms of social media attention and citations. This is why rejections of even flawless manuscripts are likely at early rounds of internal and external evaluations across most peer-reviewed journals.

Reviewers are often requested to comment on language correctness and overall readability of the evaluated manuscripts. Given the wide availability of in-house and external editing services, reviewer comments on language mistakes and typos are categorized as minor. At the same time, non-Anglophone experts’ poor language skills often exclude them from contributing to the peer review in most influential journals [ 22 ]. Comments should be properly edited to convey messages in positive or neutral tones, express ideas of varying degrees of certainty, and present logical order of words, sentences, and paragraphs [ 23 , 24 ]. Consulting linguists on communication culture, passing advanced language courses, and honing commenting skills may increase the overall quality and appeal of the reviewer accomplishments [ 5 , 25 ].

Peer reviewer credits

Various crediting mechanisms have been proposed to motivate reviewers and maintain the integrity of science communication [ 26 ]. Annual reviewer acknowledgments are widely practised for naming manuscript evaluators and appreciating their scholarly contributions. Given the need to weigh reviewer contributions, some journal editors distinguish ‘elite’ reviewers with numerous evaluations and award those with timely and outstanding accomplishments [ 27 ]. Such targeted recognition ensures ethical soundness of the peer review and facilitates promotion of the best candidates for grant funding and academic job appointments [ 28 ].

Also, large publishers and learned societies issue certificates of excellence in reviewing which may include Continuing Professional Development (CPD) points [ 29 ]. Finally, an entirely new crediting mechanism is proposed to award bonus points to active reviewers who may collect, transfer, and use these points to discount gold open-access charges within the publisher consortia [ 30 ].

With the launch of Publons ( http://publons.com/ ) and its integration with Web of Science Group (Clarivate Analytics), reviewer recognition has become a matter of scientific prestige. Reviewers can now freely open their Publons accounts and record their contributions to online journals with Digital Object Identifiers (DOI). Journal editors, in turn, may generate official reviewer acknowledgments and encourage reviewers to forward them to Publons for building up individual reviewer and journal profiles. All published articles maintain e-links to their review records and post-publication promotion on social media, allowing the reviewers to continuously track expert evaluations and comments. A paid-up partnership is also available to journals and publishers for automatically transferring peer-review records to Publons upon mutually acceptable arrangements.

Listing reviewer accomplishments on an individual Publons profile showcases scholarly contributions of the account holder. The reviewer accomplishments placed next to the account holders’ own articles and editorial accomplishments point to the diversity of scholarly contributions. Researchers may establish links between their Publons and ORCID accounts to further benefit from complementary services of both platforms. Publons Academy ( https://publons.com/community/academy/ ) additionally offers an online training course to novice researchers who may improve their reviewing skills under the guidance of experienced mentors and journal editors. Finally, journal editors may conduct searches through the Publons platform to select the best reviewers across academic disciplines.

Peer review ethics

Prior to accepting reviewer invitations, scholars need to weigh a number of factors which may compromise their evaluations. First of all, they are required to accept the reviewer invitations if they are capable of timely submitting their comments. Peer review timelines depend on article type and vary widely across journals. The rules of transparent publishing necessitate recording manuscript submission and acceptance dates in article footnotes to inform readers of the evaluation speed and to help investigators in the event of multiple unethical submissions. Timely reviewer accomplishments often enable fast publication of valuable works with positive implications for healthcare. Unjustifiably long peer review, on the contrary, delays dissemination of influential reports and results in ethical misconduct, such as plagiarism of a manuscript under evaluation [ 31 ].

In the times of proliferation of open-access journals relying on article processing charges, unjustifiably short review may point to the absence of quality evaluation and apparently ‘predatory’ publishing practice [ 32 , 33 ]. Authors when choosing their target journals should take into account the peer review strategy and associated timelines to avoid substandard periodicals.

Reviewer primary interests (unbiased evaluation of manuscripts) may come into conflict with secondary interests (promotion of their own scholarly works), necessitating disclosures by filling in related parts in the online reviewer window or uploading the ICMJE conflict of interest forms. Biomedical reviewers, who are directly or indirectly supported by the pharmaceutical industry, may encounter conflicts while evaluating drug research. Such instances require explicit disclosures of conflicts and/or rejections of reviewer invitations.

Journal editors are obliged to employ mechanisms for disclosing reviewer financial and non-financial conflicts of interest to avoid processing of biased comments [ 34 ]. They should also cautiously process negative comments that oppose dissenting, but still valid, scientific ideas [ 35 ]. Reviewer conflicts that stem from academic activities in a competitive environment may introduce biases, resulting in unfair rejections of manuscripts with opposing concepts, results, and interpretations. The same academic conflicts may lead to coercive reviewer self-citations, forcing authors to incorporate suggested reviewer references or face negative feedback and an unjustified rejection [ 36 ]. Notably, several publisher investigations have demonstrated a global scale of such misconduct, involving some highly cited researchers and top scientific journals [ 37 ].

Fake peer review, an extreme example of conflict of interest, is another form of misconduct that has surfaced in the time of mass proliferation of gold open-access journals and publication of articles without quality checks [ 38 ]. Fake reviews are generated by manipulating authors and commercial editing agencies with full access to their own manuscripts and peer review evaluations in the journal editorial management systems. The sole aim of these reviews is to break the manuscript evaluation process and to pave the way for publication of pseudoscientific articles. Authors of these articles are often supported by funds intended for the growth of science in non-Anglophone countries [ 39 ]. Iranian and Chinese authors are often caught submitting fake reviews, resulting in mass retractions by large publishers [ 38 ]. Several suggestions have been made to overcome this issue, with assigning independent reviewers and requesting their ORCID IDs viewed as the most practical options [ 40 ].

Conclusions

The peer review process is regulated by publishers and editors, enforcing updated global editorial recommendations. Selecting the best reviewers and providing authors with constructive comments may improve the quality of published articles. Reviewers are selected in view of their professional backgrounds and skills in research reporting, statistics, ethics, and language. Quality reviewer comments attract superior submissions and add to the journal’s scientific prestige [ 41 ].

In the era of digitization and open science, various online tools and platforms are available to upgrade the peer review and credit experts for their scholarly contributions. With its links to the ORCID platform and social media channels, Publons now offers the optimal model for crediting and keeping track of the best and most active reviewers. Publons Academy additionally offers online training for novice researchers who may benefit from the experience of their mentoring editors. Overall, reviewer training in how to evaluate journal submissions and avoid related misconduct is an important process, which some indexed journals are experimenting with [ 42 ].

The timelines and rigour of the peer review may change during the current pandemic. However, journal editors should mobilize their resources to avoid publication of unchecked and misleading reports. Additional efforts are required to monitor published contents and encourage readers to post their comments on publishers’ online platforms (blogs) and other social media channels [ 43 , 44 ].

The authors declare no conflict of interest.

• Library databases
• Library website

Evaluating Resources: Peer Review

What is peer review.

The term peer review can be confusing, since in some of your courses you may be asked to review the work of your peers. When we talk about peer-reviewed journal articles, this has nothing to do with your peers!

Peer-reviewed journals, also called refereed journals, are journals that use a specific scholarly review process to try to ensure the accuracy and reliability of published articles. When an article is submitted to a peer-reviewed journal for publication, the journal sends the article to other scholars/experts in that field and has them review the article for accuracy and reliability.

Find out more about peer review with our Peer Review Guide:

• Peer Review Guide

Types of peer review

Single blind.

In this process, the names of the reviewers are not known to the author(s). The reviewers do know the name of the author(s).

Double blind

Here, neither reviewers or authors know each other's names.

In the open review process, both reviewers and authors know each other's names.

What about editorial review?

Journals also use an editorial review process. This is not the same as peer review. In an editorial review process an article is evaluated for style guidelines and for clarity. Reviewers here do not look at technical accuracy or errors in data or methodology, but instead look at grammar, style, and whether an article is well written.

What is the difference between scholarly and peer review?

Not all scholarly journals are peer reviewed, but all peer-reviewed journals are scholarly.

• Things that are written for a scholarly or academic audience are considered scholarly writing.
• Peer-reviewed journals are a part of the larger category of scholarly writing.
• Scholarly writing includes many resources that are not peer reviewed, such as books, textbooks, and dissertations.

Scholarly writing does not come with a label that says scholarly . You will need to evaluate the resource to see if it is

• aimed at a scholarly audience
• reporting research, theories or other types of information important to scholars
• documenting and citing sources used to help authenticate the research done

The standard peer review process only applies to journals. While scholarly writing has certainly been edited and reviewed, peer review is a specific process only used by peer-reviewed journals. Books and dissertations may be scholarly, but are not considered peer reviewed.

Check out Select the Right Source for help with what kinds of resources are appropriate for discussion posts, assignments, projects, and more:

• Select the Right Source

How do I locate or verify peer-reviewed articles?

The peer review process is initiated by the journal publisher before an article is even published. Nowhere in the article will it tell you whether or not the article has gone through a peer review process.

You can locate peer-reviewed articles in the Library databases, typically by checking a limiter box.

• Quick Answer: How do I find scholarly, peer reviewed journal articles?

You can verify whether a journal uses a peer review process by using Ulrich's Periodicals Directory.

• Quick Answer: How do I verify that my article is peer reviewed?

What about resources that are not peer-reviewed?

Limiting your search to peer review is a way that you can ensure that you're looking at scholarly journal articles, and not popular or trade publications. Because peer-reviewed articles have been vetted by experts in the field, they are viewed as being held to a higher standard, and therefore are considered to be a high quality source. Professors often prefer peer-reviewed articles because they are considered to be of higher quality.

There are times, though, when the information you need may not be available in a peer-reviewed article.

• You may need to find original work on a theory that was first published in a book.
• You may need to find very current statistical data that comes from a government website.
• You may need background information that comes from a scholarly encyclopedia.

You will want to evaluate these resources to make sure that they are the best source for the information you need.

Note: If you are required for an assignment to find information from a peer-reviewed journal, then you will not be able to use non-peer-reviewed sources such as books, dissertations, or government websites. It's always best to clarify any questions over assignments with your professor.

• Previous Page: Evaluation Methods
• Next Page: Primary & Secondary Sources
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• Published: 13 May 2024

What are the strengths and limitations to utilising creative methods in public and patient involvement in health and social care research? A qualitative systematic review

• Olivia R. Phillips 1 , 2   na1 ,
• Cerian Harries 2 , 3   na1 ,
• Jo Leonardi-Bee 1 , 2 , 4   na1 ,
• Holly Knight 1 , 2 ,
• Lauren B. Sherar 2 , 3 ,
• Veronica Varela-Mato 2 , 3 &
• Joanne R. Morling 1 , 2 , 5  

Research Involvement and Engagement volume  10 , Article number:  48 ( 2024 ) Cite this article

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There is increasing interest in using patient and public involvement (PPI) in research to improve the quality of healthcare. Ordinarily, traditional methods have been used such as interviews or focus groups. However, these methods tend to engage a similar demographic of people. Thus, creative methods are being developed to involve patients for whom traditional methods are inaccessible or non-engaging.

To determine the strengths and limitations to using creative PPI methods in health and social care research.

Electronic searches were conducted over five databases on 14th April 2023 (Web of Science, PubMed, ASSIA, CINAHL, Cochrane Library). Studies that involved traditional, non-creative PPI methods were excluded. Creative PPI methods were used to engage with people as research advisors, rather than study participants. Only primary data published in English from 2009 were accepted. Title, abstract and full text screening was undertaken by two independent reviewers before inductive thematic analysis was used to generate themes.

Twelve papers met the inclusion criteria. The creative methods used included songs, poems, drawings, photograph elicitation, drama performance, visualisations, social media, photography, prototype development, cultural animation, card sorting and persona development. Analysis identified four limitations and five strengths to the creative approaches. Limitations included the time and resource intensive nature of creative PPI, the lack of generalisation to wider populations and ethical issues. External factors, such as the lack of infrastructure to support creative PPI, also affected their implementation. Strengths included the disruption of power hierarchies and the creation of a safe space for people to express mundane or “taboo” topics. Creative methods are also engaging, inclusive of people who struggle to participate in traditional PPI and can also be cost and time efficient.

‘Creative PPI’ is an umbrella term encapsulating many different methods of engagement and there are strengths and limitations to each. The choice of which should be determined by the aims and requirements of the research, as well as the characteristics of the PPI group and practical limitations. Creative PPI can be advantageous over more traditional methods, however a hybrid approach could be considered to reap the benefits of both. Creative PPI methods are not widely used; however, this could change over time as PPI becomes embedded even more into research.

Plain English Summary

It is important that patients and public are included in the research process from initial brainstorming, through design to delivery. This is known as public and patient involvement (PPI). Their input means that research closely aligns with their wants and needs. Traditionally to get this input, interviews and group discussions are held, but this can exclude people who find these activities non-engaging or inaccessible, for example those with language challenges, learning disabilities or memory issues. Creative methods of PPI can overcome this. This is a broad term describing different (non-traditional) ways of engaging patients and public in research, such as through the use or art, animation or performance. This review investigated the reasons why creative approaches to PPI could be difficult (limitations) or helpful (strengths) in health and social care research. After searching 5 online databases, 12 studies were included in the review. PPI groups included adults, children and people with language and memory impairments. Creative methods included songs, poems, drawings, the use of photos and drama, visualisations, Facebook, creating prototypes, personas and card sorting. Limitations included the time, cost and effort associated with creative methods, the lack of application to other populations, ethical issues and buy-in from the wider research community. Strengths included the feeling of equality between academics and the public, creation of a safe space for people to express themselves, inclusivity, and that creative PPI can be cost and time efficient. Overall, this review suggests that creative PPI is worthwhile, however each method has its own strengths and limitations and the choice of which will depend on the research project, PPI group characteristics and other practical limitations, such as time and financial constraints.

Peer Review reports

Introduction

Patient and public involvement (PPI) is the term used to describe the partnership between patients (including caregivers, potential patients, healthcare users etc.) or the public (a community member with no known interest in the topic) with researchers. It describes research that is done “‘with’ or ‘by’ the public, rather than ‘to,’ ‘about’ or ‘for’ them” [ 1 ]. In 2009, it became a legislative requirement for certain health and social care organisations to include patients, families, carers and communities in not only the planning of health and social care services, but the commissioning, delivery and evaluation of them too [ 2 ]. For example, funding applications for the National Institute of Health and Care Research (NIHR), a UK funding body, mandates a demonstration of how researchers plan to include patients/service users, the public and carers at each stage of the project [ 3 ]. However, this should not simply be a tokenistic, tick-box exercise. PPI should help formulate initial ideas and should be an instrumental, continuous part of the research process. Input from PPI can provide unique insights not yet considered and can ensure that research and health services are closely aligned to the needs and requirements of service users PPI also generally makes research more relevant with clearer outcomes and impacts [ 4 ]. Although this review refers to both patients and the public using the umbrella term ‘PPI’, it is important to acknowledge that these are two different groups with different motivations, needs and interests when it comes to health research and service delivery [ 5 ].

Despite continuing recognition of the need of PPI to improve quality of healthcare, researchers have also recognised that there is no ‘one size fits all’ method for involving patients [ 4 ]. Traditionally, PPI methods invite people to take part in interviews or focus groups to facilitate discussion, or surveys and questionnaires. However, these can sometimes be inaccessible or non-engaging for certain populations. For example, someone with communication difficulties may find it difficult to engage in focus groups or interviews. If individuals lack the appropriate skills to interact in these types of scenarios, they cannot take advantage of the participation opportunities it can provide [ 6 ]. Creative methods, however, aim to resolve these issues. These are a relatively new concept whereby researchers use creative methods (e.g., artwork, animations, Lego), to make PPI more accessible and engaging for those whose voices would otherwise go unheard. They ensure that all populations can engage in research, regardless of their background or skills. Seminal work has previously been conducted in this area, which brought to light the use of creative methodologies in research. Leavy (2008) [ 7 ] discussed how traditional interviews had limits on what could be expressed due to their sterile, jargon-filled and formulaic structure, read by only a few specialised academics. It was this that called for more creative approaches, which included narrative enquiry, fiction-based research, poetry, music, dance, art, theatre, film and visual art. These practices, which can be used in any stage of the research cycle, supported greater empathy, self-reflection and longer-lasting learning experiences compared to interviews [ 7 ]. They also pushed traditional academic boundaries, which made the research accessible not only to researchers, but the public too. Leavy explains that there are similarities between arts-based approaches and scientific approaches: both attempts to investigate what it means to be human through exploration, and used together, these complimentary approaches can progress our understanding of the human experience [ 7 ]. Further, it is important to acknowledge the parallels and nuances between creative and inclusive methods of PPI. Although creative methods aim to be inclusive (this should underlie any PPI activity, whether creative or not), they do not incorporate all types of accessible, inclusive methodologies e.g., using sign language for people with hearing impairments or audio recordings for people who cannot read. Given that there was not enough scope to include an evaluation of all possible inclusive methodologies, this review will focus on creative methods of PPI only.

We aimed to conduct a qualitative systematic review to highlight the strengths of creative PPI in health and social care research, as well as the limitations, which might act as a barrier to their implementation. A qualitative systematic review “brings together research on a topic, systematically searching for research evidence from primary qualitative studies and drawing the findings together” [ 8 ]. This review can then advise researchers of the best practices when designing PPI.

Public involvement

The PHIRST-LIGHT Public Advisory Group (PAG) consists of a team of experienced public contributors with a diverse range of characteristics from across the UK. The PAG was involved in the initial question setting and study design for this review.

Search strategy

For the purpose of this review, the JBI approach for conducting qualitative systematic reviews was followed [ 9 ]. The search terms were (“creativ*” OR “innovat*” OR “authentic” OR “original” OR “inclu*”) AND (“public and patient involvement” OR “patient and public involvement” OR “public and patient involvement and engagement” OR “patient and public involvement and engagement” OR “PPI” OR “PPIE” OR “co-produc*” OR “co-creat*” OR “co-design*” OR “cooperat*” OR “co-operat*”). This search string was modified according to the requirements of each database. Papers were filtered by title, abstract and keywords (see Additional file 1 for search strings). The databases searched included Web of Science (WoS), PubMed, ASSIA and CINAHL. The Cochrane Library was also searched to identify relevant reviews which could lead to the identification of primary research. The search was conducted on 14/04/23. As our aim was to report on the use of creative PPI in research, rather than more generic public engagement, we used electronic databases of scholarly peer-reviewed literature, which represent a wide range of recognised databases. These identified studies published in general international journals (WoS, PubMed), those in social sciences journals (ASSIA), those in nursing and allied health journals (CINAHL), and trials of interventions (Cochrane Library).

Inclusion criteria

Only full-text, English language, primary research papers from 2009 to 2023 were included. This was the chosen timeframe as in 2009 the Health and Social Reform Act made it mandatory for certain Health and Social Care organisations to involve the public and patients in planning, delivering, and evaluating services [ 2 ]. Only creative methods of PPI were accepted, rather than traditional methods, such as interviews or focus groups. For the purposes of this paper, creative PPI included creative art or arts-based approaches (e.g., e.g. stories, songs, drama, drawing, painting, poetry, photography) to enhance engagement. Titles were related to health and social care and the creative PPI was used to engage with people as research advisors, not as study participants. Meta-analyses, conference abstracts, book chapters, commentaries and reviews were excluded. There were no limits concerning study location or the demographic characteristics of the PPI groups. Only qualitative data were accepted.

Quality appraisal

Quality appraisal using the Critical Appraisal Skills Programme (CASP) checklist [ 10 ] was conducted by the primary authors (ORP and CH). This was done independently, and discrepancies were discussed and resolved. If a consensus could not be reached, a third independent reviewer was consulted (JRM). The full list of quality appraisal questions can be found in Additional file 2 .

Data extraction

ORP extracted the study characteristics and a subset of these were checked by CH. Discrepancies were discussed and amendments made. Extracted data included author, title, location, year of publication, year study was carried out, research question/aim, creative methods used, number of participants, mean age, gender, ethnicity of participants, setting, limitations and strengths of creative PPI and main findings.

