primary research article pubmed

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• Searching PubMed
• Filters and Narrowing Searches

Searching PubMed: Filters and Narrowing Searches

Created by health science librarians.

• Basic Searches

PubMed Field Tags

Use filters to focus the search, article types, clinical queries.

• Find Full-Text Articles
• Save Search Results
• Saving Searches & Creating Alerts
• My NCBI Accounts
• Literature Reviews

You can use field tags in PubMed to limit your search to only the specified fields of the citations. For instance, you can add a title field tag and only search for a word or words in article titles. Without field tags, PubMed defaults to searching every field of a citation. This means you're searching the article title, abstract/summary, author-supplied keywords, PubMed indexing terms, and other fields like author names, authors' institutions, journal names, etc.

If your search seems to have too many irrelevant results, using field tags can help narrow your search. To use field tags, add the code in brackets immediately following the search term. For instance, to only search for dogs in the titles of articles, you'd search for dogs[TI] in PubMed.

A list of common field tags is below: 

• Learn more about PubMed Field Tags

Use the filter options available in the left sidebar of the search results page to focus the search.

Important : The "Free full text" filter does not include UNC-CH journals subscriptions. The "Full text" filter is not an accurate limit to UNC-CH journal subscriptions. Use the Find @ UNC button to find full-text articles.

Show Additional Filters

The default list of filter categories in the left hand sidebar does not include all options. Click on the link labeled "Choose additional filters" to add categories to the list. Filters are available to focus your search results by article types, text availability, publication dates, species, languages, sex, subjects, journal categories, ages, and search fields. Click on the boxes to activate the filters. For more filter options click on the additional filters option.

Type of Article, Species, Sex, and Ages filters are based on terms added by indexers. When these filters are selected they remove very recent articles that have not yet been indexed. Always look at the most recent search results before adding these filters.

Activated Filters Display on Search Result Pages.  Filters stay selected during the current search session until you change or clear them.

Once the filters are selected on the above screenshot they appear as boxes on the left hand of the screen on the results page. Tick those boxes to show the changes in the search results.

Go to PubMed Help to learn more about using filters. 

Research Study Filters

Add options to the "Article types" list by clicking on the "Additional Filters" link on the left of search result screen and selecting ones you want to use.

Therapy, intervention, and prevention search results can be limited to articles reporting clinical research by selecting Clinical Trial, Meta-Analysis, Randomized Control Trial or Systematic Reviews from the "Articles types" list.       

You can then select the filter you want. Following that check the left hand box to have it appear in the search results.

• Clinical Trial : "Work that is the report of a pre-planned clinical study of the safety, efficacy, or optimum dosage schedule of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques in humans."
• Meta-Analysis : "Works consisting of studies using a quantitative method of combining the results of independent studies (usually drawn from the published literature) and synthesizing summaries and conclusions which may be used to evaluate therapeutic effectiveness, plan new studies, etc. It is often an overview of clinical trials."
• Randomized Control Trial : "Work consisting of a clinical trial that involves at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table."
• Systematic Reviews --retrieves "citations identified as systematic reviews, meta-analyses, reviews of clinical trials, evidence-based medicine, consensus development conferences, guidelines, and citations to articles from journals specializing in review studies of value to clinicians." Systematic Review Filter Search Strategy

Other Research Article Type Filters

• Comparative Study --"comparison of outcomes, results, responses, etc for different techniques, therapeutic approaches or other inputs."
• Evaluation Studies --"studies determining the effectiveness or utility of processes, personnel, and equipment."
• Research Support , ...--"organizational source for funding of research activity"

Quoted definitions are from the PubMed MeSH Browser

Clinical queries makes it easy to find research-based articles in Pubmed.   Click on "Clinical Queries" from Pubmed homepage.

Enter a search term/search terms in the box.  Click the Search button.

Clinical Study Categories displays results by diagnosis,etiology, therapy,etc. Use the drop-down menus to change the category or scope.  Select a Category: Therapy, Diagnosis, Etiology, Prognosis, or Clinical prediction guides.  Then, select a Scope: Narrow (specific search) or Broad (sensitive search).

Systematic Reviews displays citations identified as systematic reviews, meta-analyses, reviews of clinical trials, evidence-based medicine, and/or guidelines.

Medical Genetics displays citations focused on diagnosis, management, genetic counseling, and related topics.

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• Last Updated: May 14, 2024 12:50 PM
• URL: https://guides.lib.unc.edu/search-pubmed

A simplified approach to critically appraising research evidence

Affiliation.

• 1 School of Health and Life Sciences, Teesside University, Middlesbrough, England.
• PMID: 33660465
• DOI: 10.7748/nr.2021.e1760

Background Evidence-based practice is embedded in all aspects of nursing and care. Understanding research evidence and being able to identify the strengths, weaknesses and limitations of published primary research is an essential skill of the evidence-based practitioner. However, it can be daunting and seem overly complex.

Aim: To provide a single framework that researchers can use when reading, understanding and critically assessing published research.

Discussion: To make sense of published research papers, it is helpful to understand some key concepts and how they relate to either quantitative or qualitative designs. Internal and external validity, reliability and trustworthiness are discussed. An illustration of how to apply these concepts in a practical way using a standardised framework to systematically assess a paper is provided.

Conclusion: The ability to understand and evaluate research builds strong evidence-based practitioners, who are essential to nursing practice.

Implications for practice: This framework should help readers to identify the strengths, potential weaknesses and limitations of a paper to judge its quality and potential usefulness.

Keywords: literature review; qualitative research; quantitative research; research; systematic review.

©2021 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

• Evidence-Based Medicine / standards*
• Nursing Research*

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• Identifying Articles
• PubMed at Harvard
• Searching in PubMed
• My NCBI in PubMed
• Utilizing Search Results
• Scenarios in PubMed

Primary Research Article

Review article.

Identifying and creating an APA style citation for your bibliography: 

• Author initials are separated by a period
• Multiple authors are separated by commas and an ampersand (&)  
• Title format rules change depending on what is referenced
• Double check them for accuracy 

Identifying and creating an APA style in-text citation: 

• eg. (Smith, 2022) or (Smith & Stevens, 2022) 

The structure of this changes depending on whether a direct quote or parenthetical used:

Direct Quote: the citation must follow the quote directly and contain a page number after the date

eg. (Smith, 2022, p.21)

Parenthetical: the page number is not needed

For more information, take a look at Harvard Library's Citation Styles guide !

A primary research article typically contains the following section headings:

"Methods"/"Materials and Methods"/"Experimental Methods"(different journals title this section in different ways)

"Results"

"Discussion"

If you skim the article, you should find additional evidence that an experiment was conducted by the authors themselves.

Primary research articles provide a background on their subject by summarizing previously conducted research, this typically occurs only in the Introduction section of the article.

Review articles do not report new experiments. Rather, they attempt to provide a thorough review of a specific subject by assessing either all or the best available scholarly literature on that topic.

Ways to identify a review article: 

• Author(s) summarize and analyze previously published research 
• May focus on a specific research question, comparing and contrasting previously published research 
• Overview all of the research on a particular topic 
• Does not contain "methods" or "results" type sections
• << Previous: Scenarios in PubMed
• Last Updated: Oct 3, 2023 4:16 PM
• URL: https://guides.library.harvard.edu/PubMed

Harvard University Digital Accessibility Policy

Finding Primary Research Articles in the Sciences: Home

• Advanced Search-Databases
• Primary vs. Secondary
• Analyzing a Primary Research Article
• MLA, APA, and Chicago Style

This guide goes over how to find and analyze primary research articles in the sciences (e.g. nutrition, health sciences and nursing, biology, chemistry, physics, sociology, psychology). In addition, the guide explains how to tell the difference between a primary source and a secondary source in scientific subject areas.

If you are looking for how to find primary sources in the humanities and social sciences, such as direct experience accounts in newspapers, diaries, artwork and so forth, please see   Finding Primary Sources in the Humanities and Social Sciences . 

Recommended Databases

To get started, choose one of the databases below.  Once you log in, enter your search terms to start looking for primary articles. 

• Link to all Polk State College Library databases

Login Required

You must log in to use library databases and eBooks. When prompted to log in, enter your Passport credentials. 

If you have trouble, try  resetting your Passport pin , sending an email to  [email protected] ,  or calling the Help Desk at 863.292.3652 . 

You can also get help from Ask a Librarian . 

Search Tips

Keep your search terms simple.

• No need to type full sentences into the database search box.  Limit your search to 2-3 words.
• There is no need to type "research article" into the search box.

Use the "Advanced Search" feature of the database.

• This will allow you to limit your search to only peer reviewed articles or a certain time frame (for example: 2013 or later).
• Click the red tab above for tips on advanced search strategies .

Re-read the assignment guidelines often

• Does this article satisfy the scope of the assignment (e.g. a study focused on nutrition)?
• Does it meet the criteria for the assignment (e.g. an original research article)?

Not finding what you are looking for?

• Ask a Librarian!

Search and Find a Primary Research Article

Are you looking for a primary research journal article if so, that is an article that reports on the results of an original research study conducted by the authors themselves. .

You can use the library's databases to search for primary research articles.  A research article will almost always be published in a peer-reviewed journal. Therefore, it is a good idea to limit your results to peer-reviewed articles. Click on the  Advanced Search-Databases tab at the top of this guide for instructions. 

The following is _not_ primary research:

Review articles are studies that arrive at conclusions after looking over other studies. Therefore, review articles are not  primary (think "first") research.  There are a variety of review articles, including:

• Literature Reviews
• Systematic Reviews
• Meta-Analyses 
• Scoping Reviews
• Topical Reviews
• A review/assessment of the evidence

Having trouble?  Look for a  method section within the article. If the method section includes the process used to conduct the research, how the data was gathered and analyzed and any limitations or ethical concerns to the study, then it is most likely a primary research article. For example: a research article will describe the number of people (e.g. 175 adults with celiac disease) who participated in the study and who were used to collect data.

If the method section describes how the authors found articles on a topic using search terms or databases , then it is mostly likely a secondary review article and not primary research. If there is no method section, it is not a primary research article.

Other sections in a journal: 

Your search may yield these items, too. You can skip these because they are not full write-ups of research:

• Conference Proceedings 
• Symposium Publications

Example of a primary research article found in the Library's Academic Search Complete database : (these authors conducted an original research study)

• Lumia et al. (2015) Lumia, M., Takkinen, H., Luukkainen, P., Kaila, M., Lehtinen, J. S., Nwaru, B. I., Tuokkola, J., Niemelä, O., Haapala, A., Ilonen, J., Simell, O., Knip, M., Veijola, R., & Virtanen, S. M. (2015). Food consumption and risk of childhood asthma. Pediatric Allergy & Immunology, 26(8), 789–796. https://doi.org/10.1111/pai.12352

Example of a secondary article found in the Library's Academic Search Complete database : (these authors are reviewing the work of other authors)

• Rachmah et al. (2022) Rachmah, Q., Martiana, T., Mulyono, Paskarini, I., Dwiyanti, E., Widajati, N., Ernawati, M., Ardyanto, Y. D., Tualeka, A. R., Haqi, D. N., Arini, S. Y., & Alayyannur, P. A. (2022). The effectiveness of nutrition and health intervention in workplace setting: A systematic review. Journal of Public Health Research, 11(1), 1–8. https://doi.org/10.4081/jphr.2021.2312

How do I know if this article is primary?

You've found an article in the library databases but how do you know if it's primary .

Look for these sections: (terminology may vary)

• abstract  - summarizes paper in one paragraph, states the purpose of the study
• methods  - explaining how the experiment was conducted (note: if the method section discusses how a search was conducted that is _not_ primary research) 
• results  - detailing what happened and providing raw data sets (often as tables or graphs)
• conclusions  - connecting the results with theories and other research
• references  - to previous research or theories that influenced the research

Scan the article you found to see if it includes the sections above. You don't have to read the full article (yet). Look for the clues highlighted in the images below. 

Questions? Use Ask a Librarian

• Next: Advanced Search-Databases >>
• Last Updated: Apr 29, 2024 2:19 PM
• URL: https://libguides.polk.edu/primaryresearch

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Finding Primary Articles in PubMed: Home

• APA Citations

Finding Primary Articles in PubMed

From the library homepage -- library.surry.edu (opens in new window) -- click on Find Articles .

Click on the letter P or scroll through the list until you see PubMed . To limit to full text articles, click on the PubMed Central link in the PubMed description.

Type in a search for your topic. Press Enter or click the Search button.

You will retrieve a list of articles. To limit to primary research articles, click on Clinical Trial or click More to select other type of trials and original research studies.

You may also limit your article results to Free full text either on the left or you can scan below the article results for Free Article or Free PMC Article .

If the article is available for free, you will see a link to access the article in the upper right of the screen. If you can't find the article text, email Alan Unsworth, Research Librarian , to see if the article may be obtained .

• Next: APA Citations >>
• Last Updated: Nov 9, 2023 2:07 PM
• URL: https://library.surry.edu/pubmed

Identifying Primary and Secondary Research Articles

• Primary and Secondary

Primary Research Articles

Primary research articles report on a single study. In the health sciences, primary research articles generally describe the following aspects of the study:

• The study's hypothesis or research question
• Some articles will include information on how participants were recruited or identified, as well as additional information about participants' sex, age, or race/ethnicity
• A "methods" or "methodology" section that describes how the study was performed and what the researchers did
• Results and conclusion section

Secondary Research Articles

Review articles are the most common type of secondary research article in the health sciences. A review article is a summary of previously published research on a topic. Authors who are writing a review article will search databases for previously completed research and summarize or synthesize those articles,  as opposed to recruiting participants and performing a new research study.

Specific types of review articles include:

• Systematic Reviews
• Meta-Analysis
• Narrative Reviews
• Integrative Reviews
• Literature Reviews

Review articles often report on the following:

• The hypothesis, research question, or review topic
• Databases searched-- authors should clearly describe where and how they searched for the research included in their reviews
• Systematic Reviews and Meta-Analysis should provide detailed information on the databases searched and the search strategy the authors used.Selection criteria-- the researchers should describe how they decided which articles to include
• A critical appraisal or evaluation of the quality of the articles included (most frequently included in systematic reviews and meta-analysis)
• Discussion, results, and conclusions

Determining Primary versus Secondary Using the Database Abstract

Information found in PubMed, CINAHL, Scopus, and other databases can help you determine whether the article you're looking at is primary or secondary.

Primary research article abstract

• Note that in the "Objectives" field, the authors describe their single, individual study.
• In the materials and methods section, they describe the number of patients included in the study and how those patients were divided into groups.
• These are all clues that help us determine this abstract is describing is a single, primary research article, as opposed to a literature review.
• Primary Article Abstract

Secondary research/review article abstract

• Note that the words "systematic review" and "meta-analysis" appear in the title of the article
• The objectives field also includes the term "meta-analysis" (a common type of literature review in the health sciences)
• The "Data Source" section includes a list of databases searched
• The "Study Selection" section describes the selection criteria
• These are all clues that help us determine that this abstract is describing a review article, as opposed to a single, primary research article.
• Secondary Research Article

• Primary vs. Secondary Worksheet

Full Text Challenge

Can you determine if the following articles are primary or secondary?

• Last Updated: Feb 17, 2024 5:25 PM
• URL: https://library.usfca.edu/primary-secondary

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A Guide to Biology: Find Primary Articles

• Find Primary Articles
• Find Books and Background Information
• Literature Reviews
• Citing Biology Sources/Citation Management

Journals List: Do We Have this Journal?

When you have a source with a bibliography, you can see if a particular article from the bibliography is available by looking the journal's name up at the link below. Then you can use the volume and date information to navigate to the article. If we don't have access to that journal, we usually can get it from another library.

• Search the Journals List: Do We Have this Journal?

Biology Journals in Print

These print-format journals all publish primary research and review articles in the field of biology.

American Midland Naturalist Genes and Development (most current year; earlier volumes in PMC)  Nature Science Wilson Journal of Ornithology

We also subscribe in print to the following biology-related journals and magazines Environment: Science and Policy for Sustainable Development Environmental Ethics Horticulture (current issue on main floor) Loon Minnesota Birding Minnesota Conservation Volunteer National Wildlife New Scientist (current issue on main floor)

Open Access to Biology Research

When searching PubMed, you can narrow the results to "free full text." 

For a single source of open access journal articles in the life sciences, this collection from the National Library of Medicine is hard to beat.

• PubMed Central (digital archive of journal literature) This link opens in a new window Free full text scholarly journal archive of literature in the life and health sciences, managed by the National Center for Biotechnology Information at the National Library of Medicine.

Biology Databases

Often you will hear the phrase "primary articles" when starting biology research, meaning articles written by scientists reporting new research. These typically introduce the research with a review of previous research in the introduction, methodology, results, and discussion and/or conclusion. Journals in biology also publish "review articles" that provide a roundup of recent research on a topic in biology. If you are looking for primary articles or review articles in biology and biomedical topics, these databases will be especially useful.

• Biological Science This link opens in a new window Covers research in all areas of biological science, including animal behavior, biomedicine, zoology, ecology, and others. Coverage is from 1982 to the present. Includes abstracts and citations, as well as access to thousands of full text titles.
• PubMed (citations from MEDLINE and other sources) This link opens in a new window PubMed contains more than 30 million citations and abstracts of biomedical literature. Click the "Find it at Gustavus" button to link to the full text or to make an interlibrary loan request. PubMed was developed and is maintained by the National Institutes of Health.
• Web of Science (Web of Knowledge) This link opens in a new window Science Citation Index Expanded, Social Sciences Citation Index, and Arts & Humanities Citation Index of the Institute for Scientific Information (ISI). Besides indexing a wide range of journals in the sciences, social sciences, and history, this resource allows you to search for articles that cite a specific author or published work. Coverage from 1997 to the present. Click on the "Web of Science" tab to limit your search to one or more specific citation databases.

Annual Reviews

These annual books publish review articles - detailed recaps of research on questions in the field. They are an excellent place to gain a sense of the various approaches to a topic and references to the literature that supports it.

Two series are shelved in the general collection under the following call numbers:

• ADVANCES IN MARINE BIOLOGY v. 1, 1963- (QH 91 .A1 A22)
• ADVANCES IN VIRUS RESEARCH v. 1, 1953- (QR 360 .A3)

Also of interest is WILDLIFE MONOGRAPHS. Current volumes are available online ; volumes from 1956 - 2009 are sheved at QL 1 .W54.

The Annual Reviews series online also includes biology-related review articles.

• Annual Review of Biochemistry
• Annual Review of Cell and Developmental Biology
• Annual Review of Ecology, Evolution, and Systematics
• Annual Review of Entomology
• Annual Review of Genetics
• Annual Review of Genomics and Human Genetics
• Annual Review of Immunology
• Annual Review of Neuroscience

Other Science Databases

• AGRICOLA This link opens in a new window Citations and abstracts for agricultural publications from the 15th century to the present, including articles from over 600 periodicals, USDA and state experiment station and extension publications, and selected books. Subjects include animal and veterinary sciences, entomology, plant sciences, food and human nutrition, and earth and environmental sciences. Many records are linked to full-text documents online. A resource of the National Agricultural Library.
• Google Scholar This link opens in a new window This search engine points toward scholarly research rather than all Web-based sources. It is stronger in the sciences than in the humanities, with social sciences somewhere in between. One interesting feature of Google Scholar is that in includes a link to sources that cite a particular item. Not all of the articles in Google Scholar are free; the library can obtain many of them for you through Interlibrary loan.

How Do I Get the Actual Articles?

If there isn't a PDF available, look for a "find it" link. That will check to see if it's available through another of our databases. If no full text is available, it will give you an opportunity to request the article from another library. You will have to log in using your Gustavus username and password. It usually takes a day or two. Look for an email that will explain how to download the PDF. 

If you're using Google Scholar, look for either a "find it @ Gustavus" link to the right or a "more" link under the reference you're interested in.  

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• Next: Find Books and Background Information >>
• Last Updated: Apr 12, 2024 9:29 AM
• URL: https://libguides.gustavus.edu/BIO

Literature Searching

In this guide.

• Introduction
• Steps for searching the literature in PubMed
• Step 1 - Formulate a search question
• Step 2- Identify primary concepts and gather synonyms
• Step 3 - Locate subject headings (MeSH)
• Step 4 - Combine concepts using Boolean operators
• Step 5 - Refine search terms and search in PubMed
• Step 6 - Apply limits

Steps for Searching the Literature

Searching is an iterative process and often requires re-evaluation and testing by adding or changing keywords and the ways they relate to each other. To guide your search development, you can follow the search steps below. For more information on each step, navigate to its matching tab on the right menu. 

1. Formulate a clear, well-defined, answerable search question

Generally, the basic literature search process begins with formulating a clear, well-defined research question. Asking the right research question is essential to creating an effective search. Your research question(s) must be well-defined and answerable. If the question is too broad, your search will yield more information than you can possibly look through.

2. Identify primary concepts and gather synonyms

Your research question will also help identify the primary search concepts. This will allow you to think about how you want the concepts to relate to each other. Since different authors use different terminology to refer to the same concept, you will need to gather synonyms and all the ways authors might express them. However, it is important to balance the terms so that the synonyms do not go beyond the scope of how you've defined them.

3. Locate subject headings (MeSH)

Subject databases like PubMed use 'controlled vocabularies' made up of subject headings that are preassigned to indexed articles that share a similar topic. These subject headings are organized hierarchically within a family tree of broader and narrower concepts. In PubMed and MEDLINE, the subject headings are called Medical Subject Headings (MeSH). By including MeSH terms in your search, you will not have to think about word variations, word endings, plural or singular forms, or synonyms. Some topics or concepts may even have more than one appropriate MeSH term. There are also times when a topic or concept may not have a MeSH term. 

4. Combine concepts using Boolean operators AND/OR

Once you have identified your search concepts, synonyms, and MeSH terms, you'll need to put them together using nesting and Boolean operators (e.g. AND, OR, NOT). Nesting uses parentheses to put search terms into groups. Boolean operators are used to combine similar and different concepts into one query. 

5. Refine search terms and search in PubMed

There are various database search tactics you can use, such as field tags to limit the search to certain fields, quotation marks for phrase searching, and proximity operators to search a number of spaces between terms to refine your search terms. The constructed search string is ready to be pasted into PubMed. 

6. Apply limits (optional)

If you're getting too many results, you can further refine your search results by using limits on the left box of the results page. Limits allow you to narrow your search by a number of facets such as year, journal name, article type, language, age, etc. 

Depending on the nature of the literature review, the complexity and comprehensiveness of the search strategies and the choice of databases can be different. Please contact the Lane Librarians if you have any questions. 

The type of information you gather is influenced by the type of information source or database you select to search. Bibliographic databases contain references to published literature, such as journal articles, conference abstracts, books, reports, government and legal publications, and patents. Literature reviews typically synthesis indexed, peer-reviewed articles (i.e. works that generally represent the latest original research and have undergone rigorous expert screening before publication), and gray literature (i.e. materials not formally published by commercial publishers or peer-reviewed journals). PubMed offers a breadth of health sciences literature and is a good starting point to locate journal articles.

What is PubMed?

PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. Available to the public online since 1996, PubMed was developed and is maintained by the  National Center for Biotechnology Information (NCBI) , at the  U.S. National Library of Medicine (NLM) , located at the  National Institutes of Health (NIH) .

MEDLINE is the National Library of Medicine’s (NLM) premier bibliographic database that contains more than 27 million references to journal articles from more than 5,200 worldwide journals in life sciences with a concentration on biomedicine. The Literature Selection Technica Review Committee (LSTRC) reviews and selects journals for MEDLINE based on the research quality and impact of the journals. A distinctive feature of MEDLINE is that the records are indexed with NLM  Medical Subject Headings  (MeSH).

PubMed also contains citations for  PubMed Central (PMC)  articles. PMC is a full-text archive that includes articles from journals reviewed and selected by NLM for archiving (current and historical), as well as individual articles collected for archiving in compliance with funder policies.  PubMed allows users to search keywords in the bibliographic data, but not the full text of the PMC articles.

How to Access PubMed?

To access PubMed, go to the Lane Library homepage and click PubMed in "Top Resources" on the left. This PubMed link is coded with Find Fulltext @ Lane Library Stanford that links you to Lane's full-text articles online. 

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• Next: Step 1 - Formulate a search question >>
• Last Updated: Jan 9, 2024 10:30 AM
• URL: https://laneguides.stanford.edu/LitSearch

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Why Search PubMed?

PubMed is the free interface for the premier biomedical database, MEDLINE.  It was created & is maintained by the National Library of Medicine.  PubMed contains both primary & secondary literature.  Because it's a free to access, you can use it even when you leave the University of Michigan.

Articles in PubMed are indexed by MeSH ( Me dical S ubject H eadings), terms that have specific definitions within the database & help you to create more focused searches.

Running a Search

Search Results

Your results are listed on the Search Results page.

You can see that there are many results, including some that are not related to the question.

Search Tip - "Search Details"

What if your search results are not quite what you expected or they seem really off-base?  On the Advanced page (link right below the search bar), check Search Details , to see how PubMed "translated" your search.

If at least one term for each concept in your search doesn't map to a MeSH term, you should rethink your search terms or contact the library for help.

Look at how some terms were "translated," for example,  dietary intake  mapped to eating .  This is why the search results are so far off topic.  We'll need to revise the search.

Revising Your Search

Putting dietary intake and food intake in quotation marks

( "dietary intake" OR "food intake") AND (dairy products OR milk OR cheese OR yogurt)

will restrict this part of the search to those phrases.  The phrases won't map to MeSH terms, but may provide a more focused set of results.

And that's exactly what happens.

Because there are still so many results, add United States to the search: 

("dietary intake" OR "food intake") AND (dairy products OR milk OR cheese OR yogurt) AND United States

What's on this page

Choose from this list, or scroll down:   Why Search PubMed? ; Running a Search ; Search Results ; Revising Your Search ; Focusing Your Search with Filters ; Search Tip - Keeping Recent Articles in Your Search ; and Search Tip - "Search Details" .

Search Tip - Keeping Recent Articles in Your Search

To be sure that you're seeing the most recent articles on your topic in PubMed, change the default (Best Match) to Most Recent.

Focusing Your Search with Filters

F ilters , which can be found on the left side of the Search Results page, can help you focus your search appropriately.  Categories include Article types , Publication dates , Species , Languages , & Ages .

• Two filters that are almost always useful are Species / Humans (unless you're looking specifically for animal research) and Language / English .  Ages/ Adolescent will also be useful in this search.
• Some filters are always readily available:  Article type, Text Availability (which you should ignore while you're at Michigan), Publication dates.  Others you must add to the filters list.
• To add Language , Age , & other types of filters, click on the Additional filters link below the filter list. In the box that opens, select the category of filter & then the specific filters. Click the Show button to make the filters appear on the screen.  Next choose the filter(s) you want to add.
• When you apply filters, they appear above your search results.  You can clear a filter by clicking the name of the filter or the Clear link, or clear all at the top of the results.
• Remember to clear all filters when you do a new search.

Finally, if you want to see more recent articles, add a date filter.  Limiting this search to the last 5 years gives 30 results, a reasonable set of results to look through.

PubMed: Find Research Articles

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Finding Comparative Effectiveness Research

Comparative effectiveness research is the conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat and monitor health conditions in "real world" settings.

Two specialized resources are available to inform comparative effectiveness research:

Comparative Effectiveness Research  on the PubMed Topic-Specific Queries page. Provides specialized PubMed searches of published research and research in progress to help inform investigations of comparative effectiveness.

• Medline Plus  is the world’s largest medical library, it brings you information about diseases, conditions, and wellness issues in language you can understand. MedlinePlus offers reliable, up-to-date health information, anytime, anywhere, for free.

3 Ways to Find Research Articles in PubMed

1. filter (limit) to article type.

Most citations in PubMed are for journal articles. However, you may limit your retrieval based on the type of material the article represents. Use the Filters on the Results page sidebar and look at the Article Types checklist which contains a list of frequently searched publication types.

For example, choose Randomized Controlled Trial or Clinical Trial or Meta-Analysis from the list.

2. PubMed Clinical Queries 

Enter your search terms and evidence-filtered citations will appear under Clinical Study Categories. Systematic Reviews or Medical Genetics. The Clinical Queries link is found on the PubMed home page or under the More Resources drop-down at the top of the Advanced Search page.

The resulting retrieval in PubMed Clinical Queries can be further refined using PubMed's Filters, e.g., English language, humans.

3. Limit to Articles with Structured Abstracts

Many abstracts that are added to PubMed include section labels such as BACKGROUND, OBJECTIVE, METHODS, RESULTS, and CONCLUSIONS. These 'structured' abstracts appear in many different article types such as review articles, original research, and practice guidelines and facilitate skimming of citations for relevance and specific information such as research design within the Methods section.  The presence of structured abstracts in citations are a searchable feature in PubMed.  To limit to citations containing structured abstracts, include the term hasstructuredabstract in the search box.

For example: valerian AND sleep AND hasstructuredabstract

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Finding Qualitative Research Articles

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• Qualitative Research  [research that derives data from observation, interviews, or verbal interactions and focuses on the meanings and interpretations of the participants. Year introduced 2003]
• Interviews as Topic  [conversations with an individual or individuals held in order to obtain information about their background and other personal biographical data, their attitudes and opinions, etc. It includes school admission or job interviews. Year introduced: 2008 (1980)]
• Focus Groups  [a method of data collection and a qualitative research tool in which a small group of individuals are brought together and allowed to interact in a discussion of their opinions about topics, issues, or questions. Year introduced: 1993]
• Grounded Theory [The generation of theories from analysis of empirical data. Year introduced 2015]
• Nursing Methodology Research  [research carried out by nurses concerning techniques and methods to implement projects and to document information, including methods of interviewing patients, collecting data, and forming inferences. The concept includes exploration of methodological issues such as human subjectivity and human experience. Year introduced: 1991(1989)]
• Anecdotes as Topic  [brief accounts or narratives of an incident or event. Year introduced: 2008(1963)]
• Narration  [the act, process, or an instance of narrating, i.e., telling a story. In the context of MEDICINE or ETHICS, narration includes relating the particular and the personal in the life story of an individual. Year introduced: 2003]
• Video Recording  [the storing or preserving of video signals for television to be played back later via a transmitter or receiver. Recordings may be made on magnetic tape or discs (VIDEODISC RECORDING). Year introduced: 1984]
• Tape Recording  [recording of information on magnetic or punched paper tape. Year introduced: 1967(1964)]
• Personal Narratives as Topic [works about accounts of individual experience in relation to a particular field or of participation in related activities. Year introduced: 2013]
• Observational Study as Topic [A clinical study in which participants may receive diagnostic, therapeutic, or other types of interventions, but the investigator does not assign participants to specific interventions (as in an interventional study). Year introduced: 2014]

NOTE: Inconsistent indexing in PubMed. For example, grounded theory articles are not always indexed for qualitative research. Need to TextWord search for additional terms: “grounded theory”, “action research”, ethnograph* etc.

