research nurse literature

Nursing: How to Write a Literature Review

• Traditional or Narrative Literature Review

Getting started

1. start with your research question, 2. search the literature, 3. read & evaluate, 4. finalize results, 5. write & revise, brainfuse online tutoring and writing review.

• RESEARCH HELP

The best way to approach your literature review is to break it down into steps.  Remember, research is an iterative process, not a linear one.  You will revisit steps and revise along the way.  Get started with the handout, information, and tips from various university Writing Centers below that provides an excellent overview.  Then move on to the specific steps recommended on this page.

• UNC- Chapel Hill Writing Center Literature Review Handout, from the University of North Carolina at Chapel Hill.
• University of Wisconsin-Madison Writing Center Learn how to write a review of literature, from the University of Wisconsin-Madison.
• University of Toronto-- Writing Advice The Literature Review: A few tips on conducting it, from the University of Toronto.
• Begin with a topic.
• Understand the topic. 
• Familiarize yourself with the terminology.  Note what words are being used and keep track of these for use as database search keywords. 
• See what research has been done on this topic before you commit to the topic.  Review articles can be helpful to understand what research has been done .
• Develop your research question.  (see handout below)
• How comprehensive should it be? 
• Is it for a course assignment or a dissertation? 
• How many years should it cover?
• Developing a good nursing research question Handout. Reviews PICO method and provides search tips.

Your next step is to construct a search strategy and then locate & retrieve articles.

•  There are often 2-4 key concepts in a research question.
• Search for primary sources (original research articles.)
• These are based on the key concepts in your research question.
• Remember to consider synonyms and related terms.
• Which databases to search?
• What limiters should be applied (peer-reviewed, publication date, geographic location, etc.)?

Review articles (secondary sources)

Use to identify literature on your topic, the way you would use a bibliography.  Then locate and retrieve the original studies discussed in the review article. Review articles are considered secondary sources.

• Once you have some relevant articles, review reference lists to see if there are any useful articles.
• Which articles were written later and have cited some of your useful articles?  Are these, in turn, articles that will be useful to you? 
• Keep track of what terms you used and what databases you searched. 
• Use database tools such as save search history in EBSCO to help.
• Keep track of the citations for the articles you will be using in your literature review. 
• Use RefWorks or another method of tracking this information. 
• Database Search Strategy Worksheet Handout. How to construct a search.
• TUTORIAL: How to do a search based on your research question This is a self-paced, interactive tutorial that reviews how to construct and perform a database search in CINAHL.

The next step is to read, review, and understand the articles.

• Start by reviewing abstracts. 
• Make sure you are selecting primary sources (original research articles).
• Note any keywords authors report using when searching for prior studies.
• You will need to evaluate and critique them and write a synthesis related to your research question.
• Consider using a matrix to organize and compare and contrast the articles . 
• Which authors are conducting research in this area?  Search by author.  
• Are there certain authors’ whose work is cited in many of your articles?  Did they write an early, seminal article that is often cited?
• Searching is a cyclical process where you will run searches, review results, modify searches, run again, review again, etc. 
• Critique articles.  Keep or exclude based on whether they are relevant to your research question.
• When you have done a thorough search using several databases plus Google Scholar, using appropriate keywords or subject terms, plus author’s names, and you begin to find the same articles over and over.
• Remember to consider the scope of your project and the length of your paper.  A dissertation will have a more exhaustive literature review than an 8 page paper, for example.
• What are common findings among each group or where do they disagree? 
• Identify common themes. Identify controversial or problematic areas in the research. 
• Use your matrix to organize this.
• Once you have read and re-read your articles and organized your findings, you are ready to begin the process of writing the literature review.

2. Synthesize.  (see handout below)

• Include a synthesis of the articles you have chosen for your literature review.
• A literature review is NOT a list or a summary of what has been written on a particular topic. 
• It analyzes the articles in terms of how they relate to your research question. 
• While reading, look for similarities and differences (compare and contrast) among the articles.  You will create your synthesis from this.
• Synthesis Examples Handout. Sample excerpts that illustrate synthesis.

Regis Online students have access to Brainfuse. Brainfuse is an online tutoring service available through a link in Moodle. Meet with a tutor in a live session or submit your paper for review.

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In this Guide

• Access Key Resources

Overview & Steps for Searching the Literature

Step 1: formulate a research question, step 2: identify primary concepts & gather synonyms, step 3: locate medical subject headings mesh (database-specific indexing terms), step 4: combine search terms using boolean operators, step 5: apply search limits or filters, databases to search journal articles, useful websites and handouts, lane classes and tutorials.

• Find Journal Articles
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Literature searching and literature reviews are often used interchangeably but are two different steps in the research process guided by EBM.

• Literature search  is searching the literature for some studies. A search strategy is developed for one or more biomedical databases to search the literature, and gather relevant studies.
• Literature review  is reviewing the studies which have been identified through a literature search. As part of the literature review, the retrieved articles are analyzed and critically appraised. 

The following steps will help guide you through the process of literature searching in PubMed. Though we are focusing on PubMed, these steps can be used across bibliographic databases. 

• Formulate a research question
• Identify primary concepts & gather synonyms
• Locate Medical Subject Headings MeSH (database-specific indexing terms)
• Combine search terms using Boolean operators
• Apply search limits or filters

To learn more about the literature searching process, you can explore Lane Library's Literature Searching guide .

The first step in literature searching involves taking a clinical topic or problem and formulating it into a well-defined, answerable question. The development of a clear and focused question will help to streamline the searching process to locate the literature needed to begin answering the question and addressing the clinical problem. A well-defined, answerable question: 

• defines the focus of your literature search
• identifies the appropriate study design and methods
• makes searching for evidence simpler and more effective
• helps you identify relevant results and separate relevant results from irrelevant ones

What type of question are you asking?

Therapy:  effectiveness/risk of a certain treatment

Diagnosis : accuracy/usefulness of a diagnostic test/tool; application to a specific patient  

Prognosis : probable outcome, progression, or survivability of a disease or condition; likelihood of occurrence

Etiology/Harm : cause or risk factors for a disease or condition; questions about the harmful effect of an intervention or exposure on a patient

Tips for formulating a good question:

• The question is directly relevant to the most important health issue for the patient;
• The question is focused and when answered, will help the patient the most;
• The question is phrased to facilitate a targeted literature search for precise answers

Adopted from CEBM:  what makes a good clinical question   and  Center for Evidence Based Medicine: Asking focused questions  

PICO Framework

In EBM, following the PICO framework is a common way to create a focused and answerable question from a general topic. PICO is a mnemonic used to describe the four elements of a sound clinical foreground question.

PICO  stands for:

• P  - Population/Patient/Problem
• I  - Intervention  
• C  - Comparison or Control
• O  - Outcome

Alternative formats of PICO include PICOT and PICOTT:

• T  - Time
• T  - Type of question
• T  - Type of study

What is the effectiveness of Prozac vs Zoloft in treating adolescents with depression?

P : adolescents with depression

Using PICO to formulate your research question makes it easier to follow the next step in the literature searching process -- identifying primary concepts & gathering synonyms.

Primary concepts for your research question can be identified using the PICO formula from Step 1. Each of the PICO elements can form a primary concept. If your PICO does not have a  C omparison or  O utcome, or if the Outcome is broad or vague, it is okay to leave out these concepts. Sometimes, one of the elements in the PICO framework will include more than one primary concept. For example, the Population for our example includes the concept of adolescents and the concept of depression.

P :  adolescents  with  depression

I :  Prozac

C :  Zoloft

For each primary concept identified, make a list of other terms with the same or related meaning (synonyms). It is important to gather synonyms, because

Terms have different spellings, plural forms, and acronyms

Concepts are described inconsistently across time, geographies, or even among researchers

Terms have the same/close meaning, disciplinary jargon

Umbrella terms vs specific names for issues, interventions, or concepts

These terms will form the keywords of your search strategy. 

Tips for finding synonyms:

• Do a quick search to find a relevant article or two. Look at the words used in the article titles and abstracts.
• Think of specific examples or types
• Use background information to help brainstorm (e.g. UpToDate, DynaMed, textbooks)
• Explore the entry terms and related subject headings in MeSH (see Step 3)

Remember that building a search strategy is iterative. As you learn more about your topic, you can add more keywords to your search to broaden your results, or remove keywords if you are finding too many results.

What is Mesh?

Databases like PubMed use subject headings or controlled vocabularies to index (or label) articles. Subject headings are standardized terms for describing what the articles are about. Subject headings are specific to databases, and in PubMed, they are called Medical Subject Headings or MeSH. MeSH terms are structured hierarchically in a tree structure, and when you search a MeSH term, you search automatically includes all the terms that fall beneath it in the tree. Indexers add MeSH terms to journal article records in PubMed to reflect their subject content. 

MeSH terms are useful in a search to aid in locating synonyms and reduce term ambiguities. It facilitates the retrieval of relevant articles even when authors use different words or spelling to describe the same concept. For instance, using the MeSH term "Blood Pressure" will also find articles that use "pulse pressure," "diastolic pressure," and "systolic pressure."

Since MeSH terms are organized in hierarchies or MeSH trees, it also facilitates the searching for broad and narrow concepts. For instance, the MeSH term "Domestic Violence" will retrieve articles containing narrower topics such as "child abuse," "elder abuse," and "spouse abuse." But you can also expand the search, and move to a broader level, such as "Violence."

To look up a MeSH term, click on " MeSH Database " on PubMed's homepage. Type your concept into the search bar. The MeSH database will return appropriate MeSH (terms) if there are any. Not every concept will have a matching MeSH term. Remember to search for one concept at a time.

adolescents => "Adolescent"[Mesh]

Prozac => "Fluoxetine"[Mesh]

Zoloft => "Sertraline"[Mesh]

depression => "Depression"[Mesh]

When you search for a MeSH term in PubMed, use the [Mesh] tag following your search term to specify where to search for the term in the PubMed record.

You can also locate MeSH terms in PubMed by finding a relevant article and scrolling to the heading "MeSH terms" at the bottom of the article. This only works for articles that have been indexed. 

Other PubMed Search Tags

In addition to searching specifically for MeSH terms, you can also use search tags to search for keywords in particular fields of the PubMed record. When you search in PubMed, you are automatically looking for your keywords in all the record fields. Sometimes this might be too broad and bring back too many search results. You can experiment with field tags like [ti] to look for keywords only in the title or [tiab] to look for keywords only in the title or abstract. Explore all of the available search tags and reach out to your liaison librarian if you have questions using search tags.

Now that you've identified keywords for your concepts (step 2) and related MeSH terms (step 3), you can combine your search terms with Boolean Operators to build your search strategy.

Boolean Operators are a set of commands that can be used in almost every search engine, database, or online catalog to provide more focus to a search. The most basic Boolean commands are  AND  and  OR . In PubMed, you can use Boolean Operators to combine search terms, and narrow or broaden a set of results.

Narrow Results with AND

Use AND in a search to narrow your results. It tells the search engine to return results that contain ALL the search terms in a record.

adolescents AND depression

Note: Both the words  adolescents  and  depression  will be present in every record in the results.

Broaden Results with OR

Use OR in a search to broaden your results by connecting similar concepts (synonyms). It tells the search engine to return results that contain ANY of the search terms in a record.

adolescents OR youth OR teenagers

Note: Search results need to have at least one of the words  adolescents  or  youth  or teenagers .

Use parentheses ( ) to keep concepts that are alike together, and to tell the database to look for search terms in the parentheses first. It is particularly important when you use the Boolean Operator “OR”.

(adolescents OR youth OR teenagers) AND depression

Tip: You can use" Advanced Search " option in PubMed to help build your search strategy. Search concept by concept, adding ORs between all your keywords and MeSH terms for each concept. After you complete a search for each concept, you can use the "Actions" menu in the Advance Search Search History table to add combine your concept searches with AND. This will look for the overlap between your concept searches and help you avoid nesting errors.

Full Search Strategy Example:

("Adolescent"[Mesh] OR adolescent OR teen OR teens OR teenager OR youth OR youths) AND ("Depression"[Mesh] OR depressive OR depression) AND ("Fluoxetine"[Mesh] OR prozac OR fluoxetin* OR sarafem) AND ("Sertraline"[Mesh] OR zoloft OR sertraline OR altruline OR lustral OR sealdin OR gladem)

You can filter your search results using the PubMed filters in the left sidebar. You can filter by study type to look for the highest level of evidence to answer your question. You can also use date filters or filter to English language materials. If the study type you are looking for is not listed, select "Additional Filters" at the bottom of the left sidebar to see all the available options.

Note: Many PubMed filters depend on indexing, and using filters will exclude articles that do not have indexing.

You can also try PubMed's Clinical Queries to narrow your search results to the type of clinical questions you are asking (Therapy, Diagnosis, etc.).

Getting Too Many Results?

If your search retrieves too many results, you can limit the search results by

• replacing general (e.g. vague or broad) terms with more specific ones
• including additional concepts in your search
• using PubMed's sidebar filters on the left panel of the results page to restrict results by publication date, article type, population, and more

Getting Too Few Results?

If your search returns too few results, you can expand your search by

• browsing the  Similar Articles  on the abstract page for a citation to see closely related articles generated by PubMed's algorithm
• Removing specific or extraneous terms from the search string
• Using alternative terms to describe a similar concept used in the search
• CINAHL (Cumulative Index to Nursing & Allied Health) Nursing and Allied Health Literature including nursing specialties, speech and language pathology, nutrition, general health, and medicine.

Provides fulltext access to Lane's resources. Contains coverage of over 5000 journals and more than 35.5 million citations for biomedical articles, including, but not limited to, clinical trials, systematic reviews, case reports, and clinical practice guidelines.

• Embase Biomedical and pharmacological abstracting and indexing database of published literature that contains over 32 million records from over 8,500 currently published journals (1947-present) and is noteworthy for its extensive coverage of the international pharmaceutical and alternative/complementary medicine literature.
• Scopus Largest abstract and citation database of peer-reviewed literature featuring scientific journals, books and conference proceedings.
• Web of Science Multidisciplinary coverage of over 10,000 high-impact journals in the sciences, social sciences, and arts and humanities, as well as international proceedings coverage for over 120,000 conferences. Features systematic reviews that summarize the effects of interventions and makes a determination whether the intervention is efficacious or not.
• Joanna Briggs Institute Evidence Based Practice Database Provides evidence-based health information prepared by expert reviewers at Joanna Briggs Institute (JBI). It includes several databases: Best Practice Information Sheets, Consumer Information Sheets, Evidence Summaries, Recommended Practices, Systematic Review Protocols, Systematic Reviews, and Technical Reports.
• Cochrane Library Evidence-based collection of information from randomized controlled trials that contain different types of high-quality, independent systematic reviews conducted by the Cochrane Review Groups.
• PsycINFO Provides systematic coverage of the psychological literature from the 1800s to the present through articles, book chapters and dissertations.
• PsycTESTS Provides downloadable access to psychological tests, measures, scales, and other assessments as well as descriptive and administrative information. It includes both published and unpublished tests developed by researchers but not made commercially available.
• ERIC (Education Resources Information Center) Citations and abstracts to journal and report literature in all aspects of educational research. Access Instructions. . . less... Also available through EBSCO and ProQuest

Literature Searching Handouts and Checklist

• Literature searching in PubMed cheat sheet
• Search syntax for common databases cheat sheet

Evidence-Based Research Organizations & Repositories

• Center for Evidence-Based Medicine (CEBM)
• Cochrane Evidence Essentials
• Joanna Briggs Institute Evidence-Based Practice Resources
• John's Hopkins Nursing Center for Evidence-Based Practice
• Ohio State's Fuld Institute for EBP
• Oncology Nursing Society - Evidence-Based Practice Learning Library
• Sigma Repository It is a profession-based online platform that freely disseminates nursing research, research-related materials, clinical materials related to evidence-based practice and quality improvements, and educational materials.
• NLM PubMed Online Training PubMed training materials by the National Library of Medicine (NLM)
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Reviews of Literature in Nursing Research: Methodological Considerations and Defining Characteristics

Affiliation.

• 1 School of Nursing, Queen's University, Kingston, Ontario, Canada (Ms Silva and Drs Woo, Galica, Wilson, and Luctkar-Flude); School of Nursing, Federal University of Santa Catarina, Santa Catarina, Brazil (Dr Padilha and Ms Petry); and Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada (Dr Silva E Silva).
• PMID: 35213877
• DOI: 10.1097/ANS.0000000000000418

Despite the availability of guidelines about the different types of review literature, the identification of the best approach is not always clear for nursing researchers. Therefore, in this article, we provide a comprehensive guide to be used by health care and nursing scholars while choosing among 4 popular types of reviews (narrative, integrative, scoping, and systematic review), including a descriptive discussion, critical analysis, and decision map tree. Although some review methodologies are more rigorous, it would be inaccurate to say that one is preferable over the others. Instead, each methodology is adequate for a certain type of investigation, nursing methodology research, and research paradigm.

Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

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Conflict of interest statement

The authors have no conflict of interest to declare.

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• Ingham-Broomfield B. A nurses' guide to the hierarchy of research designs and evidence. Aust J Adv Nurs. 2016;33(3):38–43.
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What is a Literature Review?

A literature review is an essay that surveys, summarizes, links together, and assesses research in a given field. It surveys the literature by reviewing a large body of work on a subject; it summarizes by noting the main conclusions and findings of the research; it links together works in the literature by showing how the information fits into the overall academic discussion and how the information relates to one another; it assesses the literature by noting areas of weakness, expansion, and contention. This is the essentials of literature review construction by discussing the major sectional elements, their purpose, how they are constructed, and how they all fit together.