Data analysis

The included studies were analysed using inductive thematic analysis [ 11 ], where themes were determined by the data. The familiarisation stage took place during full-text reading of the included articles. Anything identified as a strength or limitation to creative PPI methods was extracted verbatim as an initial code and inputted into the data extraction Excel sheet. Similar codes were sorted into broader themes, either under ‘strengths’ or ‘limitations’ and reviewed. Themes were then assigned a name according to the codes.

The search yielded 9978 titles across the 5 databases: Web of Science (1480 results), PubMed (94 results), ASSIA (2454 results), CINAHL (5948 results) and Cochrane Library (2 results), resulting in 8553 different studies after deduplication. ORP and CH independently screened their titles and abstracts, excluding those that did not meet the criteria. After assessment, 12 studies were included (see Fig.  1 ).

PRISMA flowchart of the study selection process

Study characteristics

The included studies were published between 2018 and 2022. Seven were conducted in the UK [ 12 , 14 , 15 , 17 , 18 , 19 , 23 ], two in Canada [ 21 , 22 ], one in Australia [ 13 ], one in Norway [ 16 ] and one in Ireland [ 20 ]. The PPI activities occurred across various settings, including a school [ 12 ], social club [ 12 ], hospital [ 17 ], university [ 22 ], theatre [ 19 ], hotel [ 20 ], or online [ 15 , 21 ], however this information was omitted in 5 studies [ 13 , 14 , 16 , 18 , 23 ]. The number of people attending the PPI sessions varied, ranging from 6 to 289, however the majority (ten studies) had less than 70 participants [ 13 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Seven studies did not provide information on the age or gender of the PPI groups. Of those that did, ages ranged from 8 to 76 and were mostly female. The ethnicities of the PPI group members were also rarely recorded (see Additional file 3 for data extraction table).

Types of creative methods

The type of creative methods used to engage the PPI groups were varied. These included songs, poems, drawings, photograph elicitation, drama performance, visualisations, Facebook, photography, prototype development, cultural animation, card sorting and creating personas (see Table  1 ). These were sometimes accompanied by traditional methods of PPI such as interviews and focus group discussions.

The 12 included studies were all deemed to be of good methodological quality, with scores ranging from 6/10 to 10/10 with the CASP critical appraisal tool [ 10 ] (Table  2 ).

Thematic analysis

Analysis identified four limitations and five strengths to creative PPI (see Fig.  2 ). Limitations included the time and resource intensity of creative PPI methods, its lack of generalisation, ethical issues and external factors. Strengths included the disruption of power hierarchies, the engaging and inclusive nature of the methods and their long-term cost and time efficiency. Creative PPI methods also allowed mundane and “taboo” topics to be discussed within a safe space.

Theme map of strengths and limitations

Limitations of creative PPI

Creative ppi methods are time and resource intensive.

The time and resource intensive nature of creative PPI methods is a limitation, most notably for the persona-scenario methodology. Valaitis et al. [ 22 ] used 14 persona-scenario workshops with 70 participants to co-design a healthcare intervention, which aimed to promote optimal aging in Canada. Using the persona method, pairs composed of patients, healthcare providers, community service providers and volunteers developed a fictional character which they believed represented an ‘end-user’ of the healthcare intervention. Due to the depth and richness of the data produced the authors reported that it was time consuming to analyse. Further, they commented that the amount of information was difficult to disseminate to scientific leads and present at team meetings. Additionally, to ensure the production of high-quality data, to probe for details and lead group discussion there was a need for highly skilled facilitators. The resource intensive nature of the creative co-production was also noted in a study using the persona scenario and creative worksheets to develop a prototype decision support tool for individuals with malignant pleural effusion [ 17 ]. With approximately 50 people, this was also likely to yield a high volume of data to consider.

To prepare materials for populations who cannot engage in traditional methods of PPI was also timely. Kearns et al. [ 18 ] developed a feedback questionnaire for people with aphasia to evaluate ICT-delivered rehabilitation. To ensure people could participate effectively, the resources used during the workshops, such as PowerPoints, online images and photographs, had to be aphasia-accessible, which was labour and time intensive. The author warned that this time commitment should not be underestimated.

There are further practical limitations to implementing creative PPI, such as the costs of materials for activities as well as hiring a space for workshops. For example, the included studies in this review utilised pens, paper, worksheets, laptops, arts and craft supplies and magazines and took place in venues such as universities, a social club, and a hotel. Further, although not limited to creative PPI methods exclusively but rather most studies involving the public, a financial incentive was often offered for participation, as well as food, parking, transport and accommodation [ 21 , 22 ].

Creative PPI lacks generalisation

Another barrier to the use of creative PPI methods in health and social care research was the individual nature of its output. Those who participate, usually small in number, produce unique creative outputs specific to their own experiences, opinions and location. Craven et al. [ 13 ], used arts-based visualisations to develop a toolbox for adults with mental health difficulties. They commented, “such an approach might still not be worthwhile”, as the visualisations were individualised and highly personal. This indicates that the output may fail to meet the needs of its end-users. Further, these creative PPI groups were based in certain geographical regions such as Stoke-on-Trent [ 19 ] Sheffield [ 23 ], South Wales [ 12 ] or Ireland [ 20 ], which limits the extent the findings can be applied to wider populations, even within the same area due to individual nuances. Further, the study by Galler et al. [ 16 ], is specific to the Norwegian context and even then, maybe only a sub-group of the Norwegian population as the sample used was of higher socioeconomic status.

However, Grindell et al. [ 17 ], who used persona scenarios, creative worksheets and prototype development, pointed out that the purpose of this type of research is to improve a certain place, rather than apply findings across other populations and locations. Individualised output may, therefore, only be a limitation to research wanting to conduct PPI on a large scale.

If, however, greater generalisation within PPI is deemed necessary, then social media may offer a resolution. Fedorowicz et al. [ 15 ], used Facebook to gain feedback from the public on the use of video-recording methodology for an upcoming project. This had the benefit of including a more diverse range of people (289 people joined the closed group), who were spread geographically around the UK, as well as seven people from overseas.

Creative PPI has ethical issues

As with other research, ethical issues must be taken into consideration. Due to the nature of creative approaches, as well as the personal effort put into them, people often want to be recognised for their work. However, this compromises principles so heavily instilled in research such as anonymity and confidentiality. With the aim of exploring issues related to health and well-being in a town in South Wales, Byrne et al. [ 12 ], asked year 4/5 and year 10 pupils to create poems, songs, drawings and photographs. Community members also created a performance, mainly of monologues, to explore how poverty and inequalities are dealt with. Byrne noted the risks of these arts-based approaches, that being the possibility of over-disclosure and consequent emotional distress, as well as people’s desire to be named for their work. On one hand, the anonymity reduces the sense of ownership of the output as it does not portray a particular individual’s lived experience anymore. On the other hand, however, it could promote a more honest account of lived experience. Supporting this, Webber et al. [ 23 ], who used the persona method to co-design a back pain educational resource prototype, claimed that the anonymity provided by this creative technique allowed individuals to externalise and anonymise their own personal experience, thus creating a more authentic and genuine resource for future users. This implies that anonymity can be both a limitation and strength here.

The use of creative PPI methods is impeded by external factors

Despite the above limitations influencing the implementation of creative PPI techniques, perhaps the most influential is that creative methodologies are simply not mainstream [ 19 ]. This could be linked to the issues above, like time and resource intensity, generalisation and ethical issues but it is also likely to involve more systemic factors within the research community. Micsinszki et al. [ 21 ], who co-designed a hub for the health and well-being of vulnerable populations, commented that there is insufficient infrastructure to conduct meaningful co-design as well as a dominant medical model. Through a more holistic lens, there are “sociopolitical environments that privilege individualism over collectivism, self-sufficiency over collaboration, and scientific expertise over other ways of knowing based on lived experience” [ 21 ]. This, it could be suggested, renders creative co-design methodologies, which are based on the foundations of collectivism, collaboration and imagination an invalid technique in the research field, which is heavily dominated by more scientific methods offering reproducibility, objectivity and reliability.

Although we acknowledge that creative PPI techniques are not always appropriate, it may be that their main limitation is the lack of awareness of these methods or lack of willingness to use them. Further, there is always the risk that PPI, despite being a mandatory part of research, is used in a tokenistic or tick-box fashion [ 20 ], without considering the contribution that meaningful PPI could make to enhancing the research. It may be that PPI, let alone creative PPI, is not at the forefront of researchers’ minds when planning research.

Strengths of creative PPI

Creative ppi disrupts power hierarchies.

One of the main strengths of creative PPI techniques, cited most frequently in the included literature, was that they disrupt traditional power hierarchies [ 12 , 13 , 17 , 19 , 23 ]. For example, the use of theatre performance blurred the lines between professional and lay roles between the community and policy makers [ 12 ]. Individuals created a monologue to portray how poverty and inequality impact daily life and presented this to representatives of the National Assembly of Wales, Welsh Government, the Local Authority, Arts Council and Westminster. Byrne et al. [ 12 ], states how this medium allowed the community to engage with the people who make decisions about their lives in an environment of respect and understanding, where the hierarchies are not as visible as in other settings, e.g., political surgeries. Creative PPI methods have also removed traditional power hierarchies between researchers and adolescents. Cook et al. [ 13 ], used arts-based approaches to explore adolescents’ ideas about the “perfect” condom. They utilised the “Life Happens” resource, where adolescents drew and then decorated a person with their thoughts about sexual relationships, not too dissimilar from the persona-scenario method. This was then combined with hypothetical scenarios about sexuality. A condom-mapping exercise was then implemented, where groups shared the characteristics that make a condom “perfect” on large pieces of paper. Cook et al. [ 13 ], noted that usually power imbalances make it difficult to elicit information from adolescents, however these power imbalances were reduced due to the use of creative co-design techniques.

The same reduction in power hierarchies was noted by Grindell et al. [ 17 ], who used the person-scenario method and creative worksheets with individuals with malignant pleural effusion. This was with the aim of developing a prototype of a decision support tool for patients to help with treatment options. Although this process involved a variety of stakeholders, such as patients, carers and healthcare professionals, creative co-design was cited as a mechanism that worked to reduce power imbalances – a limitation of more traditional methods of research. Creative co-design blurred boundaries between end-users and clinical staff and enabled the sharing of ideas from multiple, valuable perspectives, meaning the prototype was able to suit user needs whilst addressing clinical problems.

Similarly, a specific creative method named cultural animation was also cited to dissolve hierarchies and encourage equal contributions from participants. Within this arts-based approach, Keleman et al. [ 19 ], explored the concept of “good health” with individuals from Stoke-on Trent. Members of the group created art installations using ribbons, buttons, cardboard and straws to depict their idea of a “healthy community”, which was accompanied by a poem. They also created a 3D Facebook page and produced another poem or song addressing the government to communicate their version of a “picture of health”. Public participants said that they found the process empowering, honest, democratic, valuable and practical.

This dissolving of hierarchies and levelling of power is beneficial as it increases the sense of ownership experienced by the creators/producers of the output [ 12 , 17 , 23 ]. This is advantageous as it has been suggested to improve its quality [ 23 ].

Creative PPI allows the unsayable to be said

Creative PPI fosters a safe space for mundane or taboo topics to be shared, which may be difficult to communicate using traditional methods of PPI. For example, the hypothetical nature of condom mapping and persona-scenarios meant that adolescents could discuss a personal topic without fear of discrimination, judgement or personal disclosure [ 13 ]. The safe space allowed a greater volume of ideas to be generated amongst peers where they might not have otherwise. Similarly, Webber et al. [ 23 ], , who used the persona method to co-design the prototype back pain educational resource, also noted how this method creates anonymity whilst allowing people the opportunity to externalise personal experiences, thoughts and feelings. Other creative methods were also used, such as drawing, collaging, role play and creating mood boards. A cardboard cube (labelled a “magic box”) was used to symbolise a physical representation of their final prototype. These creative methods levelled the playing field and made personal experiences accessible in a safe, open environment that fostered trust, as well as understanding from the researchers.

It is not only sensitive subjects that were made easier to articulate through creative PPI. The communication of mundane everyday experiences were also facilitated, which were deemed typically ‘unsayable’. This was specifically given in the context of describing intangible aspects of everyday health and wellbeing [ 11 ]. Graphic designers can also be used to visually represent the outputs of creative PPI. These captured the movement and fluidity of people and well as the relationships between them - things that cannot be spoken but can be depicted [ 21 ].

Creative PPI methods are inclusive

Another strength of creative PPI was that it is inclusive and accessible [ 17 , 19 , 21 ]. The safe space it fosters, as well as the dismantling of hierarchies, welcomed people from a diverse range of backgrounds and provided equal opportunities [ 21 ], especially for those with communication and memory difficulties who might be otherwise excluded from PPI. Kelemen et al. [ 19 ], who used creative methods to explore health and well-being in Stoke-on-Trent, discussed how people from different backgrounds came together and connected, discussed and reached a consensus over a topic which evoked strong emotions, that they all have in common. Individuals said that the techniques used “sets people to open up as they are not overwhelmed by words”. Similarly, creative activities, such as the persona method, have been stated to allow people to express themselves in an inclusive environment using a common language. Kearns et al. [ 18 ], who used aphasia-accessible material to develop a questionnaire with aphasic individuals, described how they felt comfortable in contributing to workshops (although this material was time-consuming to make, see ‘Limitations of creative PPI’ ).

Despite the general inclusivity of creative PPI, it can also be exclusive, particularly if online mediums are used. Fedorowicz et al. [ 15 ], used Facebook to create a PPI group, and although this may rectify previous drawbacks about lack of generalisation of creative methods (as Facebook can reach a greater number of people, globally), it excluded those who are not digitally active or have limited internet access or knowledge of technology. Online methods have other issues too. Maintaining the online group was cited as challenging and the volume of responses required researchers to interact outside of their working hours. Despite this, online methods like Facebook are very accessible for people who are physically disabled.

Creative PPI methods are engaging

The process of creative PPI is typically more engaging and produces more colourful data than traditional methods [ 13 ]. Individuals are permitted and encouraged to explore a creative self [ 19 ], which can lead to the exploration of new ideas and an overall increased enjoyment of the process. This increased engagement is particularly beneficial for younger PPI groups. For example, to involve children in the development of health food products, Galler et al. [ 16 ] asked 9-12-year-olds to take photos of their food and present it to other children in a “show and tell” fashion. They then created a newspaper article describing a new healthy snack. In this creative focus group, children were given lab coats to further their identity as inventors. Galler et al. [ 16 ], notes that the methods were highly engaging and facilitated teamwork and group learning. This collaborative nature of problem-solving was also observed in adults who used personas and creative worksheets to develop the resource for lower back pain [ 23 ]. Dementia patients too have been reported to enjoy the creative and informal approach to idea generation [ 20 ].

The use of cultural animation allowed people to connect with each other in a way that traditional methods do not [ 19 , 21 ]. These connections were held in place by boundary objects, such as ribbons, buttons, fabric and picture frames, which symbolised a shared meaning between people and an exchange of knowledge and emotion. Asking groups to create an art installation using these objects further fostered teamwork and collaboration, both at an individual and collective level. The exploration of a creative self increased energy levels and encouraged productive discussions and problem-solving [ 19 ]. Objects also encouraged a solution-focused approach and permitted people to think beyond their usual everyday scope [ 17 ]. They also allowed facilitators to probe deeper about the greater meanings carried by the object, which acted as a metaphor [ 21 ].

From the researcher’s point of view, co-creative methods gave rise to ideas they might not have initially considered. Valaitis et al. [ 22 ], found that over 40% of the creative outputs were novel ideas brought to light by patients, healthcare providers/community care providers, community service providers and volunteers. One researcher commented, “It [the creative methods] took me on a journey, in a way that when we do other pieces of research it can feel disconnected” [ 23 ]. Another researcher also stated they could not return to the way they used to do research, as they have learnt so much about their own health and community and how they are perceived [ 19 ]. This demonstrates that creative processes not only benefit the project outcomes and the PPI group, but also facilitators and researchers. However, although engaging, creative methods have been criticised for not demonstrating academic rigour [ 17 ]. Moreover, creative PPI may also be exclusive to people who do not like or enjoy creative activities.

Creative PPI methods are cost and time efficient

Creative PPI workshops can often produce output that is visible and tangible. This can save time and money in the long run as the output is either ready to be implemented in a healthcare setting or a first iteration has already been developed. This may also offset the time and costs it takes to implement creative PPI. For example, the prototype of the decision support tool for people with malignant pleural effusion was developed using personas and creative worksheets. The end result was two tangible prototypes to drive the initial idea forward as something to be used in practice [ 17 ]. The use of creative co-design in this case saved clinician time as well as the time it would take to develop this product without the help of its end-users. In the development of this particular prototype, analysis was iterative and informed the next stage of development, which again saved time. The same applies for the feedback questionnaire for the assessment of ICT delivered aphasia rehabilitation. The co-created questionnaire, designed with people with aphasia, was ready to be used in practice [ 18 ]. This suggests that to overcome time and resource barriers to creative PPI, researchers should aim for it to be engaging whilst also producing output.

That useable products are generated during creative workshops signals to participating patients and public members that they have been listened to and their thoughts and opinions acted upon [ 23 ]. For example, the development of the back pain resource based on patient experiences implies that their suggestions were valid and valuable. Further, those who participated in the cultural animation workshop reported that the process visualises change, and that it already feels as though the process of change has started [ 19 ].

The most cost and time efficient method of creative PPI in this review is most likely the use of Facebook to gather feedback on project methodology [ 15 ]. Although there were drawbacks to this, researchers could involve more people from a range of geographical areas at little to no cost. Feedback was instantaneous and no training was required. From the perspective of the PPI group, they could interact however much or little they wish with no time commitment.

This systematic review identified four limitations and five strengths to the use of creative PPI in health and social care research. Creative PPI is time and resource intensive, can raise ethical issues and lacks generalisability. It is also not accepted by the mainstream. These factors may act as barriers to the implementation of creative PPI. However, creative PPI disrupts traditional power hierarchies and creates a safe space for taboo or mundane topics. It is also engaging, inclusive and can be time and cost efficient in the long term.

Something that became apparent during data analysis was that these are not blanket strengths and limitations of creative PPI as a whole. The umbrella term ‘creative PPI’ is broad and encapsulates a wide range of activities, ranging from music and poems to prototype development and persona-scenarios, to more simplistic things like the use of sticky notes and ordering cards. Many different activities can be deemed ‘creative’ and the strengths and limitations of one does not necessarily apply to another. For example, cultural animation takes greater effort to prepare than the use of sticky notes and sorting cards, and the use of Facebook is cheaper and wider reaching than persona development. Researchers should use their discretion and weigh up the benefits and drawbacks of each method to decide on a technique which suits the project. What might be a limitation to creative PPI in one project may not be in another. In some cases, creative PPI may not be suitable at all.

Furthermore, the choice of creative PPI method also depends on the needs and characteristics of the PPI group. Children, adults and people living with dementia or language difficulties all have different engagement needs and capabilities. This indicates that creative PPI is not one size fits all and that the most appropriate method will change depending on the composition of the group. The choice of method will also be determined by the constraints of the research project, namely time, money and the research aim. For example, if there are time constraints, then a method which yields a lot of data and requires a lot of preparation may not be appropriate. If generalisation is important, then an online method is more suitable. Together this indicates that the choice of creative PPI method is highly individualised and dependent on multiple factors.