Additional MeSH terms that may be applicable to your topic include:  Attitude of Health Personnel ;  Attitude to Death ;  Attitude to Health ; or  Health Knowledge, Attitudes, Practice.

• Interview  [work consisting of a conversation with an individual regarding his or her background and other personal and professional details, opinions on specific subjects posed by the interviewer, etc. Year introduced: 2008(1993)]
• Diaries  [works consisting of records, usually private, of writers' experiences, observations, feelings, attitudes, etc. They may also be works marked in calendar order in which to note appointments and the like. (From Random House Unabridged Dictionary, 2d ed) Year introduced: 2008(1997)]
• Anecdotes  [works consisting of brief accounts or narratives of incidents or events. Year introduced: 2008(1999)]
• Personal Narratives [works consisting of accounts of individual experience in relation to a particular field or of participation in related activities. Year introduced: 2013]
• Observational Study [A clinical study in which participants may receive diagnostic, therapeutic, or other types of interventions, but the investigator does not assign participants to specific interventions (as in an interventional study).Year introduced: 2014]
• Use Text Words to find articles missed by MeSH terms (see Strategy 2)
• Select Topic - Specific Queries from the PubMed home page and then Health Services Research Queries.
• This page provides a filter for specialized PubMed searches on healthcare quality and costs.
• Enter your search topic and select Qualitative Research under Category
• 2.  Qualitative Research search filter example [copy and paste the following modified filter into PubMed and combine your subject terms with this search filter]

(((“semi-structured”[TIAB] OR semistructured[TIAB] OR unstructured[TIAB] OR informal[TIAB] OR “in-depth”[TIAB] OR indepth[TIAB] OR “face-to-face”[TIAB] OR structured[TIAB] OR guide[TIAB] OR guides[TIAB]) AND (interview*[TIAB] OR discussion*[TIAB] OR questionnaire*[TIAB])) OR (“focus group”[TIAB] OR “focus groups”[TIAB] OR qualitative[TIAB] OR ethnograph*[TIAB] OR fieldwork[TIAB] OR “field work”[TIAB] OR “key informant”[TIAB])) OR “interviews as topic”[Mesh] OR “focus groups”[Mesh] OR narration[Mesh] OR qualitative research[Mesh] OR "personal narratives as topic"[Mesh] OR (theme[TIAB] OR thematic[TIAB]) OR "ethnological research"[TIAB] OR phenomenol*[TIAB] OR "grounded theory" [TIAB] OR "grounded study" [TIAB] OR "grounded studies" [TIAB] OR "grounded research" [TIAB] OR "grounded analysis"[TIAB] OR "grounded analyses" [TIAB] OR "life story" [TIAB] OR "life stories"[TIAB] OR emic[TIAB] OR etic[TIAB] OR hermeneutics[TIAB] OR heuristic*[TIAB] OR semiotic[TIAB] OR "data saturation"[TIAB] OR "participant observation"[TIAB] OR "action research"[TIAB] OR "cooperative inquiry" [TIAB] OR "co-operative inquiry" [TIAB] OR "field study" [TIAB] OR "field studies"[TIAB] OR "field research"[TIAB] OR "theoretical sample"[TIAB] OR "theoretical samples" [TIAB] OR "theoretical sampling"[TIAB] OR "purposive sampling"[TIAB] OR  "purposive sample"[TIAB] OR "purposive samples"[TIAB]  OR "lived experience"[TIAB] OR "lived experiences"[TIAB] OR "purposive sampling"[TIAB]  OR "content analysis"[TIAB] OR discourse[TIAB] OR "narrative analysis"[TIAB] OR heidegger*[TIAB] OR colaizzi[TIAB] OR spiegelberg[TIAB] OR "van manen*"[TIAB] OR "van kaam"[TIAB] OR "merleau ponty"[TIAB] OR husserl*[TIAB] OR Foucault[TIAB] or Corbin[TIAB] OR Strauss[TIAB] OR Glaser[TIAB] 

Mixed Methods Research Design

PubMed does not have suitable MeSH terms for mixed methods research. Search your topic with the following suggested text words using the quotes and truncation symbol*:

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© 2024 University of Washington | Seattle, WA

• Open access
• Published: 16 May 2024

Searching for the social determinants of health: observations from evidence synthesis publications

• Rosie Hanneke   ORCID: orcid.org/0000-0003-1037-3495 1 &
• Amelia Brunskill 1  

Systematic Reviews volume  13 , Article number:  134 ( 2024 ) Cite this article

Metrics details

The social determinants of health (SDOH) are the focus of an exponentially increasing number of publications, including evidence syntheses. However, there is not an established standard for searching for SDOH literature. This study seeks to identify published evidence syntheses pertaining to the SDOH, analyzing the search strategies used and the studies included within these reviews. The primary objectives are to compare search strategies and create a test set of SDOH publications.

We searched PubMed, Embase, and Scopus for evidence syntheses that mentioned the SDOH in their research questions and included an SDOH search strategy. Relevant data extracted from each review included databases searched; search terms used for the SDOH; conceptual frameworks referenced; and the citations of primary studies included in the reviews, which were compiled to form a test set of cited papers. The relative recall of the respective search strategies was tested by documenting the total number of MEDLINE results each retrieved and the number of test set papers retrieved.

Sixty-four evidence syntheses were identified and included in the analysis, and 2750 cited papers were extracted. Findings indicate few commonalities across search strategies in search terms used, the total number of results retrieved, and the number of test set cited papers retrieved. One hundred and ninety-three unique MeSH terms and 1385 unique keywords and phrases were noted among the various search strategies. The number of total results retrieved by the SDOH search strategies ranged from 21,793 to over 16 million. The percentage of cited papers retrieved by the search strategies ranged from 2.46 to 97.9%. Less than 3% of the cited papers were indexed with the Social Determinants of Health MeSH.

Conclusions

There has been little consistency across evidence syntheses in approaches to searching for SDOH literature. Differences in these strategies could have a significant impact on what literature is retrieved, included in reviews, and, consequently, incorporated into evidence-based practice. By documenting these differences and creating a set of papers relevant to SDOH, this research provides a snapshot of the current challenges in searching for SDOH content and lays the groundwork for the creation of a standardized search approach for SDOH literature.

Peer Review reports

In recent years, health sciences researchers have turned their focus from individual health behaviors upstream to the social and structural determinants of health, seeking to understand larger, systemic causes of health disparities [ 1 ]. The social determinants of health (SDOH) are the focus of an exponentially increasing number of publications across health sciences disciplines in the twenty-first century [ 2 , 3 ], including evidence syntheses. A few common frameworks are cited in Table  1 , along with their respective definitions of SDOH.

There has long been a call to incorporate considerations of health equity and upstream determinants into public health evidence syntheses such as systematic, scoping, and rapid reviews [ 7 , 8 , 9 , 10 , 11 ], given that failure to properly incorporate these factors can result in limited applicability of review findings [ 12 , 13 ]. However, despite the significant literature pointing to the importance of considering equity and social determinants in reviews, there is a wide divergence in how these concepts are operationalized in review methods [ 14 ]. One guiding framework is PROGRESS and its expansion, PROGRESS-Plus [ 15 ], first published in 2014 by O’Neill and co-authors. Evidence synthesis authors are encouraged to incorporate this framework, “a list of factors associated with effects on equity,” in the design of systematic reviews and other evidence syntheses [ 16 ].

Parallel to the evolution of the SDOH conversation in health sciences research, health sciences librarians and other expert searchers have likewise turned their focus to the concepts of SDOH and health equity in recent years, particularly in the context of ongoing conversations about the importance of comprehensive search methods in evidence synthesis. In 2014, Sivan pointed to a need for systematic incorporation of SDOH terms into PubMed and other frequently used bibliographic databases [ 17 ]. This same year was the first that a Medical Subject Heading (MeSH) term for social determinants of health was introduced to MEDLINE indexing [ 18 ].

In order to capture a wider range of literature than may be identified by either subject headings or keywords alone, expert searchers frequently use search hedges or filters, both of which consist of a pre-selected combination of search terms for a specific database, to assist them in developing comprehensive search strategies. While PubMed once offered a comprehensive search query for the concept of health disparities and minority health , including some terms related to social determinants, this query is no longer updated as of 2019 [ 19 ]. Despite the near-ubiquity of the topic of SDOH in current health and library sciences conversations, there does not yet exist a validated search hedge or filter for identifying SDOH literature.

As described by Campbell, the terms filters and hedges are sometimes used interchangeably, but more traditionally filters refine a search to studies with specific characteristics, while hedges are focused on describing subject searches [ 20 ]. Under this definition, examples of filters constructed by researchers include ones pertaining to study type [ 21 , 22 ], population [ 23 , 24 ], and geography [ 25 , 26 ], while examples of constructed hedges include ones for deprescribing [ 27 ], adverse effects of medical devices [ 28 ], acute kidney injury [ 29 ], patient-based benefit-risk assessment (BRA) of medicines [ 30 ], and public involvement in health efforts [ 31 ]. For other researchers to be able to reuse the developed strategy with an informed sense of its anticipated performance, it should be validated by formal testing and reporting of its relative recall and precision when tested against a gold standard set of relevant publications.

In a study by Prady and co-authors, who developed a search filter to identify studies related to the concept of equity [ 32 ], search terms from published, equity-focused reviews were sorted into categories of concepts (e.g., health equity, social determinants) and measures (e.g., poverty, education level). The authors ultimately recommended that researchers conducting evidence syntheses employ a “combined approach” using both specific equity terms and non-specific terms relating to how equity-focused reviews are often reported. One can assume a significant overlap between the literature identified by this equity filter and that concerned with the SDOH, and the authors seem to use the terms equity and SDOH interchangeably. However, there is a need for clear, evidence-based guidance on how to search for concepts and measures explicitly derived from an SDOH framework, especially as this framework has taken center stage in recent years.

The SDOH is not a single concept with a narrow or precisely defined scope. Conceptual frameworks describing the SDOH number in the dozens and vary widely in how they define the social determinants and describe relationships among them, at times offering conflicting definitions [ 33 , 34 , 35 , 36 , 37 ]. As a result of the myriad overlapping yet divergent definitions of the concept, it can be overwhelming to know where to begin in selecting search terms when conducting a review on the SDOH. Without an up-to-date search hedge or other standards for searching on the SDOH, review authors must build their own searches for this concept when designing search strategies for systematic, scoping, and other types of reviews.

This study seeks to examine published SDOH database search strategies from a representative sample of evidence syntheses. Its primary objective is to summarize the SDOH search strategies from these reviews and explore how this information might inform best practices for systematic searching of the SDOH literature. A secondary objective is to create a test set of SDOH papers by compiling publications included in the identified reviews to use for further analysis and compare the relative recall of the reviews' search strategies. Through pursuing these two objectives, we aim to lay the groundwork for creating a validated search hedge for this concept in the future.

The work undertaken for this study had five primary components:

Identification of evidence syntheses that contain a search strategy for SDOH;

Analysis of the identified search strategies, including terms used, databases searched, and if the authors referenced a specific SDOH framework;

Extraction of included studies ("cited papers") from the evidence syntheses to form a potential test set of SDOH papers;

Analysis of cited papers test set to identify frequently-used terms and subject headings;

Comparison of SDOH search strategies for the number of results retrieved and recall of cited papers.

We searched PubMed, Embase, and Scopus on March 24, 2022, for a representative sample of systematic reviews, scoping reviews, and other evidence syntheses by searching social, determinant*, and review in the title fields. We also searched Cochrane Library for reviews with the terms social and determinant* in the title field. No restrictions were placed on the publication date. We exported these results to EndNote v20, removed duplicates, and imported the remaining records to Covidence. The primary investigator used Covidence to screen the titles and abstracts, then full-text papers, against the following inclusion criteria:

Article is an evidence synthesis or evidence synthesis protocol that explicitly addresses the concept of SDOH, including but not limited to the following evidence synthesis types: systematic review, meta-analysis, scoping review, rapid review, integrative review, critical review;

Review focuses on all aspects of health or an individual health outcome or behavior; e.g., “social determinants of physical activity,” “Social determinants of mental health,” “built environment as a social determinant of health”;

Publication includes a full search strategy, including the social determinants concept, for at least one database, i.e., there is a list of terms used to search for social determinants.

Analysis of search strategies

The search strategies of these reviews were extracted and analyzed using Microsoft Excel and Access. Relevant data extracted from each review included definitions or conceptual frameworks cited by review authors in the “ Methods ” section; databases searched; and search terms used for the SDOH, including keywords and controlled vocabulary (MeSH).

Extraction of included studies (“cited papers”) from the evidence syntheses

For each of the evidence syntheses located, we extracted the citations of primary studies that had been chosen for inclusion within that review (these will henceforth be referred to as the test set of “cited papers”). In order to create a searchable block of these papers for further analysis, we searched for each study in PubMed, noting whether it appeared in that database. If it did, we recorded its PubMed ID number (PMID) in Microsoft Excel and combined these PMIDs to form the cited papers test set.

Analysis of cited papers

We retrieved the MeSH term indexing for the cited papers test set by creating a search string for all identified PMIDs and running it in Ovid MEDLINE. This provided a count of all MeSH terms included within that set of records. In order to isolate the MeSH terms relevant to the social determinants of health, we removed the following from this list: check tags [ 38 ], terms related to geographic locations (e.g., “California”), investigative techniques (e.g., “logistic models”), and individual diseases or conditions (e.g., “diabetes mellitus”). After deleting these, we noted the remaining MeSH terms and grouped them by how frequently they were used among cited papers. We took the same approach to keywords (KW field), ordering them by frequency of use and removing ones using the same criteria as for the MeSH terms.

This set of PMIDs for the cited papers was also compared with the set of literature indexed with the MeSH term “social determinants of health.” Through this comparison, we ascertained how frequently this MeSH term was applied to the literature that researchers had identified as relevant to SDOH.

Comparison of SDOH search strategies

In April 2023, we executed each SDOH search strategy for PubMed and Ovid MEDLINE, searching them in the platform indicated by the authors. We noted the number of records identified by each search.

We translated the PubMed search strategies to Ovid MEDLINE using the Polyglot Search Translator [ 39 ]. We then ran all search strategies, including those originally in Ovid MEDLINE format and those translated from PubMed to Ovid, against the set of PMIDs from the cited papers using Ovid MEDLINE. Ovid MEDLINE was used for all strategies, irrespective of the original platform used by the review authors, due to limitations with testing long PMID strings in PubMed. We noted the number of cited papers retrieved by each SDOH search strategy to analyze the respective recall of the strategies.

Our search for evidence syntheses that contain a search strategy for SDOH in PubMed, Embase, and Scopus resulted in an initial set of 650 records, which we exported to EndNote. After removing 381 duplicates, the remaining 269 references were uploaded to Covidence (Fig.  1 ). Sixty-four reviews, described in 67 publications, were ultimately included in the analysis (complete list provided in the Additional  file 1).

Flow diagram

Definitions and conceptual frameworks

Review authors cited over 40 frameworks, models, definitions, and other publications (hereafter called “frameworks”) in their methods sections when describing the sources that guided their characterizations of the SDOH and/or their search term selection. Among the 64 reviews, 46 reviews cited at least one framework. Eighteen of these named multiple frameworks while 28 reviews cited a single framework.

The World Health Organization’s Commission on Social Determinants of Health was cited by 20 reviews, making it the most-used source. This framework, written by Solar and Irwin and published in 2008 [ 4 ] was later published in a 2010 version [ 40 ]; alternatively, some reviews cited a summarized version from The Lancet [ 41 ] . Eleven reviews cited the HealthyPeople 2020 SDOH framework [ 42 ], and two reviews cited the more recent HealthyPeople 2030 [ 5 ]. Eight reviews cited PROGRESS [ 16 ] and/or PROGRESS-Plus [ 15 ]. All other frameworks were cited either one or two times.

Sixteen reviews explicitly mentioned using these frameworks to guide the selection of search terms for their review. For example, Baker et al. reported that “General SDH and [Health Inequities] terms were identified from the WHO’s Commission on the Social Determinants of Health report and further clarified from glossaries on social epidemiology and health inequalities [ 43 ].” The other reviews cited frameworks generally, without specifying exactly the steps to which they were applied, or cited them in relation to another aspect of the study design, such as inclusion criteria or data extraction.

Databases searched

Across all the reviews, over 50 different databases were searched (Table  2 ). An exact count of databases could not be determined due to inconsistencies and imprecisions in the way authors described their database searches. In particular, the frequent reporting error of listing a vendor platform rather than the specific databases searched within it (e.g., “ProQuest”) prevents this analysis. Among the 64 reviews, 62 searched either PubMed, Ovid MEDLINE, or both PubMed and Ovid MEDLINE, or indicated that they searched MEDLINE without specifying the platform. The databases reported as “Web of Science” and “Cochrane” reflect several possible resources searched under these products. The Clarivate Web of Science platform may search different date ranges and products including citation indexes, MEDLINE, and other databases, depending on the searcher's institutional subscriptions and backfile purchases [ 44 ]. Cochrane Library also searches multiple collections, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Clinical Answers, and records from external (non-Cochrane-produced) resources [ 45 ]. The majority of reviews did not report which collections were searched within these two vendors; we have provided additional detail when it was given by the authors.

The 62 reviews whose searches included a PubMed, Ovid MEDLINE, or generic MEDLINE search strategy were collected as the core dataset to form search term analysis. One of these 62 was excluded due to the published searched strategy containing extensive additional terms that had been added by PubMed’s Automatic Term Mapping (ATM) feature; these additional terms prevented straightforward analysis of the authors’ intended search methods. The following analyses were therefore conducted on the dataset of search strategies extracted from the remaining 61 reviews.

Thirty-nine of the 61 reviews (63.9%) used MeSH terms; to be precise, these 39 search strategies explicitly indicated that the terms were searched in the MeSH field. These search strategies used anywhere from 1 MeSH term to 46 of them (median = 12, M  = 13.51). Seven terms indicated by authors to be MeSH, upon further review, were found to be neither current nor previous iterations of MeSH terms. In total, there were 193 unique MeSH terms, and one floating subheading (education), used to search for the SDOH concept. The two most commonly appearing MeSH terms (Table  3 ) were social determinants of health (in use since 2014) and socioeconomic factors (in use since 1968). Each was used in 28 of the search strategies. A full list of all MeSH terms used to search for the SDOH concept is available in the Additional file 1.

Keywords, title, and abstract terms

Fifty-eight of the 61 search strategies incorporated keywords, i.e., non-controlled vocabulary terms. The number of keywords used in each of these reviews ranged from one to 218 (median = 20, M  = 38.75), and there was a total of 1385 unique keywords and phrases used across all 58 reviews. The remaining three reviews used MeSH terms exclusively and did not search other fields such as title or abstract. Keywords that were variations of a single term (e.g., social determinants, social determinant, social determinant* with truncation) were counted individually rather than grouped together. The keywords used most frequently (Table  4 ) included a mix of both terms describing general concepts ( social determinants, socioeconomic status ) and specific keywords for individual determinants ( income, race, unemployment ). A full list of all keywords and phrases used to search for the SDOH concept is available in the Additional file 1.

Most of the reviews incorporated at least one advanced search technique into their keyword searches. Thirty-nine reviews used at least one instance of truncation or wildcard searching among their keywords. A minority of reviews ( n  = 23) used either double quotation marks or hyphens to search two or more keywords together as a bound phrase. Ten of the 13 reviews that searched Ovid MEDLINE also incorporated proximity/adjacency operators into their keyword searches.

Number of results

The SDOH portion of each review's search strategy was run in either PubMed or Ovid MEDLINE, according to which one the authors had stated they searched. We searched first for the SDOH-related terms on their own, independent of additional search concepts. An additional three search strategies were excluded at this stage, leaving 58 search strategies; because of changes to the MeSH terms used in these three reviews, it was not possible to execute the searches as they had been conducted at the time of the reviews. The number of results for these isolated SDOH search strategies ranged from 21,793 (Morone 2017) to 16,423,265 (Maness 2016). In Fig.  2 , we cluster the search strategies by the number of results to highlight how they varied within those extremes, with a plurality retrieving between one million and ten million results.

SDOH search result numbers

Cited papers

The original dataset of 64 reviews, i.e., the 61 reviews whose search strategies are described above together with the remaining three reviews, was revisited to extract data from the papers cited by each review. Twelve of the 64 reviews were excluded from this stage of analysis, either because they did not provide a clear list of citations for their included studies ( n  = 8) or because they were protocols and therefore did not yet have any studies selected for inclusion ( n  = 4).

The remaining 52 reviews reported a total of 2750 cited papers representing 2714 studies. Within this test set of 2750 cited papers, 2554 were found in PubMed and their PMIDs were noted. The other 196 cited papers are not found in PubMed.

Among the 2554 cited papers that were in PubMed, 36 duplicates were found, i.e., papers that had been cited in more than one of the evidence syntheses. After removing these, 2518 unique PMIDs remained. This set, referred to as the “cited papers” test set, represents 2518 unique publications in PubMed that have been selected by review authors as relevant to the topic of SDOH.

MeSH terms from cited papers

When the set of 2518 cited papers was searched in PubMed in combination with the “social determinants of health” MeSH term, 2.42% ( n  = 61) were retrieved. There were 1401 cited papers with a date created (DA) prior to 2014 which could not have used the “social determinants of health” MeSH term, which was added to the MeSH database in 2014 [ 46 ]. Two cited papers had no DA field. When all remaining PMIDs, which had a Date Created between 2014 and 2022 ( n  = 1115), were searched in combination with “social determinants of health”[mesh], the percentage indexed with SDOH MeSH rose to 5.47%. “Socioeconomic Factors,” the other MeSH term which appeared most frequently among SDOH search strategies, retrieved 36.73% ( n  = 925) of the cited papers.

Cited papers were indexed with 38,393 MeSH terms. After deleting 10,918 check tags (human = 2374, male = 1461, female = 1724, adult = 1115, middle-aged = 882, adolescent = 773, aged = 637, young adult = 522, child = 392, aged, 80 and over = 255, pregnancy = 249, child, preschool = 191, infant = 169, infant, newborn = 167, animals = 7), 27,475 MeSH terms remained, including duplicates. Unique MeSH terms appearing among the cited papers totaled 2,482. There were 778 MeSH terms that appeared in the indexing for a single article, each appearing once. Each of the remaining 1704 MeSH terms appeared in the MeSH terms of two or more cited papers.

After removing MeSH terms related to geographic locations, investigative techniques, and individual diseases or conditions, the 20 most frequently appearing MeSH terms were collected (Table  5 ).

Keywords from cited papers

Of the 2518 cited papers, 663 had keywords (listed in the KW field in MEDLINE), with a total of 3577 keywords total across the papers. These keywords were compiled, trimmed, and reviewed for frequency. After deleting terms that would have been check tags, geographic regions, diseases, conditions, and investigative techniques, the top 20 most frequent terms/phrases were identified which corresponded to those that appeared in twelve or more papers (see Table  6 ). For many of these, there were synonyms and variations on these terms that also appeared and sometimes the word appeared as part of a larger phrase. For example, in addition to race, there were other variations, some of which included: race and ethnic disparities, race and ethnicity, race factors, race/ethnicity, race-related stress, racial and ethnic disparities, racial bias, racial discrimination, racial disparities, racial disparity, racial health disparities, racial identity, racial misclassification, racial/ethnic differences, racial/ethnic differences in health and health care, racial/ethnic disparities, and racism. It is possible that other keywords might have been more common if all variations and synonyms were counted together.

Retrieval of cited papers by collected search strategies

The percentage of the cited papers retrieved by the search strategies varied from a low of 2.46% to a high of 97.9%. Figure  3 shows how each search strategy performed in terms of the percent retrieved versus the total number of results returned. None of the search strategies that retrieved under 6 million results retrieved over 90% of the cited papers, and only one of the studies that retrieved over 6 million retrieved under 60% of the cited papers. Several search strategies achieved a higher percentage of retrieval, i.e., better precision, than search strategies that retrieved a considerably higher number of studies overall.

Percent recall of cited papers vs. total number of results returned

The overwhelming takeaway from this analysis is that there is little to no consistency in the way that review authors are searching for literature related to the SDOH. The sole exception is perhaps the database most frequently searched, given that all but two reviews included PubMed and/or Ovid MEDLINE. Beyond this, the investigation of review methods revealed a vast range of approaches, particularly among search strategies.

Conceptual frameworks and definitions

While the World Health Organization’s CSDH framework stood out as the most-cited among the studied sample of reviews, there is not one single agreed-upon definition, model, or framework for the SDOH that is used to guide evidence syntheses conceptually. The literature supports our observation that the multiple SDOH models vary widely in their definitions of the determinants, as well as in the relationships between and among determinants and outcomes [ 35 , 36 , 37 ].

Search strategies

There were over 20 reviews that searched PubMed and/or Ovid MEDLINE yet did not indicate searching for MeSH terms. Including controlled vocabulary terms has long been considered best practice for reviews [ 47 , 48 , 49 ]. While many of these reviews may well have captured the relevant MeSH terms by searching all available fields, using field codes to indicate which fields of the records are being searched is key for reproducibility and improves search precision [ 50 , 51 ].

Among the searches that did incorporate controlled vocabulary, it was surprising to find that the MeSH term “social determinants of health” did not have a greater presence. Six of the reviews we analyzed reported conducting their searches before the MeSH term was introduced in 2014 and so would not have had it available to use for their search strategy. Among the 45 reviews that explicitly stated that their searches were conducted in or after the SDOH MeSH became available in 2014, over a third ( n  = 17, 37.78%) nevertheless omitted this seemingly essential term. Unfortunately, it was impossible to investigate this matter more precisely since 13 of the 64 reviews, or 20.3%, did not report the date that their searches were conducted, contrary to professional guidelines [ 50 ].

At the same time, even those reviews which use the SDOH MeSH term evidently cannot rely on this subject heading to retrieve much of the SDOH-related literature from MEDLINE, as only 61 (5.47%) of the 1115 cited papers indexed for MEDLINE between 2014 and 2022 were indexed with “social determinants of health.” Consequently, researchers undertaking evidence syntheses must incorporate additional terms to ensure broad retrieval of SDOH literature. This is increasingly crucial as databases move away from human indexing towards using automated processing for assigning controlled vocabulary terms. MEDLINE transitioned to an automated indexing process using the Medical Text Indexer (MTI) algorithm in 2022 [ 52 ] with mixed results [ 53 , 54 ]. This points to the continued necessity of reflecting critically on the selection of keywords in addition to MeSH terms when drafting the search strategy for an evidence synthesis study. MeSH terms suggested as potentially relevant by the search strategies as well as by the indexing of the cited papers include Socioeconomic Factors, Risk Factors, Health Services Accessibility, Health Status Disparities, Healthcare Disparities, Poverty, and Educational Status. Further testing of the sensitivity and precision achieved with these terms will be necessary before making a final determination as to their usefulness.

No clear patterns emerged among the keywords selected by authors in their search strategies. Most reviews contained a mix of specific and general terms. We had hoped to analyze in detail which searches used specific and general terms and sort the terms into quantifiable categories. The constructs of concept / measure and specific / non-specific terms used by Prady and co-authors [ 32 ] also would have been interesting to explore. Unfortunately, these distinctions were not as easily quantified as first anticipated and ultimately beyond the scope of the project at hand. We did, however, observe that the ten SDOH search strategies with the highest number of search results—over 90% of cited papers—used a mix of both general and specific terms, and the ten strategies with the lowest number of search results used only notably general terms describing broad concepts, such as determinants , disparities , and equities . This implies potentially higher recall for a search that incorporates individual determinant terms as well as general concepts.

Notably, risk factors appeared frequently as both a MeSH term and keyword among the indexing of the cited papers, yet this term did not appear in any of the search strategies we analyzed. MeSH terms appearing frequently in both published search strategies and cited papers included Socioeconomic Factors, Health Status Disparities, Healthcare Disparities, and Health Services Accessibility. Keywords appearing frequently in both published search strategies and cited papers included social determinants of health , social support , socioeconomic status , and race . All of these MeSH terms and keywords were in the top 10 most frequently used among both published reviews and cited papers.

SDOH is a wide-ranging concept that can seem daunting, or even impossible, to comprehensively cover through a list of relevant search terms. Furthermore, SDOH frameworks often focus on broad domain definitions and fail to reflect adequate nuance [ 55 ]. When it came to translating their respective conceptualizations of the SDOH to search terms, some reviews analyzed in this study seemingly attempted to create exhaustive lists; others listed only a handful of terms. While most reviews cited at least one conceptual framework, only a small number of them made a clear connection between the framework and search strategy. No obvious recommendations emerged from the data in terms of a standard number of search terms to aim for.

Recommendations for searching for SDOH literature

While the observations in the present study do not clearly lend themselves to the recommendation of any single search method, perhaps some guidance can be ascertained from the fact that the findings varied widely. Because there are so many ways to conceptualize the topic and myriad methods of searching, it seems of the highest importance that teams conducting evidence syntheses agree on a shared understanding of the SDOH concept. By selecting a framework or model to guide their review, authors can use a tangible definition of social determinants as a reference from which to derive search terms. Search strategies could be designed based on a particular framework, thus placing boundaries on the sprawling SDOH concept and giving authors a starting point while simultaneously providing clarity for the reader.