All literature reviews have major sections:

• Introduction: that indicates the general state of the literature on a given topic;
• Methodology: an overview of how, where, and what subject terms used to conducted your search so it may be reproducable
• Findings: a summary of the major findings in that field;
• Discussion: a general progression from wider studies to smaller, more specifically-focused studies;
• Conclusion: for each major section that again notes the overall state of the research, albeit with a focus on the major synthesized conclusions, problems in the research, and even possible avenues of further research.

In Literature Reviews, it is Not Appropriate to:

• State your own opinions on the subject (unless you have evidence to support such claims).  
• State what you think nurses should do (unless you have evidence to support such claims).
• Provide long descriptive accounts of your subject with no reference to research studies.
• Provide numerous definitions, signs/symptoms, treatment and complications of a particular illness without focusing on research studies to provide evidence and the primary purpose of the literature review.
• Discuss research studies in isolation from each other.

Remember, a literature review is not a book report. A literature review is focus, succinct, organized, and is free of personal beliefs or unsubstantiated tidbits.

• Types of Literature Reviews A detailed explanation of the different types of reviews and required citation retrieval numbers

Outline of a Literture Review

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How to Search

Need more articles, but can't seem to find the right ones? Try these techniques!

Backwards searching: Once you find a relevant article, check the reference list at the end of the article. This will help you find other pertinent articles. 

Forward searching : Once you find a relevant article, look at whether it has been cited in more-recent research. If a researcher cited it, it is likely that their paper will also relate to your topic. ResearchGate is a community for students and researchers. It lists where each of their publications have been cited, if at all. This can be found under the "citations" tab that pops up when you click on any publication. 

When stuck, ask yourself, "What else is related to my topic?"

Get creative! You might find useful literature that you did not initially anticipate.

Fonseca, M. (2013, November 4) 5 tips to write a great literature review. https://www.editage.com/insights/5-tips-to-write-a-great-literature-review?refer=scroll-to-1-article&refer-type=article

What is a Literature Review?

"A literature review is a critical summary of all the published works on a particular topic" (Fonseca, 2013). A literature review provides background for your paper by quickly bringing the reader up-to-date on relevant findings, controversies, and dilemmas. It is the author's chance to "set the scene" and demonstrate why their topic is of interest to academia. In your literature review, you will describe "where your project comes from and how it fits in with existing knowledge" (Lloyd, 2017-2018). Further, you will provide "an argument for why your project makes a valuable contribution" (Lloyd, 2017-2018).

References: 

Lloyd, C.(2017-2018). Literature reviews for sociology senior theses . [PowerPoint Slides]. https://socthesis.fas.harvard.edu/files/socseniorthesis/files/pres-litreview.pdf

Step One: Define Your Research Question

What are you trying to determine for your literature review? What specifically do you want to learn more about? Choose a topic that you are genuinely interested in. Next, conduct a broad search on it. Determine what trending and popular research is available, then narrow your topic down. You can refine it by one or more of the following:

• Geographic location
• Time period
• Discipline/field of study, etc.

Research terms will help define your question.

• A broad question might be something like: What is the homeless population like?
• A narrow and specific question may include: What social and political factors have affected the growth of the middle-aged homeless population in Toronto within the past five years?

Once you have determined an appropriate research question/topic, move on to planning your approach.

Dermody, K., Literature Reviews. (2020, January 23). Retrieved from https://learn.library.ryerson.ca/literaturereview.

Step Two: Plan Your Approach 

After you have landed a research question, ask yourself "Which specific terms will I use, and where am I going to begin?" Determine what kind of literature you want to look at, whether it be journal articles, books, electronic resources, newspapers, or even other literature reviews on similar topics.

Your keywords are the main concepts or ideas of your paper.  For example, the keywords for a paper on “youth employment in Canada” would be:

Use synonyms: Often there are multiple ways to express the same concept. Make sure to use synonyms in your research. For instance, "employment" can be researched as:

Lastly, use “ AND ” and “ OR .” By bridging your truncated keywords and synonyms with the capitalized search words “AND” and “OR” (known as Boolean operators), you can search for multiple concepts effectively. For more information, visit the "electronic resources" tab of this research guide. There is a box on Boolean operators. 

Step Four: Analyze Material

When searching for material, it is important to analyze your sources for credibility, accuracy, currency, and authenticity. Ask these questions when analyzing a source:

• What is the purpose of the work?
• How current is it?
• Who is the author? 
• What are the author's biases?
• Is this work peer reviewed? 
• How accurate is this information? What facts/empirical evidence support it?
• What time frame are you looking at for your literature review, and does the work fall within that range?

Step Five: Manage Your Results 

After analyzing your research and determining what sources you want to use, it's important to keep track of what you have looked through. Keep a list of the following:

• What searches you have completed.
• Which ones were successful and unsuccessful.
• What databases you used.
• What sources you want to use for your literature review.
• What else you may want to search for next.

You can do this using software such as Zotero , Mendeley , and EndNote .

Congratulations! You are making progress towards an exceptional literature review.

Literature Review vs. Annotated Bibliography  Both a literature review (A.K.A. literature synthesis) and an annotated bibliography summarize the existing body of knowledge on a given topic.

What is the difference between a literature review and an annotated bibliography?  Unlike literature reviews, annotated bibliographies summarize entire research articles. An annotated bibliography looks like this:

Annotated Bibliography

•    Summarizes each article separately.

o    First, students discuss article one, then two, etc.  o    Topic: Blood Donation

• Paragraph 1: Bonnie and Clyde (2019) wrote "this" on blood donation.
• Paragraph 2: Rose and Jack (1997) wrote "this" on blood donation.
• Paragraph 3: Mary-Kate and Ashley (2001) wrote "this" on blood donation.
• Result: Multiple summaries of individual research articles (Lloyd, 2017-2018).

•    Describes the existing body of knowledge by integrating and synthesizing the literature to create something new.

o     Topic: Blood Donation

• Paragraph 1: Information/research findings on red blood cells pulled from multiple sources.
• Paragraph 2: Information/research findings on platelets pulled from multiple sources.
• Paragraph 3: Information/research findings on white blood cells pulled from multiple sources.
• Paragraph 4: Information/research findings on the drawbacks of donating blood from multiple sources (Lloyd, 2017-2018).
• Result: The author points out "themes, concepts, gaps and disagreements" between articles (Hofer, Hanick & Townsend, 2019, p. 216). Students use these to describe the existing body of knowledge on their topic one concept at a time. 

References:

Hofer, A. R., Hanick S. L., & Townsend, L. (2019). Designing activities for conceptual teaching. Transforming information literacy instruction: Threshold concepts in theory and practice. (p. 209-224). Libraries Unlimited.

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Literature Review Overview

What is a Literature Review? Why Are They Important?

A literature review is important because it presents the "state of the science" or accumulated knowledge on a specific topic. It summarizes, analyzes, and compares the available research, reporting study strengths and weaknesses, results, gaps in the research, conclusions, and authors’ interpretations.

Tips and techniques for conducting a literature review are described more fully in the subsequent boxes:

• Literature review steps
• Strategies for organizing the information for your review
• Literature reviews sections
• In-depth resources to assist in writing a literature review
• Templates to start your review
• Literature review examples

Literature Review Steps

Graphic used with permission: Torres, E. Librarian, Hawai'i Pacific University

1. Choose a topic and define your research question

• Try to choose a topic of interest. You will be working with this subject for several weeks to months.
• Ideas for topics can be found by scanning medical news sources (e.g MedPage Today), journals / magazines, work experiences, interesting patient cases, or family or personal health issues.
• Do a bit of background reading on topic ideas to familiarize yourself with terminology and issues. Note the words and terms that are used.
• Develop a focused research question using PICO(T) or other framework (FINER, SPICE, etc - there are many options) to help guide you.
• Run a few sample database searches to make sure your research question is not too broad or too narrow.
• If possible, discuss your topic with your professor. 

2. Determine the scope of your review

The scope of your review will be determined by your professor during your program. Check your assignment requirements for parameters for the Literature Review.

• How many studies will you need to include?
• How many years should it cover? (usually 5-7 depending on the professor)
• For the nurses, are you required to limit to nursing literature?

3. Develop a search plan

• Determine which databases to search. This will depend on your topic. If you are not sure, check your program specific library website (Physician Asst / Nursing / Health Services Admin) for recommendations.
• Create an initial search string using the main concepts from your research (PICO, etc) question. Include synonyms and related words connected by Boolean operators
• Contact your librarian for assistance, if needed.

4. Conduct searches and find relevant literature

• Keep notes as you search - tracking keywords and search strings used in each database in order to avoid wasting time duplicating a search that has already been tried
• Read abstracts and write down new terms to search as you find them
• Check MeSH or other subject headings listed in relevant articles for additional search terms
• Scan author provided keywords if available
• Check the references of relevant articles looking for other useful articles (ancestry searching)
• Check articles that have cited your relevant article for more useful articles (descendancy searching). Both PubMed and CINAHL offer Cited By links
• Revise the search to broaden or narrow your topic focus as you peruse the available literature
• Conducting a literature search is a repetitive process. Searches can be revised and re-run multiple times during the process.
• Track the citations for your relevant articles in a software citation manager such as RefWorks, Zotero, or Mendeley

5. Review the literature

• Read the full articles. Do not rely solely on the abstracts. Authors frequently cannot include all results within the confines of an abstract. Exclude articles that do not address your research question.
• While reading, note research findings relevant to your project and summarize. Are the findings conflicting? There are matrices available than can help with organization. See the Organizing Information box below.
• Critique / evaluate the quality of the articles, and record your findings in your matrix or summary table. Tools are available to prompt you what to look for. (See Resources for Appraising a Research Study box on the HSA, Nursing , and PA guides )
• You may need to revise your search and re-run it based on your findings.

6. Organize and synthesize

• Compile the findings and analysis from each resource into a single narrative.
• Using an outline can be helpful. Start broad, addressing the overall findings and then narrow, discussing each resource and how it relates to your question and to the other resources.
• Cite as you write to keep sources organized.
• Write in structured paragraphs using topic sentences and transition words to draw connections, comparisons, and contrasts.
• Don't present one study after another, but rather relate one study's findings to another. Speak to how the studies are connected and how they relate to your work.

Organizing Information

Options to assist in organizing sources and information :

1. Synthesis Matrix

• helps provide overview of the literature
• information from individual sources is entered into a grid to enable writers to discern patterns and themes
• article summary, analysis, or results
• thoughts, reflections, or issues
• each reference gets its own row
• mind maps, concept maps, flowcharts
• at top of page record PICO or research question
• record major concepts / themes from literature
• list concepts that branch out from major concepts underneath - keep going downward hierarchically, until most specific ideas are recorded
• enclose concepts in circles and connect the concept with lines - add brief explanation as needed

3. Summary Table

• information is recorded in a grid to help with recall and sorting information when writing
• allows comparing and contrasting individual studies easily
• purpose of study
• methodology (study population, data collection tool)

Efron, S. E., & Ravid, R. (2019). Writing the literature review : A practical guide . Guilford Press.

Literature Review Sections

• Lit reviews can be part of a larger paper / research study or they can be the focus of the paper
• Lit reviews focus on research studies to provide evidence
• New topics may not have much that has been published

* The sections included may depend on the purpose of the literature review (standalone paper or section within a research paper)

Standalone Literature Review (aka Narrative Review):

• presents your topic or PICO question
• includes the why of the literature review and your goals for the review.
• provides background for your the topic and previews the key points
• Narrative Reviews: tmay not have an explanation of methods.
• include where the search was conducted (which databases) what subject terms or keywords were used, and any limits or filters that were applied and why - this will help others re-create the search
• describe how studies were analyzed for inclusion or exclusion
• review the purpose and answer the research question
• thematically - using recurring themes in the literature
• chronologically - present the development of the topic over time
• methodological - compare and contrast findings based on various methodologies used to research the topic (e.g. qualitative vs quantitative, etc.)
• theoretical - organized content based on various theories
• provide an overview of the main points of each source then synthesize the findings into a coherent summary of the whole
• present common themes among the studies
• compare and contrast the various study results
• interpret the results and address the implications of the findings
• do the results support the original hypothesis or conflict with it
• provide your own analysis and interpretation (eg. discuss the significance of findings; evaluate the strengths and weaknesses of the studies, noting any problems)
• discuss common and unusual patterns and offer explanations
•  stay away from opinions, personal biases and unsupported recommendations
• summarize the key findings and relate them back to your PICO/research question
• note gaps in the research and suggest areas for further research
• this section should not contain "new" information that had not been previously discussed in one of the sections above
• provide a list of all the studies and other sources used in proper APA 7

Literature Review as Part of a Research Study Manuscript:

• Compares the study with other research and includes how a study fills a gap in the research.
• Focus on the body of the review which includes the synthesized Findings and Discussion

Literature Reviews vs Systematic Reviews

Systematic Reviews are NOT the same as a Literature Review:

Literature Reviews:

• Literature reviews may or may not follow strict systematic methods to find, select, and analyze articles, but rather they selectively and broadly review the literature on a topic
• Research included in a Literature Review can be "cherry-picked" and therefore, can be very subjective

Systematic Reviews:

• Systemic reviews are designed to provide a comprehensive summary of the evidence for a focused research question
• rigorous and strictly structured, using standardized reporting guidelines (e.g. PRISMA, see link below)
• uses exhaustive, systematic searches of all relevant databases
• best practice dictates search strategies are peer reviewed
• uses predetermined study inclusion and exclusion criteria in order to minimize bias
• aims to capture and synthesize all literature (including unpublished research - grey literature) that meet the predefined criteria on a focused topic resulting in high quality evidence

Literature Review Examples

• Breastfeeding initiation and support: A literature review of what women value and the impact of early discharge (2017). Women and Birth : Journal of the Australian College of Midwives
• Community-based participatory research to promote healthy diet and nutrition and prevent and control obesity among African-Americans: A literature review (2017). Journal of Racial and Ethnic Health Disparities

• Vitamin D deficiency in individuals with a spinal cord injury: A literature review (2017). Spinal Cord

Resources for Writing a Literature Review

These sources have been used in developing this guide.

Resources Used on This Page

Aveyard, H. (2010). Doing a literature review in health and social care : A practical guide . McGraw-Hill Education.

Purdue Online Writing Lab. (n.d.). Writing a literature review . Purdue University. https://owl.purdue.edu/owl/research_and_citation/conducting_research/writing_a_literature_review.html

Torres, E. (2021, October 21). Nursing - graduate studies research guide: Literature review. Hawai'i Pacific University Libraries. Retrieved January 27, 2022, from https://hpu.libguides.com/c.php?g=543891&p=3727230

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September/October 2024 - Volume 73 - Issue 5

• Editor-in-Chief: Rita Pickler, PhD, RN, FAAN
• ISSN: 0029-6562
• Online ISSN: 1538-9847
• Frequency: 6 issues / year
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​The editorial mission of Nursing Research is to report scientific research findings that advance understanding of all aspects of health. Research across the spectrum of biological, behavioral, psychosocial, spiritual, and cultural factors in health is published. Nursing intervention and outcome research as well as qualitative and mixed methods research are within the editorial focus of Nursing Research. Basic, translational, and clinical research is published. Research about nursing systems and nursing resource management is also published as is research describing new or advanced research methods, analytic strategies, and research protocols.

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Nursing Research has a long and distinguished record in the history of nursing science. Since its launch in 1952, Nursing Research has been a “cooperative venture” of scientists, professional organizations, publisher, editorial staff, and readers to circulate scientific papers in nursing to improve care, alleviate suffering, and advance well-being. Today, Nursing Research continues as a preeminent journal in the field, and is the official journal of the Eastern Nursing Research Society (ENRS) and the Western Institute of Nursing (WIN). 

Nursing Research publishes regular papers and brief reports in the following areas:

•  Research Reports  (Original, empirical research findings in areas of interest to nursing scientists) 

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•  Brief Reports

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Balancing Nursing Science With Biobehavioral Approaches

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Enhancing Understanding and Management of Obesity: Reflections on Behavioral Weight Loss and Food Cue Reactivity

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Influence of Preterm Birth and Environmental Context on Academic Performance and Neurodevelopmental Outcomes

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Treatment Complications Associated With Hospital Admission in Oropharyngeal Cancer Patients

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Symptoms and Health-Related Quality of Life Among Older Adults Living With HIV

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Comparison of Weighting Methods to Understand Improved Outcomes Attributable to Public Health Nursing Interventions

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Reliability and Validity of Measures Commonly Utilized to Assess Nurse Well-Being

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The Arcus Experience: Bridging the Data Science Gap for Nurse Researchers

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Acute Care Use Among Patients With Multiple Chronic Conditions Receiving Care From Nurse Practitioner Practices in Health Professional Shortage Areas

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Good Place to Start: Citation Databases

Interdisciplinary Citation Databases:

A good place to start your research  is to search a research citation database to view the scope of literature available on your topic.

TIP #1: SEED ARTICLE Begin your research with a "seed article" - an article that strongly supports your research topic.  Then use a citation database to follow the studies published by finding articles which have cited that article, either because they support it or because they disagree with it.

TIP #2: SNOWBALLING Snowballing is the process where researchers will begin with a select number of articles they have identified relevant/strongly supports their topic and then search each articles' references reviewing the studies cited to determine if they are relevant to your research.