Although the limitations discussed in this review apply to creative PPI, they are not exclusive to creative PPI. Ethical issues are a consideration within general PPI research, especially when working with more vulnerable populations, such as children or adults living with a disability. It can also be the case that traditional PPI methods lack generalisability, as people who volunteer to be part of such a group are more likely be older, middle class and retired [ 24 ]. Most research is vulnerable to this type of bias, however, it is worth noting that generalisation is not always a goal and research remains valid and meaningful in its absence. Although online methods may somewhat combat issues related to generalisability, these methods still exclude people who do not have access to the internet/technology or who choose not to use it, implying that online PPI methods may not be wholly representative of the general population. Saying this, however, the accessibility of creative PPI techniques differs from person to person, and for some, online mediums may be more accessible (for example for those with a physical disability), and for others, this might be face-to-face. To combat this, a range of methods should be implemented. Planning multiple focus group and interviews for traditional PPI is also time and resource intensive, however the extra resources required to make this creative may be even greater. Although, the rich data provided may be worth the preparation and analysis time, which is also likely to depend on the number of participants and workshop sessions required. PPI, not just creative PPI, often requires the provision of a financial incentive, refreshments, parking and accommodation, which increase costs. These, however, are imperative and non-negotiable, as they increase the accessibility of research, especially to minority and lower-income groups less likely to participate. Adequate funding is also important for co-design studies where repeated engagement is required. One barrier to implementation, which appears to be exclusive to creative methods, however, is that creative methods are not mainstream. This cannot be said for traditional PPI as this is often a mandatory part of research applications.

Regarding the strengths of creative PPI, it could be argued that most appear to be exclusive to creative methodologies. These are inclusive by nature as multiple approaches can be taken to evoke ideas from different populations - approaches that do not necessarily rely on verbal or written communication like interviews and focus groups do. Given the anonymity provided by some creative methods, such as personas, people may be more likely to discuss their personal experiences under the guise of a general end-user, which might be more difficult to maintain when an interviewer is asking an individual questions directly. Additionally, creative methods are by nature more engaging and interactive than traditional methods, although this is a blanket statement and there may be people who find the question-and-answer/group discussion format more engaging. Creative methods have also been cited to eliminate power imbalances which exist in traditional research [ 12 , 13 , 17 , 19 , 23 ]. These imbalances exist between researchers and policy makers and adolescents, adults and the community. Lastly, although this may occur to a greater extent in creative methods like prototype development, it could be suggested that PPI in general – regardless of whether it is creative - is more time and cost efficient in the long-term than not using any PPI to guide or refine the research process. It must be noted that these are observations based on the literature. To be certain these differences exist between creative and traditional methods of PPI, direct empirical evaluation of both should be conducted.

To the best of our knowledge, this is the first review to identify the strengths and limitations to creative PPI, however, similar literature has identified barriers and facilitators to PPI in general. In the context of clinical trials, recruitment difficulties were cited as a barrier, as well as finding public contributors who were free during work/school hours. Trial managers reported finding group dynamics difficult to manage and the academic environment also made some public contributors feel nervous and lacking confidence to speak. Facilitators, however, included the shared ownership of the research – something that has been identified in the current review too. In addition, planning and the provision of knowledge, information and communication were also identified as facilitators [ 25 ]. Other research on the barriers to meaningful PPI in trial oversight committees included trialist confusion or scepticism over the PPI role and the difficulties in finding PPI members who had a basic understanding of research [ 26 ]. However, it could be argued that this is not representative of the average patient or public member. The formality of oversight meetings and the technical language used also acted as a barrier, which may imply that the informal nature of creative methods and its lack of dependency on literacy skills could overcome this. Further, a review of 42 reviews on PPI in health and social care identified financial compensation, resources, training and general support as necessary to conduct PPI, much like in the current review where the resource intensiveness of creative PPI was identified as a limitation. However, others were identified too, such as recruitment and representativeness of public contributors [ 27 ]. Like in the current review, power imbalances were also noted, however this was included as both a barrier and facilitator. Collaboration seemed to diminish hierarchies but not always, as sometimes these imbalances remained between public contributors and healthcare staff, described as a ‘them and us’ culture [ 27 ]. Although these studies compliment the findings of the current review, a direct comparison cannot be made as they do not concern creative methods. However, it does suggest that some strengths and weaknesses are shared between creative and traditional methods of PPI.

Strengths and limitations of this review

Although a general definition of creative PPI exists, it was up to our discretion to decide exactly which activities were deemed as such for this review. For example, we included sorting cards, the use of interactive whiteboards and sticky notes. Other researchers may have a more or less stringent criteria. However, two reviewers were involved in this decision which aids the reliability of the included articles. Further, it may be that some of the strengths and limitations cannot fully be attributed to the creative nature of the PPI process, but rather their co-created nature, however this is hard to disentangle as the included papers involved both these aspects.

During screening, it was difficult to decide whether the article was utilising creative qualitative methodology or creative PPI , as it was often not explicitly labelled as such. Regardless, both approaches involved the public/patients refining a healthcare product/service. This implies that if this review were to be replicated, others may do it differently. This may call for greater standardisation in the reporting of the public’s involvement in research. For example, the NIHR outlines different approaches to PPI, namely “consultation”, “collaboration”, “co-production” and “user-controlled”, which each signify an increased level of public power and influence [ 28 ]. Papers with elements of PPI could use these labels to clarify the extent of public involvement, or even explicitly state that there was no PPI. Further, given our decision to include only scholarly peer-reviewed literature, it is possible that data were missed within the grey literature. Similarly, the literature search will not have identified all papers relating to different types of accessible inclusion. However, the intent of the review was to focus solely on those within the definition of creative.

This review fills a gap in the literature and helps circulate and promote the concept of creative PPI. Each stage of this review, namely screening and quality appraisal, was conducted by two independent reviewers. However, four full texts could not be accessed during the full text reading stage, meaning there are missing data that could have altered or contributed to the findings of this review.

Research recommendations

Given that creative PPI can require effort to prepare, perform and analyse, sufficient time and funding should be allocated in the research protocol to enable meaningful and continuous PPI. This is worthwhile as PPI can significantly change the research output so that it aligns closely with the needs of the group it is to benefit. Researchers should also consider prototype development as a creative PPI activity as this might reduce future time/resource constraints. Shifting from a top-down approach within research to a bottom-up can be advantageous to all stakeholders and can help move creative PPI towards the mainstream. This, however, is the collective responsibility of funding bodies, universities and researchers, as well as committees who approve research bids.

A few of the included studies used creative techniques alongside traditional methods, such as interviews, which could also be used as a hybrid method of PPI, perhaps by researchers who are unfamiliar with creative techniques or to those who wish to reap the benefits of both. Often the characteristics of the PPI group were not included, including age, gender and ethnicity. It would be useful to include such information to assess how representative the PPI group is of the population of interest.

Creative PPI is a relatively novel approach of engaging the public and patients in research and it has both advantages and disadvantages compared to more traditional methods. There are many approaches to implementing creative PPI and the choice of technique will be unique to each piece of research and is reliant on several factors. These include the age and ability of the PPI group as well as the resource limitations of the project. Each method has benefits and drawbacks, which should be considered at the protocol-writing stage. However, given adequate funding, time and planning, creative PPI is a worthwhile and engaging method of generating ideas with end-users of research – ideas which may not be otherwise generated using traditional methods.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Critical Appraisal Skills Programme

The Joanna Briggs Institute

National Institute of Health and Care Research

Public Advisory Group

Public and Patient Involvement

Web of Science

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Acknowledgements

With thanks to the PHIRST-LIGHT public advisory group and consortium for their thoughts and contributions to the design of this work.

The research team is supported by a National Institute for Health and Care Research grant (PHIRST-LIGHT Reference NIHR 135190).

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Olivia R. Phillips and Cerian Harries share joint first authorship.

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Nottingham Centre for Public Health and Epidemiology, Lifespan and Population Health, School of Medicine, University of Nottingham, Clinical Sciences Building, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB, UK

Olivia R. Phillips, Jo Leonardi-Bee, Holly Knight & Joanne R. Morling

National Institute for Health and Care Research (NIHR) PHIRST-LIGHT, Nottingham, UK

Olivia R. Phillips, Cerian Harries, Jo Leonardi-Bee, Holly Knight, Lauren B. Sherar, Veronica Varela-Mato & Joanne R. Morling

School of Sport, Exercise and Health Sciences, Loughborough University, Epinal Way, Loughborough, Leicestershire, LE11 3TU, UK

Cerian Harries, Lauren B. Sherar & Veronica Varela-Mato

Nottingham Centre for Evidence Based Healthcare, School of Medicine, University of Nottingham, Nottingham, UK

Jo Leonardi-Bee

NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, NG7 2UH, UK

Joanne R. Morling

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Author contributions: study design: ORP, CH, JRM, JLB, HK, LBS, VVM, literature searching and screening: ORP, CH, JRM, data curation: ORP, CH, analysis: ORP, CH, JRM, manuscript draft: ORP, CH, JRM, Plain English Summary: ORP, manuscript critical review and editing: ORP, CH, JRM, JLB, HK, LBS, VVM.

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Correspondence to Olivia R. Phillips .

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Phillips, O.R., Harries, C., Leonardi-Bee, J. et al. What are the strengths and limitations to utilising creative methods in public and patient involvement in health and social care research? A qualitative systematic review. Res Involv Engagem 10 , 48 (2024). https://doi.org/10.1186/s40900-024-00580-4

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A novel dance intervention program for children and adolescents with developmental disabilities: a pilot randomized control trial

• Jeffrey T. Anderson 1 , 4 ,
• Christina Toolan 2 ,
• Emily Coker 3 ,
• Hannah Singer 1 , 4 ,
• Derek Pham 1 ,
• Nicholas Jackson 1 ,
• Catherine Lord 1 , 4 &
• Rujuta B. Wilson 1 , 4  

BMC Sports Science, Medicine and Rehabilitation volume  16 , Article number:  109 ( 2024 ) Cite this article

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Metrics details

Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills.

The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept.

We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist ( n  = 21, p  = 0.05). We also observed positive trends in social skills that did not reach significance.

Conclusions

Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program.

Trial Registration

ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 – Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

Peer Review reports

Organized physical activity (OPA), which is structured physical activity led by a coach or instructor, has wide benefits for physical health and wellbeing. It is well established that routine physical activity reduces risk for multiple chronic conditions and improves health outcomes [ 1 ]. Physical activity is also associated with the formation of fundamental motor skills in early childhood, highlighting its importance for motor development [ 2 ]. The World Health Organization echoed the importance of daily physical activity for children and adolescents to strengthen muscles and reduce sedentary behavior [ 3 ]. In addition, physical activity may provide benefits to the psychological wellbeing of adolescents through strengthening cognitive function networks in the brain [ 4 ]. Importantly, not all types of physical activity provide the same array of benefits; this distinction, however, has not yet been thoroughly explored. One study which investigated the relationship between structured and unstructured physical activity found that structured physical activity with guided opportunities for practice proved to be the most beneficial for motor skill development [ 5 ]. Similarly, structured indoor and outdoor activities have been shown to reduce the yearly increase of body mass index for developing children. Researchers have found a smaller increase in BMI during what is described as the adiposity rebound period of childhood for children who participate in these activities compared to those who do not [ 6 ]. These findings illustrate that within the broader context of physical activity, participation in OPA is a particularly effective way for children and adolescents to improve their physical health and wellbeing.

Despite OPA’s known benefits, much of the research around OPA focuses on typically developing children. Comparatively fewer studies investigated the benefits of OPA programs for children with neurodevelopmental disabilities (NDD), despite the fact that these children often face greater barriers to participation in physical activity. NDD, as defined in the Diagnostic and Statistical Manual, 5th edition, refers to a group of conditions including autism, attention deficit/hyperactivity disorder (ADHD), and cerebral palsy, that often emerge before grade school and are characterized by developmental deficits in personal, social, academic, or occupational domains [ 7 ]. Furthermore, it is not uncommon for children and adolescents to be diagnosed with more than one NDD [ 8 ]. Literature has shown that adolescents with NDDs are less likely to engage in OPA than neurotypical peers [ 9 , 10 , 11 ]. It is well known that individuals with NDDs often have difficulties in physical movement and mobility. In autistic patients, this can include as praxis, object manipulation, and postural stability [ 12 ], while cerebral palsy is characterized by high muscle tone and missed motor milestones. Motor challenges also have broad negative impacts on adaptive function and quality of life. Adolescents with cerebral palsy have reported higher physical quality of life, social quality of life, and overall happiness when able to be more physically active [ 13 ]. Likewise, motor difficulties in autism are negatively correlated with social skills [ 14 ]. This is significant because social challenges can lead to further barriers, including negative social interactions with peers [ 15 ] and higher feelings of loneliness [ 16 ].

In addition, there is a lack of programs led by physical education coaches with the training and knowledge to adapt the program to individual needs. Limited education for coaches regarding disability has a significant impact on the number of available and adequately trained coaches, and may negatively affect disabled individuals’ participation in sports and other forms of physical activity [ 17 ]. Semi-structured interviews with coaches of autistic athletes have shown that the coach-athlete relationship is a particularly important theme, suggesting that adapting teaching styles according to the experience of autistic individuals is an effective coaching strategy [ 18 ]. While research into this topic is sparse, these findings offer evidence that encouraging coaches to adopt adaptive teaching styles may reduce barriers to participating in physical activity programs for individuals with NDDs.

There are several examples of physical activity programs which have been successfully implemented for individuals with NDDs and have shown benefits across domains. Previous research has shown that following participation in group OPA programs, autistic children had improved overall motor skills, including aiming, catching, and balance, as well as improved social communication and social motivation [ 19 , 20 ]. Another review of movement interventions for children with intellectual disabilities found improvements in fundamental motor skills and balance [ 21 ]. Researchers have also explored dance-based OPA programs as interventions for children with NDDs, and found techniques such as mirroring and exploratory movement to benefit social and communication skills, motor skills, and behavioral domains [ 22 , 23 ]. The success of these programs demonstrates the need to further reduce the barriers individuals with NDDs face by developing and evaluating new OPA programs that are adapted for their needs.

To address this gap, we established an organized dance intervention program called the Expressive Movement Initiative (EMI) at the University of California, Los Angeles (UCLA). The course model was designed to achieve meaningful participation for each dancer by creating an adaptable framework which acknowledges individual needs. To achieve that goal, each dancer was paired individually with an undergraduate buddy who had been trained about NDDs, inclusive language, neurodiversity, and adaptive dance and movement teaching styles. Using a strength-based approach [ 18 , 24 ], this framework ensured that each dancer had the support of an individual who was equipped to support their needs. Furthermore, the use of student buddies to carry out the program greatly increased the feasibility of maintaining one-to-one pairings which in turn provided adequate support for participants and increased opportunities for meaningful social interactions. A document detailing the structure of the dance classes and the protocol for the study at the time of this publication can be found on the clinicaltrials.gov website ( https://clinicaltrials.gov/study/NCT04762290?tab=history&a=3 ). Here we present interim analysis of our study protocol. We choose to present interim analysis due to impacts of the COVID-19 global pandemic on the delivery of the intervention and participant retention. Our goals are to present [ 1 ] the feasibility of developing and implementing the EMI program, and [ 2 ] the results of two of our standardized outcome measures that were not affected by data attrition. This includes one primary outcome measure – the Motor Assessment Battery for Children Checklist (mABC-C), and one secondary outcome measure – the Social Responsiveness Scale (SRS). Other measures described in our study protocol are not presented due to attrition that resulted in incomplete datasets and will be presented when the full sample is collected and complete. We hypothesized that participants would show improvements in motor and social skills following participation in this program as indicated by the mABC-C and SRS, respectively.

Our study design and research methods were reviewed and approved by the University of California, Los Angeles Institutional Review Board (IRB#20-001680). Due to the age of the participant population and/or diagnoses that affect cognitive abilities, a legally authorized representative of all participants provided written informed consent for their data to be used in related research.

Participants

Eligible participants were between the ages of 4 and 17 with a diagnosed NDD from a healthcare provider, which was reported by parents during eligibility screening. Exclusion criteria was previous participation in EMI dance classes. There were no exclusion criteria related to the degree of intellectual/physical disability or co-occurring health conditions. Participants living in the United States were recruited for this study through flyers and social media listings. Interested families contacted the study team directly and all prospective participants were screened until recruitment goals were met. In instances where parents reported more than one diagnosed NDD, e.g., autism and co-occurring ADHD, or a NDD with a co-occurring condition that falls into a different diagnostic category, e.g., anxiety, this information was recorded onto the participant ID key by a researcher at study entry. Furthermore, parents were asked to report racial and ethnic affiliation.

All potential participants were screened in January and February of 2021. Pre-testing took place from February 15, 2021 to March 5, 2021 and follow-up visits occurred from May 2, 2021 to May 9, 2021. The trial, which was originally planned to conclude in March 2024, was interrupted after one year to perform an interim analysis on the data collected during the COVID-19 pandemic. This decision was made in order to perform a feasibility assessment and adjust the study protocol to include direct in-person measures upon resuming the trial.

Intervention design

The intervention was designed as a longitudinal waitlist-control study in which participants were randomized into active and control groups using permuted block randomization with a 2:1 active to control randomization scheme. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at UCLA [ 25 ]. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources. REDCap was also used to complete the randomization, with the allocation sequence being generated by author six and participants being enrolled by author eight. The randomization list was concealed by REDCap, with the assignment group only being known once an intervention group was assigned. Additionally, participants were stratified by language level (complex speech, phrased speech, or minimally verbal) in order to ensure an even distribution of baseline communication skills. The treatment period was 10 weeks with weekly 1-hour classes. The active and control group completed pre and post intervention surveys online via Zoom in an interview format. Whereas participants were aware of which group they had been placed in, assessments were conducted by trained research staff who were blinded to assignment group. The control group was offered participation in the dance classes after the post-intervention data collection (Fig.  1 ).

Graphical representation of the longitudinal study design. The timeline for study events as they relate to the dance intervention

The EMI dance intervention classes were carried out by trained undergraduate students. Each session consisted of an artistic director to lead the class and buddies that were paired 1:1 to each participant. Buddies received training around NDD, accessible language, and how to adapt their teaching for their buddy. This training included attending speaker presentations and reviewing weekly feedback provided by a class instructor. Due to the COVID-19 pandemic, all classes were held virtually on Zoom. To ensure the quality of virtual instruction, artistic directors and buddies received training in adapting movements for Zoom delivery. Additionally, artistic directors provided buddies with written feedback on a weekly basis to provide strategies for adjusting teaching styles to their dancer.

The structure of each class could take one of two forms, group class or buddy class, which alternated each week. Dancers started each group class with a warm up consisting of stretches and other movements, followed by an “across the floors” exercise which involved more exaggerated movement. Across the floor movements were commonly based in ballet techniques, such as “relevé walks”, “step, prep, passé,” and “reach chassé.” A short break was incorporated into every class to encourage hydration and resting. After the break, the instructor taught a short choreography to the dancers, which would first be practiced at a pace best for the participant before being paired with music. To close out group time, a musical game was played. These games would require dancers to follow a particular objective, such as balance a tissue on their head while dancing, or follow instructions embedded within a song, such as the hokey-pokey. Following this, dancers were sent into Zoom breakout rooms for a few minutes to work with their buddies. Upon their return, they were given the opportunity to share what they did with their buddy and engage in a cooldown before ending class. A visual representation of a typical group class can be seen in Fig.  2 .

Buddy classes began with a warm up and an across the floors series similar to group class. However, after this point they would be sent directly into breakout rooms with their buddies for the remainder of class, which usually lasted 40–45 min. Class plans would provide buddies with objectives to accomplish during their one-on-one session, such as play a musical game or come up with specific dance skills to practice. This structure allowed dancers to receive more individualized attention and work on learned movement skills. Much like group classes, buddy classes ended with dancers coming back to the main room, sharing what they did with their buddy, and engaging in a cooldown activity.

Group Class Agenda. The typical order of activities that occur during group class. During buddy class, dancers would spend additional time with their buddy in lieu of learning new choreography or playing a game

Measures used pre- and post-intervention

Social Skills : Social skills were assessed through parent responses to the Social Responsiveness Scale 2nd edition (SRS-2) [ 26 ]. The SRS-2 is a continuous measure of social behaviors that is normed and validated for use across the lifespan in autistic individuals as well as non-autistic individuals who may show various impairments. It captures behaviors related to 5 subscales: (a) social awareness, (b) social cognition, (c) social communication, (d) social motivation, and (e) restricted interested and repetitive behavior. The instrument contains 65 items that took parents approximately 15 min to complete.