Recommendations for authors writing about SDOH

Authors publishing original research related to the social determinants of health can use these findings to improve the discoverability of their abstracts by review teams and other searchers. Careful selection of the language used in article titles and abstracts may increase the possibility of the article being indexed with relevant terms. Notably, the MeSH term social determinants of health rarely appeared in article indexing unless that phrase also appeared in an article’s title or abstract.

Limitations

The reviews analyzed in this study are a representative sample rather than an exhaustive list of all publications on the topic of SDOH. It is possible that the inclusion of reviews on other determinants (structural, commercial, etc.) would have had an impact on our findings, as would have related concepts such as health equity and disparities. Additionally, in 2020, there were significant changes made to the search function in PubMed [ 56 ]. PubMed searches executed at the time of our study may have had different results than at the time they were originally conceived and executed.

It is important to note that these findings reflect a sample collected at a moment in time; data were gathered in 2022 and analyzed between 2022 and 2023. Language used in academia and practice is constantly in flux and likely will continue to change as the field reflects and improves upon the way these concepts are described. For example, one recent publication encouraged researchers to reconceptualize population health and social determinants work in terms of structural drivers [ 57 ] . Ongoing observation of the language used to describe concepts related to SDOH and health equity is necessary for keeping search strategies current.

Future research

The next phase of this research project will focus on the development and validation of a search hedge for identifying SDOH literature. The most commonly appearing MeSH terms and keywords from the reviews examined in this study, as well as the test set of cited papers, will be used as a foundation for constructing the hedge.

While there has been considerable interest in the concept of SDOH, and many evidence syntheses include this as part of their research question, we found little consistency in terms of how researchers approach systematic searching for this concept. The differences in the terms and approaches used mean that the scope and quantity of the literature retrieved by these searches vary markedly. This has potentially significant implications for the overall amount of literature retrieved for evidence syntheses, and consequently incorporated into evidence-based public health policy and practice, when SDOH are a component. While MEDLINE was searched by nearly all evidence syntheses via PubMed and/or Ovid, and a MeSH term exists for SDOH, this subject heading was applied to only a small minority of the cited papers set, further highlighting the challenges in searching for SDOH literature.

A search hedge developed for SDOH could improve the recall of SDOH materials, bringing consistency and comprehensiveness to evidence syntheses. It remains unclear whether a precise and sensitive hedge will be achievable; however, this study has created a test set of SDOH literature that could potentially be used for that purpose. Until the time that such a hedge is developed and validated, researchers conducting evidence synthesis projects can improve transparency by choosing an SDOH framework to guide the selection of their search terms, thereby clarifying decisions. An expansive search strategy is likely necessary to recall all relevant evidence.

Availability of data and materials

The dataset supporting the conclusions of this article is available in the University of Illinois Chicago repository, https://indigo.uic.edu/articles/dataset/Searching_for_the_social_determinants_of_health_dataset/24518497 . The dataset was submitted to the University of Illinois Chicago repository on November 7, 2023, and accepted on November 13, 2023. An updated version was submitted and accepted on April 2, 2024.

Abbreviations

Medical Subject Heading

PubMed Identification Number

• Social determinants of health

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The authors would like to express their gratitude to David DuBois and Rebecca Raszewski for their review of previous manuscript versions. They would also like to thank all UIC Library Writing Accountability Group colleagues for their continued support.

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Hanneke, R., Brunskill, A. Searching for the social determinants of health: observations from evidence synthesis publications. Syst Rev 13 , 134 (2024). https://doi.org/10.1186/s13643-024-02551-y

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Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus

• Shiheng Wang 1 ,
• Wanling Ning 2   na1 ,
• Hanqing Tang 3 ,
• Chaochao Mu 4 &
• Xiaosong Huang 5  

Arthritis Research & Therapy volume  26 , Article number:  98 ( 2024 ) Cite this article

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Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE.

Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane’s tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety.

A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P  < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P  < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo ( P  > 0.05).

Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease induced by immune system dysfunction, which may cause damage to multiple organs and systems [ 1 ]. The pathogenesis of SLE is very complicated, involving almost all parts of the immune system. Multiple genetic, epigenetic, environmental, and hormonal factors may lead to the loss of self-tolerance and disorders of adaptive and innate immune systems [ 2 ]. Therefore, the treatment of SLE is complex and challenging.

At present, the treatment of SLE still relies mainly on glucocorticoids and immunosuppressants. However, the treatment efficacy is not satisfactory. Some patients are poorly responsive to these targeted small-molecule drugs, with relevant adverse reactions [ 3 ]. In recent years, with the in-depth understanding of the pathogenesis of SLE, it has been found that disordered production and abnormal expression or level of cytokines in SLE may be the main pathogenic factors. Disorders of cytokine network are conducive to inhibiting cytokine activity and promoting cytokine survival and the production of autoantibodies [ 4 ], which provides novel insights into the research and development of relevant new drugs. For example, such targeted small-molecule drugs as Janus Kinase Inhibitors(JAKs), Bruton Tyrosine Kinase (BTK), Spleen Tyrosine Kinase(SYK), and Sphingosine 1-Phosphate Receptor(Sphingosine 1-Phosphate Receptor) are being developed for the treatment of malignant and autoimmune diseases, including SLE [ 5 ]. These drugs differ from biological disease-modifying antirheumatic drugs (DMARDs). Some DMARDs are large-molecule drugs to be administered by injection, while small-molecule drugs are orally administered and can directly enter the cytoplasm to take effect. Due to such advantages as convenient administration, low production cost, and no immunogenicity, targeted small-molecule drugs have broad clinical application prospects [ 6 ].

Targeted small-molecule drugs are gaining increasing attention from clinical investigators. Many clinical trials have been published to investigate the efficacy and safety of targeted small-molecule drugs. However, the difference in their efficacy and safety is still unclear. In the meantime, there are a number of ongoing Randomized controlled trials (RCTs) (such as NCT03920267, NCT05620407, NCT05617677, NCT05672576 and NCT05648500) about targeted small-molecule drugs in the treatment of SLE on the clinical trial registration platform ( https://beta.clinicaltrials.gov ), indicating that the efficacy and safety of targeted small-molecule drugs in the treatment of SLE remain a research hotspot. Hence, in this study, the efficacy and safety of different targeted small-molecule drugs were compared by using Bayesian network meta-analysis based on published RCTs to find out the best targeted small-molecule drugs as much as possible, so as to provide an evidence-based reference for clinical application and study.

Study registration

This study was conducted in accordance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA) and was prospectively registered in PROSPERO (ID: CRD42023420169).

Eligibility criteria

Inclusion criteria.

Population: Patients were definitely diagnosed with SLE. No restrictions were imposed on race, nationality, sex, age, and course of disease.

Intervention: Targeted small-molecule drugs (including JAKs, BTK, SYK, Proteasomes, Cereblon, and S1PR1) were used.

Comparison: Placebo.

(1) Primary outcome indicators: (1) Systemic Lupus Erythematosus Responder Index (SRI-4) response rate: A 24-item weighted score of lupus activity ranged from 0 to 105, with a higher score indicating higher disease activity and a score reduction of at least 4 points indicating being effective [ 7 ]; (2) BILAG-based Composite Lupus Assessment response(BICLA). The BILAG is used to assess the disease activity. If there is no Grade A or the number of Grade B is ≤ 1, and there is no deterioration in the disease activity (increased by less than 0.3 from baseline) according to physician’s global assessment (PGA), the drug is considered effective [ 8 ]; (3) Adverse reactions.

(2) Secondary outcome indicators: (1) CLASI-50: Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is an indicator to evaluate the severity of cutaneous lupus erythematosus, and the score ranges from 0 to 70, with a higher score indicating more severe condition and higher activity, and a 50% reduction in the CLASI-A score called CLASI-50 [ 9 ]; (2) Swollen and tender joint count (baseline - end of treatment): It reflects the degree of joint pain and swelling, and a higher score indicates a more severe condition.

 Study design: RCTs.

Exclusion criteria

P (Population): Other types of SLE, such as lupus nephritis, active central nervous system lupus and lupus vasculitis.

I (Intervention): Different administration methods of targeted small-molecule drugs at the same dosage were used.

S (Study design): Meeting abstract published without peer review. If several studies were published based on the same RCT, a study with the largest sample size, the most complete follow-up time, and the most outcome indicators was included.

Data sources and search strategy

RCTs of targeted small-molecule drugs in the treatment of SLE in PubMed, Embase, Cochrane Library, and Web of Science were systematically searched as of April 25, 2023 using the combination of subject words and free words. Search words included Systemic Lupus Erythematosus, Lupus Erythematosus Disseminatus, Libman-Sacks Disease, JAKs, Baricitinib, Agammaglobulinaemia Tyrosine Kinase, Fostamatinib. The search strategies are presented in Appendix 1 .

Study selection

We imported the retrieved literature into EndNoteX9 software and removed duplicate publications that were marked automatically and manually. As for the remaining literature, unqualified literature is deleted by reading the title and abstract; as for potentially qualified literature, the full text is downloaded and read to further screen the literature, so as to identify the original studies that are eligible for this systematic review. Literature screening was carried out independently by two investigators (Wang SH and Ning WL), and cross-check was conducted after completing the screening. Disagreements, if any, were discussed jointly with a third investigator (Tang HQ).

Data extraction

A data extraction table was designed by two investigators (Wang SH and Zhang FX) according to the information required in the study, and data were extracted independently by them. The contents included ① Basic information: Title, author, year, study design, diagnosis criteria, intervention measures, course of treatment, and outcome indicators; ② Demographic characteristics: Sample size, age, and gender; ③ Methodological information: randomization method, allocation concealment protocol, blinding method, data integrity, selective reporting od results, other bias. If the information extracted by them was inconsistent, they would discuss the problem with each other to reach a consensus.

Risk of bias in studies

Two investigators (Wang SH and Ning WL) used Cochrane’s tool for evaluating the risk of bias in RCTs [ 10 ] to assess the risk of bias in the included studies. This assessment tool included the following 7 items: generation of random sequences, allocation concealment, blinding of subjects and intervention providers, blinding of result evaluators, incomplete result data, selective reporting of results, and other sources of bias. Each item was graded as low-bias, high-bias, or unclear. The assessment results of the risk of bias were directly displayed using Revman5.4.

Synthesis methods

A Bayesian random-effects model was used to compare the efficacy of various intervention measures. The Markov Chain Monte Carlo (MCMC) method was used for modeling, and 4 Markov chains were run at the same time. The number of annealing was set to 20,000, and the modeling was completed after 50,000 simulative iterations. Deviance information criterion (DIC) was used to compare model fitting and global consistency, and we would adopt the node-splitting method to analyze local consistency if closed loops existed. In addition, these intervention measures were ranked based on surface under the cumulative ranking curve (SUCRA), and the league table was generated to compare the difference in the effects among intervention measures.

Since the included studies were multi-arm studies on targeted small-molecule drugs with different doses and courses of treatment, Bayesian network meta-regression was adopted to analyze whether there were significant differences in efficacy and safety among targeted small-molecule drugs at different doses and courses of treatment in comparison with the placebo. When the number of included studies in the meta-analysis of an outcome indicator was ≥ 10, a funnel plot would be used to intuitively reflect the publication bias. The analysis was completed using Stata 15.0 (Stata Corporation, College Station, TX) and R4.2.0 (R development Core Team, Vienna, http://www.R-project.org ). P  < 0.05 indicates that the difference is statistically significant.

Through a preliminary search, 3,245 relevant articles were obtained, and 562 duplicate articles were excluded. After reading the title and abstract, 24 articles were included, and 11 articles were included through full-text screening (3 studies of the same RCT repeatedly published with different outcomes or populations, 2 studies with no interest outcome indicators, and 6 conference abstracts without peer review). Finally, 13 studies were included [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The literature screening process is illustrated in Fig.  1 .

Literature screening process

Study characteristics

Thirteen studies were included in this analysis, involving a total of 3,622 patients, and the authors of the included studies were from the United States, the United Kingdom, Germany, Australia, and Switzerland. The year of publication was between 2016 and 2023, and most of the studies were published in recent three years. The diagnosis criteria for SLE were mainly the American College of Rheumatology classification criteria [ 24 , 25 ]. Eleven studies [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 21 , 22 , 23 ] were multi-arm studies on a targeted small-molecule drug at different doses. Targeted small-molecule drugs used in the intervention group included JAKs (Baricitinib Filgotinib, Deucravacitinib, GSK2586184), BTK (Fenebrutinib, Evobrutinib), Cereblon (Iberdomide), SYK (Lanraplenib), and S1PR1 (Cenerimod). The basic characteristics of included studies are provided in Table  1 .

Risk of bias in the included studies

In terms of randomization methods, the computer-generated random sequence method was used in 4 studies [ 11 , 14 , 17 , 18 ], and the inter-active web response system was used in 3 studies [ 19 , 21 , 22 ]. Allocation concealment was used in 4 studies [ 11 , 14 , 17 , 18 ]. The blinding method was used in all studies. Data from all studies were complete, and no selective reporting was found. The sample size of 2 studies [ 13 , 21 ] was small, which may cause publication bias. Figures  2 and 3 show the results of the risk of bias for each included study.

Risk of bias graph of all included studies

Risk of bias summary of all included studies

Meta-analysis

Sri-4 response, the correlation among intervention measures.

SRI-4 response was reported in 7 studies [ 12 , 14 , 16 , 17 , 18 , 19 , 23 ], involving 5 targeted small-molecule drugs from JAKs, BTK, and Cereblon. The comparison between targeted small-molecule drugs and the placebo was only reported in each study, and there was no pairwise comparison among targeted small-molecule drugs. The number of studies on direct comparison between Baricitinib and the placebo was the largest, and there was no closed loop, as shown in Fig.  4 . (JAKs: red; BTK: khaki; Cereblon: green; SYK: yellow; S1PR1:purple; Placebo: blue).

Network diagram of targeted drug therapy in the treatment of SLE using SRI-4 as the outcome indicator

Synthesized results

Network meta-analysis results showed that 3 targeted small-molecule drugs (Baricitinib, Deucravacitinib, and Iberdomideb) were significantly superior to the placebo in improving SRI-4 response ( P  < 0.05) (Fig.  5 ). There were differences in efficacy among some targeted small-molecule drugs. The effect of Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P  < 0.05) (Table  2 ). The top three drugs in the SUCRA ranking were Deucravacitinib (0.91), Iberdomideb (0.79), and Fenebrutinib (0.45) (Table  3 ).

Forest plot of meta-analysis of SRI-4 response of targeted small-molecule drug therapy compared with placebo

Meta-regression

Because different doses of targeted small-molecule drugs and various courses of treatment were adopted in the included studies, meta-regression was performed on the dose and the course of treatment to discuss the effect of the dose and the course of treatment on SRI-4 response. The results showed that the efficacy and safety of targeted small-molecule drugs were not significantly correlated with the dose and the course of treatment as compared to the placebo, and the results were not statistically significant (Table  4 ).

BICLA response

The correlation among each intervention measure.

BICLA response was reported in 5 studies [ 12 , 14 , 17 , 19 , 23 ], involving 3 targeted small-molecule drugs from JAKs and BTK. The comparison between targeted small-molecule drugs and the placebo was only reported in each study, and there was no pairwise comparison among targeted small-molecule drugs. The number of studies directly comparing Baricitinib and the placebo was the greatest, and there was no closed loop, as shown in Fig.  6 .

Network diagram of targeted drug therapy in the treatment of SLE using BICLA response as the outcome indicator

Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P  < 0.05) (Fig.  7 ). There were differences in the efficacy among some targeted small-molecule drugs. Deucravacitinib was more effective than Baricitinib (RR = 1.47, 95% CI (1.11, 1.94), P  < 0.05) (see Table  5 ). The top three drugs in the SUCRA ranking were Deucravacitinib (0.98), Fenebrutinib (0.56), and Baricitinib, in sequence (0.40) (Table  3 ).

Forest plot of meta-analysis of BICLA response of targeted small-molecule drug therapy compared with placebo

Due to differences in the dose of targeted small-molecule drugs and the course of treatment in the included studies, meta-regression was performed on the dose and the course of treatment to explore the effect of the dose and the course of treatment on BICLA response. The results showed that the efficacy and safety of targeted small-molecule drugs were not significantly correlated with the dose and the course of treatment as compared to the placebo, and the results were not statistically significant (Table  4 ).

Adverse reactions

Adverse reactions were reported in 11 studies [ 12 , 13 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], involving 9 targeted small-molecule drugs from JAKs, BTK, SYK, Cereblon, and S1PR1. There was one closed loop (Filgotinib-Lanraplenib-Placebo). The studies directly comparing Iberdomide and the placebo were the largest in number, as shown in Fig.  8 .

Network diagram of targeted drug therapy in the treatment of SLE using adverse reaction as the outcome indicator

There were no statistically significant differences in the adverse reactions between targeted small-molecule drugs and the placebo. The safety profile of Iberdomide was significantly lower than that of placebo (RR = 1.21, 95% CI (1.07, 1.37), P  < 0.05)(Fig.  9 ). There were differences in the adverse reactions among some targeted small-molecule drugs. Baricitinib (RR = 0.84, 95% CI (0.73, 0.95), P  < 0.05), Cenerimod (RR = 0.60, 95% CI (0.39, 0.89), P  < 0.05), Deucravacitinib (RR = 0.84, 95% CI (0.73, 0.96), P  < 0.05), and Evobrutinib (RR = 0.87, 95% CI (0.75, 0.99), P  < 0.05) had fewer adverse reactions in comparison with Iberdomide (Table  6 ). The top three drugs in the SUCRA ranking were Cenerimod (0.93), Filgotinib (0.73), and Placebo (0.66), in order (Table  3 ).

Forest plot of meta-analysis of adverse reaction of targeted small-molecule drug therapy compared with placebo

Owing to the differences in the dose of targeted small-molecule drugs and the course of treatment, meta-regression was performed on the dose and the course of treatment to investigate the effect of the dose and the course of treatment on adverse reactions. The results showed that the safety of targeted small-molecule drugs was not significantly correlated with the dose and the course of treatment as compared to the placebo, and the results were not statistically significant (Table  4 ).

Secondary outcome indicators

Our study showed that in terms of CLASI-50, Deucravacitinib was significantly superior to the placebo ( P  < 0.05). Deucravacitinib was more significantly effective than Fenebrutinib. Deucravacitinib was more significantly effective than Iberdomide. In terms of tender joint count, Baricitinib and Deucravacitinib were significantly superior to the placebo ( P  < 0.05), and there was no significant difference in the efficacy among all targeted small-molecule drugs. No significant differences were observed in swollen joint count between all targeted small-molecule drugs and the placebo, or among targeted small-molecule drugs. The detailed analysis results are shown in Appendix 2 .

Thirteen studies were included in this analysis, including 9 targeted small-molecule drugs: Baricitinib, Cenerimod, Deucravacitinib, Evobrutinib, Fenebrutinib, Filgotinib, GSK2586184, Iberdomide, and Lanraplenib. A total of 6 outcome indicators were studied. In terms of efficacy indicators, Baricitinib, Deucravacitinib, and Iberdomide significantly outperformed the placebo. The safety profile of Iberdomide was significantly lower than that of placebo. There were differences in the therapeutic effect among some targeted small-molecule drugs. The safety profile of Baricitinib, Cenerimod, Deucravacitinib, and Evobrutinib was higher than that of Iberdomide. The adverse reactions of targeted small-molecule drug therapy were mostly mild, with very few serious adverse reactions. Adverse reaction symptoms include nausea, vomiting, urinary tract infection, upper respiratory tract infection. It was reported that these symptoms can resolve spontaneously or be cured after treatment.

The meta-regression results of this study showed that doses and courses of treatment had no significant impact on the results. In terms of specific outcome indicators, there were differences in the efficacy among different targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Although the meta-regression results showed that doses and courses of treatment had no significant effects on the results, this may differ from reality. Therefore, attention shall still be paid to the choice of doses and courses of treatment in clinical practice.

Deurefacitinib is a potent, highly selective, and allosteric small-molecule inhibitor of Tyrosine Kinase 2 (TYK2) that plays its role through a new mode of binding to the Janushomology2 (JH2) pseudokinase domain, so as to keep the kinase in an inactive state. It can block the downstream signaling of Interleukin-12(IL-12), Interleukin-23(IL-23), Interleukin-23(IL-10), and type I interferon (IFN). The selectivity of Deurefacitinib for the inhibition of TYK2 is 200 times greater than that of JAK1s/JAK3s inhibition, and even 3,000 times greater than JAK2s inhibition in the cell-based analysis [ 26 , 27 ]. The trial by Catlett IM et al. [ 28 ] show that Deucravacitinib also strongly inhibits lymphopenia induced by Interferon α-2-a (IFN α-2-a). This finding is of great significance for the treatment of SLE and other autoimmune diseases. In the case of SLE, IFNα promotes the migration of lymphocytes into lymph nodes, thereby reducing lymphocyte counts in peripheral blood, and leading to lymphopenia [ 29 , 30 ]. Furthermore, SLE is characterized by a highly elevated expression of interferon regulatory gene (IRG), which is considered to have important pathophysiological significance. Therefore, Deucravacitinib inhibits the development of two pathologic characteristics of SLE. Additionally, Deucravacitinib was reported to be generally well-tolerated at single and multiple administrations for up to 12 days. All AEs were mild to moderate, with no serious or severe AEs, which was consistent with the study results of Eric Morand [ 14 ]. This indicated that Deurefacitinib exhibits good efficacy and safety in the treatment of SLE and has great potential.

Previously published meta-analysis and network meta-analysis showed that the efficacy of Belimumab was superior to that of other targeted small-molecule drugs. Belimumab is a human immunoglobulin (Ig) G1k monoclonal antibody targeting BlyS [ 31 ]. For example, MengJun Tao et al. [ 32 ]. conducted a network meta-analysis to investigate the effects of 9 biological agents on SRI-4 response in patients with SLE. Their results showed that only Belimumab was more significantly effective than the placebo in the improvement of SRI-4 response (RR = 2.03, 95% CI (1.38, 3.00), P  < 0.05), while other biological agents were not significantly superior to the placebo alone ( P  > 0.05). The study of Borba HH showed that [ 33 ] Belimumab was significantly superior to the placebo in the improvement of SRI-4 response (RR = 1.19, 95% CI (1.04, 1.37), P  < 0.05). According to the results of our study, Deurefacitinib significantly outperformed the placebo in the improvement of SRI-4 response [RR = 1.117, 95% CI (1.01, 1.24)]. The improvement in SRI-4 response with Belimumab was more significant. In terms of safety and tolerability, the study of Borba HH showed that [ 33 ] there was no significant difference between Belimumab and the placebo (RR = 1.01, 95% CI (0.99, 1.04), P  > 0.05), which was similar to the results of Singh JA [ 34 ] (RR = 0.87, 95% CI (0.68, 1.11), P  > 0.05). However, due to the difference in the included articles, RCTs of direct comparison between Deurefacitinib and Belimumab shall be conducted to further verify their difference in efficacy.

Notably, the results based on four studies of Baricitinib in the treatment of SLE showed that Baricitinib had a better therapeutic effect than placebo, and there were no significant differences in the incidence of adverse events. However, one Phase III clinical study (NCT03616912) of Baricitinib in the treatment of SLE was terminated due to safety issues. This trial showed that acute myocardial infarction (AMI), pneumonia and other serious adverse events occurred in the Baricitinib group (58/507), which may warrant attention. It’s necessary to hold a cautious attitude towards the study results, and more trials are needed to further verify the safety of Baricitinib.

Strengths and limitations

Our study has several strengths. At present, targeted small-molecule drugs in the treatment of SLE are a research hotspot, and there is still a lack of evidence on the difference in efficacy and safety among different targeted small-molecule drugs. This is the first network meta-analysis of targeted small-molecule drugs in the treatment of SLE to compare the difference in efficacy and safety among various targeted small-molecule drugs. Meanwhile, the effect of the dose and the course of treatment on efficacy and safety was also considered. In addition, strict inclusion/exclusion criteria were used to include only full-text RCTs. The included studies were published in high levels of journals, which contributes to generating high-quality evidence.

There are some limitations to our study. Due to the small number of included studies, the differences in efficacy evaluation criteria, patient characteristics, sample size, and selection of outcome indicators, as well as no description of the randomisation method and allocation concealment in some included studies, the level of evidence may be compromised. The number of original articles included for some outcome indicators was small, which may cause a bias in the results. Multiple Phase II clinical trials were included in this study. Due to their small sample size, the interpretation of results may be limited. Nevertheless, Phase II clinical trials have an important value in supplementing evidence-based evidence and shall not be excluded in systematic reviews due to its significance. There is a certain publication bias in the results, which may also affect the results. Therefore, more multi-center, high-quality RCTs with large sample sizes are needed to provide more evidence in the future.

Conclusions

Based on the evidence from this study, Baricitinib, Deucravacitinib, and Iberdomide were significantly superior to the placebo. There were differences in the efficacy among different targeted small-molecule drugs. Deucravacitinib is likely to be the best intervention measure. No significant differences were observed in safety between targeted small-molecule drugs and the placebo. Meanwhile, the dose and the course of treatment had little effect on the efficacy and safety of targeted small-molecule drugs. Due to the small number of included studies, more high-quality RCTs are needed to further verify the efficacy and safety of targeted small-molecule drugs.

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Abbreviations

Systemic Lupus Erythematosus

Randomized controlled trials

Systemic Lupus Erythematosus Responder Index response rate

BILAG-based Composite Lupus Assessment

Cutaneous Lupus Erythematosus Disease Area and Severity Index

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This work was supported by the 2016 Hunan Provincial Health and Family Planning Commission Research Program Project (C2016019).

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Shiheng Wang and Wanling Ning contributed equally to this work and should be considered as co-first authors.

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China Institute for History of Medicine and Medical Literature, China Academy of Chinese Medical Sciences, Beijing, 100700, China

Shiheng Wang

Hunan University of Chinese Medicine, Changsha Hunan, 410005, China

Wanling Ning

School of Basic Medicine, Youjiang Medical University for Nationalities, Youjiang Guangxi, Baise, 533000, China

Hanqing Tang

Traditional Chinese Medicine Department, Tianjin Nankai District Bainian Renyitang Traditional Chinese Medicine Clinic, Tianjin, 301700, China

Chaochao Mu

Hunan Provincial Brain Hospital, Changsha Hunan, 410021, China

Xiaosong Huang

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Conceptualization: Shiheng Wang; Methodology: Shiheng Wang; Formal analysis and investigation: Shiheng Wang, Fengxia Zhang; Writing original draft preparation: Shiheng Wang, Wanling Ning; Writing review and editing: Wanling Ning, Hanqing Tang; Funding acquisition: Xiaosong Huang; Resources: Xiaosong Huang; Supervision: Chaochao Mu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Wang, S., Ning, W., Tang, H. et al. Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus. Arthritis Res Ther 26 , 98 (2024). https://doi.org/10.1186/s13075-024-03331-8

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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 ,
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• Lauren B. Sherar 2 , 3 ,
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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.

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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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Use of the supportive and palliative care indicators tool (SPICT™) for end-of-life discussions: a scoping review

• Melanie Mahura 1 ,
• Brigitte Karle 2 ,
• Louise Sayers 3 ,
• Felicity Dick-Smith 3 &
• Rosalind Elliott 3 , 4  

BMC Palliative Care volume  23 , Article number:  119 ( 2024 ) Cite this article

Metrics details

In order to mitigate the distress associated with life limiting conditions it is essential for all health professionals not just palliative care specialists to identify people with deteriorating health and unmet palliative care needs and to plan care. The SPICT™ tool was designed to assist with this.

The aim was to examine the impact of the SPICT™ on advance care planning conversations and the extent of its use in advance care planning for adults with chronic life-limiting illness.

In this scoping review records published between 2010 and 2024 reporting the use of the SPICT™, were included unless the study aim was to evaluate the tool for prognostication purposes. Databases searched were EBSCO Medline, PubMed, EBSCO CINAHL, APA Psych Info, ProQuest One Theses and Dissertations Global.

From the search results 26 records were reviewed, including two systematic review, two theses and 22 primary research studies. Much of the research was derived from primary care settings. There was evidence that the SPICT™ assists conversations about advance care planning specifically discussion and documentation of advance care directives, resuscitation plans and preferred place of death. The SPICT™ is available in at least eight languages (many versions have been validated) and used in many countries.

Conclusions

Use of the SPICT™ appears to assist advance care planning. It has yet to be widely used in acute care settings and has had limited use in countries beyond Europe. There is a need for further research to validate the tool in different languages.

Key message

What is already known on this topic?

• The SPICT ™ was developed to assist clinicians to screen patients for palliative care needs.

What this review found.

• The SPICT™ assists conversations about advance care planning and facilitates changes in documented goals of care.

• The SPICT™ is available in at least eight languages (and used in many countries.

How the findings of this review may affect practice and research.

• Evidence suggests that formalising screening for palliative care needs using the SPICT™ is advantageous for advance care planning; clinicians should consider using the SPICT™ to initiate discussions with people with life limiting conditions.

• Further research is required to validate the tool in different languages and extend its use in acute care settings and with other patient cohorts.

Peer Review reports

Introduction

The demand for palliative care services globally has outpaced service availability, particularly in low and middle-income countries [ 1 ]. This is expected to continue as the population ages and the burden of noncommunicable disease increases. Thus, non-specialist palliative care health professionals may be required to manage care. The Supportive And Palliative Care Indicators Tool (SPICT™) [ 2 ] is one instrument available for non-specialist palliative care clinicians which may assist them in assessing unmet palliative needs and care planning.