BONUS POINTS: This process also helps identify key highly cited authors within a topic to help establish the "experts" in the field.

Begin by constructing a focused research question to help you then convert it into an effective search strategy.

• Identify keywords or synonyms
• Type of study/resources
• Which database(s) to search
• Asking a Good Question (PICO)
• PICO - AHRQ
• PICO - Worksheet
• What Is a PICOT Question?

Seminal Works: Search Key Indexing/Citation Databases

• Google Scholar
• Web of Science

TIP – How to Locate Seminal Works

• DO NOT: Limit by date range or you might overlook the seminal works
• DO: Look at highly cited references (Seminal articles are frequently referred to “cited” in the research)
• DO: Search citation databases like Scopus, Web of Science and Google Scholar

Web Resources

What is a literature review?

A literature review is a comprehensive and up-to-date overview of published information on a subject area. Conducting a literature review demands a careful examination of a body of literature that has been published that helps answer your research question (See PICO). Literature reviewed includes scholarly journals, scholarly books, authoritative databases, primary sources and grey literature.

A literature review attempts to answer the following:

• What is known about the subject?
• What is the chronology of knowledge about my subject?
• Are there any gaps in the literature?
• Is there a consensus/debate on issues?
• Create a clear research question/statement
• Define the scope of the review include limitations (i.e. gender, age, location, nationality...)
• Search existing literature including classic works on your topic and grey literature
• Evaluate results and the evidence (Avoid discounting information that contradicts your research)
• Track and organize references
• How to conduct an effective literature search.
• Social Work Literature Review Guidelines (OWL Purdue Online Writing Lab)

What is PICO?

The PICO model can help you formulate a good clinical question. Sometimes it's referred to as PICO-T, containing an optional 5th factor. 

Search Example

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Best Nursing Research Topics for Students

What is a nursing research paper.

• What They Include
• Choosing a Topic
• Best Nursing Research Topics
• Research Paper Writing Tips

Writing a research paper is a massive task that involves careful organization, critical analysis, and a lot of time. Some nursing students are natural writers, while others struggle to select a nursing research topic, let alone write about it.

If you're a nursing student who dreads writing research papers, this article may help ease your anxiety. We'll cover everything you need to know about writing nursing school research papers and the top topics for nursing research.  

Continue reading to make your paper-writing jitters a thing of the past.

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A nursing research paper is a work of academic writing composed by a nurse or nursing student. The paper may present information on a specific topic or answer a question.

During LPN/LVN and RN programs, most papers you write focus on learning to use research databases, evaluate appropriate resources, and format your writing with APA style. You'll then synthesize your research information to answer a question or analyze a topic.

BSN , MSN , Ph.D., and DNP programs also write nursing research papers. Students in these programs may also participate in conducting original research studies.

Writing papers during your academic program improves and develops many skills, including the ability to:

• Select nursing topics for research
• Conduct effective research
• Analyze published academic literature
• Format and cite sources
• Synthesize data
• Organize and articulate findings

About Nursing Research Papers

When do nursing students write research papers.

You may need to write a research paper for any of the nursing courses you take. Research papers help develop critical thinking and communication skills. They allow you to learn how to conduct research and critically review publications.

That said, not every class will require in-depth, 10-20-page papers. The more advanced your degree path, the more you can expect to write and conduct research. If you're in an associate or bachelor's program, you'll probably write a few papers each semester or term.

Do Nursing Students Conduct Original Research?

Most of the time, you won't be designing, conducting, and evaluating new research. Instead, your projects will focus on learning the research process and the scientific method. You'll achieve these objectives by evaluating existing nursing literature and sources and defending a thesis.

However, many nursing faculty members do conduct original research. So, you may get opportunities to participate in, and publish, research articles.

Example Research Project Scenario:

In your maternal child nursing class, the professor assigns the class a research paper regarding developmentally appropriate nursing interventions for the pediatric population. While that may sound specific, you have almost endless opportunities to narrow down the focus of your writing. 

You could choose pain intervention measures in toddlers. Conversely, you can research the effects of prolonged hospitalization on adolescents' social-emotional development.

What Does a Nursing Research Paper Include?

Your professor should provide a thorough guideline of the scope of the paper. In general, an undergraduate nursing research paper will consist of:

Introduction : A brief overview of the research question/thesis statement your paper will discuss. You can include why the topic is relevant.

Body : This section presents your research findings and allows you to synthesize the information and data you collected. You'll have a chance to articulate your evaluation and answer your research question. The length of this section depends on your assignment.

Conclusion : A brief review of the information and analysis you presented throughout the body of the paper. This section is a recap of your paper and another chance to reassert your thesis.

The best advice is to follow your instructor's rubric and guidelines. Remember to ask for help whenever needed, and avoid overcomplicating the assignment!

How to Choose a Nursing Research Topic

The sheer volume of prospective nursing research topics can become overwhelming for students. Additionally, you may get the misconception that all the 'good' research ideas are exhausted. However, a personal approach may help you narrow down a research topic and find a unique angle.

Writing your research paper about a topic you value or connect with makes the task easier. Additionally, you should consider the material's breadth. Topics with plenty of existing literature will make developing a research question and thesis smoother.

Finally, feel free to shift gears if necessary, especially if you're still early in the research process. If you start down one path and have trouble finding published information, ask your professor if you can choose another topic.

The Best Research Topics for Nursing Students

You have endless subject choices for nursing research papers. This non-exhaustive list just scratches the surface of some of the best nursing research topics.

1. Clinical Nursing Research Topics

• Analyze the use of telehealth/virtual nursing to reduce inpatient nurse duties.
• Discuss the impact of evidence-based respiratory interventions on patient outcomes in critical care settings.
• Explore the effectiveness of pain management protocols in pediatric patients.

2. Community Health Nursing Research Topics

• Assess the impact of nurse-led diabetes education in Type II Diabetics.
• Analyze the relationship between socioeconomic status and access to healthcare services.

3. Nurse Education Research Topics

• Review the effectiveness of simulation-based learning to improve nursing students' clinical skills.
• Identify methods that best prepare pre-licensure students for clinical practice.
• Investigate factors that influence nurses to pursue advanced degrees.
• Evaluate education methods that enhance cultural competence among nurses.
• Describe the role of mindfulness interventions in reducing stress and burnout among nurses.

4. Mental Health Nursing Research Topics

• Explore patient outcomes related to nurse staffing levels in acute behavioral health settings.
• Assess the effectiveness of mental health education among emergency room nurses .
• Explore de-escalation techniques that result in improved patient outcomes.
• Review the effectiveness of therapeutic communication in improving patient outcomes.

5. Pediatric Nursing Research Topics

• Assess the impact of parental involvement in pediatric asthma treatment adherence.
• Explore challenges related to chronic illness management in pediatric patients.
• Review the role of play therapy and other therapeutic interventions that alleviate anxiety among hospitalized children.

6. The Nursing Profession Research Topics

• Analyze the effects of short staffing on nurse burnout .
• Evaluate factors that facilitate resiliency among nursing professionals.
• Examine predictors of nurse dissatisfaction and burnout.
• Posit how nursing theories influence modern nursing practice.

Tips for Writing a Nursing Research Paper

The best nursing research advice we can provide is to follow your professor's rubric and instructions. However, here are a few study tips for nursing students to make paper writing less painful:

Avoid procrastination: Everyone says it, but few follow this advice. You can significantly lower your stress levels if you avoid procrastinating and start working on your project immediately.

Plan Ahead: Break down the writing process into smaller sections, especially if it seems overwhelming. Give yourself time for each step in the process.

Research: Use your resources and ask for help from the librarian or instructor. The rest should come together quickly once you find high-quality studies to analyze.

Outline: Create an outline to help you organize your thoughts. Then, you can plug in information throughout the research process. 

Clear Language: Use plain language as much as possible to get your point across. Jargon is inevitable when writing academic nursing papers, but keep it to a minimum.

Cite Properly: Accurately cite all sources using the appropriate citation style. Nursing research papers will almost always implement APA style. Check out the resources below for some excellent reference management options.

Revise and Edit: Once you finish your first draft, put it away for one to two hours or, preferably, a whole day. Once you've placed some space between you and your paper, read through and edit for clarity, coherence, and grammatical errors. Reading your essay out loud is an excellent way to check for the 'flow' of the paper.

Helpful Nursing Research Writing Resources:

Purdue OWL (Online writing lab) has a robust APA guide covering everything you need about APA style and rules.

Grammarly helps you edit grammar, spelling, and punctuation. Upgrading to a paid plan will get you plagiarism detection, formatting, and engagement suggestions. This tool is excellent to help you simplify complicated sentences.

Mendeley is a free reference management software. It stores, organizes, and cites references. It has a Microsoft plug-in that inserts and correctly formats APA citations.

Don't let nursing research papers scare you away from starting nursing school or furthering your education. Their purpose is to develop skills you'll need to be an effective nurse: critical thinking, communication, and the ability to review published information critically.

Choose a great topic and follow your teacher's instructions; you'll finish that paper in no time.

Joleen Sams is a certified Family Nurse Practitioner based in the Kansas City metro area. During her 10-year RN career, Joleen worked in NICU, inpatient pediatrics, and regulatory compliance. Since graduating with her MSN-FNP in 2019, she has worked in urgent care and nursing administration. Connect with Joleen on LinkedIn or see more of her writing on her website.

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• Literature Reviews
• Evidence-Based Practice
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What is a Literature Review?

Key questions for a literature review, examples of literature reviews, useful links, evidence matrix for literature reviews.

• Annotated Bibliographies

The Scholarly Conversation

A literature review provides an overview of previous research on a topic that critically evaluates, classifies, and compares what has already been published on a particular topic. It allows the author to synthesize and place into context the research and scholarly literature relevant to the topic. It helps map the different approaches to a given question and reveals patterns. It forms the foundation for the author’s subsequent research and justifies the significance of the new investigation.

A literature review can be a short introductory section of a research article or a report or policy paper that focuses on recent research. Or, in the case of dissertations, theses, and review articles, it can be an extensive review of all relevant research.

• The format is usually a bibliographic essay; sources are briefly cited within the body of the essay, with full bibliographic citations at the end.
• The introduction should define the topic and set the context for the literature review. It will include the author's perspective or point of view on the topic, how they have defined the scope of the topic (including what's not included), and how the review will be organized. It can point out overall trends, conflicts in methodology or conclusions, and gaps in the research.
• In the body of the review, the author should organize the research into major topics and subtopics. These groupings may be by subject, (e.g., globalization of clothing manufacturing), type of research (e.g., case studies), methodology (e.g., qualitative), genre, chronology, or other common characteristics. Within these groups, the author can then discuss the merits of each article and analyze and compare the importance of each article to similar ones.
• The conclusion will summarize the main findings, make clear how this review of the literature supports (or not) the research to follow, and may point the direction for further research.
• The list of references will include full citations for all of the items mentioned in the literature review.

A literature review should try to answer questions such as

• Who are the key researchers on this topic?
• What has been the focus of the research efforts so far and what is the current status?
• How have certain studies built on prior studies? Where are the connections? Are there new interpretations of the research?
• Have there been any controversies or debate about the research? Is there consensus? Are there any contradictions?
• Which areas have been identified as needing further research? Have any pathways been suggested?
• How will your topic uniquely contribute to this body of knowledge?
• Which methodologies have researchers used and which appear to be the most productive?
• What sources of information or data were identified that might be useful to you?
• How does your particular topic fit into the larger context of what has already been done?
• How has the research that has already been done help frame your current investigation ?

Example of a literature review at the beginning of an article: Forbes, C. C., Blanchard, C. M., Mummery, W. K., & Courneya, K. S. (2015, March). Prevalence and correlates of strength exercise among breast, prostate, and colorectal cancer survivors . Oncology Nursing Forum, 42(2), 118+. Retrieved from http://go.galegroup.com.sonoma.idm.oclc.org/ps/i.do?p=HRCA&sw=w&u=sonomacsu&v=2.1&it=r&id=GALE%7CA422059606&asid=27e45873fddc413ac1bebbc129f7649c Example of a comprehensive review of the literature: Wilson, J. L. (2016). An exploration of bullying behaviours in nursing: a review of the literature.   British Journal Of Nursing ,  25 (6), 303-306. For additional examples, see:

Galvan, J., Galvan, M., & ProQuest. (2017). Writing literature reviews: A guide for students of the social and behavioral sciences (Seventh ed.). [Electronic book]

Pan, M., & Lopez, M. (2008). Preparing literature reviews: Qualitative and quantitative approaches (3rd ed.). Glendale, CA: Pyrczak Pub. [ Q180.55.E9 P36 2008]

• Write a Literature Review (UCSC)
• Literature Reviews (Purdue)
• Literature Reviews: overview (UNC)
• Review of Literature (UW-Madison)

The  Evidence Matrix  can help you  organize your research  before writing your lit review.  Use it to  identify patterns  and commonalities in the articles you have found--similar methodologies ?  common  theoretical frameworks ? It helps you make sure that all your major concepts covered. It also helps you see how your research fits into the context  of the overall topic.

• Evidence Matrix Special thanks to Dr. Cindy Stearns, SSU Sociology Dept, for permission to use this Matrix as an example.
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• Next: Annotated Bibliographies >>
• Last Updated: Jun 6, 2024 10:40 AM
• URL: https://libguides.sonoma.edu/nursing

NRS 410 Research and Evidence-Based practice: Types of Nursing Literature

• Types of Nursing Literature
• Nursing Databases & Books
• Internet Resources
• Citation Linker/ Interlibrary loan
• Writing, Citing, and Presenting
• Search Strategies: Keywords
• Search Strategies: Subject Headings

Evidence-based literature pyramid

What is Evidence-based literature?

Evidence based literature is used to support evidence based practice (EBP) in nursing; it "involves an ability to access, summarize, and apply information from the literature to day-to-day clinical problems." Evidence based literature exists on a continuum from weaker-to-stronger evidence (see pyramid above).

Many databases have some form of check box or limiter that allows you to restrict results to evidence based literature. For instance, clicking the checkbox on the CINAHL databse for evidence-based results restricts your search to the following:

• Articles from evidence-based practice journals
• Articles about evidence-based practice
• Research articles (including systematic reviews, clinical trials, meta analyses, etc.)
• Commentaries on research studies (applying practice to research)

As you can see, the results vary in terms of the type of literature and strength of evidence.  It is up to you to select the most appropriate results.

( source Kessenich CR, "Teaching nursing students evidence-based nursing." Nurse Educator, Nov/Dec 1997, 22(6): 25-29.

Nursing literature categories

Systematic Reviews: (also known as "meta-analysis") A systematic review identifies an intervention for a specific disease or other problem in health care, and determines whether or not this intervention works. To do this authors locate, appraise and synthesize evidence from as many relevant scientific studies as possible. They summarize conclusions about effectiveness, and provide a unique collation of the known evidence on a given topic, so that others can easily review the primary studies for any intervention. Empirical research articles:  Empirical research is based on observed and measured phenomena and derives knowledge from actual experience rather than from theory or belief.   Usually published in peer-reviewed journals.

   Key characteristics to look for:

• Statement about the methodology being used 
• Research questions to be answered 
• Definition of the group or phenomena being studied 
• Process used to study this group or phenomena, including any
• controls or instruments such as tests or surveys 
• Ask yourself: Could I recreate this study and test these results?
• Read the abstract of the article for a description of the methodology

Research articles will include a bibliography of other literature reviewed, and may lead you to similar articles; its primary purpose is to present original findings. Look for the following elements

• Introduction
• Research design (participants)
• Discussion of data & methods
• Numerical data

Evidence-Based Care Sheets and Evidence-Based Articles: both evidence-based care sheets and evidence-based articles are similar to review articles (described below). These types of articles focus on summarzing research relating to specific ailments and the efficacy of their treatments, and serve as general overviews.

Review articles: Summarizes and synthesizes the results of many different original studies. Its purpose is to define the state of the literature on a particular topic, and discuss different methodologies for conducting research. Review articles are excellent sources for locating research articles, and contain helpful bibliographies.

Clinical articles: Written for practitioners. Clinical articles might present a particular case study or define a new technique.

(sources: Clemens, Rachel, "Library Research Guide for Nursing," Dept. of Nursing, Cal State University , http://guides.library.fullerton.edu/nursing/articletypes.htm ) and Cahoy, Ellysa, "What is Empirical Research," Education and Behavioral Sciences Library , Penn State University, http://www.libraries.psu.edu/psul/researchguides/edupsych/empirical.html)

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• Last Updated: Jul 18, 2024 11:40 AM
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This Guide provides access to nursing, biomedical, clinical trial, evidence based practice, and research instrument databases; drug and pharmaceutical resources; e-books; patient education resources; and professional societies of special interest to NIH Clinical Center and IC nurses. 