Motor Function. Motor function was assessed via parent responses to the Movement Assessment Battery for Children Checklist (mABC-C) [ 27 ]. This checklist is intended to be completed by a teacher or parent and contains questions pertaining to a variety of motor tasks. The mABC-C contains 30 items, which took parents approximately 10 min to complete. It is validated for use in children ages 5 through 12 with or without motor challenges as a screening tool for Developmental Coordination Disorder (DCD) [ 28 , 29 ]. The instrument yields a total motor score, wherein a higher score indicates worse motor skills as more characteristics meet criteria for DCD. The mABC-C is associated with a direct assessment battery, the Movement Assessment Battery for Children –second edition (mABC-2), which is commonly used as a tool for assessing children with suspected motor skill impairment [ 30 ]. As we were unable to conduct in-person visits due to the COVID-19 pandemic, the mABC-C was used to target relevant motor domains.

Statistical analysis

The primary analysis was intention-to-treat and included all randomly assigned participants who completed the mABC-C and the SRS in at least one study visit. Dance class attendance rate was calculated independently for the active and control groups. Linear mixed-effects modeling adjusted for age and class attendance with subject random intercept was used to evaluate the change in motor function and social skill scores after undergoing EMI dance classes. Between group differences in change over time were assessed using a group-by-time interaction term. All statistical significance was determined using a two-sided alpha level less than 0.05, and all analyses were conducted using R Version 4.2.1 [ 31 ].

A total of 43 participants were recruited and randomized for this study, of which 61 percent were male. Speech level in this sample ranged from non-speaking to fully-verbal. All participants had a diagnosed NDD, with a majority of participants having a diagnosis of autism (Table 1 ). A summary of parental racial and ethnic affiliation can be seen in Table 2 .

Out of the 43 participants who were allocated to an intervention group, 36 completed the mABC-C and SRS at baseline (n active = 21, n control = 15) and 26 participants completed them at follow-up (n active = 14, n control = 12). 30 participants received the allocated intervention (Fig.  3 ). On average, participants in the active group had an attendance rate of 82.6% while participants in the control group had an attendance rate of 61.7%. There was only one protocol deviation for a participant in the active group. This participant was lost to follow-up and did not provide post-assessment data. However, they re-engaged the study team and were given the opportunity to participate in the dance classes with the control group. The pre-assessment data for this participant is included in the intention-to-treat analysis and they have been counted as not having received the allocated intervention.

Participant Flow Diagram. Figure  3 Shows the number of participants that were screened, randomized, and ultimately included in the analysis. A power analysis was performed on the full sample size projected over the multi-year study. No power analysis was performed on the sample reported in this interim analysis

There was no significant change in either the active group ( n  = 21, p  = 0.11) or the control group ( n  = 15, p  = 0.82) on the mABC-C total score, although the active group showed a positive trend. The active group displayed a significant improvement on the “movement in an unpredictable environment” domain of the mABC-C ( n  = 21, p  = 0.05), while the control group did not show any significant change in this domain ( n  = 15, p  = 0.64). A summary of the data can be seen in Table  3 .

Across the domains of the SRS, the active group demonstrated positive trends for improvement in social communication and social motivation, neither of which were significant. We did not observe any notable changes in social awareness, social cognition, or restricted interest and repetitive behavior for the active group. There were no significant changes across any of the domains nor the total score of the SRS for the control group (Fig.  4 ).

Individual and Mean Scores for mABC-C and SRS Subscales. Figure  4   Individual scores (grayscale) and means calculated using linear mixed-effects modeling (color) are plotted for subscales of the mABC-C and the SRS. The social communication and social motivation subscales of the SRS are displayed to visualize the change in scores

The aim of this pilot study was to investigate the feasibility and impact of a novel movement-based dance intervention program for children and adolescents with NDD. Consistent with our hypothesis, we found that children in the active group showed a statistically significant improvement in movement in dynamic environments, as measured by the mABC-C, and we observed a trend of improvements in social skills on the SRS.

We measured movement skills that are related to movement in dynamic environments, which are targeted through the EMI program activities. Examples of dynamic movement activities include self-care/classroom skills, ball skills, and PE/recreational skills. Examples of specific items covered in this section of the mABC-C include, “moves body in time with music or other people,” “keeps time to a musical beat by clapping hands or tapping feet,” and, “maintains balance when frequent adjustments are required.” This type of movement occurs in a dance class setting in which students are learning how to express themselves using movement through space and time. As such, the expressive movement component of EMI likely accounts for the improvements to movement in dynamic environments. This finding is in line with other movement-based intervention studies which have found similar results on the mABC-2 when assessing the impact of their program on motor skills [ 20 ]. Motor skills are integral to many developmental and behavioral domains because they influence how one interacts with their environment. Namely, better motor skills could enhance or improve opportunities to participate in peer interactions by allowing for participation in a broader range of activities, such as sports or active games. Better motor skills may also lead to an increase in active behavior and exercise, which has benefits for social wellbeing, mental health, and cognitive benefits, including a reduction in sedentary behavior [ 32 ]. Importantly, improvements in motor skills reported in this study resulted from a relatively low-intensity program that put minimal burden on participating families. One hour of class per week in an online setting offers a more accessible option for families compared to other interventions, as it does not require transportation for participation. Thus, our findings are promising for the viability of OPA programs for children and adolescents with NDDs.

Changes in social skills were characterized by positive trends for social communication and social motivation that were not statistically significant. Participants were given opportunities for social engagement through one-to-one pairings with buddies, which were reinforced by weeks dedicating greater amount of time to buddy interactions. During group time, the instructor also frequently encouraged participants to verbally share their thoughts or experiences, such as their favorite song or what they did during buddy time. These social interactions likely account for the positive trend in social skills noted on the SRS. This result also mirrors similar works that have investigated the impact of OPA on social skills, which have yielded a mix of significant and non-significant results [ 19 ]. As will be further discussed in study limitations, several factors such as small sample size and heterogeneity of the participant sample may have impacted our ability to measure significant change in these areas. Considering the impact that negative social interactions can have on individuals with NDD [ 15 ], future research is warranted to investigate the impact of OPA programs on social skills and subsequent changes in quality of life. For example, it is possible that positive social interactions during OPA programs increase both one’s motivation to interact with peers and the effectiveness of the communication, which in turn could reduce feelings of loneliness [ 16 ].

One strength of the present study was the enrollment of individuals with varying NDDs and co-occurring diagnoses, which served to increase the generalizability of the program. Across participants of EMI, there were diagnoses of autism, ADHD, cerebral palsy, genetic syndromes, and other disabilities. As participants included males and females between the ages of 4 and 17 with no prerequisite for dancing ability, it follows that a wide range of children and adolescents with a diagnosed NDD can benefit from the presented program. This flexibility could be attributed to the training given to buddies, which emphasized adaptable teaching for the specific needs of each student. Furthermore, the decision to use a student-supported structure for class instruction increases the accessibility of the program by allowing for one-to-one pairings between buddies and dancers while remaining cost-free to families who participate.

We acknowledge that there were also several limitations in our implementation, which should be considered when interpreting the results. As a pilot study, our sample size was small and may have limited our ability to identify all effects. Furthermore, the heterogeneity of our participant sample, while positive for the reach and impact of the EMI program, may have constrained our ability to measure significant results related to social communication and social motivation. The reliance on parent reported diagnoses rather than medical records or clinical assessments is another potential limitation. In addition, the quality of our data was affected by a high amount of attrition in the second half of the study, which led to missing data. These factors could lead to a degree of sampling bias in our study population, although it is likely that global changes in the pandemic played a significant role in engagement levels, in part due to a shift back to in-person social, educational, and leisure activities after a prolonged period of these activities being restricted. Several families who did not complete the study reported that they wanted to travel or have their child return to other programs that had been on a hiatus during the pandemic. Indeed, class attendance rate, which was roughly 80% for the active group when COVID-19 restrictions remained in effect, dropped to nearly 60% for the control group after many restrictions were lifted. Finally, it was necessary for our protocol to be transitioned to fully remote due to the pandemic, which did not allow us to conduct direct measures of participants in person. Direct assessment of more detailed motor skills and social skills may have allowed us to detect changes secondary to participation in the dance intervention. Despite opportunities for one-on-one engagement, the program’s effects on social engagement may have also been attenuated due to the online format of the classes.

In this pilot study, we demonstrate the feasibility of developing and implementing an online dance intervention for individuals with NDDs. Furthermore, this intervention shows benefits in motor skills after a 10-week period with a dose of 1 h per week. Moving forward, we are utilizing direct standardized and quantitative measures of motor skills and social communication to further examine the impact of this dance intervention. Future studies will include an IQ assessment to understand whether this differentially affects the results of the intervention. Future work could also assess the impact of EMI participation on teachers and buddies in order to provide further insight into the efficacy of this approach. Our preliminary results support the growing body of research that OPA is a promising intervention for motor skills among children and adolescents with NDDs.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Full details of the trial protocol version that is reported in this paper can be found on the ClinicalTrials.gov Protocol Registration System, available at https://clinicaltrials.gov/study/NCT04762290?tab=history&a=3 .

Abbreviations

Attention deficit/hyperactivity disorder

Autism Intervention Research Network on Physical Health

Expressive Movement Initiative

Health Services and Resources Administration

Movement Assessment Battery for Children Checklist

Movement Assessment Battery for Children – second edition

Developmental coordination disorder

Neurodevelopmental disability

Organized physical activity

Social Responsiveness Scale

University of California, Los Angeles

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Acknowledgements

We acknowledge the Expressive Movement Initiative group at UCLA for their invaluable role as organizers and teachers of the dance program used in this research. We also acknowledge the Autism Intervention Research network on Physical health (AIR-P) for supporting this project.

This study was funded by the Health Resources and Services Administration (HRSA) (Grant NO.: UT2MC39440). The funding agency did not play a role in the design of the study, the collection, analysis, and interpretation of the data, nor in the writing of this manuscript. Additional funding support was received from the Department of Health and Human Services, Administration for Community Living (Grant NO.: 90DDUC0129) and the National Institute of Child Health and Human Development (Grant NO.: K23HD099275).

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Stanford School of Medicine, Stanford, CA, USA

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Contributions

JA entered and interpreted data collected during the study and drafted the manuscript. CT and HS assisted with the collection of data and data entry. EC made significant contributions to the design of the dance intervention and the randomized control trial. NJ generated the allocation sequence for randomization. DP and NJ conducted the statistical analysis for the study and advised on interpreting and reporting results. CL advised on the study design and data collection methods. RW oversaw the design and implantation of the study, the analysis and interpretation of the results, and was a major contributor in writing the manuscript. All authors read and approved the final version of this manuscript.

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Correspondence to Rujuta B. Wilson .

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Anderson, J.T., Toolan, C., Coker, E. et al. A novel dance intervention program for children and adolescents with developmental disabilities: a pilot randomized control trial. BMC Sports Sci Med Rehabil 16 , 109 (2024). https://doi.org/10.1186/s13102-024-00897-3

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Predictors for interest to participate in digital mental health therapy: a cross-sectional survey of individuals with anxiety and depression

• Tharidu Gunawardena 1 ,
• Marilyn M. Bartholmae 1 , 2 ,
• Matvey V. Karpov 1 ,
• Rohan Dod 1 ,
• Kripa Ahuja 1 ,
• Aishwarya Rajendran 1 ,
• Mayuri Kathrotia 1 &
• Sunita Dodani 1 , 3  

BMC Digital Health volume  2 , Article number:  21 ( 2024 ) Cite this article

Metrics details

Due to a multitude of factors, the onset of the COVID-19 pandemic resulted in a significant increase in mental health issues within society, including depression and anxiety. Due to the increased trend of mental health disorders in society, digital mental health therapies are more useful than ever. With the emergence of programs utilizing Internet Cognitive Behavioral Therapy (iCBT), mental health resources are easily accessible and can be widely implemented to those in need.

The aim of this study was to identify predictors for interest to participate in SilverCloud digital mental health therapy among individuals with mild to severe anxiety and/or depression based on preliminary findings from the COVIDsmart study.

COVIDSmart participants who had moderate to severe anxiety and/or depression based on the PHQ-9 and GAD-7 scores, and who consented to be contacted for future studies, were invited to complete a needs assessment survey via Research Electronic Data Capture (REDCap). This assessment used self-reported measures including medical diagnoses, mental health services received, reasons for anxiety and/or depression, the use of coping strategies, suicidal ideology using the Ask Suicide Questions tool, and whether they would be interested in receiving free digital mental therapy. Descriptive statistics were used to report participants’ demographics and a logistic regression was used to find predictors for interest in participation in SilverCloud. SAS 9.4 was used and p values < 0.05 were considered significant.

Out of the original 782 COVIDsmart participants, 634 consented to be contacted for future studies, 280 were subsequently invited to complete the SilverCloud needs assessment, and 120 individuals completed it. The largest demographic among these participants were females (70.83%) who identified as White (80.83%). The mean age was 48.74 years ( SD  = 14.66). Results revealed that having a mental health comorbidity significantly predicted the likelihood of interest in participating in the SilverCloud digital mental health program ( p  = 0.027).

Conclusions

In this study, mental illness comorbidities predicted the interest to participate in digital mental therapy. Fragmented healthcare and perceptions of unmet care needs are likely contributor factors. Further research with a diverse sample of participants is necessary for generalizability. Findings may have important implications for healthcare best practices.

Peer Review reports

Introduction

Repeatedly, it has been evident that periods of widespread human catastrophe or disaster often result in large-scale detrimental impacts on mental health. During the COVID-19 pandemic, there were not only new cases of mental health disorders but also an exacerbation of existing mental health conditions [ 1 ]. According to a briefing released by the World Health Organization in March 2022, during the first year of the COVID-19 pandemic, the prevalence of major depressive disorders and anxiety disorders had increased significantly [ 2 ]. There were multiple factors leading to a significant spike in mental health disorders. Common stressors were social isolationism, perpetual fear of COVID-19 infection, loss of employment, death of a loved one or friend and uncertainty about the future [ 3 ]. Despite many of the COVID-19 restrictions and lockdowns being relaxed since March of 2020, the damaging adverse mental health effects of the pandemic seem to have persisted throughout the United States (U.S). According to a CDC report, the prevalence of anxiety and depressive disorders has been three and four times higher, respectively, compared to pre-pandemic levels within the U.S.[ 4 ]. In 2021, mental health screenings were taken by over 5.4 million people, indicating a near 500% increase since 2019 and a 103% increase since 2020 [ 5 ].

In the state of Virginia, the COVIDsmart study was initiated to assess the effects of COVID-19 on health, behavioral and economic status of individuals in Virginia. The study gathered data from March 2021 to November 2021 through longitudinal surveys. The surveys comprised the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), a condensed version of the UCLA Loneliness Scale, and a condensed version of the Social Network Index [ 6 ]. 782 Virginia residents, spanning from 18 to 87 years, registered in the COVIDsmart study. The COVIDsmart sample consisted of mostly White (81.5%), middle aged (mean age 51), middle income (51% with income of $100,000 or higher), college educated (62.6%) females (78.6%) [ 6 , 7 ]. The COVIDsmart preliminary results revealed that 21% of participants had moderate to severe anxiety and 25% had moderate to severe depression [ 7 ]. It was evident that there was a significant presence of mental disorders among Virginia residents after the COVID-19 pandemic. This prompted us to believe that there was a considerable number of individuals that required mental health services, but simply did not receive adequate counseling or therapy, leading to unmet health needs.

Based on these preliminary findings, a significant percentage of the participants of the COVIDsmart study had experienced some level of depression or anxiety, therefore the SilverCloud study was conceived and was funded by Eastern Virginia Medical School (EVMS) to alleviate the high rates of anxiety and depression among Virginians. Designed to alleviate depression and anxiety, SilverCloud is a digital mental health program that uses Internet Cognitive Behavioral Therapy (iCBT). CBT has been a highly effective form of psychological therapy for over 50 years. As patient requirements have increased, mental healthcare delivery has evolved significantly in the past decade with the introduction of new tools. Psychological interventions, specifically CBT, have become easier to implement in the form of iCBT [ 8 ]. The benefits of iCBT include cost effectiveness and global use [ 9 ]. Additionally, patients can utilize iCBT programs from the comfort of their homes, without the need for any in-person interaction. This can be particularly useful for those who have busy schedules or reside in more remote locations.

Although the mental health digital landscape is full of CBT-based apps and other digital interventions, meta-analyses and systematic reviews suggest that iCBT targeting anxiety and depression is not always effective. For example, a 2020 study by Etzelmueller et al., provided evidence for efficacy of iCBT interventions via randomized clinical trials [ 10 ] while Liu et al., 2022, suggested some iCBT-based modules are effective in treating anxiety and depression but other modules are not. Implementation science highlighting specialized needs, resources, and training to operate digital services is necessary for the success of digital therapeutics in healthcare [ 11 ]. SilverCloud Health has achieved global reach by using implementation science strategies and is the global leader in developing and delivering evidence-based mental health interventions across healthcare systems, payors such as insurance companies and government plans, providers, employer organizations, and charity/advocacy agencies [ 12 ]. SilverCloud delivers a vast array of personalized interventions to meet the specific mental health needs of individuals. Compared to other traditional digital platforms, SilverCloud offers self-guided programs, digital coaching, progress tracking tools and mobile accessibility in a secure environment. SilverCloud programs for anxiety and depression are recommended based on PHQ-9 and GAD-7 scores. These programs encourage the development of awareness and understanding of emotions, while increasing daily enjoyable activities and motivation. CBT is used to teach healthy thinking, feelings, behaviors, and to make positive changes to overcome anxiety and/or depression. SilverCloud programs include 10 modules: Getting Started, Understanding Depression and Anxiety, Noticing Feelings, Boosting Behavior, Spotting Thoughts, Challenging Thoughts, Managing Worry, Core Beliefs (unlockable by Coach), Facing Your Fears (unlockable by coach), and Bringing It All Together. SilverCloud coaches are licensed mental health professionals who provide weekly support to motivate users to engage in the SilverCloud programs, provide daily and weekly goals, and help users apply their learnings into everyday life [ 13 ]. The preliminary randomized controlled trials, which utilized SilverCloud, indicate that this therapy is effective as a stand-alone treatment for mild to moderate anxiety and depression [ 14 ].

The objective of this study was to determine the factors that can predict interest in participating in the SilverCloud program by COVIDsmart participants. Additionally, a secondary objective was to recognize the particular traits that enhance the probability of people seeking digital mental health care. This data could have significant clinical implications as it would enable healthcare professionals to gain better insights into the mental health needs of Virginians. With a greater understanding of the characteristics of these individuals in local communities, clinicians can customize digital interventions that cater to specific groups. This approach could enhance the rates of mental health screening and treatment accessibility among vulnerable populations, leading to better patient outcomes. Additionally, utilizing this information may enable digital mental health professionals to provide tailored and suitable treatment to their patients in the future. The implementation of these strategies could potentially have a notable effect in alleviating the continuous mental health emergency at a local, national, and conceivably worldwide scale.

Study design and recruitment

In order to conduct the SilverCloud study, the participants were recruited from the original COVIDSmart study. There were several recruitment strategies implemented in the COVIDSmart study, particularly to increase the likelihood of including ethnic minorities, individuals from rural areas, and individuals from lower socioeconomic backgrounds. The strategies implemented included online articles, employer e-newsletters, purchased email lists, social media posts, television, radio, paper flyers, and digital flyers. As an incentive, electronic gift cards were used to garner participation in the study. The data collection was conducted via an online HIPAA compliant platform designed by Vibrent Health Inc. The study was a joint effort with EVMS-Sentara Healthcare Analytics and Delivery Science Institute (HADSI), George Mason University, and Vibrent Health. 782 residents of Virginia enrolled in the COVIDSmart registry from March to May 2021.