Evidence suggests that clinicians feel inadequately prepared to conduct end-of-life discussions with patients who are terminally ill [ 3 , 4 , 5 ] and are also unsure of the appropriate time to start these discussions or whether to involve a specialist palliative care team [ 5 , 6 , 7 ]. Clinicians have reported their discomfort when addressing the topic of death with seriously ill patients [ 5 ].

From the perspective of patients with advanced illness, honest information from a trusted health care professional is the preference of most [ 7 ]. A survey study conducted in Canada involving 434 patients with advanced illness found over half of patients felt it was ‘very important’ to have a sense of control over decision-making regarding their care and 56% felt it was ‘extremely important’ not to be kept alive on life support if there was little hope of recovery [ 7 ]. The default medical decision to do everything to save life may be contributing to delays in referral to a specialist palliative care team, burdensome medical treatment and poorer quality of life for many patients [ 8 ]. Thus, a standardised, reliable and validated method of assessing and planning care in collaboration with the patient is required.

The terms ‘end-of-life’ and ‘terminally ill’ have been conceptualised as synonymous and ‘apply to patients with progressive disease with months or less of expected survival.’ [ 9 ]. In the United States there is consensus that referral to specialist palliative care services is required at the time of diagnosis for patients with neurologic disease, frailty, multimorbidity, advanced cancer, organ or cognitive impairment, patients with a high symptom burden and patients with onerous family or caregiver needs [ 10 ]. However with an ageing population and increased levels of dementia and frailty non-palliative care clinicians need a tool with a common language to identify those who are nearing the end of life and to promote a palliative approach to care. According to the High Authority for Health, an independent organisation that promotes quality outcomes in the fields of health, sociology and medicine a palliative approach is, “a way of addressing end-of-life issues early on: make time to talk about ethical questions, psychological support, comfort care, the right care, and give a timely thought to the likely palliative care needs of people approaching the end-of-life.” [ 11 ], p1.

Advance care planning, “a process that supports adults at any age or stage of health in understanding and sharing their personal values, life goals, and preferences regarding future medical care” [ 12 ] is one aspect of palliative care often provided by medical professionals which may assist in ensuring people’s needs are met, and care and communication are enhanced. Early advance care planning is vital, particularly for patients with neurodegenerative conditions before they lose capacity to express their wishes [ 8 ] “to help ensure that people receive medical care that is consistent with their values, goals and preferences during serious and chronic illness.” [ 12 ] Research has revealed that patients who have had the opportunity to discuss their preferences at the end-of-life are more likely to receive care that is consistent with those preferences. Findings also include greater patient and carer satisfaction and less conflict regarding decision making when end-of-life preferences have been examined [ 13 ].

People who have life limiting conditions may benefit from the delivery of advance care planning using a systematic approach. The SPICT™, although not designed for this purpose may enhance the approach particularly when health professionals who have limited palliative care experience are required to facilitate advance care planning.

The SPICT™ [ 2 ] was designed to identify patients at risk of deteriorating or dying and to screen for unmet palliative care needs. The tool includes general indicators of deterioration and clinical indicators of life-limiting conditions. The accompanying SPICT™ guide provides prompts and tips and a suggested framework (REMAP Ready, Expect, Diagnosis, Matters, Actions and Plan) [ 14 ] for conducting future care planning conversations. The tool is reported to be simple to use and designed for use by all multidisciplinary team members in any care setting [ 13 ].

The SPICT™ was evaluated using a mixed methods participatory approach [ 2 ]. Peer review and consensus was gathered for the 15 revisions of the SPICT™ over an 18-month period. Each iteration of the tool was distributed to clinicians and policy makers internationally until consensus was reached [ 2 ]. The research team worked concurrently with clinicians in four participating units at an acute tertiary hospital in Scotland to screen all patients with advanced organ disease whose admission to hospital was unplanned ( n  = 130) using a checklist that included the SPICT™ general indicators, disease specific indicators and the surprise question (SQ), “Would you be surprised if this patient were to die in the next 6 to 12 months?”. Data were gathered over an 8-week period and patients were followed up for 12 months [ 2 ]. A significantly greater number of patients who died at 12-months had two or more admissions in the previous 6 months before being screened. These patients also had increased care needs and persistent symptoms despite optimal treatment. The researchers proposed that better identification, assessment and pre-emptive care planning could reduce the risk of unplanned hospital admission and prolonged inpatient stays [ 2 ]. Of note the patients’ diagnoses were limited to advanced illness which was non-malignant and ethnicity was homogenous [ 2 ]. The SQ was removed from subsequent versions of the SPICT™ and the rationale for removing it remains unclear. The SPICT™ continues to be revised and versions are available in different languages [ 2 ].

The intention of this review was to examine the impact of the SPICT™ on advance care planning and the extent of its use. The patient cohorts, languages, and contexts in which the SPICT™ is available and used were examined.

Review questions

The following primary question was addressed:

How does use of the SPICT™ assist with conversations about advance care planning?

Secondary review questions were:

What is the extent of the use of the SPICT™ (which patient cohorts, contexts, and countries is it used)?

In which languages has the spict™ been validated.

Does use of the SPICT™ facilitate changes in documented goals of care?

Design and methods

This scoping review was performed in accordance with the Joanna Briggs Institute Manual for Evidence Synthesis Scoping Review Framework [ 15 ] and the Meta-Analyses Scoping Review extension for scoping reviews (PRISMA-ScR) checklist [ 16 ] was used to guide the reporting.

Preliminary literature search

An initial search focussed on inpatients with a chronic illness nearing the end of life however the search was expanded to include all care settings where the SPICT™ was being used for adults with a life-limiting chronic illness to evaluate its efficacy in advance care planning. Thus the search reflected the International Association for Hospice and Palliative Care definition of palliative care “the active holistic care of individuals across all ages with serious health-related suffering due to severe illness, and especially of those near the end of life.” [ 17 ]. A life-limiting illness or condition encompasses both malignant and non-malignant diseases as well as the effects of ageing.

A preliminary search of EBSCO Medline, the Cochrane database of systematic reviews, Prospero and JBI Evidence Synthesis was conducted in June 2022. No current or planned systematic or scoping reviews specifically on this topic were identified. A systematic review by Teike Luthi, et al. [ 18 ], examining instruments for the identification of patients in need of palliative care in the hospital setting was identified. The current scoping review differs from the systematic review by Teike Luthi, et al. [ 18 ] as the aim was to identify and describe all research related to how the SPICT™ is used in end-of-life discussions and what influence this has on advance care planning and goals of care.

Inclusion criteria

Participants.

The population of interest was adult patients (> 18 years) with a life-limiting chronic illness.

The concept of interest was the SPICT™. Any studies incorporating the SPICT™ were included in this review since its development in 2010. Studies evaluating the SPICT™ for prognostication purposes were excluded as this was not the intent of this review.

Published and unpublished studies in any language for which a translation could be obtained were included. Published and unpublished studies in any setting that met the eligibility criteria were included.

Evidence sources

This scoping review included both experimental and quasi-experimental study designs. In addition, analytical observational studies including prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies were considered for inclusion. Systematic reviews that met the inclusion criteria were included. Qualitative studies, theses and dissertations were also considered if they met the inclusion criteria.

Search strategy

An initial search on this topic in the EBSCO Medline and PubMed databases was reviewed for relevant abstracts and titles to determine keywords and index terms. MESH terms used in the final search strategy included: Communication; Documentation; Palliative Care; Patient Care Planning; Advance Care Plan; Decision Making and Chronic Disease. The research abstract for this scoping review was registered on the Center for Open Science website ( https://doi.org/10.17605/OSF.IO/DN27C ) in August 2022 prior to performing the definitive search in September. The search was conducted on 28th September 2022 and date limited i.e., 2010-September 2022. The database and grey literature searches were updated on 27th January 2024 to identify further studies published beyond this date.

Electronic databases searched included EBSCO Medline, PubMed, EBSCO CINAHL, APA Psych Info, ProQuest One Theses and Dissertations Global. Publications listed on the SPICT website ( www.spict.org.uk ) were cross checked with the records included from the electronic databases, duplicates were removed and further records were added to the Endnote library for screening. Reference lists of included studies were reviewed for additional studies.

All websites searched for additional records (grey literature sources) are included in supplementary file 1 . The expanded search strategy for the EBSCO Medline database is also provided in supplementary file 1 .

Study selection

All records were collated in an EndNote library. Duplicate records were removed manually by RE. The screening process involved two independent reviewers (MM and RE) reading titles and abstracts. Full text screening was conducted independently by the same two reviewers. Any discrepancies between the two reviewers at each stage of the process was resolved following review and consultation of a third reviewer (BK). Studies that did not meet the inclusion criteria were excluded with a reason recorded. Data extracted from included studies has been recorded in the standardised data extraction form (supplementary file 2 ). Critical appraisal of included studies was not performed and thus studies were not excluded based on methodological quality.

Data synthesis

Key aspects of the included studies were summarised in tables. Also consistent with the approach for a scoping review a textual narrative synthesis [ 19 ] was performed with the primary aim of addressing the review questions.

Over 2,000 records were retrieved. Five guidelines and six conference abstracts were found but these either did not relate to the review questions or did not contain sufficient information to be included. After applying the exclusion criteria 26 reports were included in this scoping review. The flow diagram (Fig.  1 ) presents the number of records retrieved, screened, excluded and included.

Flow diagram of number of records retrieved, screened, excluded and included **Abstract and title screening involved assessing each record for relevance to the review questions i.e., if no mention of the SPICT™ or/and advance planning conversation the record was excluded from further consideration

There were multiple study designs including validation and translation ( n  = 8) studies [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] and clinical improvement projects ( n  = 3) [ 28 , 29 , 30 ]. The focus of the clinical improvement projects was to increase the identification of palliative care needs and care planning through the use of the SPICT™. Two reviews (one of these included a survey study) 18 31 and two theses were included 28 29 (Table  1 ).

Research reveals that the SPICT™ appears to assist clinicians with conversations about advance care planning by providing a proforma for essential aspects of end-of-life care, a framework for end-of-life conversations and a common language to collaborate within the multidisciplinary team.

For example, in a prospective exploratory feasibility study to explore the practical use of the SPICT™ resulted in increased palliative care planning [ 32 ]. In this study general practitioners (GPs) [ n  = 10] were trained in the use of the German version of the SPICT™ (SPICT-DE™) and during a two-month intervention period were asked to use the tool with any adult patients diagnosed with a life-limiting disease ( n  = 79) and these patients were followed up at 6 months. The GPs’ actions as recommended by the SPICT-DE™ were considered appropriate with the most frequent actions being “Agree a current and future care plan with the person and their family; support family carers” ( n  = 59 [75%)),“Review current treatment and medication to ensure the person receives optimal care; minimise polypharmacy”( n  = 53 [67%]), and “Plan ahead early if loss of decision-making capacity is likely”(n = 49 [62%]). Of note “Consider referral for specialist palliative care consultation to manage complex symptoms” was considered appropriate for 25 (32%) patients. The effect of the SPICT™ was evident at the 6-month follow-up; the most frequently initiated actions were “Review current treatment and medication to ensure the person receives optimal care; minimise polypharmacy” (n = 36 [46%]) and “Plan ahead early if loss of decision-making capacity is likely” (n = 29 [37%]).

Further implementation research by Afshar et al. [ 33 ] with GPs in Germany revealed that GPs considered that the tool supported the communication and coordination of care and considered it broadened their perspectives of the meeting the needs of people especially those with non-cancer diagnoses. Of note over 50% of patients in this study had their agreed care plan initiated at the 6-month follow-up. Some GPs who had extensive experience and training claimed that the tool had no effect on their practice. However overall more than two thirds of the sample reported that they could envisage using the SPICT-DE™ in everyday practice.

In addition, three studies found that nurses who were trained to use the SPICT™ increased their self-efficacy in identifying patients who may be nearing the end of life and promoted an advance care plan discussion with these patients 28 29 34 . 21−23 In the study set in a renal ward, patients were screened on admission to identify those nearing the end of life by nurses using the SPICT™ [ 34 ]. An alert was added to the ward patient name list when a patient was identified as nearing the end of life (‘SPICT™ positive’) which prompted a review by the physician and multidisciplinary team. In this study 16% (25/152) of newly admitted patients were screened as ‘SPICT™ positive’; all of these patients received a palliative care consult and were discharged with an advance care directive including a resuscitation plan [ 34 ]. Incidentally nurses reported a significant increase in their ability to identify patients approaching end of life.

Similarly high SPICT™ screening rates and end of life conversations and referrals were revealed in a clinical improvement project designed to improve palliative care screening and consultation on admission to the cardiopulmonary unit of a long-term acute care facility using the SPICT™ [ 29 ]. In this project involving patients requiring mechanical ventilation and cardiac monitoring, 83% (59/71) of nurses working in the unit were trained in the use of the tool and screened all 50 newly admitted patients in the study period, 48 of whom were ‘SPICT™ positive’. Only 7 received a palliative care consultation within a week of admission however all 7 of these patients received a resuscitation plan and an advanced directive. Of note the use of the SPICT™ for screening resulted in a doubling of the facility’s monthly average number of palliative care referrals (from 32 to 84). In another clinical improvement project designed to increase screening and referral for palliative care among ambulatory care patients, nurse practitioners found the SPICT™ ‘. opens the door to a discussion of palliation .’ and was ‘. helpful in determining eligibility for palliative care. .’ p 22 28 . This project using both quantitative and qualitative approaches revealed an increase in palliative care referrals from 16% ( n  = 8/50) to 50% ( n  = 25/50) after the SPICT™ was introduced.

Two studies designed to translate and validate the SPICT-DK™ (Danish) [ 21 ] and SPICT-SE™ (Swedish) [ 24 ] involving focus groups with health care professionals revealed positive responses from doctors and nurses. The tool was described as a linguistic framework among these professionals and that use of the SPICT™ gave them a common language in which to collaborate and focus when treating and caring for patients [ 21 ]. The specificity of the tool was highlighted by nurses and medical doctors [ 24 ].

Conversely the expert committee comprising family physicians and palliative and home care specialists who provided input to the translation and cross-cultural adaptation of the SPICT™ into Japanese were more circumspect [ 27 ]. These experts were concerned that the tool might not be appropriate for framing advance planning conversations as a ‘not-telling the truth’ culture was prevalent and health care was heavily siloed into specialities so that care planning was fragmented.

The SPICT™ has been used to screen for palliative care needs in many patient cohorts, settings and countries. The cohorts in which the SPICT™ has been used include people over 65 years [ 35 ], those with advanced cancer 32 36 and with chronic diseases including cardiovascular disease [ 28 ], renal disease [ 34 ] and pulmonary disease [ 29 ].

Ten of the included studies were conducted in primary care and general practice settings 20 , 21 , 22 24 25 30 , 31 , 32 37 38 . The SPICT™ was also used in outpatient clinic settings 23 28 39 and residential aged care 29 35 . One cross sectional survey of community households in India used the SPICT™ to identify patients with palliative care needs in two rural communities [ 40 ]. The SPICT™ was originally developed for use in a hospital setting but not formally validated during its development [ 2 ]. All of the contexts in which the SPICT™ has been used are listed in Table  1 .

Of the included records ten were studies conducted in European countries 20 , 21 , 22 24 30 , 31 , 32 , 33 37 38 ; seven in Asia 23 25 27 39 , 40 , 41 , 42 ; three in the USA 28 29 36 ; two in Australia 34 35 ; one in South Africa [ 43 ] one in Chile [ 26 ] and one in Peru [ 44 ], and one paper was a review performed by authors based in Switzerland [ 18 ]. Of note the systematic review and survey of European primary care GP practice to identify patients for palliative care revealed that the United Kingdom was the only European country at the time that incorporated the SPICT™ to identify palliative care needs in primary and secondary care in clinical guidelines [ 31 ].

The SPICT ™ has been translated, cross culturally adapted and validated to identify patients with palliative care needs in Danish [ 21 ] and German [ 38 ] using the Translation, Review, Adjudication, Pre-testing and Documentation (TRAPD) model. Another study by Afshar, et al. [ 32 ] further established the validity of the SPICT-DE ™ in German in general practice with a patient cohort. In addition the SPICT ™ has been translated from English to Italian [SPICT-IT ™ ] [ 22 ], Spanish [SPICT-ES ™ ] [ 20 ], Swedish [ 24 ] and Japanese [SPICT-J ™ ] [ 23 ] using the Beaton protocol for cross cultural adaptation of health measures [ 45 ]. Farfán-Zuñiga and Zimmerman-Vildoso [ 26 ] established the reliability and validity of the SPICT-ES CHTM after culturally adapting the SPICT-ES ™ using the Beaton protocol. Nurses positively evaluated the feasibility of the tool. In addition Oishi et al. [ 27 ] also performed a translation and cross-cultural adaptation of the SPICT ™ into Japanese using a similar approach. The forward-back translated Indonesian version of the tool was found to be highly reliable and valid and greatly assisted in identifying hospital patients’ unmet palliative care needs [ 41 ].

The SPICT™ for low-income settings (LIS) was translated and cross culturally adapted for use in Thailand [ 25 ]. The interrater reliability of the final SPICT-LIS™ Thai version was high when nurses and GPs used it to ascertain palliative care needs of patients in case vignettes.

A Delphi study was used to develop the SPICT™ for the South African context [ 43 ]. Modifications to the original tool included the addition of haematological and infectious diseases and trauma however the SPICT-SA™ has yet to be validated in these patient cohorts. Although not a validated study per se in research comparing the performance of the Dutch version of the tool (SPICT-NL™) and the SQ in general practice ( n  = 3,640) the SPICT™ was found to be superior to the SQ in identifying patients with palliative care needs particularly younger people [ 37 ].

Of note the SPICT4-ALL™ [ 46 ] is a simplified version of the original SPICT™ developed for family/friends and care staff to identify individual palliative care needs. It is available to download from the SPICT™ website in English, German, Danish and Spanish. Although Sudhakaran, et al. [ 40 ] successfully used it to identify palliative care needs in two communities in rural India. No studies validating or evaluating it were found in our search.

Does use of the SPICT ™ facilitate changes in documented goals of care?

There is evidence that the SPICT™ by virtue of assisting clinicians to discuss end of life care facilitates changes in documented goals of care. Specifically this was demonstrated in a pre-post intervention study in which GPs trained in palliative care and the use of the SPICT-DE™ were requested to use it in their everyday practice for 12 months with every adult patient diagnosed with a chronic, progressive disease [ 30 ]. This occurred concurrently with a public campaign focused on informing health care providers and stake holders in two counties in Germany about end-of-life care. GPs’ documentation improved after the intervention. Records of care planning increased from 33 to 51% and documentation of preferred place of death towards the end-of-life increased from 20 to 33% and patients’ wishes, and spiritual beliefs increased from 18 to 27%. Incidentally GPs’ self-reported quality of end-of-life care increased after the implementation of the SPICT-DE™ and the information campaign [ 30 ].

In a study including 187 residents in an aged care facility in Australia comparing the SPICT™ and SQ, two Directors of Nursing pre-screened residents using the SQ and if the response was ‘yes’ (SQ+) applied the SPICT™ [ 35 ]. Of the 80 (43%) residents who were SQ+, 100% of these showed signs of nearing end of life according to the SPICT™. Of these residents 39 (49%) had some form of palliative care from either GPs, a specialist palliative care physician or palliative care nurse. Nearly all 39 (97%) had a GP management plan, and 67% had an advance care directive and 67% had discussed treatment options with their care provider [ 29 ]. It is unclear whether the SPICT™ affected care planning or documentation as the study involved pre-screening with the SQ and documentation was not assessed before and after this intervention.

Death and dying are taboo in many countries and thus any discussion about end of life is challenging. However, clinicians are morally and ethically obliged to appropriately initiate discussions about advance care planning towards the end of life when patients are ready [ 47 ]. This review found that the SPICT™ may help the clinician with this conversation. Specifically, evidence suggests that the tool may be a useful proforma and a conversation ‘checklist’ to ensure that the priority areas for advance care planning are addressed. Specifically, the tool may enable an assessment of the person’s readiness to have an advance planning conversation and an exploration of their expectations, the diagnosis, what matters to them, treatment options and future plans [ 14 ]. Importantly extensive specialist training is not required to administer it; the studies in this review employed brief information interventions to prepare clinicians to use the SPICT™. Thus, the SPICT™ provides a method of ‘objectively’ assessing palliative care needs, articulating the requirement for a specialist palliative review if required and advance care planning.

This review found that the SPICT™ was used in mainly primary health care settings and predominately in European countries. Of note there were few published records of its use in countries in the Asian and African continents and North America. The tool has been translated into more than eight languages including Spanish (SPICT-ES™) [ 20 ], Italian (SPICT-IT™) [ 22 ], German (SPICT-DE™) [ 38 ] and Japanese (SPICT-J™) [ 23 ] although not all versions have been formally validated [ 25 , 26 , 27 , 33 ].

Furthermore, there is evidence to suggest that the SPICT™ may facilitate changes in the goals of care and documentation of end of life care planning and patient wishes. Incidentally the SPICT™ appears to be positively received by clinicians with some suggesting that the tool provides a common language for clinicians when collaborating to identify palliative care needs and provide palliative care.

Of note the tool did not meet the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria [ 18 ]. However arguably these criteria may not be the most appropriate criteria on which to base an assessment of the SPICT™ given that it was never meant to be used to objectively measure a parameter such as prognosis; Highet et al. [ 2 ] were clear about the remit of the tool i.e., “help clinicians working in primary and secondary care recognise when their patients might be at risk of dying and likely to benefit from supportive and palliative care in parallel with appropriate ongoing management of their advanced conditions.” [ 2 ], p11.

There is an imperative to improve recognition of palliative care needs particularly in fast paced acute care settings. Evidence suggests that a tool such as the SPICT™ is an important adjunct for initiating a conversation about end-of-life care and ensuring that key palliative care needs are identified. Importantly the SPICT™ requires little training and its brevity may be suited to settings in which there is limited opportunity to engage in lengthy conversations and in which clear unambiguous communication is key to timely referral and treatment. Formalising palliative care needs screening in an end-of-life conversation in acute care settings may reduce distress for patients and their informal care givers [ 48 ] and the SPICT™ is a relevant proforma for such a conversation. Furthermore with the increase in the numbers of people living with chronic illness globally [ 49 ] arguably the formal adoption of palliative care needs screening in all health care settings may not only reduce patient distress but may assist health care managers and policy makers to more appropriately plan services [ 50 ]. Identifying needs early in the illness trajectory may allow appropriate personalised care and services to be provided in a timely and cost effective manner thus avoiding health crises at the end of life [ 51 ].

Conversely caution should be exercised when recommending a tool to guide advance care planning and end of life conversations particularly in the setting of low health professional skill level. This was highlighted by experienced GP participants in the study by Afshar et al. [ 33 ]. The GPs did not consider that the SPICT-DE™ made any impact on their practice. A proforma or guideline cannot replace the need for exemplary health care professional communication during advance care planning and end of life conversations particularly as studies reporting the use of the SPICT™ were not specifically focused on testing its efficacy in this regard. Flexibility and sensitivity are required to assess and manage people with life limiting conditions to ensure care is individualised. Thus, a sufficiently trained and resourced workforce is vital in addition to aids such as the SPICT™.

In addition, although not the focus of this review we noticed that there was an apparent lack of attention paid to input from the family and consideration of the family context in the included studies. In practice the advance care planning conversation goes beyond using the family to identify palliative care needs and the requirement for referral. The conversation should include addressing family members’ concerns and emotions and facilitate communication between the person who is the focus of advance care planning and their family members [ 52 ].

There are translations of the English version of the SPICT™ available to download from the SPICT™ website for a number of countries including; Brazil, France, Greece, Portugal and South Africa. However, studies reporting the use of many versions of the SPICT™ indicates that formal validation has not been performed. Further validation may strengthen the efficacy and reputation of these versions of the tool. Further studies are required to establish the validity of translated versions of the SPICT™ in Swedish, Danish, Indonesian and the SPICT-LIS™ (Thai), for everyday use in other patient cohorts.

The SPICT™ has scope to be tested in other patient cohorts. Specifically more work is required to extend and test its use in acute care settings where the demand for palliative care is rising and appropriate timely referrals to specialist palliative care are vital to avoid unnecessary distress [ 51 ]. Similarly, there are research opportunities such as reliability and validity testing in relation to the SPICT-4ALL™ version which has been specifically designed to be used by family and informal carers.

Strengths and limitations

This review has strengths which warrant consideration. For example, a systematic approach based on the PRISMA-SCr methodological framework was used, and the search was extensive including 5 electronic databases and many sources of grey literature. A limitation of this review is that we were unable to access a healthcare librarian to assist with the search thus important records may have been missed. In addition, we did not have funding to arrange the translation of two studies which were identified as potentially eligible. Studies included in this scoping review were not appraised for bias thus the level of evidence for the effectiveness of the SPICT™ was not reported. Of note most studies were descriptive and thus evidence for the effectiveness in relation to review question 1 (how does the tool assist with conversations about advance care planning?) is not available.

The current scoping review aimed to assess the impact and extent of the use of the SPICT™. In summary the SPICT™ appears to enable advance care planning, review of care plans and initiation of palliative care in many settings. Previous research suggests that patients and their families greatly appreciate the opportunity to discuss end of life matters. The SPICT™ provides clinicians a proforma on which to base this conversation and a common language to collaborate for palliative care. Clinicians with advance care planning and end of life communication in all settings should consider using the SPICT™ for this purpose. Future research should focus on further validating the SPICT™ in more patient cohorts and acute care settings. Further testing of the tool beyond Europe in countries in Africa, Asia and North America is also warranted.

Data availability

Not applicable.

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We declare that this paper has not been published elsewhere and we have not submitted the paper to any other journal at the time of this submission. In addition, we Rosalind Elliott (RE), Melanie Mahura (MM), Brigitte Karle (BK), Felicity Dick-Smith (F D-S) and Louise Sayers (LS), declare that we have no known conflicts of interest in relation to the review or manuscript.All authors contributed to the research and reporting. MM lead the protocol design with input from all authors (RE, BK, FD-S and LS) and the search. MM and RE screened the search records with BK and LS acting as arbitrator. MM and BK extracted the data. Synthesis and interpretation were performed mainly by MM and BK with input from all authors. The writing was lead by MM with contributions from all authors (RE, BK, FD-S and LS). RE provided mentorship and thoroughly edited the final version. All authors (MM, RE, BK, FD-S and LS) reviewed the final version and gave their final approval for submission of the paper.

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Mahura, M., Karle, B., Sayers, L. et al. Use of the supportive and palliative care indicators tool (SPICT™) for end-of-life discussions: a scoping review. BMC Palliat Care 23 , 119 (2024). https://doi.org/10.1186/s12904-024-01445-z

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Research Article

Cardiovascular health and cancer risk associated with plant based diets: An umbrella review

Roles Conceptualization, Data curation, Formal analysis, Writing – original draft

Affiliations Department of Biomedical and Neuromotor Science, Alma Mater Studiorum–University of Bologna, Bologna, Italy, Interdisciplinary Research Center for Health Science, Sant’Anna School of Advanced Studies, Pisa, Tuscany, Italy

Roles Conceptualization, Formal analysis, Writing – review & editing

Affiliation Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

Roles Conceptualization, Methodology, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Department of Biomedical and Neuromotor Science, Alma Mater Studiorum–University of Bologna, Bologna, Italy

Roles Conceptualization, Supervision, Writing – review & editing

Affiliation Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, United States of America

Affiliation Department of Translational Medicine, University of Eastern Piedmont, (UNIUPO), Novara, Italy

Roles Conceptualization, Data curation, Writing – review & editing

Roles Conceptualization, Methodology, Supervision, Writing – review & editing

Affiliation IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neurochirurgia Ipofisi—Pituitary Unit, Bologna, Italy

• Angelo Capodici, 
• Gabriele Mocciaro, 
• Davide Gori, 
• Matthew J. Landry, 
• Alice Masini, 
• Francesco Sanmarchi, 
• Matteo Fiore, 
• Angela Andrea Coa, 
• Gisele Castagna, 

• Published: May 15, 2024
• https://doi.org/10.1371/journal.pone.0300711
• Reader Comments

Cardiovascular diseases (CVDs) and cancer are the two main leading causes of death and disability worldwide. Suboptimal diet, poor in vegetables, fruits, legumes and whole grain, and rich in processed and red meat, refined grains, and added sugars, is a primary modifiable risk factor. Based on health, economic and ethical concerns, plant-based diets have progressively widespread worldwide.

This umbrella review aims at assessing the impact of animal-free and animal-products-free diets (A/APFDs) on the risk factors associated with the development of cardiometabolic diseases, cancer and their related mortalities.

Data sources

PubMed and Scopus were searched for reviews, systematic reviews, and meta-analyses published from 1st January 2000 to 31st June 2023, written in English and involving human subjects of all ages. Primary studies and reviews/meta-analyses based on interventional trials which used A/APFDs as a therapy for people with metabolic diseases were excluded.

Data extraction

The umbrella review approach was applied for data extraction and analysis. The revised AMSTAR-R 11-item tool was applied to assess the quality of reviews/meta-analyses.

Overall, vegetarian and vegan diets are significantly associated with better lipid profile, glycemic control, body weight/BMI, inflammation, and lower risk of ischemic heart disease and cancer. Vegetarian diet is also associated with lower mortality from CVDs. On the other hand, no difference in the risk of developing gestational diabetes and hypertension were reported in pregnant women following vegetarian diets. Study quality was average. A key limitation is represented by the high heterogeneity of the study population in terms of sample size, demography, geographical origin, dietary patterns, and other lifestyle confounders.

Conclusions

Plant-based diets appear beneficial in reducing cardiometabolic risk factors, as well as CVDs, cancer risk and mortality. However, caution should be paid before broadly suggesting the adoption of A/AFPDs since the strength-of-evidence of study results is significantly limited by the large study heterogeneity alongside the potential risks associated with potentially restrictive regimens.