CINAHL Plus

ClinicalTrials.gov

Cochrane Library

Mosby's Nursing Skills

TRIP - Turning Research into Practice

Drug and Pharmaceutical Resources

Access Medicine Drug Monographs 

Drug Information Portal

NIH Clinical Center Formulary and Lexicomp Online

IBM Micromedex

UpToDate Drug Interactions

Big Data-Enabled Nursing (2017)

Clinical Leadership in Nursing and Healthcare: Values into Action (2017)

Current Medical Diagnosis and Treatment (2018)

Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 13e (2018)

Harrison’s Manual of Medicine, 19e (2016)

Harrison's Principles of Internal Medicine, 20e (2018)

Key Concepts and Issues in Nursing Ethics (2017)

MD Anderson Manual of Medical Oncology, 3e (2016)

Mentoring in Nursing and Healthcare: Supporting Career and Personal Development (2017)

Music Therapy: Research and Evidence Based Practice (2018)

Nursing Care and ECMO (2017)

Nursing Care of the Pediatric Neurosurgery Patient (2017)

Palliative Care in Pediatric Oncology (2018)

Practical Approach to Using Statistics in Health Research: From Planning to Reporting (2018)

Precision Medicine: A Guide to Genomics in Clinical Practice (2017)

Principles and Practice of Hospital Medicine, 2e (2017)

Strategic Planning for Advanced Nursing Practice (2017)

Additional titles licensed by the NIH Library are available at  AccessMedicine and  Online Journals, Books and more

Patient Education Resources

HealthReach: Heath Information in Many Languages

MedlinePlus

IBM Micromedex CareNotes

Multicultural Resources for Health Information

Nursing Research Patient Education Resources (NRPEC)

Research Patient Education Resources (RPEC)

Resources in Multiple Languages from Other Federal Agencies

UpToDate Patient Education

Professional Societies

American Association of Critical Care Nurses

American Nurses Association

Infusion Nurses Society

International Association of Clinical Research Nurses

International Society of Nurses in Genetics

Oncology Nursing Society

Sigma Global Nursing Excellence

Society of Pediatric Nurses

Transcultural Nursing Society

See also Research Instruments

Nursing Research Priorities

Research priorities.

The ANA Enterprise Research Priorities are strategically designed to address critical challenges and opportunities in nursing and healthcare. These priorities focus on enhancing healthcare access, improving safety and quality of care, and promoting the health and well-being of nurses. They also emphasize the importance of diversity, equity, and inclusion, the development of professional identity, and environmental sustainability. Together, these research priorities aim to drive impactful changes that will shape the future of nursing and healthcare on a global scale. Download the full document to learn more about how these priorities are guiding innovative research and advancing the profession.

ANA Enterprise Research Council

The ANA Enterprise Research Advisory Council provides expert guidance and recommendations to the Institute for Nursing Research & Quality Management on matters of global importance, aimed at shaping the future of nursing and healthcare. By fostering a culture of inquiry and advancing interprofessional, practice-based research, the Council drives transformative initiatives that align with the ANA Enterprise's mission to lead the profession forward.

Composed of volunteer experts, the Council unites diverse nursing voices to steer research efforts that strengthen the global impact of nursing. It ensures that frontline nurses' perspectives are central to advancing healthcare innovations. Historically focused on building research capacity, fostering collaboration, and enhancing data governance, the Council's priorities now emphasize workforce development, nurse well-being, diversity and inclusion (DEIB), expanding the scope of practice, and demonstrating the value of nursing.

Research Advisory Council

Jen bonamer.

PhD, RN, AHN-BC, NPD-BC

Nursing Professional Development – Research Specialist Education, Professional Development & Research Department Sarasota Memorial Health Care System

Jen Bonamer works as a Nursing Professional Development – Research Specialist at Sarasota Memorial Hospital in Sarasota Florida. She leads the nursing research and evidence-based practice programs and is actively focused on supporting healthy work environments and clinician well-being. Jen received her BSN from the University of Florida (Gainesville) and practiced for ten years in pediatrics (general practice and hematology/oncology/bone marrow transplant). She completed the University of South Florida’s (Tampa) Nursing BS to PhD program with her master’s of science degree (nursing education) and PhD (nursing). She is certified in both nursing professional development and advanced holistic nursing. Jen is an active member in the American Nurses Association – Enterprise (ANAE) Research Advisory Council and an independent contractor of peer review services for the Magnet program.

Catherine H. Ivory

PhD, RN-BC, NEA-BC, FAAN

Associate Nurse Executive, Nursing Excellence Vanderbilt University Medical Center

Cathy Ivory, PhD, RN-BC, NEA-BC, FAAN, Associate Nurse Executive, oversees the Office of Nursing Excellence for the Vanderbilt Health System. Through collaboration across all VUMC and Vanderbilt University entities, The Office of Nursing Excellence is responsible for professional, evidence-based nursing practice, VUMC’s shared governance and Magnet activities, and all aspects of inquiry that translates evidence into practice and improves quality, safety, patient experience, and the delivery of cost effective care across settings. Dr. Ivory facilitates nursing research activities and connects nurse investigators with collaborators across the broader research enterprise at Vanderbilt.

Dr. Ivory has more than 25 years of experience as a staff nurse, clinical specialist, system-level nursing administrator, educator, and health services researcher. Dr. Ivory’s clinical focus is perinatal nursing and she served as the 2014 President of the Association of Women’s Health, OB and Neonatal Nurses (AWHONN), representing more than 300,000 nurses who care for women and newborns. She also holds two ANCC board certifications, one as an informatics nurse (RN-BC) and one as an advanced nurse executive (NEA-BC). She was inducted as a fellow in the American Academy of Nursing in 2017.

Dr. Ivory holds a BSN, an MSN in nursing administration/healthcare informatics, and a PhD in nursing science. Her research interests include implementation science and using data generated by nurses to quantify their role in patient care, patient safety, and patient outcomes. She is passionate about the nursing profession, nursing informatics, evidence-based nursing practice, and research.

David W. Price

MD, FAAFP, FACEHP, FSACME

Professor, Family Medicine, University of Colorado Anschutz School of Medicine Senior Advisor to the President and CEO, American Board of Family Medicine Medical Education and Quality Improvement Consultant and Coach Associate, Wentz/Miller Global Services

Dr. Price is Senior Advisor to the President, American Board of Family Medicine. He is also Professor of Family Medicine at the University of Colorado School of Medicine.

Dr. Price spent 29 years in the Kaiser Permanente (KP) system in several roles, including Director of Medical Education for the Colorado Region and the (national) Permanente Federation; physician investigator with the KP Colorado Institute of Health Research; Co-director of the Kaiser Colorado Center for Health Education, Dissemination and Implementation research; Clinical Lead for Kaiser National Mental Health Guidelines; member of the Kaiser National Guideline Directors Group, and Chair of Family Medicine for the Colorado Permanente Medical Group. He served on the ABFM Board of Directors from 2003 – 2008, where he chaired the R&D and Maintenance of Certification committees and was Board Chair from 2007-2008. He is a former Senior Vice-President at the American Board of Medical Specialties. He is a past Director of the Accreditation Council for Continuing Medical Education, a past-president of the Colorado Academy of Family Physicians, past chair of the AAMC Group on Educational Affairs section on Continuing Education and Improvement, and currently serves on the AAMC Integrating Quality Initiative steering committee. He is widely published and has spoken nationally and internationally and published in areas ranging from continuing medical education/professional development, quality and practice improvement, mental health, and evidence-based medicine.

Dr. Price received his M.D. degree from Rutgers Medical School in 1985 and completed his Family Medicine Residency and chief residency at JFK Medical Center, Edison, NJ, in 1988. He is a fellow of the American Academy of Family Physicians, the Alliance for Continuing Education in the Health Professions, and the Society of Continuing Medical Education (SACME) and the recipient of the 2018 SACME Distinguished Service in CME Award.

Marianne Weiss

Professor Emerita of Nursing Marquette University College of Nursing

Dr. Weiss is Professor Emerita of Nursing at Marquette University in Milwaukee, WI. She holds a Bachelor of Science in Nursing degree from McGill University in Montreal, Canada, and Master of Science in Nursing and Doctor of Nursing Science degrees from the University of San Diego. Prior to joining the faculty of Marquette University, she held positions as clinical nurse specialist and nurse researcher in women’s services for a large healthcare system.

Dr. Weiss continues to be an active nurse researcher and research consultant. Her program of research focuses on the contribution acute care nurses make to patient outcomes. Much of her work has focused on discharge preparation, assessment of discharge readiness, and post-discharge outcomes across the range of patients discharged from acute care hospitals. Her funded research studied the impact of nurse staffing on quality and cost measures of the discharge transition from hospital to home. Dr. Weiss was the Principal Investigator for the READI multi-site study, commissioned by ANCC and conducted at 33 Magnet hospitals, that investigated implementation of discharge readiness assessment as a standard nursing practice for hospital discharge. Other related research focuses on nurse staffing, continuity of care, and nurse characteristics such as education and certification that contribute to nurse performance in achieving patient outcomes. Her goal is to document the critical role and value hospital nurses bring to patient care and outcomes during and after hospitalization.

Instrument development has been an important aspect of her work on discharge readiness. Dr. Weiss has developed and tested research scales to measure quality of discharge teaching, discharge readiness, and post-discharge coping difficulty. She has conducted tool validation studies in adult-medical surgical patients, parents of hospitalized children, and postpartum mothers. These scales have been translated into more than 15 languages and are being used extensively in clinical practice and research. Dr. Weiss collaborates frequently with researchers worldwide on the science of discharge preparation. She has published extensively with US and international colleagues.

Olga Yakusheva

Professor of Nursing and Public Health Department of Systems, Populations and Leadership Department of Health Management and Policy University of Michigan School of Nursing and School of Public Health

Dr. Yakusheva is an economist with research interests in health economics and health services research. Yakusheva's area of expertise is econometric methods for causal inference, data architecture, and secondary analyses of big data. The primary focus of Yakusheva’s research is the study of economic value of nursing/nurses. Yakusheva pioneered the development of a new method for outcomes-based clinician value-added measurement using the electronic medical records. With this work, Yakusheva was able to measure, for the first time, the value-added contributions of individual nurses to patient outcomes. This work has won her national recognition earning her the Best of AcademyHealth Research Meeting Award in 2014 and a Nomination in 2018. Yakusheva is currently a PI on a AHRQ funded R01 measuring the continuity of interprofessional ICU care and an ANF/ANCC funded research grant measuring the value-added contribution of specialty nurse certifications to nurse performance and patient outcomes.

Yakusheva is a team scientist who has contributed methodological expertise to many interdisciplinary projects including hospital readmissions, primary care providers, obesity, pregnancy and birth, and peer effects on health behaviors and outcomes

Yakusheva holds a PhD in economics, an MS in economic policy, and a BS in applied mathematics.

Colleen K Snydeman

Executive Director, Office of Quality, Safety, Informatics, & Practice and the Inaugural MGH Endowed Scholar in Nursing Practice, Nursing & Patient Care Services, Massachusetts General Hospital

Dr. Snydeman’s expertise and leadership are dedicated to delivering safe, evidenced-based, high quality patient care through the continuous improvement of practice and positive outcomes with a focused commitment to the safety and well-being of the workforce. As the executive director of Massachusetts General Hospital’s Patient Care Services Office of Quality, Safety, Informatics, & Practice I provide oversight for quality and safety programs, improvement initiatives and outcomes associated with quality nursing care (falls, pressure injuries, central line blood stream infections, catheter associated urinary tract infections, and assaults on nursing personnel). I oversee a team of nine quality and informatics specialists and have a formal, non-direct reporting relationship with 75 unit based clinical nurse specialist and nurse practice specialists.

During the unprecedented COVID-19 era I led and supported a full implementation of Circle Up Huddles in all PCS inpatient areas, implementation of hospital-wide Proning Teams (recognized by Johnson & Johnson as a top ten innovation), pressure injury research, qualitative research on the experiences of bedside nurses and respiratory therapists, and implementation of resiliency and wellbeing strategies. In collaboration with RGI analytics, we have developed an algorithm using live streaming electronic health record data to alert nurses on their iphones to changes in patient’s fall risk and the associated interventions needed to prevent falls. Preliminary statistical findings are promising.

I have over forty years of progressive nursing leadership experience. My background in nursing leadership and critical care nursing led to my dissertation work using a quasi-experimental pre/post-test design with intervention and control groups to measure the impact of a theory based adverse event nurse peer review program on safety culture and the recovery of medical errors in the critical care setting. A linear mixed model analysis suggested that critical care nurses who participated in the program had a more critical view of safety culture and work environment, along with increased accountability and responsibility for their role in using strategies to keep patients safe. Further interdisciplinary safety research is underway.

Johana Rocio, Fajardo (Almansa)

Advanced Heart Failure & Transplant Nurse Practitioner, Duke University Hospital

As a doctor of nursing practice with a specialty in heart failure, transplant and mechanical support, my research is focused on improving patient outcomes through the development and implementation of best practices for the care of advanced heart failure patients. My clinical activities are centered on reducing healthcare inequities and improving Health Related Quality of Life (HRQoL) throughout the disease trajectory by optimizing interdisciplinary management and transitional care. Additionally, I have worked on database creation for both clinical and academic purposes as well as leveraging information technology to promote clinical practice standardization, minimize medical errors, and reduce cost of care.

Lastly, I have assisted in the establishment of centers of excellence by building the organizational, clinical, and educational infrastructures to deliver integrative, efficient, and specialized care to the Amyloidosis and Sarcoidosis populations. Furthermore, I have participated as a keynote speaker at national and international medical symposiums and have served as editor in chief and writer of textbooks. During my tenure as an Assistant Professor at Georgetown University School of Medicine, my research focused on the implementation of translational and organizational research to address specific issues in clinical practice and patient care delivery. Additionally, my work in the utilization of Inotropic support in rare cardiomyopathies was recognized as innovative in the field. By providing evidence and simple clinical approaches, this body of work has changed the standards of care for rare cardiomyopathy patients and will continue to provide assistance in relevant medical settings well into the future. I have served in the capacity of Principal Investigator, Co-Investigator, task leader, and technical consultant on projects supported by the government, industry and internal funding sources. In addition, I have successfully collaborated in randomized clinical trial conduction (e.g. patient screening, enrollment, and monitoring), and produced peer-reviewed publications.

Kathy Casey

PhD, RN, NPD-BC

Professional Development Specialist, Denver Health Adjunct Professor, University of Colorado, College of Nursing Adjunct Faculty, Colorado Christian University

Kathy Casey, PhD, RN, NPD-BC, is nationally and internationally known for her Casey-Fink Survey design work supporting graduate nurse role transition, nurse retention, and readiness for professional practice.

Kathy is certified in Nursing Professional Development, and currently serves as a Professional Development Specialist at Denver Health, in Denver, Colorado. She is an Adjunct Professor at the University of Colorado College of Nursing and Adjunct Faculty teaching EBP and Research at Colorado Christian University. Kathy is a lead appraiser for the American Nurses Credentialing Center Practice Transition Accreditation Program (PTAP).

In March 2023, Kathy received the Association for Nursing Professional Development's Marlene Kramer Lifetime Achievement Award for her contributions and research on survey development for use in education and practice programs. In October 2023, Kathy will be inducted as a fellow in the American Academy of Nursing.

Kathy received her Bachelor of Science in Nursing from Pacific Lutheran University, her Master's Degree in Nursing Administration from the University of Colorado, College of Nursing, and her Doctorate in Nursing Education from the University of Northern Colorado, School of Nursing.

Kortney James

PhD, RN, PNP-C

Dr. Kortney James is a PhD prepared nurse and Associate Health Policy Researcher at RAND Corporation. Her research focuses on improving access to quality reproductive health services to minoritized populations. Dr. James is also the Associate Editor of the Nursing for Women's Health Journal, a role in which she is committed to recruiting and supporting manuscripts and research that reflect diverse perspectives and identities. Dr. James recently completed a postdoctoral fellowship in the National Clinician Scholars Program, a continuation of the Robert Wood Johnson Foundation, in the School of Medicine at the University of California, Los Angeles. During her postdoctoral fellowship Dr. James has published several manuscripts in high impact journals. Select publications include "NIH funding: Hone efforts to tackle structural racism" featured in Nature and "Factors associated with postpartum maternal functioning in Black women," featured in Journal of Clinical Medicine. Thus far, Dr. James has been awarded $230,000 to support her research related to Black perinatal mental health. She received $30,000 from the Iris Cantor UCLA Women's Health Center to support her mixed methods study that aims to identify and understand culturally and racially relevant influences on their journey to healing from perinatal mood and anxiety disorders. Dr. James also received $200,000 from the American Nurses Foundation to implement an educational intervention to support ambulatory care nurses and other healthcare staff to care for Black pregnant and postpartum people’s mental health needs with culturally relevant resources. Dr. James has a wide range of clinical experience in acute inpatient care, primary care, and public health. Dr. James is a pediatric nurse practitioner with over a decade of experience in acute newborn care and pediatric primary care. Dr. James has extensive experience in perinatal care due to her time as a registered nurse in the highest volume birthing hospital in the country with an average of around 25,000 births a year (and counting). Dr. James has also held an executive leadership position in the Office of Nursing, Maternal Child Health, and Infectious Disease divisions at the Georgia Department of Public Health in Atlanta, GA.

Ultimately, Dr. James' mission is to co-create solutions with Black women and people capable of pregnancy to achieve health equity.

For questions or inquiries please contact the ANCC Research Council members at [email protected] .

Item(s) added to cart

• Open access
• Published: 30 August 2024

Barriers in providing quality end-of-life care as perceived by nurses working in critical care units: an integrative review

• Yousef Saleh Rubbai 1 , 2 ,
• Mei Chan Chong 1 ,
• Li Yoong Tang 1 ,
• Khatijah Lim Abdullah 3 ,
• Walid Theib Mohammad 6 ,
• Samira Mohajer   ORCID: orcid.org/0000-0001-7118-1783 1 , 4 &
• Mohammad Namazinia   ORCID: orcid.org/0000-0003-2198-7556 5  

BMC Palliative Care volume  23 , Article number:  217 ( 2024 ) Cite this article

Metrics details

Despite increasing interest in quality end-of-life care (EOLC), critically ill patients often receive suboptimal care. Critical care nurses play a crucial role in EOLC, but face numerous barriers that hinder their ability to provide compassionate and effective care.