The SilverCloud study was created to address the COVIDSmart study’s preliminary results showing 21% of participants had moderate to severe anxiety and 25% had moderate to severe depression [ 15 ]. Figure 1 shows the demographics for COVIDSmart participants.

Demographics of COVIDsmart participants, N =771

Out of the 782 original COVIDsmart participants, 634 of them consented to be contacted for future studies. 280 of the COVIDSmart participants who had moderate to severe anxiety and/or depression based on the PHQ-9 and GAD-7 scores, and who consented to be contacted for future studies, were invited to complete a needs assessment questionnaire to further determine eligibility to the SilverCloud study. 120 individuals completed the SilverCloud needs assessment. The needs assessment (Appendix 1 ) evaluated self-reported measures such as medical diagnoses, mental health services received, reasons for anxiety and/or depression, the use of coping strategies, suicidal ideology (using the Ask Suicide Questions (ASQ) survey), and whether they would be interested in receiving free digital mental therapy.

Thus, the purpose of this survey was twofold: to determine their eligibility for the 8-week SilverCloud study and to assess the factors contributing to their elevated levels of anxiety and/or depression during the COVID-19 pandemic (Fig. 2 ).

Procedure for participant recruitment and enrollment

COVIDsmart participants who had an acute suicide screening based on the ASQ survey or self-reported substance abuse and dependence were not eligible to participate in SilverCloud. However, they were provided with a list of resources they could reach for immediate assistance (Appendix 2 ). This study was approved by the Eastern Virginia Medical School Institutional Review Board (IRB# 21–07-FB-0185).

Data collection

The SilverCloud needs assessment survey was created using Research Electronic Data Capture (REDCap). REDCap is a secure web-based application used to create forms and manage databases in order to support data capture and surveys for research. REDCap data is stored securely at EVMS on private, protected servers, and meets requirements for the Health Insurance Portability and Accountability Act for collection of personal health information. The needs assessment was sent via REDcap to identified potential participants.

Statistical analysis

Descriptive statistics were used to analyze the demographics of participants. To find predictors for interest to participate in SilverCloud, we used a logistic regression including the independent variables: receiving mental health care (yes or no), having coping strategies (yes or no), severity categories for GAD-7 and PHQ-9 (moderate to severe), mental illness comorbidity (yes or no), current medications for anxiety and/or depression (yes or no), race, sex, and age. The dependent variable was interest to enroll in SilverCloud (yes or no). We conducted the analysis using SAS 9.4, and p values < 0.05 were considered significant.

A total of 120 participants who were part of the COVIDsmart program completed a needs assessment for SilverCloud. Table 1 shows that the majority of SilverCloud participants were female (70.83%) and White (80.83%). The mean age of participants was 48.74 years ( SD  = 14.66, Table  2 ).

The study found that having a co-existing mental health condition was a significant predictor of the likelihood of showing interest in participating in the digital mental health SilverCloud program (p = 0.027). Among participants with moderate to severe anxiety and/or depression who were enrolled in COVIDsmart, those with a comorbidity of mental illness were 378% more inclined to be interested in SilverCloud as compared to those without a mental illness comorbidity. The mental health comorbidities reported by SilverCloud participants had a wide range, but the most common comorbidity was Posttraumatic Stress Disorder (PTSD) (28.6%), followed by eating disorder (21.4%) and Attention Deficit Hyperactivity Disorder (ADHD) (14.3%), as presented in Table  3 . These reported comorbidities were based off of self-reported survey data, and were not verified diagnoses.

However, factors such as race, gender, age, taking medication for anxiety or depression, anxiety severity, depression severity, use of coping strategies, and receiving mental health services did not have any predictive value in terms of interest in participating in SilverCloud ( p  ≥ 0.05), as shown in Table  4 .

Principle results

This study showed that the only significant factor that led COVIDsmart participants to be interested in participating in SilverCloud for depression and anxiety treatment was a mental illness comorbidity. The most common comorbidities reported included PTSD, eating disorders, and ADHD. Individuals with comorbid mental illnesses experience a cumulative medical burden, often requiring multiple physical and mental health services [ 15 , 16 ]. These individuals are more likely to experience unintegrated and uncoordinated healthcare delivery [ 17 , 18 ]. Furthermore, individuals with multiple mental health comorbidities are more likely to have perceived unmet needs for care [ 19 , 20 ]. Thus, we hypothesize that individuals who experience fragmented healthcare and perceived unmet care needs may be more willing to accept mental health treatment for new conditions.

In addition, participants who had high levels of anxiety and/or depression, but no prior experience with mental health counseling, may be more apprehensive to receive treatment due to societal stigma about treatment for mental disorders. Participants with mental disorders with high levels of experienced stigma have lower rates of recovery since they are less likely to receive mental health services for their condition [ 21 ]. In this study, it seemed as if participants with multiple mental conditions were more likely to accept digital mental health treatment. The digital therapeutic setting may remove the stigma barrier for individuals with comorbid mental illnesses.

The PHQ-9 and GAD-7 scores did not have a significant predictive value for participating in mental health therapy. Unfortunately, it is unclear as to why this is. We hypothesize that since PHQ-9 and GAD-7 scores are only indicators for depression and anxiety alone, respectively, it is possible that despite a high level of depression and/or anxiety, the mental burden on these participants may not be as taxing as it is for participants with multiple mental health comorbidities, therefore, these participants were less likely to enroll in digital mental health therapy compared to participants with multiple comorbid mental illness. The individuals who chose to enroll in digital mental therapy may require integrated healthcare approaches to address their physical/mental multi-comorbidity healthcare needs. Additionally, participants who were already receiving mental health care services as well as those who were using coping strategies such as exercising and drinking less alcohol, were not likely to be interested in digital mental therapy.

The majority of participants in the COVIDsmart study were Non-Hispanic Whites and females, which explains why a similar demographic makeup was observed in the SilverCloud study. However, the SilverCloud study had a slightly higher percentage of female and Non-Hispanic White participants compared to the COVIDsmart study. Additionally, the greatest percentage of COVIDsmart participants fell into the 46–55 age range (Fig. 1 ). This corresponds accordingly with the mean age of SilverCloud participants being 48.74 years old (Table  2 ). Despite this, neither race nor gender nor age were significant predictors of participation in digital mental health therapy. It is not clear why these particular demographics were more likely to participate in both studies. Non-Hispanic Whites are known to have higher rates of mental disorders compared to people of color, although this may be due to various factors such as discriminatory medical practices, negative cultural attitudes towards mental illness, lack of insurance, and language barriers that minorities face [ 22 , 23 ].

Future directions

Our findings suggest healthcare workers should especially turn their attention towards individuals who are already suffering from coexisting mental conditions. It is very possible that the introduction of future large-scale stressors can result in new cases or the exacerbation of milder forms of depression and anxiety in these patients. Mental health counselors, psychiatrists, and therapists should regularly screen patients with existing mental health conditions with the PHQ-9 and GAD-7 for any new developments regarding depression and anxiety. Moreover, future research is needed to further evaluate the role of healthcare fragmentation and perceptions of unmet medical care needs in the enrollment of digital mental therapies. Findings could have important implications for healthcare best practices.

Future research should expand the scope and demographics of this study. While the cause of the increase in the percentage of highly-educated female and Non-Hispanic White participants in the SilverCloud study remains unknown, it is important to consider this metric on a global scale. Large nationally representative US surveys have found that mental health of Black, Hispanic, and Asian respondents worsened relative to White respondents during the pandemic, including significant increases in depression and anxiety among racialized minorities compared to White people [ 24 ]. These surveys also showed that White respondents were the most likely to receive professional mental health care before and during the pandemic, while minority respondents demonstrated higher levels of unmet mental health care needs during the pandemic than White respondents [ 24 ]. The findings of our study showed a similar trend, wherein there was an increase in the number of White participants seeking mental health care. Although our study was limited in size compared to a nationwide study, the outcomes are comparable. Securing a diverse socio-economic and racial participation is important for generalizability of future studies.

Limitations

The study has several limitations. Firstly, it only included participants from the COVIDsmart study, which means that the sample was restricted to residents of Virginia. Secondly, research fatigue from the six-month longitudinal COVIDsmart study could have deterred some participants from taking part in the SilverCloud study, thus resulting in a smaller sample size. Thirdly, the socioeconomic and racial diversity of the SilverCloud study participants did not accurately reflect the Virginia population, as there was an overrepresentation of highly educated White females and an underrepresentation of minority groups, including those living in rural areas. The lack of participant diversity and limited scope of this study may significantly hamper its generalizability to broader populations.

Fourthly, because the SilverCloud program was only accessible online, participants without internet access in Virginia may have been less likely to participate. In the future, alternative treatment options such as traditional in-person face-to-face therapy could be considered, although this would require additional resources and higher costs. Fifth, the mental illness comorbidity was self-reported. We included the variable comorbidity (yes or no) in the logistic regression model to determine whether having a mental illness comorbidity would influence the outcome: interest to participate in SilverCloud. Sixth, high risk respondents to the needs assessment could only be provided with available resources to receive help, rather than being provided with an on demand consultation with an available clinician.

Individuals with mental illness comorbidities may have a higher tendency to seek and participate in digital mental health programs amid the COVID-19 pandemic. Digital CBT-based programs can potentially improve the accessibility of care for this group. However, programs should prepare to address the needs of patients with mental illness comorbidities as they may require multidisciplinary healthcare services. Mental health professionals and researchers need to gain a deeper understanding of the unique needs of this population.

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

Attention Deficit Hyperactive Disorder

Eastern Virginia Medical School

Internet cognitive behavioral therapy

Posttraumatic Stress Disorder

Research Electronic Data Capture

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Acknowledgements

We thank all of the participants who took part in the SilverCloud study. A preprint version of this manuscript has been published in JMIR Publications and is provided as #15 in the list of references.

SilverCloud did not provide any funding for this project. All funding was provided internally by Eastern Virginia Medical School.

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Tharidu Gunawardena, Marilyn M. Bartholmae, Matvey V. Karpov, Rohan Dod, Kripa Ahuja, Aishwarya Rajendran, Mayuri Kathrotia & Sunita Dodani

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MB, MK, and SD contributed to the study design, data collection, and data analysis. TG, RD, KA, AR, MK, MB, MK, and SD wrote and revised the main manuscript. All authors contributed to the article and approved the submitted version.

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Gunawardena, T., Bartholmae, M.M., Karpov, M.V. et al. Predictors for interest to participate in digital mental health therapy: a cross-sectional survey of individuals with anxiety and depression. BMC Digit Health 2 , 21 (2024). https://doi.org/10.1186/s44247-024-00080-1

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Phytoconstituents of Artemisia Annua as potential inhibitors of SARS CoV2 main protease: an in silico study

• Eraj Irfan 1 ,
• Erum Dilshad 1 ,
• Faisal Ahmad 2 ,
• Fahad Nasser Almajhdi   nAff3 ,
• Tajamul Hussain 4 ,
• Gholamreza Abdi 5 &
• Yasir Waheed 6 , 7   nAff8  

BMC Infectious Diseases volume  24 , Article number:  495 ( 2024 ) Cite this article

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In November 2019, the world faced a pandemic called SARS-CoV-2, which became a major threat to humans and continues to be. To overcome this, many plants were explored to find a cure.

Therefore, this research was planned to screen out the active constituents from Artemisia annua that can work against the viral main protease Mpro as this non-structural protein is responsible for the cleavage of replicating enzymes of the virus. Twenty-five biocompounds belonging to different classes namely alpha-pinene, beta-pinene, carvone, myrtenol, quinic acid, caffeic acid, quercetin, rutin, apigenin, chrysoplenetin, arteannunin b, artemisinin, scopoletin, scoparone, artemisinic acid, deoxyartemisnin, artemetin, casticin, sitogluside, beta-sitosterol, dihydroartemisinin, scopolin, artemether, artemotil, artesunate were selected. Virtual screening of these ligands was carried out against drug target Mpro by CB dock.

Quercetin, rutin, casticin, chrysoplenetin, apigenin, artemetin, artesunate, sopolin and sito-gluside were found as hit compounds. Further, ADMET screening was conducted which represented Chrysoplenetin as a lead compound. Azithromycin was used as a standard drug. The interactions were studied by PyMol and visualized in LigPlot. Furthermore, the RMSD graph shows fluctuations at various points at the start of simulation in Top1 (Azithromycin) complex system due to structural changes in the helix-coil-helix and beta-turn-beta changes at specific points resulting in increased RMSD with a time frame of 50 ns. But this change remains stable after the extension of simulation time intervals till 100 ns. On other side, the Top2 complex system remains highly stable throughout the time scale. No such structural dynamics were observed bu the ligand attached to the active site residues binds strongly.

This study facilitates researchers to develop and discover more effective and specific therapeutic agents against SARS-CoV-2 and other viral infections. Finally, chrysoplenetin was identified as a more potent drug candidate to act against the viral main protease, which in the future can be helpful.

Peer Review reports

SARS-CoV-2 first emerged in China and then transmitted to the rest of the world. It first emerged in bats and was later transmitted to humans with an intermediatory source that is still not known [ 1 ]. The virus belongs to the β-group and is a positive-sense RNA-enveloped virus. This zoonotic virus can easily adapt and become more virulent with time [ 2 ]. The diameter ranges from 65–125 nm and has four main structural proteins, which include spike glycoproteins, membrane glycoproteins, small envelope glycoproteins and nucleocapsid protein with several other proteins [ 3 ]. The life cycle of the virus depends upon two main polypeptides pp1a and pp1ab which further process 15 non-structural proteins with the help of papain-like protease and the main protease M pro [ 4 ]. This main protease is responsible for cleavage at 11 sites in the replicase protease. For this reason, M pro is selected as a potential drug target site [ 5 ]. M pro a 33.8 KDa CoV enzyme plays a major role by digesting the replicase polyproteins of the virus at 11 conserved sites. This makes M pro an efficient drug target site against the active constituents present in Artemisia annua [ 6 ]. This protease is considered a cysteine protease as it has a cysteine histidine catalytic dyad and cleaves peptide bonds at Glm-Ser/ Ala/Gly [ 7 ]. In SARS-CoV-2 14 different proteolytic sites of PLpro and 3CLpro were determined. At the N-terminal, PLpro cleaved three sites at 181–182, 818–819 and 2763–2764 and at the C-terminal it cleaves 11 different sites producing 15 non-structural proteins. These contain Nsp3 with multiple domains with a unique domain of SARS-a proteolytic enzyme and a deubiquitylation enzyme. Nsp5 is the 3CLpro, Nsp12 is RdRp (RNA dependent-RNA polymerase) and Nsp13 is a helicase [ 8 ].

The virus-infected individuals showed variations in symptoms and the rate of infection. Human coronavirus caused upper respiratory tract infections [ 9 ]. An initial study showed that almost 91% of affected individuals showed high fever, 77% had a cough, 44% individuals felt fatigued, other symptoms like salivation were shown by 28%, headache by 8%, 5% had hemoptysis and 3% faced diarrhea [ 10 ]. For the treatment of the symptoms shown, four kinds of vaccines have been developed, which include the whole virus vaccine, second one is the type of recombinant protein subunit vaccine which specifically targets the spike protein. The replication-incompetent vaccine and the nucleic (mRNA) based vaccine [ 11 ]. Many drugs were also repurposed, azithromycin has been commonly used in Pakistan and other countries. Azithromycin is used during respiratory, urinary, dermal and other bacterial infections. It is also used during chronic inflammatory disorders that include post-transplant bronchitis, diffuse pan bronchitis and rosacea [ 12 ]. Many medicinal plants such as Ar temisia annua belonging to the family Asteraceae were also exploited. This plant is rich in around 600 active metabolites and has shown anti-fungal, anti-asthmatic, hepatoprotective and antioxidant properties [ 13 ]. In Madagascar, a drink was prepared with the infusion of Artemisia annua and other plants to cure Covid-19 [ 14 ].

In addition, the development of antiviral medications that impede the activity of the SARS-CoV-2 Mpro is viable and has potential for practical use. Phytochemicals produced Ar temisia annua aid in combating illnesses caused by fungus, bacteria, and plant viruses [ 15 ]. The rationale for selecting this plant is based on the phytochemicals they contain generally have beneficial effects on health [ 16 ]. This include bioactive nutrients that have been shown to have positive effects on human health by reducing the risk of major chronic illnesses. Phytochemicals have been shown to have potential efficacy in treating many illnesses, as indicated by preclinical, clinical, and epidemiological studies, owing to their antioxidant and anti-inflammatory properties [ 17 ].

Molecular docking has been in use for the past three decades for drug designing through computer assistance. Docking is preferred while performing virtual screening for the analysis of the functions of the compounds. Results can easily be classified through docking and it can give a detailed analysis of how the ligand interacts with the protein, which can optimize the lead compounds for drug development [ 18 ]. Different docking programs use one or more search programs for prediction of possibilities of receptor-ligand complexes. For this purpose, molecular docking has become a key tool for drug discovery and molecular modeling applications. The result gives a score of the interaction, making it more reliable for predicting the ligand pose and, through that pose binding site of the ligand can easily be determined [ 19 ].

Materials and methods

Retrieving protein’s structure.

For the study, the SARS CoV-23 CLpro or M pro was selected as a potential drug target site. The crystal structure of the main protease was downloaded under the PDB ID 6lu7 ( https://www.rcsb.org/structure/6lu7 ).

Cleaning of protein’s structure

M pro is a linear chain that consists of 1–306 amino acids referring to its A chain. Extra constituents were present as side chain C and the Nitrogen and water components were removed through Pymol [ 20 ].

Determining the physicochemical properties of M pro

The physicochemical properties of the protein which are molecular weight, isoelectric point, amount of negative and positive residues, extinction coefficient, instability index, aliphatic index and GRAVY were determined using ProtParam, which is a tool of ExPAsy [ 21 ].

Ligand selection and preparation

The reported antiviral ligands of Artemisia annua were selected as potential hits. The 3D structures for the 25 selected ligands were downloaded from the PubChem database ( https://pubchem.ncbi.nlm.nih.gov/ ). The data was obtained in SDF format. The 3D structures were represented in Kekule’s form. The molecular mechanics 2 (MM2) energy of the ligands was minimized by the use of Chem3D ultra [ 22 ]. The reported compounds compactness was removed with addition of hydrogen atoms and making them flexible against the target protein. This was followed by drug likeness and lead likeness by applying Lipinski rule of five and other filters using SwissAdme [ 23 , 24 ].

Molecular docking

A blind docking software CB-Dock [ 25 ] was used for the docking of proteins and ligands. It finds the docking sites automatically and gives the calculation of the size, center and sites of bonding in 5 different poses of interaction. A grid box of x, y and z coordinated were adjusted i.e. x = -27.77, y = 13.56, z = 56.09 with size of x = 51.4, y = 62.45 and z = 53.84. The best pose is the one with the minimum vina score in KJ/mol.

Visualization of docking result

For visualization of the docked results, Pymol was used which provides a plugin that can access results easily and makes their visualization clear.

Analysis of docking result

For the 2D generation of protein–ligand complex LigPlot has been used which provides an analysis of hydrophobic and hydrogen bond interactions.

ADME and drug likeness studies

By using the PkCSM pharmacokinetics tool ADME + T properties (Absorption, Distribution, Metabolism + Toxicity) were studied and toxicity was determined of the leading compounds (Quercetin, rutin, catechin, chrysoplenetin, apigenin, artemetin, artesunate, sopolin and sitogluside) and the comparative drug (Azithromycin) [ 26 ].

The druglikeness was studied using (SwissADME server http://www.swissadme.ch/ ) Lipinski rule of 5 (octanol–water partition coefficient log P value of drug like compound be limited to 5, molecular weight should be > 500, hydrogen bond acceptance number be 10 and hydrogen bond donor number should be 5) [ 24 ].