Citation: Capodici A, Mocciaro G, Gori D, Landry MJ, Masini A, Sanmarchi F, et al. (2024) Cardiovascular health and cancer risk associated with plant based diets: An umbrella review. PLoS ONE 19(5): e0300711. https://doi.org/10.1371/journal.pone.0300711

Editor: Melissa Orlandin Premaor, Federal University of Minas Gerais: Universidade Federal de Minas Gerais, BRAZIL

Received: January 8, 2024; Accepted: March 4, 2024; Published: May 15, 2024

Copyright: © 2024 Capodici et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Cardiovascular diseases (CVDs) and cancer currently represent the leading causes of death and disability worldwide. Studies performed on large cohorts worldwide have identified several modifiable and non-modifiable risk factors. Among them, robust evidence supports diet as a major modifiable risk factor [ 1 ].

A suboptimal diet, marked by insufficient consumption of fruits, vegetables, legumes, and whole grains, coupled with an excessive intake of meat (particularly red and processed), salt, refined grains and sugar, has been shown to notably elevate both mortality rates and disability-adjusted life years. Over time, these dietary choices have led to a concerning increase in health-related issues [ 1 , 2 ].

Additionally, the reduction of products of animal origin in favor of vegetarian ones has been suggested to reduce CVD and cancer risk [ 3 , 4 ]. Several major professional and scientific organizations encourage the adoption of vegetarian and vegan diets for the prevention and treatment of a range of chronic metabolic diseases such as atherosclerosis, type 2 diabetes, hypertension and obesity [ 5 , 6 ]. Ethical, environmental, and socio-economic concerns have contributed to the widespread growth of plant-based diets, particularly vegetarian and vegan options [ 7 – 9 ]. 2014 cross-national governmental survey estimated that approximately 75 million people around the globe deliberately followed a vegetarian diet, while an additional 1,45 million were obliged to because of socio-economic factors [ 10 , 11 ].

At the same time, study heterogeneity in terms of plant-based dietary regimens (from limitation of certain types to the total exclusion of animal products), their association with other lifestyle factors, patient demographic and geographical features, associated diseases, as well as study design and duration, significantly limit the assessment of the real benefits associated with animal-free and animal-products-free diets (A/APFDs). Finally, an increasing number of studies have highlighted the potential threatening consequences of chronic vitamin and mineral deficiencies induced by these diets (e.g., megaloblastic anemia due to vitamin B12 deficiency), especially more restrictive ones and in critical periods of life, like pregnancy and early childhood [ 5 ].

Based on these premises, our umbrella review aims at assessing the impact of animal-free and animal-products-free diets (A/APFDs) on the risk factors associated with the development of cardiometabolic diseases, cancer and their related mortalities in both the adult and the pediatric population, as well as pregnant women.

Search strategy

PubMed ( https://pubmed.ncbi.nlm.nih.gov/ ) and Scopus ( https://www.scopus.com/search/form.uri?display=basic#basic ) databases were searched for reviews, systematic reviews and meta-analyses published from 1st January 2000 to 31st June 2023. We considered only articles written in English, involving human subjects, with an available abstract, and answering to the following PICO question: P (population): people of all ages; I (intervention) and C (comparison): people adopting A/APFDs vs. omnivores; O (outcome): impact of A/APFD on health parameters associated with CVDs, metabolic disorders or cancer.

Articles not specifying the type of A/APFD regimen were excluded. If not detailed, the A/APFDs adopted by study participants was defined as “mixed diet”. Vegetarian diets limiting but not completely excluding certain types of meat/fish (i.e. pesco- or pollo-vegetarian diet) were excluded. Studies focusing on subjects with specific nutritional needs (i.e., athletes or military personnel) -except pregnant women-, or with known underlying chronic diseases (i.e., chronic kidney disease), as well as articles focusing on conditions/health parameters related to disorders different from CVDs or cancer, and, finally, reviews/meta-analyses including interventional studies assessing A/APFDs comparing it with pharmacological interventions were excluded.

Ad hoc literature search strings, made of a broad selection of terms related to A/APFDs, including PubMed MeSH-terms, free-text words and their combinations, combined by proper Boolean operators, were created to search PubMed database: ((vegetari* OR vegan OR Diet , Vegetarian[MH] OR fruitar* OR veganism OR raw-food* OR lacto-veget* OR ovo-vege* OR semi-veget* OR plant-based diet* OR vegetable-based diet* OR fruit-based diet* OR root-based diet OR juice-based diet OR non-meat eate* OR non-meat diet*) AND ((review[Publication Type]) OR (meta-analysis[Publication Type]))) AND (("2000/01/01"[Date—Publication] : "2023/06/31"[Date—Publication])) and Scopus database: ALL(vegetari* OR vegan OR Diet , Vegetarian OR fruitar* OR veganism OR raw-food* OR lacto-veget* OR ovo-vege* OR semi-veget* OR plant-based diet* OR vegetable-based diet* OR fruit-based diet* OR root-based diet OR juice-based diet OR non-meat eate* OR non-meat diet) AND SUBJAREA(MEDI OR NURS OR VETE OR DENT OR HEAL OR MULT) PUBYEAR > 1999 AND (LIMIT-TO (DOCTYPE , "re"))

Research design and study classification

An umbrella review approach [ 12 ] was applied to systematically assess the effect of A/APFDs on risk factors related to CVDs, metabolic disorders and cancer as derived from literature reviews, systematic reviews and meta-analyses ( Table 1 ).

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https://doi.org/10.1371/journal.pone.0300711.t001

Study selection

The list of articles identified by literature search was split into 5 equivalent parts, each assigned to a couple of readers (AC, DG, CW, ML, AM, FS, MF, AAC, GC and FG), who independently and blindly read the title and then the abstract of each article to define its pertinence. Papers included in the umbrella review had to focus on one/some of the following A/APFDs: vegans, lacto-vegetarians, ovo-vegetarians, lacto-ovo-vegetarians. No restriction was applied for age, gender, ethnicity, geographical origin, nor socio economic status. Primary studies, reviews/meta-analyses not written in English, or focusing on non-previously mentioned dietary regimens (including the Mediterranean diet) were excluded. Abstract meetings, editorials, letters to the editor, and study protocols were also excluded. To reduce study heterogeneity, at least in terms of dietary regimens, we excluded studies based on vegetarian regimens limiting but not avoiding fish or poultry, and prospective trials directly comparing A/AFPDs to pharmacological interventions.

In case of discordance between readers, we resorted to discussion amongst the authors to resolve it, based on the article’s abstract or, if not decisive, the full text. The study selection process is summarized in Fig 1 .

https://doi.org/10.1371/journal.pone.0300711.g001

This review was registered on PROSPERO (Record ID: 372913 https://www.crd.york.ac.uk /prospero/display_record.php?RecordID=372913 ).

Quality literature analysis

Three raters (AC, DG, FS) independently and blindly assessed the quality of the systematic reviews and meta-analyses using the revised AMSTAR-R 11-item tool, developed by the PEROSH group [ 13 ]. In case of disagreement, the score of each item and the final decision were discussed among the three raters.

Data extraction and reporting

Ten investigators (AC, DG, GM, ML, AM, FS, MF, AAC, GC, FG) independently extracted data from eligible articles. Disagreements in data extraction were resolved by consensus. Using a predefined protocol and a Microsoft Excel sheet, the following data were extracted: first author’s affiliation country; type of review; type of diet; target population; number of aggregated participants; total cholesterol; HDL-cholesterol; LDL-cholesterol; triglycerides; apolipoprotein B; C-Reactive Protein (CRP); Body Mass Index (BMI); body weight; fasting glucose; glycosylated hemoglobin (HbA1c); systolic blood pressure; diastolic blood pressure; cardiac events (type; risk); cardiovascular diseases (type; risk); gestational diabetes; gestational hypertension; cancer (type; risk); death due to CVDs/cancer (risk). Data were reported as mean difference (MD), weighted mean difference (WMD), standardized mean difference (SMD), and 95%CI, while the estimated risk could be reported as relative risk (RR), odds ratio (OR), or hazard ratio (HR), according to the data reported by the study authors. Articles assessing the risk of gestational diabetes and hypertension, as well as risk of low birth weight, and their determinants were examined separately.

Results from studies focusing on both vegetarian and vegan diets were analyzed and reported separately if authors had stratified the results according to the type of diet. On the contrary, if data from vegan and vegetarian subjects were mixed, we arbitrarily considered all of them as “vegetarian”.

Group 1: Cardiovascular endpoints and risk factors

I. total cholesterol (tc)..

Eight studies examined the levels of total serum cholesterol (TC) in vegetarians. Two focused on the general population and included 5,561 [ 14 ] and 576 [ 15 ] respectively, and, based on data meta-analysis, found a significant reduction in TC among vegetarians and people who assumed plant-based proteins (MD: -1.56 mmol/L; 95%CI: −1.73, −1.39; and -0.11 mmol/L; 95%CI: −0.22, −0.01, respectively).

Data were confirmed by Wang et al. (N = 832 total; Ovolacto/lacto-vegetarians: 291) [ 16 ], showing a greater dietary effect in subjects with a BMI ranging from 18.5 to 25 kg/m 2 (mean TC reduction: −0.94 mmol/L; 95%CI: −1.33, −0.55), and from 25 to 30 kg/m 2 (−0.58 mmol/L; 95%CI: −0.89, −0.27), than in those with a BMI >30 kg/m 2 (−0.16 mmol/L; 95%CI: −0.30, −0.01), and by Xu et al. (N = 783) [ 17 ], reporting lower TC in overweight and obese people (WMD: −0.37 mmol/L; 95%CI: −0.52, −0.22) adopting a vegetarian diet.

Another systematic review by Elliott et al., including 27 randomized controlled trials on plant based vs. normal western diets [ 18 ], found lower TC levels in vegetarians. These results were in line with other two descriptive reviews, the first including 2,890 overweight/obese adults [ 19 ], the second 8,969 vegetarian children aged 0–18 years [ 20 ]. Furthermore, a meta-analysis by Liang et al. described significantly lower TC (from -0.36 to -0.24 mmol/L) in people adopting plant based diets vs. people adopting western habitual diets [ 21 ].

Moreover, the review and meta-analysis by Dinu et al. [ 14 ], based on 19 studies for a total of 1,272 adults, reported significantly lower levels of TC among vegans than in omnivores (WMD: −1.72 mmol/L; 95%CI: −1.93, −1.51).

II. High-density lipoprotein cholesterol (HDL-C).

Eight reviews focused on the effects of vegetarian diet on serum high-density lipoprotein cholesterol (HDL-C) levels. Six [ 15 , 17 , 18 , 21 – 23 ] found no significant difference between vegetarians and omnivores, when considering normal weight and overweight/obese people. On the contrary, the study by Dinu et al. [ 14 ], based on 51 studies, for a total of 6,194 vegetarian adults, reported a WMD −0.15 mmol/L (95%CI: −0.19, −0.11). Liang et al. [ 21 ] analyzed 4 studies and reported a pooled estimated MD of −0.10 mmol/L (95%CI: −0.14, −0.05; p<0.001) in vegetarian diet adopters vs. western diets adopters. Finally, Zhang et al. [ 22 ] did not find any statistically significant differences in HDL-C levels when assessing vegetarian diets compared to non-vegetarians; on the same note Dinu et al. [ 14 ], analyzing data from 15 studies, for a total of 1,175 adults, found no significant differences in HDL-C levels between vegans and people following other dietary regimens.

III. Low-density lipoprotein cholesterol (LDL-C).

Ten reviews summarized the effect of vegetarian diets on serum levels of low-density lipoprotein cholesterol (LDL-C). Seven [ 14 – 18 , 21 , 23 ] found significantly lower LDL-C levels associated with vegetarian diet, both in the general population and in diabetic patients. In particular, Elliot et al. [ 18 ], analyzing 43 observational and interventional studies, described lower LDL-C in people adopting plant based diets; a significant difference was reported by the study of Liang et al. [ 21 ] based on 68 studies (MD: -0.29 to -0.17), and similar to data by Lamberg et al. [ 15 ], based on 13 RCTs including for a total of 576 participants (MD: -0.14 mmol/L; 95%CI: -0.25, -0.02). The impact of vegetarian diet appeared even greater in overweight or obese people, according to the analysis by Xu et al. [ 17 ], based on 7 RCTs (N = 783; MD: -0.31 mmol/L; 95%CI: -0.46, -0.16). Two reviews [ 19 , 20 ] reported similar results in overweight/obese patients and children aged 0–18 years, but no meta-analyses were conducted. Wang et al. [ 16 ] reported a MD of −0.34 mmol/L (95%CI: −0.57, −0.11; p<0.001) in the general adult population. Ferdowsian et al. [ 23 ] reported an overall reduction of LDL-C associated with vegetarian diet, but no synthesis analyses were performed. Dinu et al. [ 14 ] analyzed 46 studies encompassing 5,583 vegetarians and found a WMD of -1.18 mmol/L (95%CI: -1.34, -1.01). Finally, Viguiliouk et al. [ 24 ] reported a MD of −0.12 mmol/L (95%CI: −0.20, −0.04) in 6 trials involving 602 diabetic patients.

Four reviews identified a significant reduction in LDL-C in vegans as compared to omnivores [ 14 , 19 , 23 , 25 ]. Benatar et al. [ 25 ] analyzed 31 studies, for a total of 3,355 healthy vegan adults and 53,393 non-vegan controls and found MD of -0.49 mmol/L (95%CI: -0.62, -0.36; p<0.0001). Ferdowsian et al. [ 23 ] reported a reduction of LDL-C in healthy vegans, and Ivanova et al. [ 19 ] in overweight patients, but no meta-analysis was performed. Finally, Dinu et al. [ 14 ] analyzed 13 studies, for a total of 728 healthy vegan adults, and found a significant LDL-C reduction (WMD: −1.27 mmol/L; 95%CI: −1.66, −0.88).

IV. Triglycerides (TG).

Seven systematic reviews [ 14 , 16 – 18 , 20 , 23 , 26 ] analyzed serum triglycerides (TG) in vegetarians vs. omnivores. Specifically, Wang et al. [ 16 ] described no differences between the two, with a pooled estimated effect of 0.04 mmol/L (95%CI: −0.05, 0.13; p = 0.4). Zhang et al. [ 26 ] analyzing 12 studies for a total of 1,300 subjects, found a MD of −1.28 mmol/L (95%CI; −2.14, −0.42). Schürmann et al. and Ferdowsian et al. [ 20 , 23 ] reported lower TG in vegetarians in both children and adults but did not perform data meta-analysis. Dinu et al. [ 14 ] analyzed 55 studies including 4,008 vegetarians and found a WMD of −0.63 mmol/L (95%CI: −0.97, −0.30; p = 0.02). Conversely, in the review by Elliott et al. [ 18 ] no differences were reported in triglycerides. Xu et al. [ 17 ] reported a significant increase of TG (WMD: 0.29 mmol/L; 95%CI: 0.11, 0.47) in vegetarians as compared to meat eaters.

The effect of vegan diet on TG remains debated as one review [ 23 ] reported significative changes in TGs (-0.14 mmol/L, CI -0.24 to -0.05), while another [ 14 ] did not find any differences between vegans and omnivores since, after having analyzed 13 studies for 483 vegans, they reported a WMD of -0.52 mmol/L (95%CI: -1.13; 0.09).

V. C-reactive protein (CRP).

Three studies reported lower C-reactive protein (CRP) levels in normal weight, overweight and obese vegetarians as compared to non-vegetarians. Craddock et al. and Menzel et al. reported a WMD of -0.61 mg/L (95%CI: -0.91, -0.32; p = 0.0001) [ 27 ]; -0.25 mg/L (95%CI: -0.49, 0; p = 0.05) [ 28 ], respectively.

Data derived from the analysis by Menzel et al. [ 28 ] in vegan subjects were in line with previously mentioned studies performed in vegetarians (WMD: -0.54 mg/L; 95%CI: -0.79, -0.28; p<0.0001).

Two reviews [ 29 , 30 ] focused on the effects of mixed vegetarian diets on CRP levels. The first [ 29 ] included 2,689 obese patients and found a WMD of -0.55 mg/L (95%CI: -0.78, -0.32; I 2 = 94.4%), while the other [ 30 ], based on 2,398 normal weight subjects found no significant differences between vegetarians and omnivores in the primary analysis; alas, when considering a minimum duration of two years vegetarianism they described lower CRP levels vs. omnivores (Hedges’ g = -0.29; 95%CI: -0.59, 0.01).

VI. Plant-based diets and lipids.

Three studies [ 23 , 26 , 31 ] assessed the lipid profile in people following plant-based diets (without differentiating among diet subtypes) in comparison with omnivores. All of them found significantly lower levels of TC, HDL-C and LDL-C in subjects following plant-based diets. Specifically, Yokoyama et al. [ 31 ] reported a WMD of −1.62 mmol/L (95%CI: −1.92, −1.32; p< 0.001; I 2 = 81.4) for TC, −1.27 mmol/L (95%CI: −1.55, −0.99; p< 0.001; I 2 = 83.3) for LDL-C, −0.2 mmol/L (95%CI: −0.26, −0.14; p< 0.001; I 2 = 49.7) for HDL-C, and −0.36 mmol/L; 95%CI: −0.78, 0.06; p = 0.092; I 2 = 83.0) for TG when considering observational studies, and of −0.69 mmol/L (95%CI: −0.99, −0.4; p<0.001; I 2 = 54.8) for TC, −0.69 mmol/L (95%CI: −0.98, −0.37; p<0.001; I 2 = 79.2) for LDL-C, −0.19 mmol/L (95%CI: −0.24, −0.14; p<0.001; I 2 = 8.5) for HDL-C, and a non-statistically significant increase of TG based on prospective cohort studies. Additionally, Zhang et al. [ 26 ] in their meta-analysis, including 1,300 subjects, found a SMD of -1.28 mmol/L in TG (95% CI -2.14 to -0.42).

Finally, Picasso et al. [ 32 ] did not find any differences in triglycerides for mixed vegetarian diets (MD: 0.04 mmol/L; 95%CI: -0.09, 0.28), but did find statistically significant differences in HDL-C (MD: -0.05 mmol/L; 95%CI: -0.07, -0.03).

VII. Blood pressure.

A . Systolic blood pressure (SBP) . Various studies found significantly lower mean levels of systolic blood pressure (SBP) levels in vegetarians compared to the general population [ 33 – 36 ]. Specifically, Gibbs et al. [ 33 ] reported a SMD of -5.47 mmHg (95%CI: -7.60, -3.34; p<0.00001) in ovo-lacto-vegetarians, as did Lee et al. [ 34 ] reporting a SMD of -1.75 mmHg (95%CI: -5.38, 1.88; p = 0.05); furthermore, they reported a SBP decreased by -2.66 mmHg (95%CI: -3.76, -1.55), in people adopting generic vegetarian diets. Moreover, Garbett et al. [ 35 ] reported a 33% lower prevalence of hypertension in vegetarians vs. nonvegetarians. On the contrary, Schwingshackl et al. [ 36 ], analyzing data from 67 clinical trials overall including 17,230 pre-hypertensive and hypertensive adult patients with a BMI between 23.6 and 45.4 kg/m 2 , followed for 3 to 48 months, did not find any significant reductions in SBP associated with vegetarian diet.

Four reviews investigated the differences in SBP between vegans and non-vegans. Benatar et al. and Lee et al. [ 25 , 34 ] reported significantly lower mean SBP levels in vegans vs. omnivores (MD: -2.56 mmHg; 95%CI: -4.66, -0.45; and WMD: -3.12 mmHg; 95%CI: -4.54, -1.70; p<0.001, respectively). On the other hand, Gibbs et al. [-1.30 mmHg (95%CI: -3.90,1.29)] and Lopez et al. (-1.33 mmHg; 95%CI: −3.50, 0.84; P = 0.230) [ 33 , 37 ] did not find any significant difference in mean SBP levels between vegans and omnivores.

Both reviews [ 32 , 38 ] focusing on SBP in mixed-plant-based dietary patterns found significantly lower levels in vegetarians than in omnivores. The meta-analysis by Picasso et al. [ 32 ], based on 4 RCTs did not find any differences, alas, analyzing 42 cross sectional studies, they described a MD of -4.18 mmHg (95%CI -5.57, -2.80; p<0.00001), in agreement with Yokoyama et al. [ 38 ], who reported a MD of -4.8 mmHg (95%CI: -6.6, -3.1; p<0.001; I 2 = 0) according to the 7 controlled trials, 6 of which being randomized (311 participants), included in the analysis, and of -6.9 mmHg (95%CI: -9.1, -4.7; p<0.001; I 2 = 91.4) based on the other 32 observational studies (21,604 participants).

B . Diastolic blood pressure (DBP) . Garbett et al. [ 35 ] reported reduced mean diastolic blood pressure (DBP) values in vegetarians vs. omnivores, confirmed by the analysis of Gibbs et al. [ 33 ] (WMD: –2.49 mmHg; 95%CI: –4.17, –0.80; p = 0.004; I 2 = 0%) in ovo-lacto-vegetarians, by Lee et al. [ 34 ] [WMD: -1.69 mmHg (95%CI: -2.97, -0.41; p<0.001)] who included 15 randomized controlled trials (N = 856) performed in vegetarians; and by Yokoyama et al. [ 38 ], who highlighted a MD -2.2 mmHg (95%CI: -3.5, -1.0; p<0.001; I 2 = 0%) and -4.7 mmHg (95%CI: -6.3, -3.1; p<0.001; I 2 = 92.6%) according to data from 7 controlled trials (N = 311) and 32 observational studies (N = 21,604), respectively. Conversely, Schwingshackl et al. [ 36 ] did not find significant differences between vegetarians and non-vegetarians.

Three reviews [ 25 , 34 , 37 ] examined the impact of vegan vs. non-vegan diet on DBP and described statistically significant reductions. Benatar et al. described reduction of DBP, corresponding to a MD of -1.33 mmHg (95%CI: -2.67, -0.02) [ 25 ]. Lee et al. described a reduction in DBP of a WMD of -1.92 mmHg (95%CI: -3.18, -0.66; p<0.001) [ 34 ]. Finally, Lopez et al. [ 37 ] described the same reduction amounting to WMD: -4.10 mmHg (95%CI: -8.14, -0.06).

Four studies agreed upon the lower mean DBP levels in subjects following mixed vegetarian diets as compared to omnivores [ 32 – 34 , 38 ], quantified as MD -3.03 mmHg (95%CI: -4.93, 1.13; p = 0.002) by Picasso et al. [ 32 ], and −2.2 mmHg (95%CI: −3.5, −1.0; p<0.001) and −4.7 mmHg (95%CI: −6.3, −3.1; p <0.001) by the analysis performed on clinical trials and observational studies, respectively, by Yokoyama et al. [ 38 ].

VIII. Body weight and body mass index (BMI).

Berkow et al. [ 39 ] identified 40 observational studies comparing weight status of vegetarians vs. non-vegetarians: 29 reported that weight/BMI of vegetarians of both genders, different ethnicities (i.e., African Americans, Nigerians, Caucasians and Asians), and from widely separated geographic areas, was significantly lower than that of non-vegetarians, while the other 11 did not find significant differences between the two groups. In female vegetarians, weight was 2.9 to 10.6 kg (6% to 17%) and BMI 2.7% to 15.0% lower than female non-vegetarians, while the weight of male vegetarians was 4.6 to 12.6 kg (8% to 17%) lower and the BMI 4.6% to 16.3% lower than that of male non-vegetarians. The review by Schürmann et al. [ 20 ], focusing on 8,969 children aged 0–18 years old found similar body weight in both vegetarian and vegan children as compared to omnivore ones. Dinu et al. [ 14 ] analyzed data from 71 studies (including 57,724 vegetarians and 199,230 omnivores) and identified a WMD BMI of -1.49 kg/m 2 (95%CI: -1,72, -1,25; p<0.0001) in vegetarians when compared to omnivores.

Barnard et al. [ 40 ] found a significant reduction in weight in pure ovolactovegetarians (−2.9 kg; 95% CI −4.1 to −1.6; P<0.0001), compared to non-vegetarians from control groups; furthermore, they found in vegans the mean effect was of -3.2 kg (95% CI: -4.0;-2.4, P: <0.0001); overall they included 490 subjects in their analysis, excluding subjects who did not complete the trials.

Benatar et al. [ 25 ]–including 12,619 vegans and 179,630 omnivores from 40 observation studies–and Dinu et al. [ 14 ]–based on 19 cross sectional studies, for a total of 8,376 vegans and 123,292 omnivores–reported the same exact result, with a mean lower BMI in vegans vs omnivores, equal to -1.72 kg/m 2 (95%CI: -2.30, -1.16) and -1.72 kg/m 2 (95%CI: -2.21,-1.22; p<0.0001), respectively. The meta-analysis by Long et al. [ 41 ], performed on 27 studies, reported a MD of -0.70 kg/m 2 (95%CI: -1.38, -0.01) for BMI in vegans vs. omnivores. A systematic review and meta-analysis by Agnoli et al. [ 42 ] found mean BMI to be lower in subjects adhering to mixed vegetarian diets as compared to omnivores. Additionally, Tran et al. [ 43 ] described weight reductions in clinically healthy patients, as well as in people who underwent vegetarian diets as a prescription, but no meta-analysis was performed.

Finally, Huang et al. [ 44 ] found significant differences in both vegans and vegetarians, who were found to have lost weight after having adopted the diet as a consequence of being assigned to the intervention group in their randomized studies. For vegetarians the WMD was -2.02 kg (95%CI: -2.80 to -1.23), when compared to mixed diets, and for vegans the WMD was -2.52 kg (95%CI: -3.02 to -1.98), when compared to vegetarians.

IX. Glucose metabolism.

Viguiliouk et al. [ 24 ] found a significant reduction in HbA1c (MD: −0.29%; 95%CI: −0.45, −0.12) and fasting glucose (MD: −0.56 mmol/L; 95%CI: −0.99, −0.13) in vegetarians vs. non-vegetarians.

The meta-analysis by Dinu et al. [ 14 ], reported for vegetarians (2256) vs omnivores (2192) WMD: -0.28 mmol/L (95%CI: -0.33, -0.23) in fasting blood glucose.

These findings were confirmed by Picasso et al. [ 32 ] who found a MD of -0.26 mmol/L (95% CI: -0.35, -0.17) in fasting glucose in mixed-vegetarian diets as compared to omnivores.

A meta-analysis by Long et al. [ 41 ], based of 27 cross sectional studies, showed a MD for homeostasis model assessment of insulin resistance -measured as HOMA-IR, a unitless measure ideally less than one- of -0.75 (95%CI: -1.08, -0.42), fasting plasma glucose in vegetarians who adhered also to an exercise intervention as compared to omnivores.

Lee & Park [ 45 ] reported a significantly lower diabetes risk (OR 0.73; 95%CI: 0.61, 0.87; p<0.001) in vegetarians vs. non-vegetarians, being the association stronger in studies conducted in the Western Pacific region and Europe/North America than in those from Southeast Asia.

Regarding vegans, the review by Benatar et al. [ 25 ] determined a mean reduction of 0.23 mmol/L (95%CI: -0.35, -0.10) of fasting blood glucose in vegans (N = 12,619) as compared to omnivores (N = 179,630). The finding was in line with Dinu et al. [ 14 ], who reported a WMD of -0.35 mmol/L (95%CI: -0.69, -0.02; p = 0.04) of fasting blood glucose in vegans (n = 83) than omnivores (n = 125).

A systematic review, finally, including 61 studies [ 42 ] found mean values of fasting plasma glucose, and T2D risk to be lower in subjects following mixed vegetarian diets as compared to omnivores.

X. Cardiovascular events.

Huang et al. [ 46 ] found a significantly lower risk of ischemic heart disease (IHD) (RR: 0.71; 95%CI: 0.56, 0.87), but no significant differences for cerebrovascular mortality between vegetarians and non-vegetarians. The review by Remde et al. [ 47 ] was not conclusive, as only a few studies showed a reduction of the risk of CVDs for vegetarians versus omnivores, while the others did not find any significant results.

Dybvik et al. [ 48 ] based on 13 cohort studies for a total of 844,175 participants (115,392 with CVDs, 30,377 with IHD and 14,419 with stroke) showed that the overall RR for vegetarians vs. nonvegetarians was 0.85 (95%CI: 0.79–0.92, I 2 = 68%; 8 studies) for CVD, 0.79 (95%CI: 0.71–0.88, I 2 = 67%; 8 studies) for IHD, 0.90 (95%CI: 0.77–1.05, I 2 = 61%; 12 studies) for total stroke, while the RR of IHD in vegans vs. omnivores was 0.82 (95%CI: 0.68–1.00, I 2 = 0%; 6 studies).

The meta-analysis by Kwok et al. [ 49 ], based on 8 studies including 183,321 subjects comparing vegetarians versus non-vegetarians. They identified a significant reduction of IHD in the Seventh Day Adventist (SDA) cohort, who primarily follow ovo-lacto-vegetarian diets, while other non-SDA vegetarian diets were associated only with a modest reduction of IHD risk, raising the concern that other lifestyle factors typical of SDA and, thus not generalizable to other groups, play a primary role on outcomes. IHD was significantly reduced in both genders (RR: 0.60; 95%CI: 0.43, 0.83), while the risk of death and cerebrovascular disease and cardiovascular mortality risk reduction was significantly reduced only in men. No significant differences were detected for the risk of cerebrovascular events.

The meta-analysis by Lu et al. [ 50 ] -657,433 participants from cohort studies- reported a lower incidence of total stroke among vegetarians vs. nonvegetarians (HR = 0.66; 95%CI = 0.45–0.95; I 2 = 54%), while no differences were identified for incident stroke.

The descriptive systematic review by Babalola et al. [ 3 ] reported that adherence to a plant-based diet was inversely related to heart failure risk and advantageous for the secondary prevention of CHD, particularly if started from adolescence. Another review by Agnoli et al. [ 42 ], confirmed a lower incidence of CVDs associated with mixed vegetarian diets as compared to omnivorous diets. Finally, Chhabra et al. [ 51 ] found that vegetarian diet, particularly if started in adolescence and associated with vitamin B intake, can reduce the risk of stroke.