An integrative literature review was conducted to investigate barriers impacting the quality of end-of-life care. This review process involved searching database like MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, EBSCO, and ScienceDirect up to November 2023. Search strategies focused on keywords related to barriers in end-of-life care and critical care nurses from October 30th to November 10th, 2023. The inclusion criteria specified full-text English articles published between 2010 and 2023 that addressed barriers perceived by critical care nurses. This integrative review employs an integrated thematic analysis approach, which combines elements of deductive and inductive analysis, to explore the identified barriers, with coding and theme development overseen by the primary and secondary authors.

Out of 103 articles published, 11 articles were included in the review. There were eight cross-sectional descriptive studies and three qualitative studies, which demonstrated barriers affecting end-of-life care quality. Quality appraisal using the Mixed Method Appraisal Tool was completed by two authors confirmed the high credibility of the selected studies, indicating the presence of high-quality evidence across the reviewed articles. Thematic analysis led to the three main themes (1) barriers related to patients and their families, (2) barriers related to nurses and their demographic characteristics, and (3) barriers related to health care environment and institutions.

This review highlights barriers influencing the quality of end of life care perceived by critical care nurses and the gaps that need attention to improve the quality of care provided for patients in their final stages and their fsmilies within the context of critical care. This review also notes the need for additional research to investigate the uncover patterns and insights that have not been fully explored in the existing literature to enhance understanding of these barriers. This can help to inform future research, care provision, and policy-making. Specifically, this review examines how these barriers interact, their cumulative impact on care quality, and potential strategies to overcome.

Peer Review reports

Introduction

It was estimated that 56.8 million people, including 25.7 million at the end of life, need palliative care; however, only about 14% of people who need palliative care currently receive it [ 1 ]. The need for acute care settings increased in response to life-threatening emergencies and the acute exacerbation of diseases [ 2 , 3 ]. These settings were developed to meet the need for providing optimal health care, saving patient lives and decreasing the rate of mortality using advanced technology [ 2 , 4 ]. Caring in intensive care units sometimes involves withholding or withdrawing treatments that have lasted a lifetime, and in these cases, the role of ICU nurses goes from providing life-saving measures to end-of-life care [ 5 ]. Care at the end of a life is a special kind of health care for individuals and families who are living with a life-limiting illness [ 6 ]. End-of-life care (EOLC) includes a crucial component of intensive care nurses’ work; nurses are in a unique position to cooperate with families to provide care for patients at the end of their lives [ 7 , 8 , 9 , 10 43 ].

Advanced technology in critical care units has led to improved nursing care in many areas, such as End-Of-Life-Care (EOLC) [ 11 ]. This type of care has moved towards enhancing comfort and reducing patients’ suffering [ 12 ]. As EOLC involves enhancing the physical, emotional, and spiritual quality of life for critically ill patients, traditional measures are now challenged as advanced technology has revolutionized nursing care through innovations such as adjustable beds and pressure-relieving mattresses, which help optimize patient comfort, and advanced communication technologies, for example, video conferencing facilitating communication between patients, families, and healthcare providers, allowing for ongoing support, counseling, and decision-making discussions throughout the end-of-life journey. Therefore, quality EOLC has become a significant concern for healthcare decision-makers, healthcare providers, researchers, patients, and families [ 13 ]. Despite the increased interest and demand in providing good EOLC, this care is still limited In the critical care and does not meet the recommended standards [ 14 ]. Critical Care Nurses spend more time with patients compared to other members of the multidisciplinary team. They serve as implementers, educators, and coordinators in end-of-life care. Their role in delivering EOLC is essential as they are presumably prepared to provide this care and meet patients and their family’s needs, including pain control, management of physical, emotional, spiritual, and social needs, and communication with patients and their families [ 15 ]. Therefore, it is important to look into the factors that impede the provision of quality end-of-life care from their perspectives. Many barriers affecting the provision of EOLC in critical care areas have been reported in the literature [ 13 , 16 , 17 ].

End-of-life care (EOLC) involves caring for and managing terminally ill patients and families. The quality of EOLC in critical care units has been evaluated based on factors such as patient/family involvement in decision-making, professional communication between health professionals and patients/families, care quality, support types, illness and symptom management, spirituality, and organizational support for critical care nurses [ 18 ]. Furthermore, working in a critical care unit environment is stressful and emotionally taxing for health professionals such as nurses. Carers of terminally ill patients may experience distressing emotions such as helplessness, loss of power, sadness, and hopelessness [ 18 ]. These feelings make it difficult to provide optimal end-of-life care. Additionally, nurses focus on managing symptoms, disease prognosis, treatment options, and physical aspects, but in fact, caring in critical care units follows a universal and holistic model. Previous research has shown that patients and families are not receiving adequate care at the end of life.

Researchers categorized factors that affect EOLC into barriers and challenges [ 13 ]. Barriers have been classified into three categories: patient and family-related, nurses and other health care workers’ related, and health care institutions’ related [ 16 , 17 ].

Barriers related to communication between health care providers and patients and families and characteristics of critical care nurses, including nurses’ age, gender, educational level, and end-of-life care training, significantly affect providing good EOLC [ 19 , 20 , 21 , 22 , 23 ]. this integrative review aims to go beyond merely identifying and categorizing barriers. By synthesizing results from a wide range of studies, the review seeks to uncover patterns and insights that have not been fully explored in the existing literature to enhance understanding of these barriers. This can help to inform future research, care provision, and policy-making. Specifically, this review will examine how these barriers interact, their cumulative impact on care quality, and potential strategies to overcome Despite the fact that EOLC is decisive to patient care, appropriate provision of this service is still lacking in several aspects. In the ICUs, EOLC must be considered an essential factor. However, owing to the existing practices of nurses, the adequate delivery of EOLC tends to bear various inefficiencies.

Nurses and other healthcare staff seem to come across multiple barriers that hinder their ability to offer effective care to critically ill patients. Considering the given dearth of research in this context, we intend to present a comprehensive insight into the issue. In this review, we focused on EOLC provided by critical care nurses, who were defined as nurses dealing with patients suffering from acute health problems due to injury, surgery, or exacerbated chronic diseases and need close monitoring in units such as intensive care units (surgical, medical, and pediatric) and cardiac care units. Due to the importance of exploring these barriers in determining the quality of EOLC, this integrative review paper was conducted to examine and highlight evidence from the literature on these barriers that affect the provision of quality EOLC. This paper explores and identifies current published peer-reviewed studies addressing barriers that affect the quality of EOLC as perceived by critical care nurses. This integrative review seeks to answer the following question: What barriers affect the quality of end-of-life care perceived by nurses working in critical care units?

An integrative review design was the most suitable method to explore and produce a new understanding from various types of literature (experimental, non-experimental, and theoretical) to enhance understanding of the phenomenon under investigation (i.e., EOLC). This method also facilitated nursing science by informing further research, care provision, and policy-making. It also highlights strengths, weaknesses, limitations, and gaps in knowledge, and supports what is already known about theories relevant to our topic [ 24 ]. Therefore, this design helps meet this review’s purposes.

Search strategies

The search process involved four phases which were developed by the first author (YR) and validated by two expert authors (MCC and KLA) as follows: (1) identifying the problems related to the research question, (2) conducting a systematic literature search, (3) screening the articles to develop themes, and (4) performing critical analysis to develop the themes.

From October 30, 2023, to November 10, 2023, electronic literature searches were conducted using major databases such as MEDLINE, Cochrane, CINAHL, EBSCO, and ScienceDirect.

Search methods were defined using the MeSH (Medical Subject Headings) descriptors of the keywords “end-of-life care,” “barriers,” and “critical care nurses.” Additionally, the reference lists of all identified articles were manually searched for additional studies. The operators used in this search included “AND” and “OR,” as well as the truncation tools of each database. A refined search was performed with terms such as “critical care nurses’ perceptions” OR “opinions” AND “quality end-of-life care” OR “quality of death and dying.” Subsequently, terms like “barriers” OR “obstacles” OR “challenges” AND “quality end-of-life care” OR “quality of death and dying” were employed. Finally, the descriptors “critical care nurses’ perceptions,” “barriers,” and “quality end-of-life care” were used (Fig.  1 ).

PRISMA search flow diagram

Inclusion and exclusion criteria

The inclusion criteria for this search to select relevant articles were as follows: (1) Full-text articles, (2) Papers published in the English language from 2010 to 2023, and (3) Articles that specifically describe the barriers perceived by critical care nurses that affect the quality of end-of-life care.

Intervention studies and studies that describe barriers to providing quality end-of-life care from other perspectives, such as physicians and patients’ families were excluded. For the studies who included nurses and other health care workers within the context of critical care, the researchers included the results that relevant to nurses and excluded the others.

Data extraction

The data extraction and analysis were carried out to collect and consolidate the data from the selected studies into a standard format relevant to the research field. The extracted data included specific descriptions of the settings, populations, study methods, and outcome measures (Table  31 ). Two authors (YSR and KLA) independently extracted the data and reached an agreement after discussion with the third author (MCC).

Included and excluded studies

Following the review process, the authors made the final decision on studies that met the study criteria. Out of a total of 103 articles, 9 duplicates were removed. The abstracts of the remaining 94 articles were initially found to be somewhat relevant to the research topic. However, after examining the articles in terms of research methodology and results, 36 articles that matched the selection criteria for this study were ultimately chosen. The full text of the 36 articles was reexamined based on the title first for suitability. Subsequently, the abstracts of the studies were reviewed, leading to the exclusion of 23 articles for various reasons, leaving 13 studies for further consideration in this study. However, two articles were disqualified as they did not contain a specific research methodology or reviewed literature papers; they relied solely on theoretical information. This step resulted in the inclusion of 11 research articles in this integrative review of the literature (Table  1 ).

Quality appraisal

To ensure the methodology’s quality and avoid bias in the design, highly credible and respected search engines were adopted to select peer-reviewed studies according to the inclusion criteria in this review. The articles chosen in this review were categorized into two sections based on study design and research methodology: quantitative and qualitative studies. These were evaluated manually and independently for each study, with any disagreements resolved by two experts (KLA, Professor, and MCC, Associate Professor) who have experience in research methodology, using the Mixed Methods Appraisal Tool (MMAT) version 2018 [ 25 ]. This tool includes specific criteria for evaluating the quality of quantitative, qualitative, and mixed-method studies. The MMAT consists of a checklist of five research components for each type of study with a rating scale including “Yes,” “No,” and “Can’t tell.” The overall results suggest that the evidence quality across the ten studies was high (Table  2 ).

Data synthesis

Thematic analysis in this review involves a systematic process of coding and theme development, using both inductive and deductive approaches. This method ensures a comprehensive synthesis of diverse data sources, providing valuable insights into the research topic [ 24 , 26 ]. Thematic analysis was employed for all studies to investigate the subject of interest. The coding for the themes in this review followed the six recommended phases: Familiarizing with the data; making initial codes; searching for themes; reviewing themes and making a thematic plan; defining and naming themes; generating the final picture of the report [ 24 ]. The coding was conducted by the primary author (YSR) and confirmed by the three secondary authors (LH, SM, and LY). Any discrepancies were discussed and resolved through consensus.

Search outcomes

The search process yielded a total of 103 articles. All articles resulting from the search process were independently reviewed by all authors in this study for the research process, purpose, methodology, tools, main findings, recommendations, and limitations.

Characteristics of included studies

Eight cross-sectional descriptive studies and three qualitative studies were selected, which were conducted in the following countries: two from the USA [ 27 , 28 ] and a single study from each of the following countries: Saudi Arabia [ 22 ], Jordan [ 29 ], Egypt [ 12 ], Malaysia [ 13 ], Scotland [ 30 ], Poland [ 31 ], Hong Kong [ 32 ], South Africa [ 33 ], and China [ 34 ].

In this comprehensive analysis of 11 studies, a diverse range of methodologies and findings were examined across different countries and healthcare settings. The studies included a mix of quantitative and qualitative approaches, with sample sizes varying from small convenience samples to larger cohorts. Key barriers to providing End of Life Care (EOLC) were identified, such as challenges in communication with families, lack of support from managers, and insufficient training in EOLC. The studies highlighted the importance of addressing these barriers to improve the quality of care provided by nurses in critical care settings. Notably, demographic characteristics and their impact on EOLC provision were not consistently addressed across the studies, indicating a potential area for further research and exploration in this field (Table  31 ).

The thematic analysis of included studies revealed several key themes and sub-themes related to barriers in End of Life Care (EOLC). These themes encompassed various aspects, including challenges related to patients and their families, healthcare institutions and the environment, as well as barriers specific to nurses. Communication and collaboration between patients, nurses, and families included issues such as seeking updates about patient status, misunderstandings about life-saving measures, misunderstanding poor prognosis, troubled family dynamics, and conflicts within families regarding life support decisions [ 22 , 34 ]. Additionally, barriers related to Institution Policy and procedures highlighted concerns such as insufficient standard procedures, communication challenges in decision-making, inadequate ICU design, inappropriate staffing policies, and deficiencies in rooms, supplies, and noise control. Furthermore, barriers associated with nurses encompassed their emotional experiences and socio-demographic characteristics [ 12 ] (Table  4 ).

Among the results of the selected articles on nurses’ perceptions of barriers affecting quality EOLC, three main themes were identified: (1) Communication and collaboration between patients, nurses, and families (2) Institution Policy and procedural barriers, and (3) barriers related to nurses and their demographics. An overlap in some of these areas, such as the themes addressing barriers related to patients and their families, was identified [ 11 , 22 , 35 ]. This overlap indicates a high level of consensus between the authors in identifying the barriers affecting the quality of end-of-life care.

Communication and collaboration between patients, nurses, and families

After reviewing the existing body of literature in this domain, it was observed that some familial factors had been largely perceived as prominent barriers to providing EOLC by the nurses. Although some authors concluded family issues as the highest-ranking concern for nurses in providing quality EOLC, there were variations in the type of barriers they encountered [ 11 , 28 , 35 ]. For example, continuous requests for updates on patients’ status from their families were identified as the top-rated barrier affecting the quality of EOLC from the perspective of critical care nurses. In addition, family misunderstandings about life-saving measures, as well as doubts and uncertainties regarding prognosis, resulted in a lack of time for nurses to provide quality EOLC, as they spent significant time explaining these matters [ 29 ]. Similarly, continuous phone calls from family members seeking updates on patients’ conditions were ranked highest (M = 4.23) among barriers affecting EOLC [ 28 ]. Additionally, dealing with distressed family members also received the highest total mean score (M = 3.3) [ 13 ]. On the contrary, another study found that out of 70 nurses, the practice of calling nurses for updates on patients’ conditions had the lowest impact on EOLC practice (62.2%), while misunderstanding about life-saving measures (65.7%) played a crucial role in determining the quality of EOLC [ 36 ]. The study concluded that the primary barrier related to patients and their families was the lack of understanding among family members about what life-saving measures entailed. Similarly, another source also reported consistent findings indicating that families often did not accept poor prognoses for patients and struggled to grasp the significance of life-saving measures [ 22 ].

Furthermore, previous studies have indicated that barriers affecting EOLC and thereby the quality of care include the presence of family members with patients, inadequate communication with patients’ families, lack of involvement in discussions about patient care decisions, conflicts among family members regarding decisions to cease or continue life support treatment, and unrealistic expectations regarding prognosis [ 22 , 30 , 37 ].

Communication and collaboration among doctors and nurses are vital in designing an effective healthcare plan for patients. However, inadequate and inappropriate collaboration and support, such as conflicting opinions, disagreements, and insufficient cooperation between them, can lead to various difficulties that may result in poor patient care [ 22 ]. Research scholars who have conducted studies in this area have acknowledged that agreement between nurses and physicians regarding care directions for patients at the end of life is one of the most critical barriers to enhancing the quality of EOLC [ 29 ].

Similarly, another study found that poor communication between nurses and physicians resulted in inappropriate decision-making and disagreement about care plans, which subsequently impacted the quality of care [ 13 ]. Additionally, inadequate and poor communication between nurses and other healthcare teams diverted attention from the goal of care [ 28 ].

Failures in communication between nurses and other healthcare providers can lead to misunderstandings of care messages, which can affect EOLC practices [ 30 ]. It also highlighted the lack of communication and cooperation between doctors and other healthcare team members; nurses emphasized the need for a communication training course [ 11 ].

Good communication between nurses and physicians and consideration of nurses’ opinions were found to enhance the quality of EOLC [ 12 ]. Furthermore, educating critical care nurses about communication and collaboration skills was reported as crucial for improving the quality of EOLC [ 13 ].

Barriers related to nurses

The given three sub-themes were identified regarding the impact of nurses-related barriers and the influence of some of their demographic factors on the quality of EOLC:

Lack of opportunities for training and education.

Emotional and psychological issue.

Nurses’ socio -demographic factors.