Molecular dynamics simulations

Molecular Docking Studies can predict ligand binding states in static conditions. Docking provides a static depiction of how a chemical interacts with the active site of a protein [ 27 ]. To compute atom motions over time, MD simulations employ Newton's classical equation of motion. Amber16 software was applied for the complex system to check the carbon alpha atom structural deviation throughout the time scale [ 28 ]. They can predict ligand binding status in physiological environments [ 29 , 30 ]. Protein Preparation was done using chimera with 750 steepest and conjugate gradients with a total of 1500 steps to perform complicated optimization and minimization on the receptor-ligand combination. Both the systems were prepared against the Top1 and Top2 complex system using the System Builder tool. TIP3P (Transferable Intermolecular Interaction Potential 3 Points) of AMBER16 tool was chosen as a solvent model with an orthorhombic box. To neutralize the models, counter ions were introduced. 0.15 M sodium chloride (NaCl) was added to mimic physiological circumstances. The NPT ensemble with a temperature of 300 K and a pressure of 1 atm was utilized throughout the simulation. Before running the simulation, the models were relaxed. The trajectories were collected every 200 ps, and the system was prepared by introducing minimization, heating, equilibrium and pressure states. Final production of the simulation has been run via Amber 16 and RMSD (root mean square deviation) of the protein and ligand over time was used to test the stability of the simulations. The total simulations time given for both the systems was applied for 100 ns. Followed by trajectories analysis with RMSD, RMSF, SASA, Hydrogen bonds analysis, PCA and Binding free energies calculations.

Refining of protein

The 3D structure was obtained from PDB (Protein Data Bank) under the name 6LU7 with the DOI number https://doi.org/10.2210/pdb6LU7/pdb [ 31 ]. The structure obtained was attached with an N3 inhibitor, through PyMol the inhibitor and the extra side chain C was removed as shown in Fig.  1 . Domains I and II had an anti-parallel β barrel structure, whereas Domain III has a globular structure consisting of 5 anti-parallel α helices. Domain III was connected by Domain II by a loop region consisting of 185–200 residues [ 6 ].

Refining of 6LU7

Physicochemical properties of protein

By using ProtParam a tool of ExPASy the physiochemical properties were studied. Table 1 shows the collective weight of negative and positive amino acid residues as 33,796.64. The pI value indicates acidic nature of M pro . The low value of GRAVY indicates good interactions with water molecules and values for instability index and aliphatic indexes show the stability of the protein.

Identification of functional domains of protein

Functional domains are the active part of the protein that are used for interaction with other proteins and substances. The InterPro job ID for finding the functional domains of 6LU7 is https://www.ebi.ac.uk:443/interpro//result/InterProScan/iprscan5-R20210417-071019-0353-62313319-p2m/ . Two promoters A and B combine to form a 306 amino acid long polypeptide consisting of three domains. Domain I is 8–101 residues, Domain II is 102–184 residues and Domain III are 201–303 residues. There is a cleft between domain I and II which acts as a binding site [ 6 ].

Selection of ligands

Ligand selection was based on the best resolution structure, chemical class of the crystals bound to the protein and binding affinities. The most important is the conformation of the ligand. The active constituents of the selected plant were searched from the world’s largest chemical databank, i.e. PubChem [ 14 , 24 , 32 , 33 , 34 ]. From PubChem 25 active constituents of Artemisia annua based on resolution, chemical class, binding affinity and conformations, the 3D structures were downloaded in SDF format. The energies of the downloaded structures were minimized using MM2 force field in chem draw 3D software so that no effect on the docking score occurs. The selected ligands include Alpha-pinene, Beta-pinene, Carvone, Myrtenol, Quinic acid, Caffeic acid, Quercetin, Rutin, Apigenin, Chrysoplenetin, Arteannunin b, Artemisnin, Scopoletin, Scoparone, Artemisnic acid, Deoxyartemisnin, Artemetin, Casticin, Sitogluside, Beta-sitosterol, Dihydroartemisnin, Scopolin, Artemether, Artemotil and Artesunate (Table S2) [ 13 , 14 , 32 , 33 , 35 ].

Drug-likeliness and toxicity prediction

Drug likeness of the compounds was done by Lipinski Rule of Five which indicates that the molecular weight of a protein should be ≤ 500, log P ≤ 5, H-bond donors ≤ 5, and H-bond acceptors ≤ 10. The rules are followed by orally administered drugs. A compound following three of the rules is considered a drug [ 24 , 36 ]. Supplementary Table S1 shows that Rutin does not follow Lipinski rule whereas Sitogluside disobeys two of the rules.

Toxicity prediction

PkCSM [ 37 ] an online tool was used to check the toxicity of the ligands and that of the standard drug. Table 2 shows the results of toxicity prediction. The table shows that both artemisinin and dihydroartemisinin are AMES toxic which means that they can be mutagenic and can later be carcinogenic. Rutin and beta-sitosterol are hERG II inhibitors that can lead to the potassium channel inhibition leading to QT syndrome. Myrtenol and artemisinic acid are sensitive to skin. The values of T.pyriformis toxicity show that β-pinene, artemisinic acid and scopoletin are toxic. Sitogluside and beta-sitosterol are minimally toxic.

Molecular docking was performed using M pro as receptor protein and the ligands selected above. The protein in PDB format and the ligands in SDF format were docked. The CB dock server was applied and then check the input files by converting them into pdbqt format files using OpenBabel and MGL Tools [ 38 , 39 ]. Then CB dock predicts the cavities of the receptor and calculates the centers and sizes of the top five cavities. Among the five best conformations the best one was selected based on a high-affinity score of the interaction between the protein and the ligand [ 40 ]. Ligands showing the best binding score between the selected ligands and the protein M pro are shown in Table  3 .

Ligands like quercetin, rutin, casticin, chrysoplenetin, apigenin, artemetin, artesunate, scopolin and sitogluside have shown good docking results. Rutin shows a binding score of -8.9 kJ/mol with a log P value of -1.6871. Apigenin shows a binding score of -7.8 kJ/mol with a log P value of 2.5768. chrysoplenetin shows a binding score of -7.7 kJ/mol and logP vale is 2.9056. Quercetin, Artemetin, casticin and sitogluside show vina score as -7.6 kJ/mol with log P values as 1.988, 3.2086, 2.9056 and 5.849 respectively. Scopolin and artesunate show a score of -7.5 kJ/mol with log P values as -1.0197 and 2.6024. Ligands like quercetin, rutin and apigenin had already been reported to be docked against M pro by using Auto dock wizard as reported by Oluwaseun Taofeek in 2020. Quercetin showed a score of -7.2 which is less than the docking score by CB-dock. Rutin showed a score of -7.7 kJ/mol and apigenin gave a binding score of -6.8 kJ/mol which is less than that shown by CB-dock [ 41 ].

Interaction of ligands and protein

The deducted docked results were analyzed using LigPlot and PyMol. The interaction between the ligands and the receptor protein was predicted through LigPlot + [ 42 ]. The graphical system of LigPlot automatically generates 2D pictures of interactions from its 3d coordinates. The 2D diagrams of the interaction of the ligands with the best docking score and the standard drug with the protein are shown in Fig.  2 a-J. Whereas Table  4 shows the hydrogen and hydrophobic interactions.

A Interaction of quercetin with M pro , B Interaction of rutin with M pro , C Interaction of apigenin with M pro , D Interaction of chrysoplenetin with M pro , E Interaction of artemetin with M pro , F Interaction of casticin with M pro , G Interaction of sitogluside at cavity 1 with M pro , H Interaction of sitogluside at cavity 4 with M pro ( I ) Interaction of scopolin with M pro and ( J ) 2 J Interaction of artesunate with M pro

ADME properties of ligands

pkCSM is the second tool used for the assessment of ADME properties [ 18 ].

Table S3 shows the result of absorption properties of ligands. Quercetin, rutin, sitogluside, scopolin and artesunate show low CaCO 2 solubility. Rutin shows poor intestinal absorption. All ligands act as P-glycoprotein substrates. Artemetin and sitogluside act as P-glycoprotein I inhibitors and artemetin, sitogluside, casticin and chrysoplenetin act as P-glycoprotein II inhibitors. Azithromycin shows a low CaCO 2 solubility and water solubility. It has a lower value of skin permeability and is a P-glycoprotein substrate and P-glycoprotein I inhibitor. The Pkcsm absorption properties of artemetin, casticin, scopolin, and artesunate have already been reported by Zarina Khurshid in 202. The absorption parameters of quercetin, rutin and apigenin have been studied by Oluwaseun Taofeek in 2020 [ 41 ].

Distribution

Distribution properties (Table S4) show that quercetin, casticin, scopolin and rutin cannot cross the blood brain barrier. Quercetin, rutin, casticin, scopolin, artesunate and chrysoplenetin are not CNS permeable. Azithromycin shows a low VDss value which means the drug would not be properly distributed. The distribution parameters of quercetin, rutin and apigenin have already been studied by Oluwaseun Taofeek [ 23 ] and that of artemetin, scopolin, artesunate and casticin have been reported by Zarina Khurshid [ 40 ].

All the ligands were not CYP2D6 substrates, chrysoplenetin, artemetin, casticin, sitogluside and artesunate were all CYP3A4 substrates. Quercetin, apigenin, chrysoplenetin, artemetin and casticin were all CYP1A2 inhibitors. Apigenin, chrysoplenetin, artemetin and casticin were CYP2C19 inhibitors. Only artemetin was a CYP2C9 inhibitor. All the ligands were not CYP2D6 inhibitors, chrysoplenetin and casticin were CYP3A4 inhibitors (Table  5 ). Pkcsm metabolic properties of scopolin, artesunate, artemetin and casticin have been reported by Zarina Khurshid [ 40 ]. Some of the metabolism parameters of quercetin, rutin and apigenin have been recorded by Oluwaseun Taofeek [ 41 ].

Table 6 indicates that all the ligands and standard drugs are not renal OCT2 substrates which means that they would not be cleared out from the body.

Pkcsm excretion properties of scopolin, artesunate, artemetin and casticin have been reported previously [ 40 ]. Quercetin, rutin, and apigenin have been recorded by Oluwaseun Taofeek [ 41 ].

Lead compound identification

After the first knockout by Lipinski’s rule and the second by the study of pharmacokinetics rutin was knocked out. Other ligands based on docking score and properties were taken to the next level. After that chrysoplenetin was selected as the lead compound depending upon its pharmacokinetics and pharmacodynamics.

Comparison of standard drug with lead compound

The lead compound chrysoplenetin was compared with the standard drug azithromycin and their physiochemical and pharmacokinetic properties were compared for the assessment of bioavailability, safety, efficiency, and drug-likeness.

Lipinski’s rule comparison

The comparison shows that azithromycin breaks two of Lipinski’s rules that are of molecular weight and H-bond acceptor as the molecular weight exceeds the limit of 500, and the H-bond acceptance value exceeds 10. The lead compound however follows all the given Lipinski’s rules (Table S4).

ADMET properties comparison

Toxicity comparison.

The value of toxicity parameters of Azithromycin shows that this drug can be toxic to liver, but other parameters are in the range of positive values. Azithromycin cannot cause any sensitivity to the skin and is also not an inhibitor of hERG I and hERG II. The dose value of 1.927 is also tolerable. With that a no to AMES toxicity indicates that it is not carcinogenic.

The toxicity comparison is based on 9 models (Table  7 ). Model I of AMES toxicity shows that none of these are mutagenic, Model II shows that chrysoplenetin has a low value of dose. The third model shows that both are not hERGI and hERGII inhibitors. The fourth and fifth model of oral rat acute and chronic toxicity value give the value of a low dose that could result in an adverse effect. The hepatotoxicity model shows that azithromycin is hepatotoxic. Model seven indicates that neither of the two are skin sensitive. Toxicity model 8 and 9 indicate that azithromycin is somewhat toxic.

Absorption properties comparison

The parameter of absorption is based on 6 models (Table  8 ). CaCO 2 solubility suggests that chrysoplenetin is absorbed more than azithromycin. Intestinal absorption of azithromycin is also low. Chrysoplenetin is a P-glycoprotein II inhibitor whereas azithromycin is a P-glycoprotein I inhibitor.

Metabolic properties comparison

Metabolic properties indicate that azithromycin is a CYP3A4 substrate whereas chrysoplenetin is a CYP3A4 substrate and an inhibitor to CYP1A2, CYP2C19 and CYP3A4 (Table  9 ).

Distribution properties comparison and PAINS alert

Table 10 shows that azithromycin has poor distribution to the brain, and it will not be able to pass the central nervous system. Further it has been investigated for PAINS alert as well to check whether the compounds interact with human proteins inadvertently or not. Upon investigating both compounds 0 PAINS alert were inferred showing no interactions with human protein targets.

Excretion properties comparison

The excretion properties of both the compounds are in the safe range. Chrysoplenetin has more total clearance than azithromycin (Table  11 ).

Physicochemical properties comparison

This screening tells that azithromycin has 38 carbon atoms, 72 hydrogen atoms, 2 nitrogen atoms and 12 oxygen atoms whereas chrysoplenetin has 19 carbon atoms, 18 hydrogen atoms and 8 oxygen atoms. The number of atoms indicates that chrysoplenetin is a simple bio-compound in comparison to azithromycin. Azithromycin can donate 5 hydrogen atoms whereas chrysoplenetin can donate 2 hydrogen atoms showing the oxidation state of each. Azithromycin accepts 14 hydrogen atoms which are against Lipinski’s rule. The molecular weight of azithromycin also exceeds the rule limit of 500 g/mol. Chrysoplenetin has 5 rotatable bonds while azithromycin has 7 rotatable bonds (Table  12 ).

Docking score comparison

Both the standard drug and lead compound were docked against M pro . Table 13 shows the docking results which indicate that the binding score of azithromycin is -6.8 and that of chrysoplenetin is -7.7. The result indicates that chrysoplenetin can block or bind with M pro more efficiently than azithromycin.

Docking analysis comparison

The docking results are analyzed by Discovery Studio [ 43 ] based on the number of hydrogen bonds, number of hydrophobic interactions, steric interactions and number of interacting amino acids. Figure  3 shows the interaction of azithromycin and chrysoplenetin with the receptor. Azithromycin has formed only one hydrogen bond and ten hydrophobic interactions whereas chrysoplenetin forms seven hydrogen and nine hydrophobic interactions. Table 14 gives the details of this interaction. The binding site of the protease with previously reported inhibitors has been reinvestigated during the interaction of chrysoplenetin. It has been inferred that chrysoplenetin binds to the same residues sites where previously reported inhibitors has been found active [ 44 , 45 , 46 ].

Top1- Interaction of azithromycin with receptor, Top2-Interaction of chrysoplenetin with receptor

Protein conformational dynamics are the most important aspect of its function. The functional information of a protein molecule is contained in its structure. The structure must be thoroughly examined to comprehend its functional variability [ 47 ]. MD simulation using AMBER was utilized in this work to investigate the conformational component of protein–ligand interactions. RMSD depicts the backbone analysis and Cα atom dynamics of a docked protein during a 100 ns time for both complexes. A high fluctuation at 20-30 ns was observed with a maximum value was observed in Top1 (Azithromycin) and in Top2 (Chrysoplenetin), this has been depicted among 15-55 ns and the stability for the rest of the time scale has been observed for the rest of the simulation time interval. Herein, Fig.  4 (A) shows that the average RMSD value for docked protein was 4.69 Å, with a maximum peak of 7.87 Å. The RMSD graph does not support any dramatic domain alterations within the protein–ligand complex's structural framework. Whereas the average RMSD value for the Top2 complex observed was 1.71 Å with a maximum RMSD of 3.87 Å. Trajectory analysis was utilized to identify the protein substructures that generated the RMSF trend. This is followed by the RMSF value against both complex, where the average RMSF value recorded for Top1 is 1.7 Å with a maximum value of 5.2 Å and minimum value of 0.7 Å. The RMSD graph revealed substantial structural changes at 15 ns, 25 ns, 45 ns, and 65 ns, after which the protein stabilized. Figure  4 depicts the structural changes that occurred in the docked protein complex at various periods. RMSF quantifies the flexibility and variation of Cα residue structures across time. The average RMSF for the Top2 complex of docked protein for 100 ns was 1.61 Å, with a high of 4.2 Å, and significant changes at residues 76,103, 203 to 279, as well as at the end of the graph for residues 518 and 599. These were largely protein-loop areas where no structural deviation has been observed but shows fluctuations at RMSF level.

A Top1 depicts the RMSD and ( B ) RMSF plot of the C-alpha atoms of ligand-bound proteins throughout time interval. The figures suggest that the protein in the complex with Tocofersolan attained stability at 37 ns till the end of the simulations. Whereas this has been validated in the RMSF graph which attains stability of the system with few minor fluctuations at some loop region residual sites especially from 200–300 residual sites. This is followed by the B-Top2 figure, depicting the stable RMSD with a minor deviation at 20 ns showing a max RMSD of 3.8 Å. D depicting the RMSF of Top2 complex system with fluctuation at surface residues at the time scale of 100 ns

SASA analysis

We determined the solvent accessible surface area (SASA) of residues that were linked to significant Drug-Target interaction or catalytic activity, owing to intriguing findings from RMSD and RMSF analysis. When comparing the Top1 to Top2 complex system, the SASA profile (Fig.  5 ) clearly shows the reduction in the SASA of the critical residues. The enzymatic activities of targeted proteins are inhibited in both systems because of the limited accessibility to critical residues inside complex systems, hence reducing the likelihood of complex interactions. According to the SASA analysis, there must have been some conformational changes in the protein surface, or the amino acid residue moved from the accessible area to the buried region because of complex formation. Stability of the key residues has been monitored throughout the simulation time intervals at the time scale of 100 ns. The average value recorded for Top1 complex system was 325.56 Å 2 and 191.74 Å 2 respectively offering a possible dynamics and stability of the system.

Depicting the dynamics of the Solvent surface residues of both complex system during the time scale of 100 ns

Hydrogen bond analysis

Hydrogen bonds play an important role during simulation reflecting the stability of the system. This was observed by applying the amber16 tools by giving all the frames of simulation time intervals. It has been inferred that Top1 complex system shows hydrogen bonds among the atom of the residues that include OD1 of Asn142 with O9 of ligand atom. This bond was continuously interacting with the residue till 100 ns time intervals with some minor breakage. This was followed by other hydrogen bonds i.e. Asn142-OD1-LIG-H10 and Glu-O-LIG-H111. Thus, making the Top1 in a stable position inside the active site. On other side the Top2 ligand have a strong hydrogen bonds interaction that includes Gly43 interacting the O3 and O4 atom of the inhibitor molecule followed by Cys145 AND Ser 144 of the target residues.

Binding free energies analysis

The total binding free energy and complex stability were mostly determined by the energy terms i.e. van der Waals (Evdw), electrostatic (Eele), and solvation (Esolvation), among other energy factors that contributed to the drug-target binding energy. Because end point free-energy modelling techniques, such as MM/PBSA, are known to provide more accurate results than docking binding energy, these were used to investigate the binding free energies of both complexes. Table 15 provides an overview of the binding free energy of both compound complexes. After analysis, the average binding free energy of the Top1 complexes was found to be -45.5898 kcal/mol in MMGBSA and -42.875 kcal/mol during MMPBSA approach. Figure  6 also provide the other binding energies factor which infers the complex's electrostatic (-10.8859 kcal/mol), van der Waals (vdW) (-50.56 kcal/mol), polar surface (-7.1783 kcal/mol) nonpolar surface (-5.678 kcal/mol).Whereas, the Top2 complex system depicting the total binding free of (-44.2875 kcal/mol) for MMGBSA and (-43.376 kcal/mol), with electrostatic energy of (-11.0774 kcal/mol), van der Waals (vdW) (-57.1607 kcal/mol), polar surface energy (-8.8117 kcal/mol) and nonpolar surface energy (–5.6832 kcal/mol). Herein, for the Top1 and Top2 complex system the calculations of free energy showed that vdW energy plays a significant role in binding free energy, thus indicating the Top2 complex system shows a low binding energies with high affinity during the time intervals of 100 ns, thus helps the complex become transiently stable.