Gan et al. [ 52 ] described a lower risk of CVDs (RR 0.84; 95% CI 0.79 to 0.89; p < 0.05) in high, vs. low, adherence plant based diets, but the same association was not confirmed for stroke (RR 0.87; 95% CI: 0.73, 1.03).

Group 2: Pregnancy outcomes

The meta-analysis by Foster et al. [ 53 ], performed on 6 observational studies, found significantly lower zinc levels in vegetarians than in meat eaters (-1.53 ± 0.44 mg/day; p = 0.001), but no association with pregnancy outcomes, specifically no increase in low children birth weight. The finding was confirmed by Tan et al. [ 54 ], who similarly reported no specific risks, but reported that Asian (India/Nepal) vegetarian mothers exhibited increased risks to deliver a baby with Low Birth Weight (RR: 1.33 [95%CI:1.01, 1.76, p =  0.04, I 2 = 0%]; nonetheless, the WMD of neonatal birth weight in five studies they analyzed suggested no difference between vegetarians and omnivores.

To our knowledge, no reviews/meta-analyses have assessed the risk of zinc deficiency and its association with functional outcomes in pregnancy in relation to mixed or vegan diets.

Group 3: Cancer

The meta-analysis by Parra-Soto et al. [ 55 ], based on 409,110 participants from the UK Biobank study (mean follow-up 10.6 years), found a lower risk of liver, pancreatic, lung, prostate, bladder, colorectal, melanoma, kidney, non-Hodgkin lymphoma and lymphatic cancer as well as overall cancer (HR ranging from 0.29 to 0.70) determined by non-adjusted models in vegetarians vs. omnivores; when adjusted for sociodemographic and lifestyle factors, multimorbidity and BMI, the associations remained statistically significant only for prostate cancer (HR 0.57; 95%CI: 0.43, 0.76), colorectal cancer (HR 0.73; 95%CI: 0.54, 0.99), and all cancers combined (HR 0.87; 95%CI 0.79, 0.96). When colorectal cancer was stratified according to subtypes, a lower risk was observed for colon (HR 0.69; 95%CI: 0.48, 0.99) and proximal colon (HR 0.43; 95%CI: 0.22, 0.82), but not for rectal or distal cancer.

Similarly, the analysis by Huang et al. [ 46 ], based on 7 studies for a total of 124,706 subjects, reported a significantly lower overall/total cancer incidence in vegetarians than non-vegetarians (RR 0.82; 95%CI: 0.67, 0.97).

Zhao et al. [ 56 ] found a lower risk of digestive system cancer in plant-based dieters (RR = 0.82, 95%CI: 0.78–0.86; p< 0.001) and in vegans (RR: 0.80; 95%CI: 0.74, 0.86; p<0.001) as compared to meat eaters.

Additionally, DeClercq et al. [ 57 ] reported a decreased risk of overall cancer and colorectal cancer, but inconsistent results for prostate cancer and breast cancer; this was substantiated by Godos et al. [ 58 ] found no significant differences in breast, colorectal, and prostate cancer risk between vegetarians and non-vegetarians.

The umbrella review by Gianfredi et al. [ 59 ], did describe a lower risk of pancreatic cancer associated with vegetarian diets.

Dinu et al. [ 14 ] reported a reduction in the risk of total cancer of 8% in vegetarians, and of 15% in vegans, as compared to omnivores. They described lower risk of cancer among vegetarians (RR 0.92; 95%CI 0.87, 0.98) and vegans (RR: 0.85; 95%CI: 0.75,0.95); nonetheless, they also described non-significant reduced risk of mortality from colorectal, breast, lung and prostate cancers. Regarding the latter, a meta-analysis by Gupta et al. [ 60 ] on prostate cancer risk found a decreased hazard ratio for the incidence of prostate cancer (HR: 0.69; 95%CI: 0.54–0.89, P<0.001) in vegetarians as compared to omnivores from the evidence coming from 3 studies. In the vegan population, similar results were observed from the only included study (HR: 0.65; 95%CI: 0.49–0.85; p<0.001).

Group 4: Death by cardiometabolic diseases and cancer

According to Huang et al. [ 46 ], the mortality from IHD (RR: 0.71; 95%CI: 0.56, 0.87), circulatory diseases (RR: 0.84; 95%CI: 0.54, 1.14) and cerebrovascular diseases (RR: 0.88; 95%CI: 0.70, 1.06) was significantly lower in vegetarians than in non-vegetarians.

The analysis by Dinu et al. [ 14 ] performed on 7 prospective studies, overall including 65,058 vegetarians, reported a 25% reduced mortality risk from ischemic heart diseases (RR 0.75; 95%CI: 0.68, 0.82; p<0.001), but no significant differences were found analyzing 5 cohort studies in terms of mortality from CVDs, cerebrovascular diseases, nor colorectal, breast, prostate, and lung cancer. Regarding vegans, they analyzed 6 cohort studies, and found no differences in all-cause mortality, but significant differences in cancer incidence (RR: 0.85; 95%CI: 0.75, 0.95), indicating a protective effect of vegan diets.

The literature search did not identify studies focusing on mortality risk for cardiometabolic and cancer diseases in vegans.

Quality of the included studies

The quality of the 48 reviews and meta-analyses included in this umbrella review was assessed through the AMSTAR-R tool. Results are reported in S1 Table . Overall, the average quality score was 28, corresponding to mean quality. However, 36 studies (75%) scored between 60% and 90% of the maximum obtainable score, and can, therefore, be considered of good/very good quality. The least satisfied item on the R-AMSTAR grid was #8 -scientific quality of included studies used to draw conclusions-, where as many as 19 studies (39.6%) failed to indicate the use of study-related quality analysis to make recommendations. This finding should be read in conjunction with the missing quality analysis in 15 studies (31.3%)–Item #7 scientific quality of included studies assessed and documented-. Item #10, regarding publication bias, was the second least met item, in which 18 studies (37.5%) did not perform any analysis on this type of bias. 16 studies (33.3%) lacked to indicate careful exclusion of duplicates (Item #2), but also the presence of conflict of interest (Item #11). This point is certainly another important piece to consider in the overall quality assessment of these articles. All these considerations give us a picture of a general low quality of the publications found, lowering the strength of evidence as well as the external validity of the results.

This umbrella review provides an update on the benefits associated with the adoption of A/AFPDs in reducing risk factors associated with the development of cardiometabolic diseases and cancer, considering both the adult and the pediatric population, as well as pregnant women.

Compared to omnivorous regimens, vegetarian and vegan diets appear to significantly improve the metabolic profile through the reduction of total and LDL cholesterol [ 14 – 21 , 23 , 25 ], fasting blood glucose and HbA1c [ 14 , 24 , 25 , 37 , 39 – 41 ], and are associated with lower body weight/BMI, as well as reduced levels of inflammation (evaluated by serum CRP levels [ 27 , 30 ]), while the effect on HDL cholesterol and triglycerides, systolic and diastolic blood pressure levels remains debated. A much more limited body of literature suggested vegetarian, but not vegan diets also reduce ApoB levels further improving the lipid profile [ 61 ].

It should be remarked that, in the majority of the cases, people adopting plant-based diets are more prone to engage in healthy lifestyles that include regular physical activity, reduction/avoidance of sugar-sweetened beverages, alcohol and tobacco, that, in association with previously mentioned modification of diet [ 62 ], lead to the reduction of the risk of ischemic heart disease and related mortality, and, to a lesser extent, of other CVDs.

The adoption of vegan diets is known to increase the risk of vitamin B-12 deficiency and consequent disorders–for which appropriate supplementation was recommended by a 2016 position paper of the Academy of Nutrition and Dietetics’ [ 5 ], but, apparently, does not modify the risk of pregnancy-induced hypertension nor gestational diabetes mellitus [ 53 , 54 ].

The three meta-analyses [ 46 , 55 , 57 ] that analyzed the overall risk of cancer incidence in any form concordantly showed a reduction in risk in vegetarians compared to omnivores. These general results were inconsistent in the stratified analyses for cancer types, which as expected involved smaller numbers of events and wider confidence intervals, especially for less prevalent types of cancers.

The stratified analyses in the different reviews did not show any significant difference for bladder, melanoma, kidney, lymphoma, liver, lung, or breast cancer. Conversely the three meta-analyses that addressed colorectal cancer [ 55 , 57 , 58 ] showed a decrease in risk in two out of three with one not showing a significant difference in vegetarians versus omnivores for the generic colorectal tract.

Interestingly, one review [ 55 ] showed how analysis with even more specific granularity could reveal significant differences in particular subsets of cancers, e.g., distal, and proximal colon. Also, another recent review found significant results for pancreatic cancer [ 59 ].

Our umbrella review seems consistent with other primary evidence that links the consumption of red processed meats to an increased risk of cancers of the gastro-intestinal tract [ 63 ]. The association certainly has two faces, because while a potential risk of cancer given by increased red meat consumption can be observed, the potential protective factor given by increased fruit and vegetable consumption, shown by other previous evidence, must also be considered [ 64 ].

It has also been described that vegetarians, in addition to reduced meat intake, ate less refined grains, added fats, sweets, snacks foods, and caloric beverages than did nonvegetarians and had increased consumption of a wide variety of plant foods [ 65 ]. Such a dietary pattern seems responsible for a reduction of hyperinsulinemia, one of the possible factors for colorectal cancer risk related to diet and food intake [ 66 , 67 ]. In the same manner, some research has suggested that insulin-like growth factors and its binding proteins may relate to cancer risk [ 68 , 69 ]. This dietary pattern should not be regarded as a universal principle, as varying tendencies have been observed among vegetarians and vegans in different studies. This pattern of consumption may potentially negate the anticipated beneficial effects of their diets.

Also, some protective patterns can be attributed to the effects of bioactive compounds of plant foods, these being primary sources of fiber, carotenoids, vitamins, minerals, and other compounds that have been associated with anti-cancer properties [ 70 , 71 ]. The protective patterns are likely attributed to the mechanistic actions of the many bioactives found in plant foods such as fiber, carotenoids, vitamins, and minerals with plausible anti-cancer properties. These ranged from epigenetic mechanisms [ 72 ], to immunoregulation, antioxidant and anti-inflammatory activity [ 73 , 74 ].

Finally, increased adiposity could be another pathway by which food intake is associated with these types of cancers. Since our umbrella review has demonstrated that vegetarian diets are associated with lower BMI, this might be another concurrent factor in the decreased risk for pancreatic and colorectal cancers in vegetarians.

Inflammatory biomarkers and adiposity play pivotal roles in the genesis of prostate cancer [ 75 , 76 ], hence the same etiological pathways might be hypothesized even for the increase of this type of cancer in people adopting an omnivorous diet.

The study presents several noteworthy strengths in its methodological approach and thematic focus. It has employed a rigorous and comprehensive search strategy involving two major databases, PubMed, and Scopus, spanning over two decades of research from 1 st January 2000 to 31 st June 2023, thereby ensuring a robust and exhaustive collection of pertinent literature. By utilizing an umbrella review, the research enables the synthesis of existing systematic reviews and meta-analyses, providing a higher level of evidence and summarizing a vast quantity of information. Furthermore, its alignment with current health concerns, specifically targeting cardiovascular diseases and cancer, makes the study highly relevant to ongoing public health challenges and positions it as a valuable resource for informing preventive measures and dietary guidelines. The deployment of blinded and independent assessments by multiple raters and investigators fortifies the research by minimizing bias and reinforcing the reliability of the selection, quality assessment, and data extraction processes. Quality assessment is standardized using the revised AMSTAR-R 11-item tool, and transparency is fostered through registration on PROSPERO, thus enhancing the credibility of the study. Lastly, the study’s detailed analysis and reporting, particularly the extraction of specific health measures such as cholesterol levels, glucose levels, blood pressure, and cancer risks, contribute to the comprehensiveness of the data synthesis, thereby underlining the overall integrity and significance of the research.

Main limitations to data analysis and interpretation are intrinsic to the original studies and consist in the wide heterogeneity in terms of sample size, demographic features, and geographical origin of included subjects, dietary patterns–not only in terms of quality, but, even more important and often neglected, quantity, distribution during the day, processing, cooking methods–and adherence, and other lifestyle confounders. In this regard, it is worth to mention that the impact of diet per se on the development of complex disorders (i.e. CVDs and cancer) and related mortality is extremely difficult to assess [ 71 ], especially in large populations, characterized by a highly heterogeneous lifestyle. It should also be considered the heterogeneity in dietary and lifestyle habits among countries, according to which the adoption of A/AFPDs could modify significantly habits in some countries, but not in others, and consequently have an extremely different impact on the risk of developing cardiometabolic disorders and cancer [ 25 ]. Furthermore, due to the nature of umbrella reviews, the present work may not include novel associations which were excluded from the analyzed reviews, as the main aim was to summarize secondary studies, such as reviews and meta-analyses. Finally, studies assessing the benefit of A/AFPDs on cancer risk are also limited by the heterogeneity in the timing of oncological evaluation and, therefore, disease progression, as well as in the histological subtypes and previous/concomitant treatments [ 72 – 75 ].

In conclusion, this umbrella review offers valuable insights on the estimated reduction of risk factors for cardiometabolic diseases and cancer, and the CVDs-associated mortality, offered by the adoption of plant-based diets through pleiotropic mechanisms. Through the improvement of glycolipid profile, reduction of body weight/BMI, blood pressure, and systemic inflammation, A/AFPDs significantly reduce the risk of ischemic heart disease, gastrointestinal and prostate cancer, as well as related mortality.

However, data should be taken with caution because of the important methodological limitation associated with the original studies. Moreover, potential risks associated with insufficient intake of vitamin and other elements due to unbalanced and/or extremely restricted dietary regimens, together with specific patient needs should be considered, while promoting research on new and more specific markers (i.e. biochemical, genetic, epigenetic markers; microbiota profile) recently associated with cardiometabolic and cancer risk, before suggesting A/AFPDs on large scale.

Supporting information

S1 table. r-amstar..

https://doi.org/10.1371/journal.pone.0300711.s001

S2 Table. PRISMA 2020 checklist.

https://doi.org/10.1371/journal.pone.0300711.s002

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Deprescribing in older adults with polypharmacy

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• Peer review
• Anna Hung , assistant professor 1 2 3 * ,
• Yoon Hie Kim , assistant professor 4 * ,
• Juliessa M Pavon , associate professor 4 5
• 1 Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA
• 2 Duke-Margolis Center for Health Policy, Durham, NC, USA
• 3 Center of Innovation to Accelerate Discovery and Practice Transformation, Durham VA Health Care System, Durham, NC, USA
• 4 Division of Geriatrics, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
• 5 Geriatrics Research, Education, and Clinical Center (GRECC) Durham VA Health Care System, Durham, NC, USA
• * Co-first authors
• Correspondence: A Hung, anna.hung{at}duke.edu

Polypharmacy is common in older adults and is associated with adverse drug events, cognitive and functional impairment, increased healthcare costs, and increased risk of frailty, falls, hospitalizations, and mortality. Many barriers exist to deprescribing, but increased efforts have been made to develop and implement deprescribing interventions that overcome them. This narrative review describes intervention components and summarizes findings from published randomized controlled trials that have tested deprescribing interventions in older adults with polypharmacy, as well as reports on ongoing trials, guidelines, and resources that can be used to facilitate deprescribing. Most interventions were medication reviews in primary care settings, and many contained components such as shared decision making and/or a focus on patient care priorities, training for healthcare professionals, patient facing education materials, and involvement of family members, representing great heterogeneity in interventions addressing polypharmacy in older adults. Just over half of study interventions were found to perform better than usual care in at least one of their primary outcomes, and most study interventions were assessed over 12 months or less.

Introduction

Polypharmacy, commonly defined as taking at least five drug treatments, is common in older populations. 1 2 The prevalence of this condition, when combined across multiple countries, is about 45% in older populations (those aged 65 years or older) compared with 27% in younger populations (those aged under 65 years). 1 Although older adults are more likely to have multiple chronic conditions, and guidelines often recommend multiple drug treatments, studies have found that polypharmacy can lead to problems such as adverse drug events, drug–drug interactions, drug treatment non-adherence, 3 4 cognitive and functional impairment, 5 and increased risk of frailty, disability, falls, hospitalizations, and mortality. 6 7 8

Polypharmacy is also associated with the use of potentially inappropriate medications, 9 10 which is linked to increased risk of hospitalization and visits to the emergency room. 11 Furthermore, polypharmacy can result in higher healthcare costs; the total healthcare costs of patients with polypharmacy are twice as high as those of patients without polypharmacy. 12 Affordability of drug treatments is already problematic, given that, for example, nearly one third of older adults in the United States with multiple chronic conditions spend more than 20% of their income on medical care. 13

One way to tackle polypharmacy is via deprescribing, which can be defined as the “systematic process of identifying and discontinuing drugs when existing or potential harms outweigh existing or potential benefits within the context of an individual patient’s care goals, functional status, life expectancy, values, and preferences.” 14 This process is often supervised by a healthcare professional, but shared decision making is critical, because deprescribing decisions need to consider patient and care partner values and preferences. 15 16 Contrary to a simplistic goal of reducing the number of drug treatments, the essence of deprescribing lies in achieving a nuanced balance: acknowledging the concept of “appropriate polypharmacy.” 17 18 This approach recognizes that certain medical conditions can warrant the use of multiple drug treatments to effectively manage symptoms, prevent complications, and improve overall patient wellbeing. Deprescribing, in this context, seeks not to diminish the drug treatment count arbitrarily, but rather to ensure judicious and contextually appropriate drug treatment use.

Coined in 2003, the term “deprescribing” has witnessed significant growth in usage, research, and the development of supporting networks, and has gained particular momentum since 2016. 19 This evolution highlights the growing acknowledgment of deprescribing as a crucial strategy in optimizing drug treatment regimens to meet the specific needs and goals of individual patients. Concurrently, the substantial growth in randomized controlled trials evaluating deprescribing interventions attests to the increasing emphasis on evidence based approaches. Several excellent reviews of deprescribing interventions in older adults exist, but they differ slightly in focus; for example, some are limited to comprehensive medication review interventions, or target a specific population such as community dwelling, frail, or multimorbid. 20 21 22 23 This narrative review summarizes randomized controlled trials that assess deprescribing interventions addressing polypharmacy in older adults.

Prevalence of polypharmacy

Over the past few decades, polypharmacy has become a common and widespread problem among older adults. In the US, for example, the prevalence of polypharmacy among adults aged 65 and older increased from 13% in 1998 to 43% in 2014, 24 25 with the most recent estimates from 2017-2018 at 45%. 26 This increase was driven in particular by the growing use of cardioprotective and antidepressant drug treatments, 24 and the highest prevalence of polypharmacy is seen among populations with heart disease. 26 Additional reasons for increases in the use of drug treatments include the start of Medicare Part D (ie, prescription drug coverage for older adults) in 2006, as well as quadrupled spending on direct-to-consumer pharmaceutical advertising (from $985 million in 1996 to $4.24 billion in 2005). 27

Similarly, a survey conducted across 17 European countries and Israel also revealed a high prevalence of polypharmacy in adults aged 65 and older, varying from 26% to 40%, with the lowest estimates in Switzerland, Croatia, and Slovenia and the highest estimates in Portugal, Israel, and the Czech Republic. 28 In other regions of the world, the prevalence of polypharmacy was 46% in Hong Kong, 39% in Taiwan, 32% in South Korea, and 20% in Australia. 29

Whereas polypharmacy is a pervasive phenomenon in contemporary healthcare, particularly as individuals contend with complex and coexisting health conditions, a distinction must be made between inappropriate polypharmacy and appropriate polypharmacy, which ensures optimal patient care. Inappropriate polypharmacy refers to the excessive, unnecessary, or unmonitored use of drug treatments, potentially leading to adverse effects, drug–drug interactions, and diminished overall wellbeing. On the contrary, appropriate polypharmacy entails the deliberate and evidence based use of multiple drug treatments to serve the specific needs of a patient, often stemming from the complexity of their medical conditions. In the context of deprescribing, the focus shifts to identifying instances of inappropriate polypharmacy and streamlining drug treatment regimens, to align with the principles of appropriate polypharmacy. Thus, the objective of deprescribing is to tailor treatment regimens to individual patient needs, minimize potential adverse effects, and ensure that the remaining prescribed drug treatments contribute meaningfully to a patient’s overall health and quality of life, while accounting for the principles of evidence based practice.

Barriers to deprescribing

Patient barriers.

Despite the need to tackle inappropriate polypharmacy, deprescribing is not commonplace. Published literature has identified a myriad of barriers at the patient, provider, and system levels. One example of a patient barrier is uncertainty of outcomes from deprescribing (and a fear of negative consequences). Other patient barriers could be poor access to deprescribing education, or difficulty in understanding medical jargon. 30 31 Deprescribing of a drug treatment can also represent a radical change for patients with a chronic condition, who might have been told for a long time to focus on achieving adequate disease control (eg, low A1c in the case of diabetes). 32

Provider barriers

Meanwhile, providers can also lack training and evidence on how to deprescribe (eg, how to taper and monitor), and can also lack knowledge and experience in engaging in complex conversations about deprescribing. 31 33 34 35 Providers themselves might fear the potential consequences of discontinuing drug treatments (eg, potential adverse drug withdrawal events, inadequate disease control) especially if they do not have guaranteed follow-up with the patient. Another provider barrier is inertia around making changes to drug treatments when patients are not experiencing any drug treatment related problems. Additional provider barriers include consultation constraints (eg, insufficient time or resources to support deprescribing), uncertainty around discontinuing a drug treatment that, for example, was initiated by another provider, uncertainty around roles and responsibilities among providers, and poor communication and collaboration among providers. 31 33 34 35 Many of these barriers are due to the healthcare environment in which providers work.

System barriers

Many system barriers exist. One example is a culture of diagnosing and prescribing in medicine. 31 33 34 Evidence based guidelines often recommend prescribing medicine but do not make recommendations on when to later stop the medicine. Evidence based guidelines also focus on a single disease, and evidence based guidelines for older adults with multimorbidity are lacking. Care itself for these older adults is fragmented, with multiple specialists and potential delays and/or mishaps in communication, which can further contribute to inappropriate polypharmacy. Additionally, the payment incentive structure in healthcare does not encourage complicated conversations around deprescribing, in-depth consideration of patient care goals, and often there is a lack of shared decision making tools and resources. 31 33 34 Also, performance metrics for providers and insurance plans can inadvertently encourage inappropriate overuse of drug treatments (to ensure adequate disease control) and make it difficult for deprescribing to attain individual patient goals. 36

Barriers across settings

These barriers are not uniform across healthcare settings; primary care, hospitals, long term care, and private settings face unique challenges. 30 35 37 For instance, primary care confronts challenges using a diagnostic and prescribing culture, while hospitals contend with competing inpatient tasks, patient resistance during hospitalization, and post-discharge follow-up concerns. Long term care settings grapple with resource shortages and coordination gaps, and private settings face obstacles related to awareness, commitment, and incentives for deprescribing. Healthcare providers, including physicians, pharmacists, and nurses, exhibit varied attitudes and knowledge gaps, influencing deprescribing implementation. Specific drug treatment classes, such as benzodiazepines, introduce unique challenges, including patient beliefs, lack of knowledge, and emotional attachments to the drug treatment. 38 39

Implementation strategies

Overcoming these barriers is paramount for successful deprescribing, and implementation science can offer valuable tools and strategies. Key implementation strategies for successful deprescribing include structured education and training for providers and patients to enhance knowledge and confidence, patient centered approaches like shared decision making and motivational interviewing, offering non-pharmacological alternatives to reduce drug treatment reliance, and providing resources such as clinical decision support tools and deprescribing algorithms. 40 Additionally, fostering improved communication and collaboration among healthcare settings and providers is crucial for maintaining continuity and consistency of care. Integrating implementation science principles requires understanding healthcare system complexities, securing provider buy-in, and tailoring interventions to specific contexts, as recent research underscores the value of this approach in overcoming barriers and optimizing facilitators in diverse healthcare landscapes.

Facilitators to deprescribing

Studies have identified patient, provider, and system facilitators that cover a wide spectrum. 30 31 33 35 Most older adults (84-88%) are willing to deprescribe their drug treatment, based on provider recommendations. 41 42 In fact, 67% of older adults report wanting to reduce the number of drug treatments they are taking, and this desire increases when they are taking more drug treatments. 43 Patient willingness and attitudes toward deprescribing vary, but it should be noted that this desire on average does exist.

Shared decision making processes with clear communication and a gradual introduction of the topic, as well as active patient and caregiver involvement, can enable deprescribing. Examples of provider facilitators include training to achieve in-depth drug treatment knowledge related to deprescribing outcomes (eg, potential adverse drug withdrawal events) along with multidisciplinary provider teams that have clear roles and responsibilities related to deprescribing decisions.

Examples of system facilitators include resources and tailored support tools to enable deprescribing conversations, deprescribing guidelines, and evidence on optimal deprescribing practices. 30 31 33 35 The greater availability and acceptability of non-pharmacological alternatives, which allows for substitution of the deprescribed drug treatment, can also allow for patients and providers to feel more comfortable with deprescribing. At the broader system level, insurance plans have medication therapy management programs and have been incentivized through quality measures to monitor and encourage discontinuation of potentially inappropriate medications. 44

Finally, increasing awareness of drug treatment overload; for example, media campaigns and reducing industry influence can also help facilitate a culture that normalizes deprescribing. 45 Facilitators and barriers to deprescribing are important to consider in deprescribing interventions, and in our review of studies, we extracted various intervention components that would deal with some of these facilitators and barriers.

Source and selection criteria

A literature review was conducted to identify published randomized controlled trials of deprescribing interventions in older adults with polypharmacy. Searches were conducted in PubMed and Embase on 2 April 2023 using the free text search terms, “deprescribing” and “polypharmacy”, and filtering on randomized controlled trials, controlled studies, systematic reviews, and meta-analyses. We included studies that were published from 1 January 2012 to the day of the search and were in English. We limited our search to randomized controlled trials that enrolled those at least 65 years of age and with polypharmacy (defined as taking at least five drug treatments). We excluded pilot/exploratory randomized controlled trials and ancillary publications of the randomized controlled trial (eg, trial protocol only, process evaluation). We also manually searched through references of identified studies and systematic reviews of broader scope interventions for older adults with polypharmacy, and included studies if deprescribing was a part of the intervention (either explicitly by the term “deprescribing” or implicitly by reporting reduction in drug treatments as a trial outcome). Two reviewers reviewed each article and any discrepancies were resolved through discussion. We described intervention components and summarized key findings based on primary outcomes and any key secondary outcomes that were reported in the publication abstract. This distinction was made because many of the trials included a very long list of secondary outcomes. We then categorized whether the study intervention was found to have a statistically significant effect (p<0.05) on: (a) at least one primary outcome; (b) if not, at least one of the key secondary outcomes; or (c) neither primary nor key secondary outcomes. We acknowledge that if a randomized controlled trial tested many outcomes, then there could be multiplicity concerns. For this narrative review, we report on these outcomes without adjustment and are limited by what was reported on in the randomized controlled trial.

Secondarily, we searched for ongoing randomized controlled trials of deprescribing interventions in older adults with polypharmacy and applied the same inclusion/exclusion criteria as aforementioned. We defined the randomized controlled trial as “ongoing” if the primary outcome results had not yet been published as a manuscript. To identify these ongoing studies, we documented any trials that had published protocols from the aforementioned PubMed and Embase searches that did not yet have primary outcomes results reported in a manuscript, and also searched through the ClinicalTrials.gov and the International Standard Randomised Controlled Trial Number Registry databases.

When conducting this narrative review, we identified several completed studies 46 47 48 49 50 and ongoing studies 51 52 that were excluded because they included slightly younger populations (minimum of 50, 55, or 60 years of age). Similar to prior reviews, we chose an age cutoff of ≥65 because interventions and outcomes can vary for different ages. 20 21 22 For example, the Beers criteria that are intended for use in older adults aged ≥65 define a commonly used list of potentially inappropriate medications that might be used if interventions are targeting older adults. 53 Similarly, additional studies were excluded if they did not specify that the recruited patients had to be using a minimum of five drug treatments (ie, the most common definition of polypharmacy), because the scope of this narrative review was older adults with polypharmacy.

Out of 433 articles identified, 21 articles met all eligibility criteria ( fig 1 ). Of these articles, 15 took place in primary care (11 in primary care practices and four in community pharmacies), four focused on hospital transitions, and two on nursing home settings ( fig 2 ). Most studies took place in Europe or North America, and over half (12 of 21) were cluster randomized controlled trials (see supplementary table 1). While the majority (12 of 21) targeted patients aged ≥65, four studies targeted patients aged ≥70, and five studies targeted patients aged ≥75 ( figs 3-7 ). The majority (12 of 21) examined populations with at least five drug treatments, while eight studies used higher thresholds (eg, at least 7, 8, 10, or 15 drug treatments). Three studies additionally targeted deprescribing of specific drug classes (eg, benzodiazepines, psychotropics, anticholinergics). In addition to targeting older populations with polypharmacy, five studies further focused on frail populations or those with multiple chronic conditions, alongside specific disease states such as dementia or cardiovascular disease.

Flow diagram of included studies.

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Number of studies by targeted setting.

Summary of findings from published deprescribing randomized controlled trials in older adults with polypharmacy (part 1). *Unless noted, the control arm was usual care. †Results on secondary outcomes were included if they were notable enough to be included in the abstract. Focus on adjusted results and intention-to-treat analyses when available. DRP=drug related problem; EQ=EuroQol; HRQoL=health related quality of life; MAI=Medication Appropriateness Index; PCP=primary care physician; PIM=potentially inappropriate medication; SD=standard deviation; SPPiRE=Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care.