Lack of opportunities for training and education

It was reported that critical care nurses were not adequately prepared to provide EOLC; nurses needed to increase their knowledge about cultural aspects, ethical issues, skills, communication, and training regarding the continuity of care and the management of physical and psychosocial symptoms [ 11 , 13 , 28 ]. Furthermore, nurses who did not participate in any EOLC training course perceived more barriers to delivering quality EOLC than those who had participated in introductory training courses [ 13 , 28 ]. Attia et al. [ 12 ]. reported that 60% of critical care nurses perceived that they had received poor education and training concerning family grieving, symptom management, and quality EOLC. Furthermore, Holms et al. [ 30 ]. found that all participants acknowledged that they had received very little formal education and training on EOLC, particularly those who worked in intensive care. In a study by Jordan et al. [ 37 ], nurses emphasized that EOLC education is essential during the orientation period before starting their ICU jobs.

Emotional and psychological issue

Five articles in this review have studied the effect of nurses’ feelings and emotions as barriers to providing quality EOLC [ 11 , 13 , 28 , 30 , 37 ]. Nurses stated that they feel sad when they cannot help the patients to die peacefully, and they lack emotional support, considering this one of the main barriers to providing EOLC [ 11 ]. Staff morale distress was reported repeatedly during interviews with ICU nurses about their experience of EOLC. This feeling of despair is accompanied by many causes, such as lack of staff experience, poor communication, inadequate training about EOLC, lack of a suitable environment, and lack of support from senior staff [ 30 ]. Nurses acknowledged that they felt like they were participating in decisions to withdraw or withhold life-sustaining treatment, resulting in conflicting emotions and feeling helpless in advocating for the patients with mixed feelings of sadness, grief, anger, and frustration [ 37 ]. Lastly, Crump et al. [ 28 ] and Omar Daw Hussin et al. [ 13 ] observed that critical care nurses received inadequate emotional support from managers and experts within healthcare institutions, which affects the quality of EOLC they provide.

Nurses’ socio -demographic factors

It has been identified that some socio-demographic characteristics of nurses also play a significant role in shaping their opinions regarding perceived barriers. For example, age, education, experience in the field, and other similar factors profoundly impact their perceptions of the barriers to providing EOLC. A study by Omar Daw Hussin et al. [ 13 ] revealed that nurses ( n  = 553) aged 21–30 years old had the highest mean total score for barrier factors to provide quality EOLC compared to other age groups. This was also higher in diploma holders than in nurses with certificates and bachelor’s degrees. Regarding years of experience as critical care nurses, they found that nurses with minimal years of experience (1–10 years) had the highest mean total score for difficulties. Similarly, Chan et al. [ 38 ] found that nurses’ age, qualifications, and experience in caring for patients at EOL were significantly associated with their perceived barriers. Nurses’ distress in intensive care units was linked to various factors, one of which is the lack of experience in providing EOLC, as reported by Holms et al. [ 30 ].

Institution Policy and procedural barriers

Healthcare facilities and the surrounding environment where patients stay have a significant influence on their quick recovery, mental and physical health, as well as health progress [ 11 ]. Therefore, healthcare institutions ought to establish a healthy environment for patients’ well-being. However, in the current review, it was understood that nurses identified a group of barriers related to hospital settings, such as the insufficiency of standard procedures pertaining to EOLC in place at the institution, inappropriate staffing policies in the ICU, lack of rooms prepared for EOLC, insufficient supplies to assist families in EOLC, and a noisy environment with bright lights in patients’ rooms [ 11 ]. Likewise, researchers concluded that intensive care unit nurses face time constraints due to heavy workloads; they also reported that intensive care units have poor designs that interrupt patients’ privacy and affect the provision of quality EOLC [ 12 , 28 ]. Previous studies identified a lack of EOLC rules and guidelines governing the provision of quality EOLC in critical care units, such as limited visiting hours, guiding preferred care pathways, and excessive paperwork burdens [ 12 , 13 , 30 ].

In this section, we discuss the results of this review on the barriers to providing quality end-of-life care derived from the literature and compare them with the results of previous studies.

The themes emerging from the data helped us understand that some familial factors play a decisive role in hindering timely and effective EOLC provision to patients. Our findings are consistent with Beckstrand et al. [ 36 ] and Friedenberg et al. [ 39 ], who also found that families’ lack of understanding or insufficient understanding of the life-saving measures performed for patients often contributes to delayed EOLC provision, due to their ambiguous opinions and uncertainty about the treatment given. Additionally, before taking any action, barriers related to other factors such as cultural aspects, not covered in this paper, should not be disregarded as they may have a significant influence on the outcomes.

There was agreement among all the authors in this review that communication and collaboration issues were at the forefront of factors that affect the quality of EOLC.in critical care setings, poor communication and collaboration between nurses and physicians makes nurses perceive their roles as secondary in the decision-making process. Additionally, critical care nurses also noted that interrupted communication leads to misunderstandings and conflicts in decision-making, diverting them from the goal of EOLC. It was also agreed that communication breakdown and conflicts in decision-making among healthcare teams impact the quality of care for patients with chronic end-stage diseases [ 40 ].

Reviewing the selected studies made us aware that nurses perceived inadequate training and education about EOLC significantly impacts their practice in delivering quality EOLC. The nurses also acknowledged the importance of receiving training and education regarding EOLC, such as symptom management, dealing with grieving families, and communication skills during the orientation period before starting their work in critical care units. Therefore, critical care nurses need to enhance their knowledge about cultural aspects, ethical issues, communication skills, and training related to the continuity of care and the management of physical and psychosocial symptoms [ 36 ].

Apart from training issues, we found that the feeling of not being able to provide proper care to some patients, consistent distress due to increased workload, or managing patients with critical conditions such as prolonging unavoidable death could be attributed to their deteriorating mental health, which they perceive as a barrier to offering EOLC. These results were also supported by Calvin et al. [ 41 ], who found that novice cardiac care unit nurses expressed more fear and discomfort while caring for dying patients and communicating with their families.

This review further shows that healthcare organizations lack policies and guidelines that govern EOLC, such as staffing policies and scheduling visiting hours, leading to a shortage of nurses, increased workload, and decreased presence of family members with their patients. This lack of policies was also indicated in their study [ 36 ]. Critical care units in this review have a poor design that challenges nurses when providing EOLC and interrupts patient privacy. This is consistent with Sheward et al. [ 42 ], who found that the poor design of critical care units may compromise patients’ confidentiality and affect the provision of quality EOLC.

In summary, our findings revealed that some familial factors play a decisive role in hindering timely and effective EOLC provision to patients. Moreover, nurses perceived that inadequate training and education about EOLC significantly impact their practice in providing good EOLC. Therefore, these aspects of our results are confirmed by broader literature, as evidenced before. The ceuurent review highlights the importance of enhancing family communication throught the needs for conducting education and training programs among health care profesionals in crirical care settings about communication skills. Additionally, healthcare organizations lack policies and guidelines that lead to a shortage of nurses, increased workload, and decreased family members’ presence with their patients, governing EOLC. Thus, this integrative review addresses the question of what barriers affect the quality of end-of-life care as perceived by nurses working in critical care units. Combining diverse methodologies can lead to inadequate rigor, imprecision, bias, flawed analysis, synthesis, and deductions. Therefore, there is a need for future studies to further refine the key indicators.

Strengths and limitations

The selected studies were conducted in several countries, which may enhance the generalizability of the study findings. The limitations of this review study are that it focused mainly on descriptive and non-experimental studies. Additionally, the assessment of quality appraisal for selected studies was subjective to the authors according to MMAT, which could affect the studies’ appraisal. The selection of only English articles may introduce bias regarding barriers beyond EOLC in countries where English is not commonly spoken.

The review indicated that healthcare organizations must provide critical care nurses with evidence-based pathways and guidelines to guide them in providing EOLC, increase emotional support from nursing managers and supervisors, and improve critical care settings design. Further studies need to be conducted on the barriers that affect the quality of EOLC and suggestions to overcome these barriers at the level of patients and families, nurses, physicians, other healthcare providers, and healthcare organizations to enhance teamwork and collaboration and improve the quality of EOLC.

This review also calls for additional research to be conducted to explore the barriers that affect the quality of end-of-life care. These studies should investigate barriers at multiple levels, including those affecting patients and families, nurses, physicians, other healthcare providers, and healthcare organizations. By identifying and understanding these barriers, recommendations can be made to overcome them, ultimately enhancing teamwork, collaboration, and the overall quality of end-of-life care.

International implications for practice

Many tools can be easily used to assess barriers to end-of-life care in critical care settings. We recommend monitoring and evaluating them regularly among nurses because they are significantly linked to the quality of end-of-life care. Furthermore, we advise to assess the quality of end-of-life care from patients and their families perspectives and provide them with greif and emotional support if they are unable to contribute in providing feedback that help in assissing the quality of end-of- life care. Refreshing training and education courses about end-of-life care aspects are significantly associated with the quality of care. We advise nursing management to conduct such courses for critical care nurses periodically. In general, there is an opportunity for improvement in terms of the quality of end-of-life care in critical care settings. As the critical care unit is part of a larger institution, it is worthwhile for the hospital’s management to adjust their policies regarding staffing, ICU design, visiting hours, and provide evidence-based guidelines so they can enhance the quality of end-of-life care.

Data availability

The data used to support the findings of this study are included within the article.

Abbreviations

End-Of-Life-Care

Mixed Method Appraisal Tool

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Knowledge mapping and evolution of research on older adults’ technology acceptance: a bibliometric study from 2013 to 2023

• Xianru Shang   ORCID: orcid.org/0009-0000-8906-3216 1 ,
• Zijian Liu 1 ,
• Chen Gong 1 ,
• Zhigang Hu 1 ,
• Yuexuan Wu 1 &
• Chengliang Wang   ORCID: orcid.org/0000-0003-2208-3508 2  

Humanities and Social Sciences Communications volume  11 , Article number:  1115 ( 2024 ) Cite this article

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• Science, technology and society

The rapid expansion of information technology and the intensification of population aging are two prominent features of contemporary societal development. Investigating older adults’ acceptance and use of technology is key to facilitating their integration into an information-driven society. Given this context, the technology acceptance of older adults has emerged as a prioritized research topic, attracting widespread attention in the academic community. However, existing research remains fragmented and lacks a systematic framework. To address this gap, we employed bibliometric methods, utilizing the Web of Science Core Collection to conduct a comprehensive review of literature on older adults’ technology acceptance from 2013 to 2023. Utilizing VOSviewer and CiteSpace for data assessment and visualization, we created knowledge mappings of research on older adults’ technology acceptance. Our study employed multidimensional methods such as co-occurrence analysis, clustering, and burst analysis to: (1) reveal research dynamics, key journals, and domains in this field; (2) identify leading countries, their collaborative networks, and core research institutions and authors; (3) recognize the foundational knowledge system centered on theoretical model deepening, emerging technology applications, and research methods and evaluation, uncovering seminal literature and observing a shift from early theoretical and influential factor analyses to empirical studies focusing on individual factors and emerging technologies; (4) moreover, current research hotspots are primarily in the areas of factors influencing technology adoption, human-robot interaction experiences, mobile health management, and aging-in-place technology, highlighting the evolutionary context and quality distribution of research themes. Finally, we recommend that future research should deeply explore improvements in theoretical models, long-term usage, and user experience evaluation. Overall, this study presents a clear framework of existing research in the field of older adults’ technology acceptance, providing an important reference for future theoretical exploration and innovative applications.

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Introduction.

In contemporary society, the rapid development of information technology has been intricately intertwined with the intensifying trend of population aging. According to the latest United Nations forecast, by 2050, the global population aged 65 and above is expected to reach 1.6 billion, representing about 16% of the total global population (UN 2023 ). Given the significant challenges of global aging, there is increasing evidence that emerging technologies have significant potential to maintain health and independence for older adults in their home and healthcare environments (Barnard et al. 2013 ; Soar 2010 ; Vancea and Solé-Casals 2016 ). This includes, but is not limited to, enhancing residential safety with smart home technologies (Touqeer et al. 2021 ; Wang et al. 2022 ), improving living independence through wearable technologies (Perez et al. 2023 ), and increasing medical accessibility via telehealth services (Kruse et al. 2020 ). Technological innovations are redefining the lifestyles of older adults, encouraging a shift from passive to active participation (González et al. 2012 ; Mostaghel 2016 ). Nevertheless, the effective application and dissemination of technology still depends on user acceptance and usage intentions (Naseri et al. 2023 ; Wang et al. 2023a ; Xia et al. 2024 ; Yu et al. 2023 ). Particularly, older adults face numerous challenges in accepting and using new technologies. These challenges include not only physical and cognitive limitations but also a lack of technological experience, along with the influences of social and economic factors (Valk et al. 2018 ; Wilson et al. 2021 ).

User acceptance of technology is a significant focus within information systems (IS) research (Dai et al. 2024 ), with several models developed to explain and predict user behavior towards technology usage, including the Technology Acceptance Model (TAM) (Davis 1989 ), TAM2, TAM3, and the Unified Theory of Acceptance and Use of Technology (UTAUT) (Venkatesh et al. 2003 ). Older adults, as a group with unique needs, exhibit different behavioral patterns during technology acceptance than other user groups, and these uniquenesses include changes in cognitive abilities, as well as motivations, attitudes, and perceptions of the use of new technologies (Chen and Chan 2011 ). The continual expansion of technology introduces considerable challenges for older adults, rendering the understanding of their technology acceptance a research priority. Thus, conducting in-depth research into older adults’ acceptance of technology is critically important for enhancing their integration into the information society and improving their quality of life through technological advancements.

Reviewing relevant literature to identify research gaps helps further solidify the theoretical foundation of the research topic. However, many existing literature reviews primarily focus on the factors influencing older adults’ acceptance or intentions to use technology. For instance, Ma et al. ( 2021 ) conducted a comprehensive analysis of the determinants of older adults’ behavioral intentions to use technology; Liu et al. ( 2022 ) categorized key variables in studies of older adults’ technology acceptance, noting a shift in focus towards social and emotional factors; Yap et al. ( 2022 ) identified seven categories of antecedents affecting older adults’ use of technology from an analysis of 26 articles, including technological, psychological, social, personal, cost, behavioral, and environmental factors; Schroeder et al. ( 2023 ) extracted 119 influencing factors from 59 articles and further categorized these into six themes covering demographics, health status, and emotional awareness. Additionally, some studies focus on the application of specific technologies, such as Ferguson et al. ( 2021 ), who explored barriers and facilitators to older adults using wearable devices for heart monitoring, and He et al. ( 2022 ) and Baer et al. ( 2022 ), who each conducted in-depth investigations into the acceptance of social assistive robots and mobile nutrition and fitness apps, respectively. In summary, current literature reviews on older adults’ technology acceptance exhibit certain limitations. Due to the interdisciplinary nature and complex knowledge structure of this field, traditional literature reviews often rely on qualitative analysis, based on literature analysis and periodic summaries, which lack sufficient objectivity and comprehensiveness. Additionally, systematic research is relatively limited, lacking a macroscopic description of the research trajectory from a holistic perspective. Over the past decade, research on older adults’ technology acceptance has experienced rapid growth, with a significant increase in literature, necessitating the adoption of new methods to review and examine the developmental trends in this field (Chen 2006 ; Van Eck and Waltman 2010 ). Bibliometric analysis, as an effective quantitative research method, analyzes published literature through visualization, offering a viable approach to extracting patterns and insights from a large volume of papers, and has been widely applied in numerous scientific research fields (Achuthan et al. 2023 ; Liu and Duffy 2023 ). Therefore, this study will employ bibliometric methods to systematically analyze research articles related to older adults’ technology acceptance published in the Web of Science Core Collection from 2013 to 2023, aiming to understand the core issues and evolutionary trends in the field, and to provide valuable references for future related research. Specifically, this study aims to explore and answer the following questions:

RQ1: What are the research dynamics in the field of older adults’ technology acceptance over the past decade? What are the main academic journals and fields that publish studies related to older adults’ technology acceptance?

RQ2: How is the productivity in older adults’ technology acceptance research distributed among countries, institutions, and authors?

RQ3: What are the knowledge base and seminal literature in older adults’ technology acceptance research? How has the research theme progressed?

RQ4: What are the current hot topics and their evolutionary trajectories in older adults’ technology acceptance research? How is the quality of research distributed?

Methodology and materials

Research method.

In recent years, bibliometrics has become one of the crucial methods for analyzing literature reviews and is widely used in disciplinary and industrial intelligence analysis (Jing et al. 2023 ; Lin and Yu 2024a ; Wang et al. 2024a ; Xu et al. 2021 ). Bibliometric software facilitates the visualization analysis of extensive literature data, intuitively displaying the network relationships and evolutionary processes between knowledge units, and revealing the underlying knowledge structure and potential information (Chen et al. 2024 ; López-Robles et al. 2018 ; Wang et al. 2024c ). This method provides new insights into the current status and trends of specific research areas, along with quantitative evidence, thereby enhancing the objectivity and scientific validity of the research conclusions (Chen et al. 2023 ; Geng et al. 2024 ). VOSviewer and CiteSpace are two widely used bibliometric software tools in academia (Pan et al. 2018 ), recognized for their robust functionalities based on the JAVA platform. Although each has its unique features, combining these two software tools effectively constructs mapping relationships between literature knowledge units and clearly displays the macrostructure of the knowledge domains. Particularly, VOSviewer, with its excellent graphical representation capabilities, serves as an ideal tool for handling large datasets and precisely identifying the focal points and hotspots of research topics. Therefore, this study utilizes VOSviewer (version 1.6.19) and CiteSpace (version 6.1.R6), combined with in-depth literature analysis, to comprehensively examine and interpret the research theme of older adults’ technology acceptance through an integrated application of quantitative and qualitative methods.