Top1 and Top2 complex depicting the hot spot residues involved in hydrogen bonds during the simulation time intervals after 100 ns time scale

PCA analysis

To deduce the mechanical characteristics, such as structural movements and variations, of both complexes Principal Component Analysis (PCA) analysis was performed. Using vectorial representations, a collection of eigenvectors representing the motion of each individual component was obtained from the MD trajectories as shown in Fig.  7 . Results evaluated shows the mobility of protein residues in both the system and it has been analyzed that both the drug bind to the active residues shows a slight deviation and alteration during the simulation time intervals. Clusters residues in the Top1 and Top2 system moving towards the lower state energies with drug molecules moving deep inside the active cavity of the target protein. Herein, Top2 complex system shows more deviation on x-axis as compared to Top1 which depicts the residues are moving towards high lower state level making the system more stable.

PCA analysis. Top1 and Top2 complex systems show the movement of residues in comparison at the end of the simulation time intervals

With the emergence of the human SARS Coronavirus 2, many questions related to the evolution and introduction of the virus in the human race were raised. The biological community was indulged in finding answers to the reservoirs of the virus, its spread and its effect on the human race [ 48 ]. It was found that upon transcription the beta coronavirus produces 800KD polypeptide, which is cleaved by papain-like protease and 3-chymotrypsin-like protease to generate various non-structural proteins that are involved in viral replication [ 49 ]. The main protease protein having an essential role in the replication of viruses served as an amazing drug target site [ 5 ]. Many drugs were used against M pro and few vaccines were developed for the inhibition of virus replication. Azithromycin has been commonly used in Pakistan and other countries. It has shown vital results during respiratory, chronic inflammatory disorders and bronchiolitis [ 12 ] for this reason it is used as a control. Medicinal plants have shown therapeutic properties, Artemisia annua is a herb used against malaria and other fevers. In Madagascar, a drink was prepared with an infusion of Artemisia annua to cure Covid-19 [ 14 ]. For this purpose, the plant was exploited, and 25 active constituents were selected to be docked against the main protease.

CB-dock a blind docking tool was used. Docking focuses on cavity binding so that ratio of accuracy is higher [ 50 ]. For performing docking the 3D structure of a protein in pdb format and the 3D structure of the ligand in sdf format was uploaded. The pose with minimum vina scores in KJ/mol was selected [ 51 ]. The docking results were visualized in PyMol and the 2D representation was generated in LigPlot. After studying the ADMET properties of the ligands and passing them from the Lipinski Rule, 9 out of 25 ligands were selected which were quercetin, rutin, casticin, chrysoplenetin, apigenin, artemetin, artesunate, scopolin and sitogluside. After their analysis, chrysoplenetin was selected as the lead compound and was compared with the standard drug azithromycin.

Predictions of ADMET using in silico methods are essential for drug development, but they are subject to constraints including dependence on high-quality data, the application of the model, comprehension of intricate biological processes, variability between individuals, and difficulties in precisely predicting toxicity. The aforementioned constraints require enhancements in predicting methodologies and the incorporation of other scientific methodologies [ 52 ]. Hrein, Azithromycin was shown to break the molecular weight and H-bond acceptor rule of Lipinski [ 24 ] whereas chrysoplenetin follows all the rules. Azithromycin was proved to be hepatotoxic when toxicity comparison was done by pkcsm. In the T.pyriformis (model 8) toxicity test, azithromycin was proved to be somewhat toxic. The intestinal absorption of azithromycin is also less than chrysoplenetin. Furthermore, Azithromycin showed a binding score of -6.8 kcal/mol forming only one hydrogen bond and ten hydrophobic bonds whereas chrysoplenetin showed a score of -7.7 kcal/mol forming seven hydrogen bonds and nine hydrophobic bonds. According to MD simulations, the drug receptor complex became stable in the physiochemical environment as its shape altered over time. Despite minor alterations inside chain and loop mobility, the inhibitor remained stable. The structural stability of the docked complex following simulation studies implies that the chosen ligand might be a viable lead chemical. Results were quite interesting as the protein in complex with chrysoplenetin attained high stability throughout the simulations time interval. Where a little change has been recorded in the RMSF. Binding free energies, SASA analysis, Hydrogen bond analysis and PCA analysis has shown a high ground stability of chrysoplenetin in complex with a target protein during the simulation time interval of 100 ns. All these studies showed that chrysoplenetin is a better drug candidate against the reported protein structure. Herein, Molecular dynamics (MD) simulations provide a comprehensive depiction of the fluctuations and conformational changes seen in biological systems by replicating the actual motions of atoms and molecules over a period of time. These parameters, including stability, binding affinity, and conformational alterations, play a crucial role in establishing the biological significance of the complex system. Such knowledge provided is of great use in furthering our comprehension of biological molecules and their complexes, as well as in the development of novel pharmaceuticals and treatments.

Conclusions

Covid-19 has created massive problems for the human race. M pro was revealed to be an active drug target. Some plants were exploited for their efficiency against M pro . 25 ligands from the plant Artemisia annua showing antiviral properties were selected. Based on the inhibition effect involving hydrogen bonding and hydrophobic interaction, chrysoplenetin was selected as a lead compound which was then compared with the standard drug azithromycin. The inhibition process is explained by how the inhibitor binds and how the target protein acts as a catalyst. Likewise, the structure dynamics of the docked protein reveal useful information that can be used to improve the drug's effectiveness against the comparison between these two shows that chrysoplenetin can be better and more effective against M pro . This research contributes to the global effort to combat SARS-CoV-2 and provides a foundation for addressing future viral threats by emphasizing the potential of chrysoplenetin as a therapeutic agent. The recognition of chrysoplenetin as a highly effective inhibitor presents opportunities for additional comprehensive investigations, such as clinical trials, to ascertain its safety and efficacy in human subjects. Furthermore, the approaches and insights acquired have the potential to expedite the identification of innovative inhibitors targeting new viral proteases, thereby enhancing our readiness for prospective pandemics.

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Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research, King Saud University through Vice Deanship of Scientific Research Chairs; COVID-19 Virus Research Chair.

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Fahad Nasser Almajhdi

Present address: COVID-19 Virus Research Chair, Botany and Microbiology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia

Yasir Waheed

Present address: Near East University, Operational Research Center in Healthcare, TRNC Mersin 10, Nicosia, 99138, Turkey

Authors and Affiliations

Department of Bioinformatics and Biosciences, Faculty of Health and Life Sciences Capital, University of Science and Technology, (CUST), Islamabad, Pakistan

Eraj Irfan & Erum Dilshad

Foundation University Medical College, Foundation University Islamabad, Islamabad, 44000, Pakistan

Faisal Ahmad

Center of Excellence in Biotechnology Research, King Saud University, 11451, Riyadh, Saudi Arabia

Tajamul Hussain

Department of Biotechnology, Persian Gulf Research Institute, Persian Gulf University, Bushehr, 75169, Iran

Gholamreza Abdi

Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos, 1401, Lebanon

MEU Research Unit, Middle East University, Amman, 11831, Jordan

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Eraj Irfan: Concept, methodology, formal analysis, data curation, manuscript writing, final approval. Erum Dilshad: Concept, methodology, formal analysis, data curation, manuscript editing, Supervision, final approval. Faisal Ahmad: methodology, formal analysis, data curation, manuscript writing, manuscript editing, final approval. Fahad N Almajhdi: methodology, formal analysis, data curation, manuscript editing, Supervision, resources, final approval. Tajamul Hussain: methodology, formal analysis, data curation, manuscript editing, resources, final approval. Gholamreza Abdi: methodology, formal analysis, data curation, manuscript editing, resources, final approval. Yasir Waheed: Concept, methodology, formal analysis, data curation, manuscript editing, Supervision, resources, final approval.

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12879_2024_9387_moesm1_esm.docx.

Supplementary Materials 1: Table S1. Applicability of Lipinski rule. Table S2 Selected ligands with structural information. Table S3 Absorption properties of the ligands and standard drug. Table S4 Distribution properties of the ligands and standard drug. Table S5 Lipinski’s Rule Comparison.

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Irfan, E., Dilshad, E., Ahmad, F. et al. Phytoconstituents of Artemisia Annua as potential inhibitors of SARS CoV2 main protease: an in silico study. BMC Infect Dis 24 , 495 (2024). https://doi.org/10.1186/s12879-024-09387-w

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Genome wide analysis of carotenoid cleavage oxygenases ( CCO ) gene family in Arachis hypogaea (peanut) under biotic stress

• Arsalan Ahmad 1 ,
• Adnan Sami 2 ,
• Umer Habib 3 ,
• Muhammad Ali 4 ,
• Muhammad Shafiq 5 ,
• Muhammad Zeshan Haider 6 ,
• Shahbaz Ahmad 7 ,
• Baber Ali 8 ,
• Steve Harakeh 9 , 10 ,
• Rania M. Makki 11 ,
• Talha Chaudhary 12 &
• Fathia A. Soudy 13  

BMC Genomics volume  25 , Article number:  469 ( 2024 ) Cite this article

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Carotenoid cleavage oxygenases ( CCOs ) enzymes play a vital role in plant growth and development through the synthesis of apocarotenoids and their derivative. These chemicals are necessary for flower and fruit coloration, as well as the manufacture of plant hormones such as abscisic acid (ABA) and strigolactones, which control a variety of physiological processes. The CCOs gene family has not been characterized in Arachis hypogaea . Genome mining of A. hypogaea identifies 24 AhCCO gene members. The AhCCO gene family was divided into two subgroups based on the recent study of the Arabidopsis thaliana CCO gene family classification system. Twenty-three AhCCO genes, constituting 95.8% of the total, were regulated by 29 miRNAs, underscoring the significance of microRNAs (miRNAs) in governing gene expression in peanuts. AhCCD19 is the only gene that lacks a miRNA target site. The physicochemical characteristics of CCO genes and their molecular weights and isoelectric points were studied further. The genes were then characterized regarding chromosomal distribution, structure, and promoter cis-elements. Light, stress development, drought stress, and hormone responsiveness were discovered to be associated with AhCCO genes, which can be utilized in developing more resilient crops. The investigation also showed the cellular location of the encoded proteins and discovered that the peanut carotenoid oxygenase gene family’s expansion was most likely the result of tandem, segmental, and whole-genome duplication events. The localization expresses the abundance of genes mostly in the cytoplasm and chloroplast. Expression analysis shows that AhCCD7 and AhCCD14 genes show the maximum expression in the apical meristem, lateral leaf, and pentafoliate leaf development, while AhNCED9 and AhNCED13 express in response to Aspergillus flavus resistance. This knowledge throws light on the evolutionary history of the AhCCO gene family and may help researchers better understand the molecular processes behind gene duplication occurrences in plants. An integrated synteny study was used to find orthologous carotenoid oxygenase genes in A. hypogaea , whereas Arabidopsis thaliana and Beta vulgaris were used as references for the functional characterization of peanut CCO genes. These studies provide a foundation for future research on the regulation and functions of this gene family. This information provides valuable insights into the genetic regulation of AhCCO genes. This technology could create molecular markers for breeding programs to develop new peanut lines.

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Introduction

Carotenoid cleavage oxygenase ( CCO ) is an enzyme that plays a role in the biosynthesis of the phytohormones ABA and strigolactone (SL) as well as in biological functions such as light absorption, electron transfer, and oxygen-free radical removal [ 1 ]. These are non-heme iron oxygenases that help in carotenoids oxidate remodeling and produce apocarotenoids, which control phytohormone regulation, pigments, and defensive compounds in plants [ 2 ]. There are approximately 50 carotenoids that are specifically precursors of vitamin A, which play a key role against cancer disease. It also contributes to the color of fruits like red, yellow, and orange [ 3 ]. CCO have has conserved histidine that might help in iron-binding and also contain a peptide sequence at the carboxyl terminus that constitutes a family signature sequence. In A. thaliana , the CCO gene family have nine members [ 4 ]. Out of nine, two CCDs are involved in sequential cleavage that is stimulated by CCD7 and CCD8 , which produce shoot-branching inhibiting hormone [ 5 ]. The CCO genes belong to a long-established family. The maize ( Zea mays ) abscisic acid -deficient viviparous mutant, vp14, had the first CCO gene expression. Later, nine vp14 homologs were found in A. thaliana [ 6 ]. These are terpenoid substances made by phototrophic organisms, such as plants, certain eubacteria, and fungi [ 7 ]. In order to create different apocarotenoids and their derivatives, CCOs can precisely cleave the conjugated double bond of the carotenoid polyene chain. Plant CCOs can be further divided into the 9-cis-epoxycarotenoid ( NCED ) and carotenoid cleavage dioxygenase ( CCD ) subfamilies based on whether the substrates are epoxidized.

Abscisic acid (ABA) is a 15-C weak acid discovered in the 1960s that has a variety of functions in plant development and growth, including embryo maturation, seed dormancy, germination, cell division and elongation, floral induction, and responses to environmental challenges such as pathogen attack, dehydration, salinity etc [ 8 ]. Initially thought to be a growth inhibitor, abscisic acid is now recognized as a crucial plant hormone that controls plant growth [ 9 ]. ABA not only regulates the stomatal pathway but is also involved in gene expression and regulating cis-acting elements [ 10 ]. Disease resistance is negatively regulated by ABA’s interference with biotic stress signaling, which is controlled by salicylic acid, jasmonic acid, and ethylene [ 11 ].

In plants, carotenoid cleavage dioxygenase ( CCD ) emits several volatile phytohormones and aroma compounds. The actual cleavage mechanism is still not understood. This enzyme group has more importance in terms of nutritional value. These hormones cause symbiotic mycorrhizal fungi to branch and attach to plant roots, or they can be transmitted to plant aerial portions to prevent branching or tillering, which is a major agronomic feature in grasses [ 12 ]. CCD is known specifically for its double bond cleavage, which is different in plants and animals. The catalization occurs at 9, 10, and 9′, 10′ double bonds [ 13 ]. Carotenoids serve as precursors in the synthesis of regulatory molecules within plants, including β-cyclocitral, as well as newly identified regulatory metabolites like anchorene, iso-anchorene, and zaxinone. These derivatives are made by selective oxidative cleavage of carotenoids, primarily triggered by CCDs [ 14 ]. CCD genes have distinct functions in different crops: in tomatoes, they contribute to flavor volatiles; in petunias, β-ionone (a recognized key contributor to floral fragrance in various plant species [ 15 ]) synthesis; and in Brassica oleracea , responses to drought and salt stresses [ 2 ]. In grapevine, CCD is known for producing the flavor and aroma related apocarotenoid in both fruits and flowers [ 5 ]. In the grapevine, it has been discovered that a total of nine CCDs genes play a crucial role in the synthesis of the shoot-branching inhibiting hormone, strigolactone. This synthesis process is specifically enhanced through sequential cleavage catalyzed by the Arabidopsis CCD7 and CCD8 genes [ 16 ].

9-cis-epoxycarotenoid dioxygenase ( NCED ) is also an essential enzyme that stimulates ABA biosynthesis, as shown by genomic studies of plants [ 17 ]. It was cloned from the maize plant and then from other plant species responsible for the production of xanthoxin (an intermediate compound in ABA synthesis) [ 18 ]. Now the NCED gene has been translated and expressed in various plants, including beans, cowpeas, avocados, grapes, Arabidopsis , sweet cherries, and citrus, since it was first discovered in the maize vp14 mutant. In sweet cherries, the NCED gene ( PavNCED5 ) influences the bud dormancy [ 19 ]. The expression of NCED (PvNCED1 ) in Phaseolus vulgaris under drought conditions demonstrated a substantial connection between NCED (PvNCED1 ) and ABA levels in dry leaves and roots, suggesting that NCED controls ABA production under water stress [ 20 ]. Tobacco and tomato were the first plants in which overexpression of NCED resulted in excessive accumulation of ABA. In tomato, this led to greater water usage efficiency due to an increase in root hydraulic conductivity and a decrease in stomatal conductance (g s ) [ 21 ]. In rice, the NCED genes OsNCED6 and OsNCED10 defend against salt stress, whereas OsCCD7 and OcCCD8 are involved in grain and inflorescence development [ 22 ].The genes HaNCED16 and HaNCED19 were expressed in response to drought stress revealed in recent studies [ 23 ].

Peanuts are an economical and nutritious source of food worldwide. A. hypogaea produces different products like peanut butter and peanut oil that help to meet nutritional values as well as lower body mass index (BMI) [ 24 ]. A total of 24 AhCCO genes were discovered that might play a role in peanuts’ resistance to various fungal pathogens. The cis-elements of A. hypogaea regulate responses to low temperature and light, anaerobic induction, jasmonate signaling, and both biotic and abiotic stress [ 25 , 26 ]. ABA plays a key role in regulating physiological processes like fruit development, biotic and abiotic stresses. In this study, we identified CCO genes from the peanut genomes and investigated their evolutionary relationship, gene structure, protein motifs, and expression profiles in various organs, stages of fruit development, and responses to abiotic and biotic stress. This discovery expands our understanding of CCO genes involved in growth, development, and stress responses and provides the basis for peanut genetic enhancement.

Materials and methods

Identification of the  cco gene family, physiochemical properties and subcellular localization.

The CCO protein sequence was retrieved from the National Center for Biotechnology Information (NCBI) with the domain RPE65. The protein sequence of A. hypogaea , along with (A) thaliana and (B) vulgaris , was retrieved from the phytozome database ( https://phytozome-next.jgi.doe.gov/ , accessed on June 2, 2023). The genes with conserved RPE65or PF03055 domains were considered the true CCO genes. Physicochemical properties of the CCO protein in A. hypogaea , such as mRNA length, chromosomal start and end position taken from the Phytozome and other parameters such as number of amino acids, molecular weight, theoretical pI value, grand average of hydropathicity (GRAVY), instability index, were taken from the ExPASy ( https://web.expasy.org/protparam/ , accessed on June 4th, 2023) online tool and protein subcellular localization prediction using WoLF PSORT ( https://wolfpsort.hgc.jp/ , accessed on June 7th, 2023).

Analysis for comparative phylogenetic tree

The analysis was performed between the peptide sequences of A. hypogaea , (A) thaliana , and (B) vulgaris for the construction of a phylogenetic tree. The CCO sequence of proteins that was used to make a phylogenetic tree in MEGA-11 ( https://www.megasoftware.net/ ) software with the method of neighbor-joining (NJ) and setting 1000 replications for the bootstrapping value. The final structure was done on iTOL ( https://itol.embl.de/ ).

Conserved motif analysis and gene structure

The conserved motifs of CCO gene family proteins in A. hypogaea were examined using Multiple Expectation Maximization for Motif Elicitation (MEME) ( https://meme-suite.org/meme/tools/meme ). The motif’s maximum value was set to 20, and its maximum length ranged from 6 to 50. The conserved motifs were then shown using the TB-tools ( https://bio.tools/tbtools ) program. The intron exon substructure of CCO family genes was visualized using analytical tools from the Gene Structure Display Server (GSDS, https://gsds.gao-lab.org/  , accessed on June 13th, 2023).

Chromosomal Location of  AhCCO  genes

Phytozome ( https://phytozome-next.jgi.doe.gov/ ) provided details about the CCO locations, including the length of the chromosome, the chromosome it is on, and its precise location within the chromosome. Using the TB-tools software, the image displaying the location of CCO on the chromosome was created.

Cis regulating gene analysis

The 1000-bp upstream sequence of the translation initiation codon of AhCCO was extracted from the Phytozome on June 15th, 2023.

PlantCare ( https://bioinformatics.psb.ugent.be/webtools/plantcare/html/  , accessed on June 14th, 2023) database was used for cis-acting regulatory element prediction.

MiRNA analysis and protein-protein interaction

Using the CDS sequences of all the CCO genes with the default parameters, psRNATarget ( https://www.zhaolab.org/psRNATarget/  , accessed on June 17th, 2023) was used to find the AhCCO gene-related micro-RNA (miRNA) sequences. The STRING database was used to predict potential interactions among the proteins ( https://string-db.org/  , accessed on June 18th, 2023).