Summary of findings from published deprescribing randomized controlled trials in older adults with polypharmacy (part 2). *Unless noted, the control arm was usual care. †Results on secondary outcomes were included if they were notable enough to be included in the abstract. Focus on adjusted results and intention-to-treat analyses when available. CI=confidence interval; DBI=drug burden index; DRP=drug related problem; GP=general practitioner; GPGP= Good Palliative-Geriatric Practice; HRQoL=health related quality of life; OR=odds ratio; PIM=potentially inappropriate medication; STOPP/START=Screening Tool of Older Person's Prescriptions/Screening Tools to Alert Doctors to Right Treatment.

Summary of findings from published deprescribing randomized controlled trials in older adults with polypharmacy (part 3). *Unless noted, the control arm was usual care. †Results on secondary outcomes were included if they were notable enough to be included in the abstract. Focus on adjusted results and intention-to-treat analyses when available. ADE=adverse drug event; ADWE=adverse drug withdrawal event; CI=confidence interval; DRP=drug related problem; GP=general practitioner; HRQoL=health related quality of life; MAI=Medication Appropriateness Index; PACIC=Patient Assessment of Care for Chronic Conditions; SD=standard deviation; STOPPFrail=Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy; STRIPA=Systematic Tool to Reduce Inappropriate Prescribing Assistant; TRIM=Tool to Reduce Inappropriate Medications.

Summary of findings from published deprescribing randomized controlled trials in older adults with polypharmacy (part 4). HR=hazard ratio; PIM=potentially inappropriate medication; S$=Singapore dollar; VAS=Visual Analogue Scale.

Frequency of intervention components.

All studies compared the intervention with usual care. We found a wide variety of interventions, with most including more than one component to overcome different barriers to deprescribing. Common intervention components explicitly described in studies included medication reviews, shared decision making processes and/or a focus on patient care priorities, active involvement of a multidisciplinary team, training for healthcare professionals, electronic clinical decision support tools or websites, patient facing deprescribing educational materials, and involvement of family ( fig 7 ). Below, we summarize the intervention and key findings from each randomized controlled trial according to setting. We highlight whether study interventions were found to have a significant impact on at least one primary outcome assessed; or if not, at least one key secondary outcome; or none, and report on that impacted outcome ( figs 3-7 ). Within setting, we also organize the studies based on the components included in the intervention. This categorization is helpful in framing our findings, but not absolute, as there could be overlap and variation in how much focus was given to each of the components.

Primary care

Historically, medication reviews with the patient have been a common approach to optimizing drug treatment management among older adults with polypharmacy in the primary care setting. These medication reviews typically consist of a healthcare professional, such as a pharmacist, reviewing a patient’s list of drug treatments, identifying potential drug related problems, meeting with the patient, and providing recommendations to the patient, physician, or both. Medication reviews can be broad in nature and include patient education and/or drug treatment changes such as reductions in dose, discontinuing a drug treatment, or adding drug treatments when appropriate. In our review, two thirds (10 of 15) of primary care interventions centered around medication reviews, and all affected at least one primary or secondary outcome (with a majority (7 of 10) affecting the primary outcome; figs 3-7 ).

Medication reviews can vary depending on how the drug treatment data are collected, who is performing the review, and the extent to which follow-up is performed, along with whether additional components (such as training for the healthcare professional) are provided. In one study, a medication review conducted by a pharmacist based on a questionnaire completed by patients led to a larger reduction in the number of drug treatments in the intervention group versus the control group at 12 months (p<0.046; primary outcome). 60 In another study, pharmacist conducted medication reviews were preceded by a three day training course for pharmacists and succeeded by six month follow-up with the patient. 61 Recommendations were made to patients, their physicians, or both, and this intervention led to a greater reduction (0.21 ± 0.06 drugs, 95% confidence interval 0.092 to 0.335) in the number of drug treatments in the intervention group compared with the control group, improved quality of life in the intervention group (p<0.001), and a dominant strategy in a cost–utility analysis (all primary outcomes).

In addition to healthcare professional training, another component commonly added to medication review interventions was the active involvement of a multidisciplinary team, which can improve communication and minimize provider barriers around uncertainty in role regarding changes to the patient’s drug treatment regimen. In one such medication review intervention, a primary care provider would send records to a homecare specialist, who would collect information to help inform a pharmacist’s medication review. This medication review was then followed up with recommendations that were sent back to the homecare specialist and primary care provider. 62 This intervention was found to decrease the mean drug treatment appropriateness index score (indicating improvement in appropriateness) from the control phase to the intervention phase at 15 months (p≤0.001; primary outcome). In another medication review intervention, the multidisciplinary team included a geriatrician and a family practitioner who met after a medication review and clinical geriatric assessment. This intervention led to a higher mean health related quality of life (HRQoL) score in the intervention group versus the control group (p=0.03; primary outcome). 63

Yet another component added to medication reviews was an electronic decision support website and a focus on patient care priorities or shared decision making, which can align deprescribing decisions with patient goals, facilitate communication between patients and providers, and reduce uncertainty in the deprescribing process. In one study, general practices were given access to a website that provided an educational module and template for general practitioners to conduct medication reviews that identified potentially inappropriate medications, opportunities for deprescribing, and patient priorities for care. 64 This study found a larger reduction in the number of drug treatments in the intervention group versus control group at six months (p=0.045; primary outcome). In a second study, general practices were given a deprescribing guideline and training sessions on family conferences, during which a medication review took place with a frail patient and their family caregivers. 65 While no effect was found on the primary outcome (number of hospitalizations in 12 months), the number of drug treatments (p=0.001) and number of potentially inappropriate medications (p=0.04; secondary outcomes) were lower in the intervention group than in the control group at six months.

Four more medication review interventions involved both multidisciplinary teams and focused on patient goals or shared decision making. In one of these studies, community pharmacists conducted medication reviews with patients with a drug burden index of ≥1 and subsequently met to discuss with the patient’s general practitioner, with patient expectations and desires as key elements in final decisions. 66 This study did not find an impact in the proportion of patients who reduced their drug burden index by ≥0.5 at three months (primary outcome), but did find an impact on cognitive function (p=0.021) and fewer sedative side effects (p=0.024; secondary outcomes). Another study included a medication review by three experts (internal medicine specialist, clinical pharmacologist, and evidence based medicine expert) who provided specific recommendations for drug discontinuation to a general practitioner, who was invited to act on the recommendations based on a shared decision making process with the patient. 67 This intervention was not found to affect hospital admissions or death (primary outcome) but did lead to fewer falls (p=0.04; secondary outcome). In a third study, a pharmacist performed a medication review with the final decisions agreed upon by both the physician and the patient in a face-to-face visit. This intervention led to fewer drug treatments (p=0.001) immediately after the review, and a greater likelihood of drug treatment discontinuation, dose adjustment, and substitution at three, six, and 12 months (primary outcomes). In a fourth study, the medication review conducted by the pharmacist incorporated goal setting by the patient and was followed up with face-to-face meetings with the patient’s general practitioner and discussion and follow-up with the patient. Compared with the control group, this intervention led to an improvement in HRQoL (3.4 points, 95% confidence interval 0.94 to 5.8, p=0.006) and a reduction in the number of health problems with moderate to severe impact on daily life in the intervention group (−0.34 problems, 95% confidence interval −0.62 to −0.044, p=0.024) at six months (primary outcomes).

Beyond medication reviews with patients, other interventions focused on patient facing deprescribing educational materials, 2 deprescribing clinical decision support tools, 3 or both. 1 Patient facing deprescribing educational materials can empower patients to take a more active role in deprescribing decisions, thereby serving as facilitators to deprescribing. Of the two interventions focused on patient facing deprescribing educational materials, one was focused on benzodiazepines and provided specific information around the risks of benzodiazepine use and a stepwise tapering protocol. 68 This study was conducted by community pharmacies and reduced benzodiazepine use (27% of the intervention group discontinued benzodiazepine use v 5% of the control group, risk difference 23%, 95% confidence interval 14% to 32%) at six months (primary outcome). The other study mailed a general deprescribing educational brochure and questionnaire to patients with dementia or mild cognitive impairment and their family members prior to a primary care visit. 69 This was coupled with clinician notification and deprescribing tip sheets, but the intervention was not found to impact the primary outcomes (ie, number of long term drug treatments or proportion of individuals prescribed ≥1 potentially inappropriate medication) at six months.

Deprescribing clinical decision support tools coupled with shared decision making processes can help overcome patient, provider, and system barriers to deprescribing. Two such studies applied clinical decision support tools that reviewed drug treatments, and identified potential problems for providers to then make subsequent treatment changes based on shared decision making with the patient. 70 71 Neither study was found to impact their primary outcome (ie, hospital admission or death within 24 months, drug treatment appropriateness at 12 months); however, one study did find a greater reduction in number of drug treatments (p<0.001), which was a secondary outcome. 70 A fifth study combined use of a clinical decision support tool in primary care clinics with individualized patient facing materials that included brief coaching on how to discuss concerns with the provider. 72 The intervention was found to be associated with significantly more active patient communication, facilitative clinician communication, and drug treatment related communication among patients and clinicians (primary outcomes).

At hospital discharge, four study interventions focused on sending deprescribing reports to clinicians 2 and medication reviews. 2 Interventions generating individualized deprescribing reports can help providers with specific, actionable steps in deprescribing, such as which drug treatment to deprescribe, level of priority (among multiple drug treatments that should be deprescribed), and how to taper and monitor. In one study, a deprescribing plan was generated by a study physician, 73 and in the second study, a report providing deprescribing opportunities was generated by clinical decision support software. 74 In the first study, the report was sent to the patient’s physician, and in the second study, the report was sent to physicians, pharmacists, patients, and family members. Although the second study was not shown to reduce adverse drug events (primary outcome), both interventions led to deprescribing, as evidenced by a greater reduction in the mean number of drug treatments after three months (−2.6 intervention group v −0.36 control group, mean difference 2.25, 95% confidence interval 1.18 to 3.32; primary outcome for the first study) or increased deprescribing within 30 days (29.8% control group v 55.4% intervention group, adjusted risk difference 22.2%, 95% confidence interval 16.9% to 27.4%; secondary outcome for the second study).

Two additional studies involved either a pharmacist 75 or a physician 76 conducting a medication review, and then sending recommendations to the patient’s general practitioner. In the second study, two intervention arms were tested to allow for further patient engagement in one of those arms (eg, a drug treatment record sent to the patient). 76 Across both studies, the interventions were not found to affect prescribing appropriateness, prescribing quality (eg, number of drug treatments, number of potentially inappropriate medications), or HRQoL (all primary outcomes). One study did report on implementation outcomes; for example, that 750 causes of drug related problems were identified, and that general practitioners implemented 42.4% of recommendations. 75

Nursing homes

The two interventions targeting nursing home populations were both medication reviews involving multidisciplinary teams including pharmacists, physicians, and nurses. The first intervention also optionally involved family members for patients with cognitive impairment, and was not found to reduce falls at six months (primary outcome), but was found to reduce mortality (p<0.001) and hospitalization (p<0.001; secondary outcomes). 77 The second study focused on older populations (aged ≥75 years) taking ≥10 drug treatments (specifically, ≥3 psychotropics), and was found to reduce the number of patients with ≥1 potentially inappropriate medication and the number of patients using ≥10 drugs at two months (p=0.007 and p=0.001, respectively; primary outcomes). 78

In summary, various deprescribing interventions in older adults with polypharmacy have been tested in randomized controlled trials across different settings, with most (15 of 21 studies) conducted in primary care settings. The majority of interventions centered around medication reviews, with a mix of including additional components, such as a focus on shared decision making and/or patient care priorities, multidisciplinary teams, training for healthcare professionals, electronic clinical decision support tools or websites, patient facing deprescribing educational materials, and involvement of family. Such diverse intervention components represent how complicated deprescribing is and what is needed to overcome the myriad of existing patient, provider, and system barriers to deprescribing. Medication reviews with patients were generally successful in primary care settings (7 of 10 studies showing an impact on at least one primary outcome, and all showing an effect on at least one primary or key secondary outcome), but not always successful in other settings such as the hospital (two of two studies not showing an effect on primary or key secondary outcomes), although the number of studies was very small. Great variation in the mix of intervention components, as well as diversity in study population, led to small sample sizes within each stratum, making it difficult to determine if one particular component was considered to be more or less successful. Ongoing randomized controlled trials of deprescribing interventions in older adults with polypharmacy will provide more evidence, and further patterns should emerge as the number of studies grows.

Primary outcomes assessed across studies included drug treatment related outcomes (13 studies), HRQoL or health problems with impact on daily life, clinical outcomes such as falls, emergency room visits, hospitalizations, and deaths, cost, and outcomes related to shared decision making or patient/clinician communication ( fig 8 ), and even greater diversity was observed in the secondary outcomes collected (see supplementary table 1). Of the 21 studies, just over half 11 reported a significant effect on at least one primary outcome. Another six showed an effect on at least one of the key secondary outcomes, and four did not show an effect on primary or key secondary outcomes. The variability in results can be attributed to not only heterogeneity in intervention, but also the choice of primary outcomes. Notably, several studies emphasized the inadequacy of using clinical outcomes like hospitalization and death as a sole measure for deprescribing success, owing to challenges in translating the impact of discontinuing drugs into such downstream outcomes. Several studies using HRQoL as their primary outcome, and one study focusing on shared decision making and patient-provider communication as its primary outcomes, further underscored the need for a more comprehensive understanding of appropriate key clinical endpoints in deprescribing interventions.

Frequency of primary outcome assessed and if an effect was shown.

Furthermore, variability in drug treatment related outcomes across deprescribing studies adds to the complexity. Among primary outcomes, drug treatment related outcomes included number of drug treatments; number or proportion of potentially inappropriate medications; medication appropriateness index, drug burden index or other prescribing appropriateness criteria; drug related problems or adverse drug events; drug treatment changes (such as discontinuation, dose adjustment, or substitution; and proportion with ≥10 drug treatments ( fig 9 ). This diversity hinders the comparison and generalization of findings, emphasizing the need for standardized measures. To tackle these problems, the use of core outcome sets can provide a standardized approach to outcome measurement and enhance comparability across diverse populations and settings in deprescribing research. 79 80 81 Commonly recommended outcomes within core outcome sets include drug treatment appropriateness, drug related problems, and hospitalizations associated with drug treatments, ensuring a more consistent and comprehensive evaluation of deprescribing interventions.

Frequency of specific drug treatment related primary outcomes.

In addition to outcome variability, difficulties such as overestimating intervention effects, limited provider acceptance, intervention spillover effects, and challenges in tracking pharmacy adherence in real world settings contribute to study variability. Recognizing the necessity of longer observation periods aligns with the complex nature of deprescribing interventions over time. Best practices for successful deprescribing interventions require targeting provider behavior change, employing methods to limit contamination effects in trials (eg, cluster randomized trials), powering studies for clinically meaningful effect sizes, and emphasizing longer follow-up periods. These practices contribute to a more robust understanding of deprescribing interventions and guide the development of effective strategies. While study follow-up periods varied ( fig 10 ), with six months being the most commonly used timeframe, and 22 of 25 primary outcome measures within 12 months, the question of whether deprescribing interventions have long term effects remains unanswered. Two studies with 24 months of follow-up conducted in general practices indicated effectiveness in reducing falls and the number of drug treatments taken, suggesting potential long term benefits. However, further evidence is needed to establish the sustained efficacy of deprescribing interventions over extended periods.

Frequency of follow-up period for primary outcome.

Emerging interventions

Four ongoing randomized controlled trials are testing deprescribing interventions in older adults with polypharmacy in Canada, Germany, and Ireland, and are all focused on older adults who are being seen in primary care practices ( table 1 ). The first two randomized controlled trials are investigating training for healthcare professionals. In the SPIDER cluster randomized controlled trial, targeting those taking ≥10 drug treatments in Canada, primary care practices will develop interprofessional learning collaboratives and work with quality improvement coaches. 54 55 The intervention will be compared with usual care, and the primary outcome will be reduction of potentially inappropriate medications at 12 months. Secondary outcomes include cost effectiveness, as well as patient and care provider perceptions of the intervention.

Characteristics of ongoing deprescribing randomized controlled trials in older adults with polypharmacy

• View inline

Next, the PARTNER cluster randomized controlled trial in Germany targeting patients using ≥1 psycholeptic, sedative, or anticholinergic drug treatments comprises a multilevel, multicomponent intervention. 56 Firstly, educational material will be provided for general practitioners and pharmacists on deprescribing psycholeptics, sedatives, and anticholinergics, and a moderated interprofessional workshop will take place. Secondly, leaflets will be used to encourage patient empowerment during a patient-pharmacist consultation. Thirdly, a patient-general practitioner consultation involving shared decision making will take place. This intervention will be compared with usual care, plus a patient-pharmacist consultation updating plans for drug treatment (but without a focus on psycholeptics, sedatives, or anticholinergics). The primary trial outcome will be reduction in exposure to psycholeptics, sedatives, or anticholinergics as measured by a point reduction of ≥0.15 in drug burden index at six months. Secondary outcomes include drug treatment related outcomes, such as frequency of deprescribing and frequency of other potentially inappropriate medications as well as quality of life and clinical outcomes such as falls, fall related hospitalizations, cognition, and insomnia.

Two additional trials are testing interventions focused on medication reviews. In the TAPER randomized controlled trial targeting those ≥70 years in Canada, a multidisciplinary comprehensive medication review focused on reducing drug treatment burden and conducted by pharmacists and physicians with patients will be compared with usual care. 57 The primary outcome will be the number of drug treatments at six months and there are numerous secondary outcomes related to drug treatment use (eg, successful discontinuation or dose reduction, changes in drug treatment side effects and symptoms), quality of life, clinical outcomes like cognition, physical functional ability, and falls, healthcare resource use and cost effectiveness, and patient-reported deprescribing measures, such as confidence in drug treatment discontinuation and experience with the deprescribing process.

Lastly, a cluster randomized controlled trial in Ireland will use targeted medication reviews, in which pharmacists will meet with both patients and prescribers. 58 59 The intervention will be compared with usual care, and the primary outcome will be the number of potentially inappropriate medications at four months. Secondary outcomes include drug treatment related outcomes (eg, polypharmacy, drug treatment changes, adverse drug reactions, adverse drug withdrawal events), quality of life, and patient reported deprescribing measures (eg, patient attitudes toward deprescribing and the necessity of drug treatments).

In summary, four ongoing randomized controlled trials are being conducted in primary care practices, with a mix of intervention components such as medication reviews, patient empowerment leaflets, and training for healthcare professionals. The primary outcomes are all drug treatment related, such as reduction in potentially inappropriate medication or based on a score measuring drug treatment appropriateness (eg, medication appropriateness index or drug burden index), and are measured over 4-12 months of follow-up. Secondary outcomes are numerous, and include newer patient reported deprescribing measures (eg, attitude toward deprescribing and confidence in drug treatment discontinuation), as well as implementation outcomes (eg, costs, and patient/provider perception of, experience with, and satisfaction with the deprescribing intervention).

Deprescribing guidelines, algorithms, and additional resources have been developed in recent years for specific drug classes such as proton pump inhibitors, 82 diabetes drug treatments, 83 antipsychotics, 84 benzodiazepines and Z drugs, 85 and dementia drug treatments 86 by the deprescribing.org research team. 87 Another research team has also developed deprescribing guides for antidepressants, anticholinergics for Parkinsonism, antimuscarinics, sedating antihistamines, and opioids. 88 Medstopper is a freely available web based tool that provides recommendations related to tapering and more. 89 Additionally, countries such as Wales have produced guidance documents around management of polypharmacy in older adults, including recommendations on how to deprescribe specific drug classes. 90 Not all drug classes have deprescribing guidelines, and evidence is still needed to support recommendations around optimal tapering and monitoring strategies. While a previous review identified several drug classes at increased risk of adverse drug withdrawal events, 91 further evidence (such as through deprescribing trials) is needed to better understand the risk and severity of adverse drug withdrawal events after deprescribing, how this varies, and how to minimize these potential risks. 92 To help fill these evidence gaps, multiple deprescribing networks are growing in Canada, 93 Australia, 94 the US, 95 and Europe. 96

Additionally, disease specific guidelines are also beginning to include consideration of discontinuation or de-intensification of treatment, especially among older adults with multiple comorbidities and polypharmacy. For example, the American Diabetes Association guidelines and the American Geriatrics Society guidelines both recommend de-intensification of diabetes drug treatments and individualized glycemic targets among older adults with multiple comorbidities. 97 98

Polypharmacy in older adults is associated with an increased risk of using potentially inappropriate medications, 9 10 and several guidelines relate to potentially inappropriate medications. These guidelines include the Beers criteria in the US, 99 the STOPP/START (screening tool of older persons’ prescriptions/screening tools to alert doctors to right treatment) criteria in Europe 100 and Japan, 101 the PRISCUS list in Germany, 102 the European Union (7) potentially inappropriate medications (EU(7)-PIM) list which was developed by experts from seven European countries, 103 STOPPFrail (screening tool of older persons’ prescriptions in frail adults with limited life expectancy) criteria in frail populations with limited life expectancy, 104 RASP, 105 and NORGEP. 106 Other approaches and tools developed to help clinicians determine drug treatment appropriateness include the drug burden index, 107 the anticholinergic risk scale, 108 the medication appropriateness index, 109 and the medication regimen complexity index. 110 Across study interventions identified in this review, the most commonly used guidelines to identify potentially inappropriate medications were the STOPP, STOPP/START or STOPPFrail criteria (7 of 21) and Beers criteria (6 of 21; fig 11 ). Other ways to identify potentially inappropriate medications were based on country specific guidance, drug interaction databases (eg, LexiComp, UpToDate), EU(7)-PIM, NORGEP, or targeting specific drug classes such as benzodiazepines or opioids.

Frequency of guideline used to identify potentially inappropriate medications. STOPP=screening tool of older persons’ prescriptions; START=screening tool to alert doctors to right treatment study. *Included country specific guidelines, the EU(7)-PIM list, NORGEP, drug-drug interaction databases (eg, LexiComp, UpToDate), and targeting specific drug classes like benzodiazepines and opioids. †Study interventions could apply more than one guideline.

Furthermore, quality measures have also been used over the years to discourage potentially inappropriate medication use. For example, in the US, the Centers for Medicare and Medicaid Services has evaluated potentially inappropriate medication use in older populations through various quality measures for Part D prescription drug insurance plans, either generally (eg, high risk drug treatments in older people largely based on Beers criteria), or focused on specific drug classes and disease states (eg, antipsychotic use among older adults with dementia, multiple anticholinergic drug treatments, or multiple central nervous system active drug treatments in older adults with polypharmacy). 44 Prescription drug plans are incentivized to reach out to beneficiaries and reduce potentially inappropriate medication use to perform well on these measures, because these measures can potentially influence beneficiary enrollment and bonus payments. In 2022, a new quality measure focused on deprescribing benzodiazepines in older adults was developed, 111 indicating that future deprescribing quality measures could be used alongside guidelines to incentivize deprescribing at a large scale. Similarly, the Centers for Medicare and Medicaid Services also applies quality measures for nursing homes to monitor antipsychotic and sedative use. 112

In summary, recently developed deprescribing guidelines and algorithms have focused on collating evidence and providing recommendations (eg, whether and how to taper) for specific drug classes. A variety of potentially inappropriate medication guidelines to help identify inappropriate drug treatment use exists, and quality measures can be used to incentivize reduction of inappropriate drug treatment use. As disease specific guidelines begin to include deintensification of treatment and the number of studies testing various deprescribing interventions grows, future guidelines should report on the intervention components and implementation strategies that have led to successful deprescribing interventions, and how these vary across setting.

Conclusions

This review summarizes published and ongoing deprescribing randomized controlled trials in older adults with polypharmacy, and describes important barriers and facilitators to deprescribing, as well as guidelines and resources that can support deprescribing. Medication reviews in primary care settings continue to represent a majority of deprescribing interventions, with many interventions incorporating a mix of components. Other intervention components included a focus on shared decision making and/or patient care priorities, active involvement of multidisciplinary teams, training for healthcare professionals, patient facing educational materials, and involvement of family members, which shows how complicated deprescribing can be. Just over half of interventions were found to be efficacious based on assessment of primary outcome alone, suggesting that applying such intervention components can help to overcome barriers in deprescribing. Most outcomes were assessed within 12 months of follow-up, and varied widely: drug treatment related (eg, number of drug treatments or number of potentially inappropriate medications), clinical outcomes (eg, hospital, death), HRQoL, and more. Ongoing trials are focused on primary care settings and are adding newer patient reported deprescribing outcome measures (eg, attitude toward deprescribing and confidence in drug treatment discontinuation), as well as implementation outcomes (eg, costs, and patient/provider perception of, experience with, and satisfaction with the deprescribing intervention).

Questions for future research

How effective are deprescribing interventions in the long term (>2 years)? What patient, provider, and system factors are associated with reinitiating treatments following deprescribing, and how should these be dealt with? How sustainable are deprescribing interventions in real world clinical settings, and what are the associated costs (eg, to support staff)?

What is the ideal primary outcome and core outcome set? How might these outcomes be based on setting, deprescribing intervention component, and study population?

To what degree have patients been involved as stakeholders in the design of deprescribing interventions, and to what extent do they affect effectiveness and implementation? How might patient input affect measures around adverse drug events?

How does deprescribing differ across populations; for example, in under-resourced populations? How do social determinants of health and the influence of cultural traditions and provider bias limit the effectiveness and implementation of current deprescribing interventions?

How do system level barriers like uncoordinated health services delivery affect deprescribing? How do disparate healthcare access, mistrust in health systems, poor communication, and provider negligence in considering patients’/caregivers’ values, healthcare beliefs, and literacy levels affect patients’/caregivers’ deprescribing decisions?

What types of culturally tailored interventions, shared decision making, and educational tools specific to deprescribing are most effective?

How patients were involved in the creation of this article

We thank the US Deprescribing Research Network Stakeholder Engagement Core and the two patient stakeholders who provided valuable feedback, including specific future directions for the ‘‘Questions for future research’’ section.

Acknowledgments

AH acknowledges the US Deprescribing Research Network Junior Investigator Intensive Program and the AGING Initiative Multiple Chronic Conditions Scholars Program.

State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors.

Funding: AH is supported by VA HSR&D (Career Development Award IK2 HX003359) and by the US Deprescribing Research Network (R24AG064025). JMP is supported by a Career Development Award K23AG058788 from the National Institute on Aging.

Sponsor’s role: The funders had no role in the design, analysis, or preparation of the paper. The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: AH reports funding from the US Deprescribing Research Network (R24AG064025), honorariums and conference support from Academy of Managed Care Pharmacy, and honorariums from the Journal of Managed Care and Specialty Pharmacy. No other authors declare interests.

Contributing author statement: All authors made substantial contributions to the conception of the work, drafting/reviewing for important intellectual content, final approval of the version to be published, and agree to be accountable for all aspects of the work. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Provenance and peer review: commissioned; externally peer reviewed.

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Types of Study in Medical Research

Bernd röhrig.

1 MDK Rheinland-Pfalz, Referat Rehabilitation/Biometrie, Alzey

Jean-Baptist du Prel

2 Zentrum für Präventive Pädiatrie, Zentrum für Kinder- und Jugendmedizin, Mainz

Daniel Wachtlin

3 Interdisziplinäres Zentrum Klinische Studien (IZKS), Fachbereich Medizin der Universität Mainz

Maria Blettner

4 Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Johannes Gutenberg Universität Mainz

The choice of study type is an important aspect of the design of medical studies. The study design and consequent study type are major determinants of a study’s scientific quality and clinical value.

This article describes the structured classification of studies into two types, primary and secondary, as well as a further subclassification of studies of primary type. This is done on the basis of a selective literature search concerning study types in medical research, in addition to the authors’ own experience.

Three main areas of medical research can be distinguished by study type: basic (experimental), clinical, and epidemiological research. Furthermore, clinical and epidemiological studies can be further subclassified as either interventional or noninterventional.

Conclusions

The study type that can best answer the particular research question at hand must be determined not only on a purely scientific basis, but also in view of the available financial resources, staffing, and practical feasibility (organization, medical prerequisites, number of patients, etc.).

The quality, reliability and possibility of publishing a study are decisively influenced by the selection of a proper study design. The study type is a component of the study design (see the article "Study Design in Medical Research") and must be specified before the study starts. The study type is determined by the question to be answered and decides how useful a scientific study is and how well it can be interpreted. If the wrong study type has been selected, this cannot be rectified once the study has started.

After an earlier publication dealing with aspects of study design, the present article deals with study types in primary and secondary research. The article focuses on study types in primary research. A special article will be devoted to study types in secondary research, such as meta-analyses and reviews. This article covers the classification of individual study types. The conception, implementation, advantages, disadvantages and possibilities of using the different study types are illustrated by examples. The article is based on a selective literature research on study types in medical research, as well as the authors’ own experience.

Classification of study types

In principle, medical research is classified into primary and secondary research. While secondary research summarizes available studies in the form of reviews and meta-analyses, the actual studies are performed in primary research. Three main areas are distinguished: basic medical research, clinical research, and epidemiological research. In individual cases, it may be difficult to classify individual studies to one of these three main categories or to the subcategories. In the interests of clarity and to avoid excessive length, the authors will dispense with discussing special areas of research, such as health services research, quality assurance, or clinical epidemiology. Figure 1 gives an overview of the different study types in medical research.

Classification of different study types

*1 , sometimes known as experimental research; *2 , analogous term: interventional; *3 , analogous term: noninterventional or nonexperimental

This scheme is intended to classify the study types as clearly as possible. In the interests of clarity, we have excluded clinical epidemiology — a subject which borders on both clinical and epidemiological research ( 3 ). The study types in this area can be found under clinical research and epidemiology.