Data source

Web of Science is a comprehensively recognized database in academia, featuring literature that has undergone rigorous peer review and editorial scrutiny (Lin and Yu 2024b ; Mongeon and Paul-Hus 2016 ; Pranckutė 2021 ). This study utilizes the Web of Science Core Collection as its data source, specifically including three major citation indices: Science Citation Index Expanded (SCIE), Social Sciences Citation Index (SSCI), and Arts & Humanities Citation Index (A&HCI). These indices encompass high-quality research literature in the fields of science, social sciences, and arts and humanities, ensuring the comprehensiveness and reliability of the data. We combined “older adults” with “technology acceptance” through thematic search, with the specific search strategy being: TS = (elder OR elderly OR aging OR ageing OR senile OR senior OR old people OR “older adult*”) AND TS = (“technology acceptance” OR “user acceptance” OR “consumer acceptance”). The time span of literature search is from 2013 to 2023, with the types limited to “Article” and “Review” and the language to “English”. Additionally, the search was completed by October 27, 2023, to avoid data discrepancies caused by database updates. The initial search yielded 764 journal articles. Given that searches often retrieve articles that are superficially relevant but actually non-compliant, manual screening post-search was essential to ensure the relevance of the literature (Chen et al. 2024 ). Through manual screening, articles significantly deviating from the research theme were eliminated and rigorously reviewed. Ultimately, this study obtained 500 valid sample articles from the Web of Science Core Collection. The complete PRISMA screening process is illustrated in Fig. 1 .

Presentation of the data culling process in detail.

Data standardization

Raw data exported from databases often contain multiple expressions of the same terminology (Nguyen and Hallinger 2020 ). To ensure the accuracy and consistency of data, it is necessary to standardize the raw data (Strotmann and Zhao 2012 ). This study follows the data standardization process proposed by Taskin and Al ( 2019 ), mainly executing the following operations:

(1) Standardization of author and institution names is conducted to address different name expressions for the same author. For instance, “Chan, Alan Hoi Shou” and “Chan, Alan H. S.” are considered the same author, and distinct authors with the same name are differentiated by adding identifiers. Diverse forms of institutional names are unified to address variations caused by name changes or abbreviations, such as standardizing “FRANKFURT UNIV APPL SCI” and “Frankfurt University of Applied Sciences,” as well as “Chinese University of Hong Kong” and “University of Hong Kong” to consistent names.

(2) Different expressions of journal names are unified. For example, “International Journal of Human-Computer Interaction” and “Int J Hum Comput Interact” are standardized to a single name. This ensures consistency in journal names and prevents misclassification of literature due to differing journal names. Additionally, it involves checking if the journals have undergone name changes in the past decade to prevent any impact on the analysis due to such changes.

(3) Keywords data are cleansed by removing words that do not directly pertain to specific research content (e.g., people, review), merging synonyms (e.g., “UX” and “User Experience,” “aging-in-place” and “aging in place”), and standardizing plural forms of keywords (e.g., “assistive technologies” and “assistive technology,” “social robots” and “social robot”). This reduces redundant information in knowledge mapping.

Bibliometric results and analysis

Distribution power (rq1), literature descriptive statistical analysis.

Table 1 presents a detailed descriptive statistical overview of the literature in the field of older adults’ technology acceptance. After deduplication using the CiteSpace software, this study confirmed a valid sample size of 500 articles. Authored by 1839 researchers, the documents encompass 792 research institutions across 54 countries and are published in 217 different academic journals. As of the search cutoff date, these articles have accumulated 13,829 citations, with an annual average of 1156 citations, and an average of 27.66 citations per article. The h-index, a composite metric of quantity and quality of scientific output (Kamrani et al. 2021 ), reached 60 in this study.

Trends in publications and disciplinary distribution

The number of publications and citations are significant indicators of the research field’s development, reflecting its continuity, attention, and impact (Ale Ebrahim et al. 2014 ). The ranking of annual publications and citations in the field of older adults’ technology acceptance studies is presented chronologically in Fig. 2A . The figure shows a clear upward trend in the amount of literature in this field. Between 2013 and 2017, the number of publications increased slowly and decreased in 2018. However, in 2019, the number of publications increased rapidly to 52 and reached a peak of 108 in 2022, which is 6.75 times higher than in 2013. In 2022, the frequency of document citations reached its highest point with 3466 citations, reflecting the widespread recognition and citation of research in this field. Moreover, the curve of the annual number of publications fits a quadratic function, with a goodness-of-fit R 2 of 0.9661, indicating that the number of future publications is expected to increase even more rapidly.

A Trends in trends in annual publications and citations (2013–2023). B Overlay analysis of the distribution of discipline fields.

Figure 2B shows that research on older adults’ technology acceptance involves the integration of multidisciplinary knowledge. According to Web of Science Categories, these 500 articles are distributed across 85 different disciplines. We have tabulated the top ten disciplines by publication volume (Table 2 ), which include Medical Informatics (75 articles, 15.00%), Health Care Sciences & Services (71 articles, 14.20%), Gerontology (61 articles, 12.20%), Public Environmental & Occupational Health (57 articles, 11.40%), and Geriatrics & Gerontology (52 articles, 10.40%), among others. The high output in these disciplines reflects the concentrated global academic interest in this comprehensive research topic. Additionally, interdisciplinary research approaches provide diverse perspectives and a solid theoretical foundation for studies on older adults’ technology acceptance, also paving the way for new research directions.

Knowledge flow analysis

A dual-map overlay is a CiteSpace map superimposed on top of a base map, which shows the interrelationships between journals in different domains, representing the publication and citation activities in each domain (Chen and Leydesdorff 2014 ). The overlay map reveals the link between the citing domain (on the left side) and the cited domain (on the right side), reflecting the knowledge flow of the discipline at the journal level (Leydesdorff and Rafols 2012 ). We utilize the in-built Z-score algorithm of the software to cluster the graph, as shown in Fig. 3 .

The left side shows the citing journal, and the right side shows the cited journal.

Figure 3 shows the distribution of citing journals clusters for older adults’ technology acceptance on the left side, while the right side refers to the main cited journals clusters. Two knowledge flow citation trajectories were obtained; they are presented by the color of the cited regions, and the thickness of these trajectories is proportional to the Z-score scaled frequency of citations (Chen et al. 2014 ). Within the cited regions, the most popular fields with the most records covered are “HEALTH, NURSING, MEDICINE” and “PSYCHOLOGY, EDUCATION, SOCIAL”, and the elliptical aspect ratio of these two fields stands out. Fields have prominent elliptical aspect ratios, highlighting their significant influence on older adults’ technology acceptance research. Additionally, the major citation trajectories originate in these two areas and progress to the frontier research area of “PSYCHOLOGY, EDUCATION, HEALTH”. It is worth noting that the citation trajectory from “PSYCHOLOGY, EDUCATION, SOCIAL” has a significant Z-value (z = 6.81), emphasizing the significance and impact of this development path. In the future, “MATHEMATICS, SYSTEMS, MATHEMATICAL”, “MOLECULAR, BIOLOGY, IMMUNOLOGY”, and “NEUROLOGY, SPORTS, OPHTHALMOLOGY” may become emerging fields. The fields of “MEDICINE, MEDICAL, CLINICAL” may be emerging areas of cutting-edge research.

Main research journals analysis

Table 3 provides statistics for the top ten journals by publication volume in the field of older adults’ technology acceptance. Together, these journals have published 137 articles, accounting for 27.40% of the total publications, indicating that there is no highly concentrated core group of journals in this field, with publications being relatively dispersed. Notably, Computers in Human Behavior , Journal of Medical Internet Research , and International Journal of Human-Computer Interaction each lead with 15 publications. In terms of citation metrics, International Journal of Medical Informatics and Computers in Human Behavior stand out significantly, with the former accumulating a total of 1,904 citations, averaging 211.56 citations per article, and the latter totaling 1,449 citations, with an average of 96.60 citations per article. These figures emphasize the academic authority and widespread impact of these journals within the research field.

Research power (RQ2)

Countries and collaborations analysis.

The analysis revealed the global research pattern for country distribution and collaboration (Chen et al. 2019 ). Figure 4A shows the network of national collaborations on older adults’ technology acceptance research. The size of the bubbles represents the amount of publications in each country, while the thickness of the connecting lines expresses the closeness of the collaboration among countries. Generally, this research subject has received extensive international attention, with China and the USA publishing far more than any other countries. China has established notable research collaborations with the USA, UK and Malaysia in this field, while other countries have collaborations, but the closeness is relatively low and scattered. Figure 4B shows the annual publication volume dynamics of the top ten countries in terms of total publications. Since 2017, China has consistently increased its annual publications, while the USA has remained relatively stable. In 2019, the volume of publications in each country increased significantly, this was largely due to the global outbreak of the COVID-19 pandemic, which has led to increased reliance on information technology among the elderly for medical consultations, online socialization, and health management (Sinha et al. 2021 ). This phenomenon has led to research advances in technology acceptance among older adults in various countries. Table 4 shows that the top ten countries account for 93.20% of the total cumulative number of publications, with each country having published more than 20 papers. Among these ten countries, all of them except China are developed countries, indicating that the research field of older adults’ technology acceptance has received general attention from developed countries. Currently, China and the USA were the leading countries in terms of publications with 111 and 104 respectively, accounting for 22.20% and 20.80%. The UK, Germany, Italy, and the Netherlands also made significant contributions. The USA and China ranked first and second in terms of the number of citations, while the Netherlands had the highest average citations, indicating the high impact and quality of its research. The UK has shown outstanding performance in international cooperation, while the USA highlights its significant academic influence in this field with the highest h-index value.

A National collaboration network. B Annual volume of publications in the top 10 countries.

Institutions and authors analysis

Analyzing the number of publications and citations can reveal an institution’s or author’s research strength and influence in a particular research area (Kwiek 2021 ). Tables 5 and 6 show the statistics of the institutions and authors whose publication counts are in the top ten, respectively. As shown in Table 5 , higher education institutions hold the main position in this research field. Among the top ten institutions, City University of Hong Kong and The University of Hong Kong from China lead with 14 and 9 publications, respectively. City University of Hong Kong has the highest h-index, highlighting its significant influence in the field. It is worth noting that Tilburg University in the Netherlands is not among the top five in terms of publications, but the high average citation count (130.14) of its literature demonstrates the high quality of its research.

After analyzing the authors’ output using Price’s Law (Redner 1998 ), the highest number of publications among the authors counted ( n  = 10) defines a publication threshold of 3 for core authors in this research area. As a result of quantitative screening, a total of 63 core authors were identified. Table 6 shows that Chen from Zhejiang University, China, Ziefle from RWTH Aachen University, Germany, and Rogers from Macquarie University, Australia, were the top three authors in terms of the number of publications, with 10, 9, and 8 articles, respectively. In terms of average citation rate, Peek and Wouters, both scholars from the Netherlands, have significantly higher rates than other scholars, with 183.2 and 152.67 respectively. This suggests that their research is of high quality and widely recognized. Additionally, Chen and Rogers have high h-indices in this field.

Knowledge base and theme progress (RQ3)

Research knowledge base.

Co-citation relationships occur when two documents are cited together (Zhang and Zhu 2022 ). Co-citation mapping uses references as nodes to represent the knowledge base of a subject area (Min et al. 2021). Figure 5A illustrates co-occurrence mapping in older adults’ technology acceptance research, where larger nodes signify higher co-citation frequencies. Co-citation cluster analysis can be used to explore knowledge structure and research boundaries (Hota et al. 2020 ; Shiau et al. 2023 ). The co-citation clustering mapping of older adults’ technology acceptance research literature (Fig. 5B ) shows that the Q value of the clustering result is 0.8129 (>0.3), and the average value of the weight S is 0.9391 (>0.7), indicating that the clusters are uniformly distributed with a significant and credible structure. This further proves that the boundaries of the research field are clear and there is significant differentiation in the field. The figure features 18 cluster labels, each associated with thematic color blocks corresponding to different time slices. Highlighted emerging research themes include #2 Smart Home Technology, #7 Social Live, and #10 Customer Service. Furthermore, the clustering labels extracted are primarily classified into three categories: theoretical model deepening, emerging technology applications, research methods and evaluation, as detailed in Table 7 .

A Co-citation analysis of references. B Clustering network analysis of references.

Seminal literature analysis

The top ten nodes in terms of co-citation frequency were selected for further analysis. Table 8 displays the corresponding node information. Studies were categorized into four main groups based on content analysis. (1) Research focusing on specific technology usage by older adults includes studies by Peek et al. ( 2014 ), Ma et al. ( 2016 ), Hoque and Sorwar ( 2017 ), and Li et al. ( 2019 ), who investigated the factors influencing the use of e-technology, smartphones, mHealth, and smart wearables, respectively. (2) Concerning the development of theoretical models of technology acceptance, Chen and Chan ( 2014 ) introduced the Senior Technology Acceptance Model (STAM), and Macedo ( 2017 ) analyzed the predictive power of UTAUT2 in explaining older adults’ intentional behaviors and information technology usage. (3) In exploring older adults’ information technology adoption and behavior, Lee and Coughlin ( 2015 ) emphasized that the adoption of technology by older adults is a multifactorial process that includes performance, price, value, usability, affordability, accessibility, technical support, social support, emotion, independence, experience, and confidence. Yusif et al. ( 2016 ) conducted a literature review examining the key barriers affecting older adults’ adoption of assistive technology, including factors such as privacy, trust, functionality/added value, cost, and stigma. (4) From the perspective of research into older adults’ technology acceptance, Mitzner et al. ( 2019 ) assessed the long-term usage of computer systems designed for the elderly, whereas Guner and Acarturk ( 2020 ) compared information technology usage and acceptance between older and younger adults. The breadth and prevalence of this literature make it a vital reference for researchers in the field, also providing new perspectives and inspiration for future research directions.

Research thematic progress

Burst citation is a node of literature that guides the sudden change in dosage, which usually represents a prominent development or major change in a particular field, with innovative and forward-looking qualities. By analyzing the emergent literature, it is often easy to understand the dynamics of the subject area, mapping the emerging thematic change (Chen et al. 2022 ). Figure 6 shows the burst citation mapping in the field of older adults’ technology acceptance research, with burst citations represented by red nodes (Fig. 6A ). For the ten papers with the highest burst intensity (Fig. 6B ), this study will conduct further analysis in conjunction with literature review.

A Burst detection of co-citation. B The top 10 references with the strongest citation bursts.

As shown in Fig. 6 , Mitzner et al. ( 2010 ) broke the stereotype that older adults are fearful of technology, found that they actually have positive attitudes toward technology, and emphasized the centrality of ease of use and usefulness in the process of technology acceptance. This finding provides an important foundation for subsequent research. During the same period, Wagner et al. ( 2010 ) conducted theory-deepening and applied research on technology acceptance among older adults. The research focused on older adults’ interactions with computers from the perspective of Social Cognitive Theory (SCT). This expanded the understanding of technology acceptance, particularly regarding the relationship between behavior, environment, and other SCT elements. In addition, Pan and Jordan-Marsh ( 2010 ) extended the TAM to examine the interactions among predictors of perceived usefulness, perceived ease of use, subjective norm, and convenience conditions when older adults use the Internet, taking into account the moderating roles of gender and age. Heerink et al. ( 2010 ) adapted and extended the UTAUT, constructed a technology acceptance model specifically designed for older users’ acceptance of assistive social agents, and validated it using controlled experiments and longitudinal data, explaining intention to use by combining functional assessment and social interaction variables.

Then the research theme shifted to an in-depth analysis of the factors influencing technology acceptance among older adults. Two papers with high burst strengths emerged during this period: Peek et al. ( 2014 ) (Strength = 12.04), Chen and Chan ( 2014 ) (Strength = 9.81). Through a systematic literature review and empirical study, Peek STM and Chen K, among others, identified multidimensional factors that influence older adults’ technology acceptance. Peek et al. ( 2014 ) analyzed literature on the acceptance of in-home care technology among older adults and identified six factors that influence their acceptance: concerns about technology, expected benefits, technology needs, technology alternatives, social influences, and older adult characteristics, with a focus on differences between pre- and post-implementation factors. Chen and Chan ( 2014 ) constructed the STAM by administering a questionnaire to 1012 older adults and adding eight important factors, including technology anxiety, self-efficacy, cognitive ability, and physical function, based on the TAM. This enriches the theoretical foundation of the field. In addition, Braun ( 2013 ) highlighted the role of perceived usefulness, trust in social networks, and frequency of Internet use in older adults’ use of social networks, while ease of use and social pressure were not significant influences. These findings contribute to the study of older adults’ technology acceptance within specific technology application domains.

Recent research has focused on empirical studies of personal factors and emerging technologies. Ma et al. ( 2016 ) identified key personal factors affecting smartphone acceptance among older adults through structured questionnaires and face-to-face interviews with 120 participants. The study found that cost, self-satisfaction, and convenience were important factors influencing perceived usefulness and ease of use. This study offers empirical evidence to comprehend the main factors that drive smartphone acceptance among Chinese older adults. Additionally, Yusif et al. ( 2016 ) presented an overview of the obstacles that hinder older adults’ acceptance of assistive technologies, focusing on privacy, trust, and functionality.

In summary, research on older adults’ technology acceptance has shifted from early theoretical deepening and analysis of influencing factors to empirical studies in the areas of personal factors and emerging technologies, which have greatly enriched the theoretical basis of older adults’ technology acceptance and provided practical guidance for the design of emerging technology products.