Gene duplication and synteny analysis

Ka/Ks ratios were used to estimate the divergence time of the AhCCO genes. The substitution rates were calculated using TB-tools. The Ks value was entered into the “T = Ks/2r” equation, where “r” is equal to 8.12*10^-9, to estimate the time of divergence (DT) [ 27 ]. MCScanX v1.0 (Multiple Collinearity Scan toolkit) was used to analyse the gene duplication occurrences. Syntenic and dual syntenic maps were created in order to determine the synteny link between the genes of A. hypogaea , (A) thaliana and (B) vulgaris .

Transcriptomic analysis/gene expression analysis

RNA seq analysis data of the AhCCO gene was extracted (GEO; accessed on June 23rd, 2023; accession no. GSE180915) from different plant parts like the lateral leaflet and terminal leaflet using petioles and seeds to study the transcriptomic effect on compound leaf development in A. hypogaea. Another piece of data from the RNA-seq study of the AhCCO gene was used to study the resistance of peanut pre-harvest seeds in response to Aspergillus flavus . Data related to compound leaf development of peanut and response to A. flavus retrieved from the NCBI Gene Expression Omnibus (GEO) (accessed on June 26th, 2023; accession no. GSE102782).

Identification of genes in peanut

In a genome-wide study of peanuts, 24 CCO genes were identified (Table  1 ). Gene names, chromosomal locations, chromosomal direction, gene lengths, exon numbers, molecular weights (Mw in kDa), protein size, and isoelectric points (pI) are also shown in Table  1 . This study shows the coding sequence (CDS) ranges from 231 bp (bp) ( AhCCD4 ) to max. 1905 bp ( AhCCD17 ), while the molecular weight (Mw) lies between 8612.91 ( AhCCD4 ) and 71589.99 ( AhCCD17 ) in all 24 genes of peanut. The following CCO gene lengths range from 76 ( AhCCD4 ) to 633 ( AhNCED9 ), and pI values vary from 4.62 ( AhCCD19 ) to 8.64 ( AhCCD3 ).

Analysis for miRNA (MicroRNA) target site

MiRNA target site prediction shows that there were 29 miRNA target sites in 23 (95.8%) AhCCO genes (including CCD and NCED ). 12 mature miRNAs (nucleotides) specifically target the gene AhCCD15 , whereas 11 miRNAs target the genes AhNCED9 and AhCCD22 . Other genes are targeted by mature miRNAs ranging from 1 to 10. AhCCD19 is the only gene that lacks a particular miRNA. In all genes, the length of these miRNAs varies from 16 to 22. 20 miRNAs observed play a significant role in cleavage, while 25 control translation. Some of them are involved in both cleavage and translation.

Conserved motif domain analysis for CCO gene family

The conserve domain motif analysis depicts that all motifs are conserved under the domain of the superfamily RPE65. In addition, Fig. 1 comprehensively shows that genes AhCCD12, AhCCD19, and AhCCD20 have two motifs, while AhCCD10, AhCCD21, AhCCD4, AhCCD3, AhCCD1, AhCCD2, AhCCD5 , and  AhCCD6 have 3 motifs only. All remaining genes have motifs that vary from six to seventeen, but motif-1 was conserved and is present in all genes of A. hypogaea , as shown in Fig. 1 .

The distribution of 20 motifs of the peanut CCO protein family. Some member of the NCED and CCD protein has a conserved motif

Phylogenetic relationship of CCO protein

The construction of the phylogenetic tree of the CCO proteins of A. hypogaea , B. vulgaris , and A. thaliana was done in Mega-11 software (Fig.  2 ). The analysis exhibits 24 genes of A. hypogaea , seven of B. vulgaris , and nine of A. thaliana contributing to the phylogenetic tree. Genomic tree visualizes two main groups, CCD and NCED , in sugarbeet, peanut, and Arabidopsis evolutionary analysis . Group-1 contain all CCD genes shown in red, while Group-2 contain NCED shown in green.

Illustrates the phylogenetic relationships among 40 CCO genes from three plant families: A. hypogaea , (A) thaliana and (B) vulgaris . Groupings are established through Arabidopsis phylogenetic tree reconstruction and evolutionary trait analysis. This figure visually represents the division of these 40 CCO genes among the three crop species, following the Arabidopsis phylogenetic grouping system

Cis regulatory element (CREs) analysis

The CAT-box, which is a cis-acting regulatory element related to meristem expression, was found to exist in one AhCCO promoter (Fig.  3 ). A number of cis-acting elements involved in phytohormone-responsiveness, such as AuxRR-core, CGTCA-motif, TGACG-motif, TGA-element, ABRE, P-box, GARE-motif, and TCA-element, were identified in the CCO promoters. Methyl jasmonate-responsive elements, including CGTCA-motif and TGACG-motif, appeared in most CCO promoters. Notably, ABRE, which is involved in ABA responsiveness, was observed in most of CCO promoters. There were also many types of stress-induced cis-acting elements in the CCO promoters, such as ARE, LTR, MBS, TC-rich repeats, DRE, and GC-motif. ARE is essential for anaerobic induction and was found in most promoters (seven out of 24 AhCCO promoter). TC-rich repeats, which are involved in defense and stress responsiveness, were detected in five AhCCO promoters. The LTR cis-acting elements, which are involved in low-temperature, responsiveness, were found in many promoters (three AhCCO ). The DRE cis-acting element, which is involved in dehydration, low-temperature and salt stress, was specific to the AhCCO promoter, while the GC-motif involved in anoxic specific inducibility only existed in the AhCCO promoters. GTGGC-motif, I-box, LS7, chs-CMA2a, chs-Unit 1 m1, 4cl-CMA1b, and ACE that are present in genes AhCCD24, AhCCD14, AhNCED18, AhCCD14, AhCCD15, AhCCD8, AhCCD10 respectively play important role in regulating light-responsive elements, and GARE-motif controls the gibberellin-responsive element that play a role in signal transduction, grain germination, and certain transcription factors that regulate gene expression.

The graphical representation of cis-regulatory analysis of CCO genes with their function intensity. The intensity is defined by the range of red (highest) to white (lowest) during plant biochemical and physiological processes

Gene duplication and gene mapping of CCO genes

The gene duplication of CCO was calculated using TB-tools (Fig.  4 ). The ka/ks (non-synonymous substitution rate and synonymous substitution rate) values that show the CCO genes of A. hypogaea range from 0 ( AhCCD1_AhCCD5 ), which is the lowest, to value 1.45 ( AhCCD20_AhCCD22 ), which is the highest among all. The paralogous-gene pair AhCCD7_AhCCD17 has the greatest value of 346.442478 (million years ago) and the lowest value of 0.786267402 (million years ago) of gene pair AhCCD11_AhCCD23 for segmental duplication. The ka/ks value less than 1 indicates purifying selection, except gene pairs ( AhCCD4_AhCCD20, AhCCD19_AhCCD22, AhCCD4_AhCCD22, and AhCCD20_AhCCD22 ) have a value greater than 1 indicating positive or diversifying selection [ 28 , 29 ]. Gene mapping analysis reveals the presence of a single gene on chromosomes 3, 5, 6, 13, 15, and 16. Chromosomes 8, 14, and 18 each harbor two genes, while chromosomes 10 and 20 contain three genes. Chromosome 19 stands out with six identified genes.

The ratio of mutations involving non-synonymous substitutions (Ka) to mutations involving synonymous substitutions (Ks) is shown as Ka/Ks

Sub-cellular localization of CCO genes

In peanuts, the localization of CCO genes within cells is abundant, most in the cytoplasm and chloroplast (Fig. 5 ). Other organelles, like the peroxisome and mitochondria, also contain CCO genes in quantity but less in number.

The heat map displays the sub-cellular distribution of AhCCO genes in plant cells, indicating their presence in the nucleus, cytoplasm, chloroplast, golgi apparatus, mitochondria, plasmid, and peroxisomes. Blue signifies absence, white suggests minimal functional presence, and mild orange indicates significant functional importance of the gene in the specific region

Intron/exon structure analysis

The intron-exon analysis shows that 10 out of 24 genes have just two exons and one intron. These genes might be descended from a common ancestor. Two genes contain only one exon and no intron. Other genes have exon-intron ranges from 14–13 as the maximum to a 7–6 ratio as the minimum (Fig. 6 ). The research demonstrates how different genes with the same number of exons and introns predict gene structure.

The phylogenetic representation of the intron-exon structure demonstrates that NCED genes have fewer coding sequences than CCD genes. In the meanwhile, the some NCED and CCD gene are conserved in the number of introns and exons. Genes AhCCD14 and AhCCD15 have highest exons of 14 while AhNCED9 and AhNCED18 have least of only one exon

Protein-protein interaction of different genes

Only nine genes (out of 24) show linkage that describes the tight interaction with their molecular structure in protein-protein interaction structure analysis. The genes AhCCD24 , AhCCD17 , and AhNCED16 have the most linkage (Fig. 7 ), whereas AhCCD22 and AhCCD21 have the least, according to the STRING database [ 30 ]. These genes are involved in a variety of roles, including biological processes and molecular functions.

Protein interaction figure depicted the predicted and known interactions among the identified AhCCO genes. Most of the AhCCO genes make interaction to identified genes AhCCD24, AhCCD17 , and AhNCED16 shown in Fig. 7

Chromosomal localization of AhCCO genes

There are a total of 12 chromosomes found, containing 24 peanut CCO genes spread on different chromosomal numbers (Fig. 8 ). Chromosome 19 has the most genes (6 genes; 25%), chromosome 10 and 20 have 3 (12.5%), chromosome 18, 8, 14 have 2 (8.3%), and chromosome 13, 15, 5, 6, 3 and 16 have only single genes (4.16%).

Chromosomal mapping shows the paralogues of CCO genes with plausible locations. Genes are duplicated during selection pressure and genomic rearrangement, resulting in the retention of ancestral function and the gain of stable functional characteristics in the peanut genome

Additional analysis of synteny (depicted in Figs. 9 a, b, and c) revealed the genetic linkage between chromosome 1 of A. thaliana and A. hypogaea genes ( AhNCED9 , AhNCED18 ), and chromosome 2 of A. thaliana with genes ( AhNCED13 , AhNCED16 ). Furthermore, the linkage was observed between chromosomes 1, 2, and 8 of B. vulgaris with A. hypogaea genes ( AhNCED9 , AhNCED18 ), genes ( AhCCD14 , AhCCD15, AhCCD8, AhCCD11, AhCCD23 ), and genes ( AhCCD17 , AhCCD24 ) respectively.

To reveal the similarity and gene duplication distribution, single ( a ) and additional dual synteny analyses of A. hypogaea were conducted. Arachis-Arabidopsis ( b ), Arachis-Beta ( c ) depicted the linkage gene duplication of both specimens. The genomes mentioned plant species have been found to share minor structural and gene duplication sharing

Gene expression analysis of different A. hypogaea organ

A brief study of the CCO gene family in the context of A. hypogaea (peanut) research has resulted in the discovery of 24 genes. Four of these genes ( AhCCD7, AhCCD14, AhCCD23, and AhCCD17 ) have been found to be up-regulated in the apical meristem (AM) (Fig. 10 ). The gene AhCCD14 is up-regulated during lateral leaf (LL) development; however, another two genes ( AhCCD12 and AhCCD21 ) are up-regulated during pentafoliate leaf (PFL) development. Significantly, one gene from the apical meristem, two from the lateral leaf, and one from the pentafoliate leaf development stages indicate down-regulatory patterns. This study shows the complex regulatory role of these genes in different phases of A. hypogaea growth, stress responses, the nutrient cycle and gas exchange mechanisms also in development.

Heatmap show the development of compound Lateral leaf (LL), Apical Meristem (AM) and Pentafoliate Leaf (PFL) Triggered by up-regulatory genes shown. AM Control, LL Control and PFL Control were the Leaves of Mutant cultivar of peanut plant while AM Treatment, LL Treatment and PFL Treatment were the wild type

Gene expression analysis of biotic stress on A. hypogaea plant parts and resistance

The observed response of two distinct genes out of 24, AhNCED9 and AhNCED13 , both of which exhibit considerable up-regulation, is especially important to our investigation (Fig. 11 ). This elevated expression profile is seen in the context of peanut pre-harvest seeds that demonstrated resistance to the fungus A. flavus [ 31 ]. A single gene in the investigated retrieval seems to be down-regulated, increasing the variety of regulatory responses. This in-depth assessment reveals the genetic complexity behind the peanut plant’s resistance mechanisms in combating the effects of the fungal disease, providing a description of potential approaches to enhancing peanut crop resilience and productivity in the presence of A. flavus .

Heatmap shows the resistance of the pathogen fungus ( A. flavus ) of peanut plants to their pre-harvest stage that is triggered by an up-regulated gene in red as the maximum

Using bioinformatics tools, an enormous number of CCOs genes have been found and analyzed in many species in recent years. Advancements in the AhCCO peanut family’s research and development have lagged behind those seen in other species. There is currently inadequate information available on CCOs in A. hypogaea . The major mechanisms driving species evolution, producing novel gene functions, and fostering the creation of gene families are gene loss and duplication. Members of the CCO gene family have been found in a variety of plants. Gene duplication indicates the diversifying or purifying selection based on ka/ks value. Four AhCCD paralogous-gene pairs show diversifying selection because of ka/ks values greater than 1 among all. This categorization further aids in discerning gene functions based on their respective categories. As a result, phylogenetic analysis could play a role in the development of functional genomics. The phylogenetic analysis predicts the gene categorization of CCD and NCED in different crops like A. hypogaea, B. vulgaris , and  A. thaliana  and also shows the genes that are involved in pigmentation and stress response. A. hypogaea, B. vulgaris , and  A. thaliana  show four (16%), six (66%), and four (57%), respectively, of NCED genes in a total of twenty-four, nine, and seven CCO genes in crops. The NCED subfamily likely diverged after dicots and monocots split, while the CCD subfamily diverged before angiosperms split. The phenomenon of CCO gene variances could be the result of gene duplication in various crops. The intron-exon structure analysis (Fig. 6 ) shows the genes that have a range of intron-exons 6-7 to 14–13, except for two AhNCED genes ( AhNCED9 and AhNCED18 ) that are intronless. This intron-deficient structure used to be believed to be critical for plants’ quick response to stress via ABA production and ABA-mediated signal transduction [ 32 ]. In general, most AhCCO genes contain two exons. In the present investigation, a substantial proportion of AhCCO genes, specifically 20 genes (83.3%), exhibited cytoplasmic abundance, while 12 genes (50%) were identified within the chloroplast, and 11 genes (45.8%) were located within the mitochondria. Notably, the genes detected within the chloroplasts are likely implicated in chlorophyll synthesis via the photosynthesis pathway.

The conserved motif domain-RPE65 expresses the motif compositions and gene structures that are widely distributed in 24 AhCCO genes and exhibit the range of motif from 6 to 17, except that 2 (8.33%) AhCCD genes express exclusively two motifs and eight (33.3%) AhCCD genes express three motifs. Previous research has shown that CCO genes play essential roles in ABA regulation and plant stress response [ 20 , 33 ]. The 24 AhCCO genes were found on all 12 chromosomes; however, chromosome 19 has the most genes (25%), while the others have less than 12%. The CCO promoters also contained a variety of stress-induced cis-acting elements, including ARE, LTR, MBS, TC-rich repeats, DRE, and GC-motifs. However, most of the AhCCO promoters contained an ABRE cis-element, which has significance in ABA responsiveness [ 34 , 35 ].

Plant reactions to biotic and abiotic stress have been discovered to be triggered by miRNAs [ 36 , 37 ]. Several miRNA families were predicted to regulate the expression of CCO genes in peanut, but ahy-miR394 miRNA that plays a role in regulating plant defense responses to abiotic stress revealed in our research [ 26 ]. It was predicted that ahy-miR394 targets the CCO gene ( AhCCD15 ), which suggests that it could be involved in abiotic stress regulation. Other miRNA may have a role in ABA regulation and several stress responses. Gene expression patterns are frequently associated with gene function. The transcriptomic analysis reveals the multifaceted influence of distinct CCD and NCED genes on the biotic stress response, growth, and development of A. hypogaea . These findings provide insights into the diverse contributions of CCD ( AhCCD12, AhCCD21 )genes to the development of various plant parts such as the lateral (LL), apical meristem (AM), and pentafoliate leaf (PFL), as well as their involvement in abiotic stress responses. Conversely, the NCED genes ( AhNCED9 and AhNCED13) appear to be particularly associated with pathogenic fungal resistance, representing a distinct and specialized role in the plant's defense mechanisms. These genes help the peanut plant regulate the nutrient cycle and growth of compound lateral and pentafoliate leaf development.

This is the most comprehensive study of the AhCCO gene family in terms of evolutionary relationships, gene structures, conserved motifs, cis-acting areas, and gene expression patterns in A. hypogaea . The study of these AhCCO genes reveals their evolutionary relationship to other CCO genes from different crops and helps to find out their closely related functions. Furthermore, an extensive study of cis-acting elements inside CCO gene promoters revealed an abundance of cis-acting elements involved with important functions such as growth, development, phytohormone response, and stress response. The finding precisely suggests that the CCO gene family could be involved with a variety of regulatory and transcriptional processes. Subcellular localization predictions demonstrated that a significant amount of AhCCO proteins are functionally located inside the cytoplasm and chloroplast. Particularly, the gene expression study revealed that AhCCD7 and AhCCD14 were overexpressed during the early stages of the development of compound leaves, whereas AhNCED18 was over-expressed in response to biotic stresses such as pathogenic fungal resistance. The findings of this research hold important significance for improving our understanding of the genetic complexities underlying AhCCO genes. Furthermore, these results provide potential for encouraging the development of more robust A. hypogaea cultivars capable of withstanding both growth barriers and biotic stresses, thus contributing to the long-term improvement of peanut farming.

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All data generated or analyzed during this study are included in this published article.

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Acknowledgements

This research work was funded by the Institutional Fund projects under grant no. (IFPIP: 1856-141-1443). Therefore, the authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University (KAU), Deanship of Scientific Research (DSR), Jeddah, Saudi Arabia..

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Department of Entomology, Faculty of Agricultural Sciences, University of the Punjab, Lahore, 54590, Pakistan

Arsalan Ahmad

Department of Plant Breeding and Genetics, Faculty of Agricultural Sciences, University of the Punjab, Lahore, 54590, Pakistan

Department of Horticulture, PMAS Arid Agriculture University, Rawalpindi, 46000, Pakistan

Muhammad Ali

Department of Horticulture, Faculty of Agriculture Sciences, University of the Punjab, Lahore, 54590, Pakistan

Muhammad Shafiq

Muhammad Zeshan Haider

Shahbaz Ahmad

Department of Plant Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan

King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia

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Yousef Abdul Latif Jameel Scientific Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

Department of Biological Sciences, Faculty of Science, King Abdulaziz University (KAU), Jeddah, 21589, Saudi Arabia

Rania M. Makki

Faculty of Agricultural and Environmental Sciences, Hungarian University of Agriculture and Life Sciences, Godollo, 2100, Hungary

Talha Chaudhary

Genetics and Genetic Engineering Department, Faculty of Agriculture, Benha University, Moshtohor, 13736, Egypt

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Conceptualization, AA, AS and UH; Data curation, MA, BA, MS, MZH; Formal analysis, FAS, SA, BA; Funding acquisition TC, SH, FAS, RMM; Investigation, AA, AS and UH; Methodology, SA, MA, MS, MZH; Supervision, MS; Writing – original draft, AA, AS and UH, MA, BA, MS, MZH; Writing – review & editing. AA, AS, MA, BA, TC, MS, MZH, SA, FAS, SH, RMM.

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Ahmad, A., Sami, A., Habib, U. et al. Genome wide analysis of carotenoid cleavage oxygenases ( CCO ) gene family in Arachis hypogaea (peanut) under biotic stress. BMC Genomics 25 , 469 (2024). https://doi.org/10.1186/s12864-024-10351-w

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Received : 17 September 2023

Accepted : 25 April 2024

Published : 14 May 2024

DOI : https://doi.org/10.1186/s12864-024-10351-w

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