Basic research

Basic medical research (otherwise known as experimental research) includes animal experiments, cell studies, biochemical, genetic and physiological investigations, and studies on the properties of drugs and materials. In almost all experiments, at least one independent variable is varied and the effects on the dependent variable are investigated. The procedure and the experimental design can be precisely specified and implemented ( 1 ). For example, the population, number of groups, case numbers, treatments and dosages can be exactly specified. It is also important that confounding factors should be specifically controlled or reduced. In experiments, specific hypotheses are investigated and causal statements are made. High internal validity (= unambiguity) is achieved by setting up standardized experimental conditions, with low variability in the units of observation (for example, cells, animals or materials). External validity is a more difficult issue. Laboratory conditions cannot always be directly transferred to normal clinical practice and processes in isolated cells or in animals are not equivalent to those in man (= generalizability) ( 2 ).

Basic research also includes the development and improvement of analytical procedures—such as analytical determination of enzymes, markers or genes—, imaging procedures—such as computed tomography or magnetic resonance imaging—, and gene sequencing—such as the link between eye color and specific gene sequences. The development of biometric procedures—such as statistical test procedures, modeling and statistical evaluation strategies—also belongs here.

Clinical studies

Clinical studies include both interventional (or experimental) studies and noninterventional (or observational) studies. A clinical drug study is an interventional clinical study, defined according to §4 Paragraph 23 of the Medicines Act [Arzneimittelgesetz; AMG] as "any study performed on man with the purpose of studying or demonstrating the clinical or pharmacological effects of drugs, to establish side effects, or to investigate absorption, distribution, metabolism or elimination, with the aim of providing clear evidence of the efficacy or safety of the drug."

Interventional studies also include studies on medical devices and studies in which surgical, physical or psychotherapeutic procedures are examined. In contrast to clinical studies, §4 Paragraph 23 of the AMG describes noninterventional studies as follows: "A noninterventional study is a study in the context of which knowledge from the treatment of persons with drugs in accordance with the instructions for use specified in their registration is analyzed using epidemiological methods. The diagnosis, treatment and monitoring are not performed according to a previously specified study protocol, but exclusively according to medical practice."

The aim of an interventional clinical study is to compare treatment procedures within a patient population, which should exhibit as few as possible internal differences, apart from the treatment ( 4 , e1 ). This is to be achieved by appropriate measures, particularly by random allocation of the patients to the groups, thus avoiding bias in the result. Possible therapies include a drug, an operation, the therapeutic use of a medical device such as a stent, or physiotherapy, acupuncture, psychosocial intervention, rehabilitation measures, training or diet. Vaccine studies also count as interventional studies in Germany and are performed as clinical studies according to the AMG.

Interventional clinical studies are subject to a variety of legal and ethical requirements, including the Medicines Act and the Law on Medical Devices. Studies with medical devices must be registered by the responsible authorities, who must also approve studies with drugs. Drug studies also require a favorable ruling from the responsible ethics committee. A study must be performed in accordance with the binding rules of Good Clinical Practice (GCP) ( 5 , e2 – e4 ). For clinical studies on persons capable of giving consent, it is absolutely essential that the patient should sign a declaration of consent (informed consent) ( e2 ). A control group is included in most clinical studies. This group receives another treatment regimen and/or placebo—a therapy without substantial efficacy. The selection of the control group must not only be ethically defensible, but also be suitable for answering the most important questions in the study ( e5 ).

Clinical studies should ideally include randomization, in which the patients are allocated by chance to the therapy arms. This procedure is performed with random numbers or computer algorithms ( 6 – 8 ). Randomization ensures that the patients will be allocated to the different groups in a balanced manner and that possible confounding factors—such as risk factors, comorbidities and genetic variabilities—will be distributed by chance between the groups (structural equivalence) ( 9 , 10 ). Randomization is intended to maximize homogeneity between the groups and prevent, for example, a specific therapy being reserved for patients with a particularly favorable prognosis (such as young patients in good physical condition) ( 11 ).

Blinding is another suitable method to avoid bias. A distinction is made between single and double blinding. With single blinding, the patient is unaware which treatment he is receiving, while, with double blinding, neither the patient nor the investigator knows which treatment is planned. Blinding the patient and investigator excludes possible subjective (even subconscious) influences on the evaluation of a specific therapy (e.g. drug administration versus placebo). Thus, double blinding ensures that the patient or therapy groups are both handled and observed in the same manner. The highest possible degree of blinding should always be selected. The study statistician should also remain blinded until the details of the evaluation have finally been specified.

A well designed clinical study must also include case number planning. This ensures that the assumed therapeutic effect can be recognized as such, with a previously specified statistical probability (statistical power) ( 4 , 6 , 12 ).

It is important for the performance of a clinical trial that it should be carefully planned and that the exact clinical details and methods should be specified in the study protocol ( 13 ). It is, however, also important that the implementation of the study according to the protocol, as well as data collection, must be monitored. For a first class study, data quality must be ensured by double data entry, programming plausibility tests, and evaluation by a biometrician. International recommendations for the reporting of randomized clinical studies can be found in the CONSORT statement (Consolidated Standards of Reporting Trials, www.consort-statement.org ) ( 14 ). Many journals make this an essential condition for publication.

For all the methodological reasons mentioned above and for ethical reasons, the randomized controlled and blinded clinical trial with case number planning is accepted as the gold standard for testing the efficacy and safety of therapies or drugs ( 4 , e1 , 15 ).

In contrast, noninterventional clinical studies (NIS) are patient-related observational studies, in which patients are given an individually specified therapy. The responsible physician specifies the therapy on the basis of the medical diagnosis and the patient’s wishes. NIS include noninterventional therapeutic studies, prognostic studies, observational drug studies, secondary data analyses, case series and single case analyses ( 13 , 16 ). Similarly to clinical studies, noninterventional therapy studies include comparison between therapies; however, the treatment is exclusively according to the physician’s discretion. The evaluation is often retrospective. Prognostic studies examine the influence of prognostic factors (such as tumor stage, functional state, or body mass index) on the further course of a disease. Diagnostic studies are another class of observational studies, in which either the quality of a diagnostic method is compared to an established method (ideally a gold standard), or an investigator is compared with one or several other investigators (inter-rater comparison) or with himself at different time points (intra-rater comparison) ( e1 ). If an event is very rare (such as a rare disease or an individual course of treatment), a single-case study, or a case series, are possibilities. A case series is a study on a larger patient group with a specific disease. For example, after the discovery of the AIDS virus, the Center for Disease Control (CDC) in the USA collected a case series of 1000 patients, in order to study frequent complications of this infection. The lack of a control group is a disadvantage of case series. For this reason, case series are primarily used for descriptive purposes ( 3 ).

Epidemiological studies

The main point of interest in epidemiological studies is to investigate the distribution and historical changes in the frequency of diseases and the causes for these. Analogously to clinical studies, a distinction is made between experimental and observational epidemiological studies ( 16 , 17 ).

Interventional studies are experimental in character and are further subdivided into field studies (sample from an area, such as a large region or a country) and group studies (sample from a specific group, such as a specific social or ethnic group). One example was the investigation of the iodine supplementation of cooking salt to prevent cretinism in a region with iodine deficiency. On the other hand, many interventions are unsuitable for randomized intervention studies, for ethical, social or political reasons, as the exposure may be harmful to the subjects ( 17 ).

Observational epidemiological studies can be further subdivided into cohort studies (follow-up studies), case control studies, cross-sectional studies (prevalence studies), and ecological studies (correlation studies or studies with aggregated data).

In contrast, studies with only descriptive evaluation are restricted to a simple depiction of the frequency (incidence and prevalence) and distribution of a disease within a population. The objective of the description may also be the regular recording of information (monitoring, surveillance). Registry data are also suited for the description of prevalence and incidence; for example, they are used for national health reports in Germany.

In the simplest case, cohort studies involve the observation of two healthy groups of subjects over time. One group is exposed to a specific substance (for example, workers in a chemical factory) and the other is not exposed. It is recorded prospectively (into the future) how often a specific disease (such as lung cancer) occurs in the two groups ( figure 2a ). The incidence for the occurrence of the disease can be determined for both groups. Moreover, the relative risk (quotient of the incidence rates) is a very important statistical parameter which can be calculated in cohort studies. For rare types of exposure, the general population can be used as controls ( e6 ). All evaluations naturally consider the age and gender distributions in the corresponding cohorts. The objective of cohort studies is to record detailed information on the exposure and on confounding factors, such as the duration of employment, the maximum and the cumulated exposure. One well known cohort study is the British Doctors Study, which prospectively examined the effect of smoking on mortality among British doctors over a period of decades ( e7 ). Cohort studies are well suited for detecting causal connections between exposure and the development of disease. On the other hand, cohort studies often demand a great deal of time, organization, and money. So-called historical cohort studies represent a special case. In this case, all data on exposure and effect (illness) are already available at the start of the study and are analyzed retrospectively. For example, studies of this sort are used to investigate occupational forms of cancer. They are usually cheaper ( 16 ).

Graphical depiction of a prospective cohort study (simplest case [2a]) and a retrospective case control study (2b)

In case control studies, cases are compared with controls. Cases are persons who fall ill from the disease in question. Controls are persons who are not ill, but are otherwise comparable to the cases. A retrospective analysis is performed to establish to what extent persons in the case and control groups were exposed ( figure 2b ). Possible exposure factors include smoking, nutrition and pollutant load. Care should be taken that the intensity and duration of the exposure is analyzed as carefully and in as detailed a manner as possible. If it is observed that ill people are more often exposed than healthy people, it may be concluded that there is a link between the illness and the risk factor. In case control studies, the most important statistical parameter is the odds ratio. Case control studies usually require less time and fewer resources than cohort studies ( 16 ). The disadvantage of case control studies is that the incidence rate (rate of new cases) cannot be calculated. There is also a great risk of bias from the selection of the study population ("selection bias") and from faulty recall ("recall bias") (see too the article "Avoiding Bias in Observational Studies"). Table 1 presents an overview of possible types of epidemiological study ( e8 ). Table 2 summarizes the advantages and disadvantages of observational studies ( 16 ).

1 = slight; 2 = moderate; 3 = high; N/A, not applicable.

*Individual cases may deviate from this pattern.

Selecting the correct study type is an important aspect of study design (see "Study Design in Medical Research" in volume 11/2009). However, the scientific questions can only be correctly answered if the study is planned and performed at a qualitatively high level ( e9 ). It is very important to consider or even eliminate possible interfering factors (or confounders), as otherwise the result cannot be adequately interpreted. Confounders are characteristics which influence the target parameters. Although this influence is not of primary interest, it can interfere with the connection between the target parameter and the factors that are of interest. The influence of confounders can be minimized or eliminated by standardizing the procedure, stratification ( 18 ), or adjustment ( 19 ).

The decision as to which study type is suitable to answer a specific primary research question must be based not only on scientific considerations, but also on issues related to resources (personnel and finances), hospital capacity, and practicability. Many epidemiological studies can only be implemented if there is access to registry data. The demands for planning, implementation, and statistical evaluation for observational studies should be just as high for observational studies as for experimental studies. There are particularly strict requirements, with legally based regulations (such as the Medicines Act and Good Clinical Practice), for the planning, implementation, and evaluation of clinical studies. A study protocol must be prepared for both interventional and noninterventional studies ( 6 , 13 ). The study protocol must contain information on the conditions, question to be answered (objective), the methods of measurement, the implementation, organization, study population, data management, case number planning, the biometric evaluation, and the clinical relevance of the question to be answered ( 13 ).

Important and justified ethical considerations may restrict studies with optimal scientific and statistical features. A randomized intervention study under strictly controlled conditions of the effect of exposure to harmful factors (such as smoking, radiation, or a fatty diet) is not possible and not permissible for ethical reasons. Observational studies are a possible alternative to interventional studies, even though observational studies are less reliable and less easy to control ( 17 ).

A medical study should always be published in a peer reviewed journal. Depending on the study type, there are recommendations and checklists for presenting the results. For example, these may include a description of the population, the procedure for missing values and confounders, and information on statistical parameters. Recommendations and guidelines are available for clinical studies ( 14 , 20 , e10 , e11 ), for diagnostic studies ( 21 , 22 , e12 ), and for epidemiological studies ( 23 , e13 ). Since 2004, the WHO has demanded that studies should be registered in a public registry, such as www.controlled-trials.com or www.clinicaltrials.gov . This demand is supported by the International Committee of Medical Journal Editors (ICMJE) ( 24 ), which specifies that the registration of the study before inclusion of the first subject is an essential condition for the publication of the study results ( e14 ).

When specifying the study type and study design for medical studies, it is essential to collaborate with an experienced biometrician. The quality and reliability of the study can be decisively improved if all important details are planned together ( 12 , 25 ).

Acknowledgments

Translated from the original German by Rodney A. Yeates, M.A., Ph.D.

Conflict of interest statement

The authors declare that there is no conflict of interest in the sense of the International Committee of Medical Journal Editors.

• Open access
• Published: 15 May 2024

Factors and management techniques in odontogenic keratocysts: a systematic review

• Mario Dioguardi 1 ,
• Cristian Quarta 1 ,
• Diego Sovereto 1 ,
• Giorgia Apollonia Caloro 2 ,
• Andrea Ballini 1 ,
• Riccardo Aiuto 3 ,
• Angelo Martella 4 ,
• Lorenzo Lo Muzio 1 &
• Michele Di Cosola 1  

European Journal of Medical Research volume  29 , Article number:  287 ( 2024 ) Cite this article

Metrics details

Odontogenic keratocysts exhibit frequent recurrence, distinctive histopathological traits, a tendency towards aggressive clinical behavior, and a potential linkage to the nevoid basal cell carcinoma syndrome. The aim of this systematic review is to compile insights concerning the control of this condition and assess the effectiveness of various treatment approaches in reducing the likelihood of recurrence.

Materials and methods

The following systematic review adhered to the PRISMA guidelines. The systematic revision was registered on PROSPERO and  structured around the questions related to the population, intervention, control, outcome and study design (PICOS).

After conducting a search on the PubMed database, we initially identified 944 records. After using end-note software to remove duplicate entries, results totally with 462 distinct records. A thorough review of the titles and abstracts of these articles led to the selection of 50 papers for in-depth examination. Ultimately, following the application of our eligibility criteria, we incorporated 11 articles into our primary outcome analysis.

Among the studies examined, the most common location for these lesions was found to be in the area of the mandibular ramus and the posterior region of the mandible. In cases where the exact location wasn’t specified, the mandible emerged as the predominant site. When we considered the characteristics of these lesions in studies that mentioned locularity, most were described as unilocular in two studies, while in two other studies, the prevalence of multilocular lesions was observed. Risk factors associated with keratocyst recurrence include younger patient age, the presence of multilocular lesions, larger lesion size, and a longer anteroposterior dimension. Certain treatment methods have demonstrated a lack of relapses. These include the use of 5-fluorouracil, marsupialization, enucleation with peripheral ostectomy or resection, enucleation and curettage, as well as resection without creating continuity defects. However, it is important to note that further research is essential. Prospective studies and randomized trials are needed to collect more comprehensive evidence regarding the effectiveness of various treatment approaches and follow-up protocols for managing odontogenic keratocysts.

Clinical relevance

Odontogenic keratocysts still enter into differential diagnoses with other lesions that affect the jaw bones such as ameloblastama and other tumor forms, furthermore it is not free from recurrence, therefore the therapeutic approach to the lesion aimed at its elimination can influence both the possible recurrence and complications, knowledge of the surgical methods that offer the most predictable and clinically relevant result for the management of follow-up and recurrences.

Introduction

The odontogenic keratocyst (OKC) is a developmental cyst that originates from remnants of the dental lamina within the jawbones [ 1 ]. Several studies have reported a preference for males [ 1 , 2 , 3 ], with an incidence peak around the third decade [ 4 ] and a nearly equal distribution in other decades, with another small peak between 50 and 70 years of age [ 1 ]. It can occur in any area of the jawbones but is most commonly found in the mandible, with a particular preference for the mandibular angle extending to the mandibular ramus [ 4 ].

Diagnosis of OKC is typically  radiological. Radiographs commonly reveal well-defined radiolucent areas with  rounded or scalloped margins that are well demarcated; these areas can present as either multilocular or unilocular [ 5 ].

In the 2022 classification, OKC remains classified as a cyst; molecular studies have detected frequent mutations in the tumor suppressor gene PTCH1, a gene that activates the SHH pathway, leading to aberrant epithelial proliferation [ 1 ], sparking debates on whether OKC is a cyst or a cystic neoplasm. It was labeled as a keratocystic odontogenic tumor in 2005 [ 5 ], thus considered a cystic neoplasm, and later reclassified as a cyst in the 2017 classification [ 1 ].

Keratocysts are characterized by a high recurrence rate, specific histological features, aggressive clinical behavior, and can be associated with the nevoid basal cell carcinoma syndrome [ 6 ].

The mechanism of recurrence was proposed by Brannon [ 7 ] in 1976, suggesting it was due to three different mechanisms:

Incomplete removal of the cyst,

Growth of new keratocysts from satellite cysts,

Development of a new keratocyst in the area adjacent to the site of the primary keratocyst, interpreted as recurrence.

Odontogenic keratocysts can be treated with various surgical methods, which can be divided into conservative approaches and invasive approaches or a combination thereof [ 8 ]; in the literature, enucleation, marsupialization, resection, and the use of adjunct therapies such as Carnoy’s solution and cryotherapy are reported [ 1 , 4 , 9 ].

Despite many studies in the literature examining several therapeutic approaches in managing this lesion, it is still not clear which method provides lower recurrence rates without causing significant morbidity [ 10 ]; the purpose of this systematic review is to gather information on the management of this lesion and evaluate which treatment method results in fewer recurrences.

The following systematic review adhered to the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) protocol guidelines [ 11 ].

The systematic revision was registered on PROSPERO with number of: CRD42023480051.

The study was structured around the questions related to the population, intervention, control, outcome and study design (PICOS):

Population (P): individuals with non-syndromic or syndromic odontogenic keratocyst (initial cases) diagnosed histologically;

Intervention (I): surgical interventions for patients with odontogenic keratocystic, such as enucleation, enucleation coupled with curettage, enucleation with additional therapeutic measures (such as Carnoy's solution application, cryotherapy), marsupialization or decompression, with or without subsequent cystectomy and adjunctive therapy, and resection;

Control (C): not applicable;

Outcome (O): recurrence of KOT (Keratocystic Odontogenic Tumor) associated with distinct surgical treatments and characteristics of the keratocysts analyzed;

Study design (S): prospective randomized controlled clinical trials, controlled clinical investigations (either prospective or retrospective), and case series that explored and compared the diverse surgical approaches concerning recurrence over a suitable follow-up period (minimum of 1 year).

The formulation of the PICOS question can be summarized as follows: “What characteristics do the odontogenic keratocysts analyzed in the studies have? Which surgeries had the least recurrences during the follow-up?”.

Following the initial selection phase of records identified in various databases, potentially eligible articles were qualitatively assessed. This assessment aimed to investigate which surgical treatment was the most reliable in giving the least number of recurrences.

Eligibility criteria

This text discusses the process of selecting research articles for a study related to the recurrence of KOT associated with distinct surgical interventions, such as enucleation, with or without curettage and additional therapeutic measures, marsupialization or decompression, with or without subsequent cystectomy and adjunctive therapy, and resection.

The process involved initially identifying potentially eligible articles based on their abstracts. These articles were then subjected to a thorough examination of their full content to determine their suitability for both qualitative and quantitative analyses.

The criteria for including articles in the full-text analysis were studies relating to KOT treatments in which the number of recurrences and the general characteristics of the lesions are reported.

The exclusion criteria were applied to exclude the following types of studies:

Studies involving animals or conducted in a laboratory setting (in vitro)

Letters to the editor

Articles that did not adequately specify the type of surgical method used

Studies with an inadequate follow-up period (less than 1 year)

Clinical studies conducted more than 30 years ago (only studies from the last 30 years were included because classifications and surgical and therapeutic techniques have been constantly changing and improving, with generally earlier diagnoses and more suitable treatments with lower recurrence rates. Therefore, to avoid increasing the heterogeneity of the included studies and to prevent bias in the aggregated treatment results, the reviewers collectively decided to include only studies from 1989 onwards)

Review articles

Research methodology

Studies have been identified through bibliographic research on electronic databases.

The literature search was conducted on the search engines “PubMed”. The search on the providers was conducted between 02.09.2023 and 12.09.2023, and the last search for a partial update of the literature was conducted on 18.09.2023.

The following search terms were used on PubMed: “KOT” AND “Recurrence” (37 records), “odontogenic keratocyst marsupialization” (285 records), “odontogenic keratocyst enucleation” (622 records).

Screening methodology

The selection criteria and their combinations for searching were established prior to the record identification stage through mutual consensus between the two reviewers  (M.D. and M.D.C.) responsible for choosing potentially eligible articles. Following this, the records acquired were then assessed separately by the two independent reviewers, with a third reviewer  (A.B.) serving as an decision-maker in cases of uncertainty.

The screening process involved evaluating the titles and abstracts of articles, and in cases where there was uncertainty, a more in-depth examination of the article's content was conducted to remove records that were not relevant to the topics under review.

Following a search in the PubMed database, 944 records were initially located. Subsequently, after applying end-note software to eliminate duplications, 462 unique records remained. Upon reviewing the titles and abstracts of these articles, after this initial screening, a total of 50 articles were selected for a thorough examination of their full text by two reviewers. From these 50 articles, the ones that met the criteria for qualitative analysis for the outcome were identified. Finally, applying the eligibility criteria, we included 16 articles for the primary outcome analysis (Fig.  1 ).

Flowchart of the different phases of the systematic review

Study characteristics and data extraction

The included studies for the quantitative analysis were: Maurette et al. [ 12 ]; Nakamura et al. [ 13 ]; Bataineh and al Qudah [ 14 ]; Leung et al. [ 15 ]; Kolokythas et al. [ 9 ]; Berge et al. [ 16 ]; Pogrel and Jordan, [ 17 ]; Tabrizi et al. [ 18 ]; Zecha et al. [ 19 ]; Moellmann et al. [ 20 ]; Caminiti et al.[ 21 ], Stoelinga [ 4 ]; Dammer et al. [ 2 ]; Marker et.al. [ 22 ]; August et al.[ 23 ]; Brøndum and Jensen [ 24 ].

The extracted data included the journal (author, data, and reference); study design; number of patients (males/females); number of lesions; number of lesions associated with basal cell naevus syndrome (BCNS); mean age (range); site where the lesions were diagnosed; locularity (multilocular or unilocular); type of treatment; mean follow-up.

Finally, for each study, the number of relapses relating to each treatment was observed.

The data extracted are shown in Table  1 and 2 .

Risk of bias

The risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) for cohort studies, assigning a value from 0 to 3 for each item, the assessment of the risk of bias was assessed by the first reviewer, and was deemed acceptable for all included studies, details are shown in Table  3

The articles included in this review analyze different types of keratocyst treatment and lesion characteristics.

Among the first to coin the term 'odontogenic keratocyst' was Philipsen in 1956, who, in a literature review, proposed the term 'odontogenic keratocyst' for all odontogenic cysts that exhibit epithelial keratinization [ 25 ].

The terminology, as adopted by Pindborg in 1962 and 1963 and also used by Toller in 1967, replaced the term ‘primordial cyst’ with ‘odontogenic keratocyst’, identifying 33 odontogenic keratocysts (study not included in this review) [ 26 , 27 , 28 , 29 ]

One of the early retrospective studies conducted on odontogenic keratocysts was performed by Pindborg, who retrospectively identified 26 keratinized cysts out of a total of 791 odontogenic cysts in 1962 [ 27 ].

The odontogenic keratocysts are often described in literature as benign cysts occurring within the bones, and they exhibit a propensity for infiltrative and aggressive growth patterns. These cysts make up an estimated 2–21.8% of all cysts affecting the jaw [ 24 , 25 ]. Moreover, there is a potential association between these cysts and genetic mutations, notably linked to nevoid basal cell carcinoma syndrome (NBCCS), a condition characterized by the presence of multiple OKCs in the jaw region [ 26 ]; this is also found in one of the articles included in this review [ 13 ], while in others the association was not specified [ 14 , 17 ] or there was no association at all [ 9 , 12 , 15 , 16 , 18 , 19 , 20 , 21 ]; many of these studies have placed the correlation with this syndrome in the exclusion criteria, as in the patients who are affected by it the probability that these cysts will reappear is high, and therefore it would be difficult to distinguish a recurrent event from the appearance of a new cyst [ 21 ]

These cysts are notorious for their tendency to grow aggressively in their immediate prossimity and for having a notably high rate of recurrence. Several contributing factors underpin this recurrence, including the use of inadequate treatment methods, incomplete elimination of the cyst, a high rate of cell division (mitotic index) within the cyst's epithelial cells, a larger cyst size, and the specific location of the cyst. The latter factor becomes especially problematic if it is challenging to access surgically [ 25 , 27 ]. Although they exhibit hostile conduct, OKC generally induce limited bone enlargement as they tend to proliferate within the intramedullary region, effectively growing within the bone [ 30 ].

Substantial lesions marked by substantial cortical plate erosion and engagement with neighboring structures may not produce symptoms in individuals, resulting in a delayed diagnosis [ 31 ].

The most frequent location of the lesions in the studies analyzed is at the level of the mandibular ramus and in the posterior mandible [ 12 , 13 , 14 , 15 , 16 , 19 ], and where the precise localization of the lesions is not specified, the mandible is the most frequent site [ 9 , 18 , 20 , 21 ]. In the studies in which locularity is specified among the characteristics of the lesions, the majority of the lesions were unilocular in two studies [ 13 , 21 ], while in two other studies the quantity of multilocular lesions was greater [ 14 , 15 ]. Younger patient age, multilocularity of the lesion, larger size, and longer anteroposterior dimension of the keratocyst have been identified as risk factors for keratocyst recurrence [ 15 ].

The treatments that have not had relapses are that with 5-fluorouracil [ 21 ], marsupialization [ 13 , 17 , 18 ], enucleation with peripheral ostectomy or resection [ 9 ], enucleation and curettage [ 12 ], and resection without continuity defects [ 14 ].

Decompression has been studied in 5 articles [ 9 , 12 , 22 , 23 , 24 ]; this method has the advantage of having minimal surgical morbidity and reduced risk to anatomical structures associated with the lesion, such as developing nerves or teeth [ 22 ]. Decompression and marsupialization techniques involve creating a communication between the cyst and the oral cavity, relieving pressure and allowing cyst shrinkage and bone apposition [ 12 ]. Clinical and radiographic resolution of OKCs after marsupialization is relatively rapid, typically within 19 months [ 17 ]. In studies where marsupialization alone was used for treatment, there were no relapses in two studies [ 17 , 18 ], while Zecha et al. [ 19 ] found four cases of relapse in ten patients treated with marsupialization.

Decompression and marsupialization are non-invasive treatment options for keratocysts, but require patient cooperation, including regular irrigation and follow-up [ 17 , 18 ].

Topical 5-fluorouracil is known for its antiproliferative effects on keratocystic epithelium and satellite cysts; furthermore, its use has some advantages, such as technical ease and the lack of neurotoxicity [ 21 ] and, in the only study of this review in which it were used in the treatment, there were no relapses [ 21 ].

Other treatment modalities used to reduce keratocyst recurrence are resection of the affected maxillary segment and enucleation with additional treatments such as curettage or ostectomy [ 9 , 14 ], which in these studies have not given recurrences, which, as regards resection, is a similar result to other studies in the literature [ 4 , 8 , 32 ]. However, despite the remarkably high success rate of this approach, resection is not widely embraced as a standard procedure, primarily due to concerns regarding its aggressiveness and associated postoperative complications, including morbidity [ 33 ]. Enucleation, often combined with curettage (the process of scraping the walls of the lesion cavity) or ostectomy (the surgical removal of bone tissue), is commonly used to treat keratocysts; although a more conservative treatment than resection, the effectiveness of this modality may be limited in cases where vital structures, such as the exposed inferior alveolar nerve, are at risk or when there is a perforation of the bony wall exposing the overlying mucosal tissue [ 15 ].

Carnoy’s solution was used in three studies [ 15 , 20 , 21 ] and of these studies one used the modified Carnoy’s solution [ 21 ]. The FDA avoid the use of Carnoy's solution containing chloroform in the United States, leading to the adoption of a modified formula. However, the modified formula has been found to have a higher relapse rate, suggesting the potential role that traditional Carnoy’s solution may have in treatment [ 34 ].

There are risk factors associated with the recurrence of odontogenic keratocyst, such as age, multilocularity, lesion size and radiographic characteristics.

The various surgical techniques used to treat keratocysts have potential benefits, including preservation of jaw function, reduction of the potential for recurrence, and eradication of the cystic lesion.

Marsupialization or decompression are advantageous conservative treatment options that aim to minimize surgical invasiveness while effectively managing keratocysts.

Long-term follow-up and monitoring of patients treated for these lesions is important to detect recurrence early.

There is a need for further research, prospective studies and randomized trials to gather more evidence on the effectiveness of different treatment methods and follow-up protocols for odontogenic keratocysts.

Availability of data and materials

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

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Mario Dioguardi, Cristian Quarta, Diego Sovereto, Andrea Ballini, Lorenzo Lo Muzio & Michele Di Cosola

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Conceptualization, M.D.and C.Q.; methodology, M.D.; software, M.D. and D.S.; validation, M.D. and A.B.; formal analysis, M.D.; investigation, M.D. and C.Q.; data curation, M.D. and D.S.; bibliographic reserach, C.Q. and R.A.; writing—original draft preparation, M.D. and C.Q.; writing—review and editing, M.D. and A.B.; visualization, D.S and M.D..; supervision L.L.M.., and M.D.C.; Critical revision of the manuscript for important intellectual content M.D., C.Q.; and A.B.; Bioinformatic analysis review, A.M.; project administration, L.L.M. All authors have read and agreed to the published version of the manuscript.

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Dioguardi, M., Quarta, C., Sovereto, D. et al. Factors and management techniques in odontogenic keratocysts: a systematic review. Eur J Med Res 29 , 287 (2024). https://doi.org/10.1186/s40001-024-01854-z

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Received : 26 January 2024

Accepted : 22 April 2024

Published : 15 May 2024

DOI : https://doi.org/10.1186/s40001-024-01854-z

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