Research hotspots, evolutionary trends, and quality distribution (RQ4)

Core keywords analysis.

Keywords concise the main idea and core of the literature, and are a refined summary of the research content (Huang et al. 2021 ). In CiteSpace, nodes with a centrality value greater than 0.1 are considered to be critical nodes. Analyzing keywords with high frequency and centrality helps to visualize the hot topics in the research field (Park et al. 2018 ). The merged keywords were imported into CiteSpace, and the top 10 keywords were counted and sorted by frequency and centrality respectively, as shown in Table 9 . The results show that the keyword “TAM” has the highest frequency (92), followed by “UTAUT” (24), which reflects that the in-depth study of the existing technology acceptance model and its theoretical expansion occupy a central position in research related to older adults’ technology acceptance. Furthermore, the terms ‘assistive technology’ and ‘virtual reality’ are both high-frequency and high-centrality terms (frequency = 17, centrality = 0.10), indicating that the research on assistive technology and virtual reality for older adults is the focus of current academic attention.

Research hotspots analysis

Using VOSviewer for keyword co-occurrence analysis organizes keywords into groups or clusters based on their intrinsic connections and frequencies, clearly highlighting the research field’s hot topics. The connectivity among keywords reveals correlations between different topics. To ensure accuracy, the analysis only considered the authors’ keywords. Subsequently, the keywords were filtered by setting the keyword frequency to 5 to obtain the keyword clustering map of the research on older adults’ technology acceptance research keyword clustering mapping (Fig. 7 ), combined with the keyword co-occurrence clustering network (Fig. 7A ) and the corresponding density situation (Fig. 7B ) to make a detailed analysis of the following four groups of clustered themes.

A Co-occurrence clustering network. B Keyword density.

Cluster #1—Research on the factors influencing technology adoption among older adults is a prominent topic, covering age, gender, self-efficacy, attitude, and and intention to use (Berkowsky et al. 2017 ; Wang et al. 2017 ). It also examined older adults’ attitudes towards and acceptance of digital health technologies (Ahmad and Mozelius, 2022 ). Moreover, the COVID-19 pandemic, significantly impacting older adults’ technology attitudes and usage, has underscored the study’s importance and urgency. Therefore, it is crucial to conduct in-depth studies on how older adults accept, adopt, and effectively use new technologies, to address their needs and help them overcome the digital divide within digital inclusion. This will improve their quality of life and healthcare experiences.

Cluster #2—Research focuses on how older adults interact with assistive technologies, especially assistive robots and health monitoring devices, emphasizing trust, usability, and user experience as crucial factors (Halim et al. 2022 ). Moreover, health monitoring technologies effectively track and manage health issues common in older adults, like dementia and mild cognitive impairment (Lussier et al. 2018 ; Piau et al. 2019 ). Interactive exercise games and virtual reality have been deployed to encourage more physical and cognitive engagement among older adults (Campo-Prieto et al. 2021 ). Personalized and innovative technology significantly enhances older adults’ participation, improving their health and well-being.

Cluster #3—Optimizing health management for older adults using mobile technology. With the development of mobile health (mHealth) and health information technology, mobile applications, smartphones, and smart wearable devices have become effective tools to help older users better manage chronic conditions, conduct real-time health monitoring, and even receive telehealth services (Dupuis and Tsotsos 2018 ; Olmedo-Aguirre et al. 2022 ; Kim et al. 2014 ). Additionally, these technologies can mitigate the problem of healthcare resource inequality, especially in developing countries. Older adults’ acceptance and use of these technologies are significantly influenced by their behavioral intentions, motivational factors, and self-management skills. These internal motivational factors, along with external factors, jointly affect older adults’ performance in health management and quality of life.

Cluster #4—Research on technology-assisted home care for older adults is gaining popularity. Environmentally assisted living enhances older adults’ independence and comfort at home, offering essential support and security. This has a crucial impact on promoting healthy aging (Friesen et al. 2016 ; Wahlroos et al. 2023 ). The smart home is a core application in this field, providing a range of solutions that facilitate independent living for the elderly in a highly integrated and user-friendly manner. This fulfills different dimensions of living and health needs (Majumder et al. 2017 ). Moreover, eHealth offers accurate and personalized health management and healthcare services for older adults (Delmastro et al. 2018 ), ensuring their needs are met at home. Research in this field often employs qualitative methods and structural equation modeling to fully understand older adults’ needs and experiences at home and analyze factors influencing technology adoption.

Evolutionary trends analysis

To gain a deeper understanding of the evolutionary trends in research hotspots within the field of older adults’ technology acceptance, we conducted a statistical analysis of the average appearance times of keywords, using CiteSpace to generate the time-zone evolution mapping (Fig. 8 ) and burst keywords. The time-zone mapping visually displays the evolution of keywords over time, intuitively reflecting the frequency and initial appearance of keywords in research, commonly used to identify trends in research topics (Jing et al. 2024a ; Kumar et al. 2021 ). Table 10 lists the top 15 keywords by burst strength, with the red sections indicating high-frequency citations and their burst strength in specific years. These burst keywords reveal the focus and trends of research themes over different periods (Kleinberg 2002 ). Combining insights from the time-zone mapping and burst keywords provides more objective and accurate research insights (Wang et al. 2023b ).

Reflecting the frequency and time of first appearance of keywords in the study.

An integrated analysis of Fig. 8 and Table 10 shows that early research on older adults’ technology acceptance primarily focused on factors such as perceived usefulness, ease of use, and attitudes towards information technology, including their use of computers and the internet (Pan and Jordan-Marsh 2010 ), as well as differences in technology use between older adults and other age groups (Guner and Acarturk 2020 ). Subsequently, the research focus expanded to improving the quality of life for older adults, exploring how technology can optimize health management and enhance the possibility of independent living, emphasizing the significant role of technology in improving the quality of life for the elderly. With ongoing technological advancements, recent research has shifted towards areas such as “virtual reality,” “telehealth,” and “human-robot interaction,” with a focus on the user experience of older adults (Halim et al. 2022 ). The appearance of keywords such as “physical activity” and “exercise” highlights the value of technology in promoting physical activity and health among older adults. This phase of research tends to make cutting-edge technology genuinely serve the practical needs of older adults, achieving its widespread application in daily life. Additionally, research has focused on expanding and quantifying theoretical models of older adults’ technology acceptance, involving keywords such as “perceived risk”, “validation” and “UTAUT”.

In summary, from 2013 to 2023, the field of older adults’ technology acceptance has evolved from initial explorations of influencing factors, to comprehensive enhancements in quality of life and health management, and further to the application and deepening of theoretical models and cutting-edge technologies. This research not only reflects the diversity and complexity of the field but also demonstrates a comprehensive and in-depth understanding of older adults’ interactions with technology across various life scenarios and needs.

Research quality distribution

To reveal the distribution of research quality in the field of older adults’ technology acceptance, a strategic diagram analysis is employed to calculate and illustrate the internal development and interrelationships among various research themes (Xie et al. 2020 ). The strategic diagram uses Centrality as the X-axis and Density as the Y-axis to divide into four quadrants, where the X-axis represents the strength of the connection between thematic clusters and other themes, with higher values indicating a central position in the research field; the Y-axis indicates the level of development within the thematic clusters, with higher values denoting a more mature and widely recognized field (Li and Zhou 2020 ).

Through cluster analysis and manual verification, this study categorized 61 core keywords (Frequency ≥5) into 11 thematic clusters. Subsequently, based on the keywords covered by each thematic cluster, the research themes and their directions for each cluster were summarized (Table 11 ), and the centrality and density coordinates for each cluster were precisely calculated (Table 12 ). Finally, a strategic diagram of the older adults’ technology acceptance research field was constructed (Fig. 9 ). Based on the distribution of thematic clusters across the quadrants in the strategic diagram, the structure and developmental trends of the field were interpreted.

Classification and visualization of theme clusters based on density and centrality.

As illustrated in Fig. 9 , (1) the theme clusters of #3 Usage Experience and #4 Assisted Living Technology are in the first quadrant, characterized by high centrality and density. Their internal cohesion and close links with other themes indicate their mature development, systematic research content or directions have been formed, and they have a significant influence on other themes. These themes play a central role in the field of older adults’ technology acceptance and have promising prospects. (2) The theme clusters of #6 Smart Devices, #9 Theoretical Models, and #10 Mobile Health Applications are in the second quadrant, with higher density but lower centrality. These themes have strong internal connections but weaker external links, indicating that these three themes have received widespread attention from researchers and have been the subject of related research, but more as self-contained systems and exhibit independence. Therefore, future research should further explore in-depth cooperation and cross-application with other themes. (3) The theme clusters of #7 Human-Robot Interaction, #8 Characteristics of the Elderly, and #11 Research Methods are in the third quadrant, with lower centrality and density. These themes are loosely connected internally and have weak links with others, indicating their developmental immaturity. Compared to other topics, they belong to the lower attention edge and niche themes, and there is a need for further investigation. (4) The theme clusters of #1 Digital Healthcare Technology, #2 Psychological Factors, and #5 Socio-Cultural Factors are located in the fourth quadrant, with high centrality but low density. Although closely associated with other research themes, the internal cohesion within these clusters is relatively weak. This suggests that while these themes are closely linked to other research areas, their own development remains underdeveloped, indicating a core immaturity. Nevertheless, these themes are crucial within the research domain of elderly technology acceptance and possess significant potential for future exploration.

Discussion on distribution power (RQ1)

Over the past decade, academic interest and influence in the area of older adults’ technology acceptance have significantly increased. This trend is evidenced by a quantitative analysis of publication and citation volumes, particularly noticeable in 2019 and 2022, where there was a substantial rise in both metrics. The rise is closely linked to the widespread adoption of emerging technologies such as smart homes, wearable devices, and telemedicine among older adults. While these technologies have enhanced their quality of life, they also pose numerous challenges, sparking extensive research into their acceptance, usage behaviors, and influencing factors among the older adults (Pirzada et al. 2022 ; Garcia Reyes et al. 2023 ). Furthermore, the COVID-19 pandemic led to a surge in technology demand among older adults, especially in areas like medical consultation, online socialization, and health management, further highlighting the importance and challenges of technology. Health risks and social isolation have compelled older adults to rely on technology for daily activities, accelerating its adoption and application within this demographic. This phenomenon has made technology acceptance a critical issue, driving societal and academic focus on the study of technology acceptance among older adults.

The flow of knowledge at the level of high-output disciplines and journals, along with the primary publishing outlets, indicates the highly interdisciplinary nature of research into older adults’ technology acceptance. This reflects the complexity and breadth of issues related to older adults’ technology acceptance, necessitating the integration of multidisciplinary knowledge and approaches. Currently, research is primarily focused on medical health and human-computer interaction, demonstrating academic interest in improving health and quality of life for older adults and addressing the urgent needs related to their interactions with technology. In the field of medical health, research aims to provide advanced and innovative healthcare technologies and services to meet the challenges of an aging population while improving the quality of life for older adults (Abdi et al. 2020 ; Wilson et al. 2021 ). In the field of human-computer interaction, research is focused on developing smarter and more user-friendly interaction models to meet the needs of older adults in the digital age, enabling them to actively participate in social activities and enjoy a higher quality of life (Sayago, 2019 ). These studies are crucial for addressing the challenges faced by aging societies, providing increased support and opportunities for the health, welfare, and social participation of older adults.

Discussion on research power (RQ2)

This study analyzes leading countries and collaboration networks, core institutions and authors, revealing the global research landscape and distribution of research strength in the field of older adults’ technology acceptance, and presents quantitative data on global research trends. From the analysis of country distribution and collaborations, China and the USA hold dominant positions in this field, with developed countries like the UK, Germany, Italy, and the Netherlands also excelling in international cooperation and research influence. The significant investment in technological research and the focus on the technological needs of older adults by many developed countries reflect their rapidly aging societies, policy support, and resource allocation.

China is the only developing country that has become a major contributor in this field, indicating its growing research capabilities and high priority given to aging societies and technological innovation. Additionally, China has close collaborations with countries such as USA, the UK, and Malaysia, driven not only by technological research needs but also by shared challenges and complementarities in aging issues among these nations. For instance, the UK has extensive experience in social welfare and aging research, providing valuable theoretical guidance and practical experience. International collaborations, aimed at addressing the challenges of aging, integrate the strengths of various countries, advancing in-depth and widespread development in the research of technology acceptance among older adults.

At the institutional and author level, City University of Hong Kong leads in publication volume, with research teams led by Chan and Chen demonstrating significant academic activity and contributions. Their research primarily focuses on older adults’ acceptance and usage behaviors of various technologies, including smartphones, smart wearables, and social robots (Chen et al. 2015 ; Li et al. 2019 ; Ma et al. 2016 ). These studies, targeting specific needs and product characteristics of older adults, have developed new models of technology acceptance based on existing frameworks, enhancing the integration of these technologies into their daily lives and laying a foundation for further advancements in the field. Although Tilburg University has a smaller publication output, it holds significant influence in the field of older adults’ technology acceptance. Particularly, the high citation rate of Peek’s studies highlights their excellence in research. Peek extensively explored older adults’ acceptance and usage of home care technologies, revealing the complexity and dynamics of their technology use behaviors. His research spans from identifying systemic influencing factors (Peek et al. 2014 ; Peek et al. 2016 ), emphasizing familial impacts (Luijkx et al. 2015 ), to constructing comprehensive models (Peek et al. 2017 ), and examining the dynamics of long-term usage (Peek et al. 2019 ), fully reflecting the evolving technology landscape and the changing needs of older adults. Additionally, the ongoing contributions of researchers like Ziefle, Rogers, and Wouters in the field of older adults’ technology acceptance demonstrate their research influence and leadership. These researchers have significantly enriched the knowledge base in this area with their diverse perspectives. For instance, Ziefle has uncovered the complex attitudes of older adults towards technology usage, especially the trade-offs between privacy and security, and how different types of activities affect their privacy needs (Maidhof et al. 2023 ; Mujirishvili et al. 2023 ; Schomakers and Ziefle 2023 ; Wilkowska et al. 2022 ), reflecting a deep exploration and ongoing innovation in the field of older adults’ technology acceptance.

Discussion on knowledge base and thematic progress (RQ3)

Through co-citation analysis and systematic review of seminal literature, this study reveals the knowledge foundation and thematic progress in the field of older adults’ technology acceptance. Co-citation networks and cluster analyses illustrate the structural themes of the research, delineating the differentiation and boundaries within this field. Additionally, burst detection analysis offers a valuable perspective for understanding the thematic evolution in the field of technology acceptance among older adults. The development and innovation of theoretical models are foundational to this research. Researchers enhance the explanatory power of constructed models by deepening and expanding existing technology acceptance theories to address theoretical limitations. For instance, Heerink et al. ( 2010 ) modified and expanded the UTAUT model by integrating functional assessment and social interaction variables to create the almere model. This model significantly enhances the ability to explain the intentions of older users in utilizing assistive social agents and improves the explanation of actual usage behaviors. Additionally, Chen and Chan ( 2014 ) extended the TAM to include age-related health and capability features of older adults, creating the STAM, which substantially improves predictions of older adults’ technology usage behaviors. Personal attributes, health and capability features, and facilitating conditions have a direct impact on technology acceptance. These factors more effectively predict older adults’ technology usage behaviors than traditional attitudinal factors.

With the advancement of technology and the application of emerging technologies, new research topics have emerged, increasingly focusing on older adults’ acceptance and use of these technologies. Prior to this, the study by Mitzner et al. ( 2010 ) challenged the stereotype of older adults’ conservative attitudes towards technology, highlighting the central roles of usability and usefulness in the technology acceptance process. This discovery laid an important foundation for subsequent research. Research fields such as “smart home technology,” “social life,” and “customer service” are emerging, indicating a shift in focus towards the practical and social applications of technology in older adults’ lives. Research not only focuses on the technology itself but also on how these technologies integrate into older adults’ daily lives and how they can improve the quality of life through technology. For instance, studies such as those by Ma et al. ( 2016 ), Hoque and Sorwar ( 2017 ), and Li et al. ( 2019 ) have explored factors influencing older adults’ use of smartphones, mHealth, and smart wearable devices.

Furthermore, the diversification of research methodologies and innovation in evaluation techniques, such as the use of mixed methods, structural equation modeling (SEM), and neural network (NN) approaches, have enhanced the rigor and reliability of the findings, enabling more precise identification of the factors and mechanisms influencing technology acceptance. Talukder et al. ( 2020 ) employed an effective multimethodological strategy by integrating SEM and NN to leverage the complementary strengths of both approaches, thus overcoming their individual limitations and more accurately analyzing and predicting older adults’ acceptance of wearable health technologies (WHT). SEM is utilized to assess the determinants’ impact on the adoption of WHT, while neural network models validate SEM outcomes and predict the significance of key determinants. This combined approach not only boosts the models’ reliability and explanatory power but also provides a nuanced understanding of the motivations and barriers behind older adults’ acceptance of WHT, offering deep research insights.

Overall, co-citation analysis of the literature in the field of older adults’ technology acceptance has uncovered deeper theoretical modeling and empirical studies on emerging technologies, while emphasizing the importance of research methodological and evaluation innovations in understanding complex social science issues. These findings are crucial for guiding the design and marketing strategies of future technology products, especially in the rapidly growing market of older adults.

Discussion on research hotspots and evolutionary trends (RQ4)

By analyzing core keywords, we can gain deep insights into the hot topics, evolutionary trends, and quality distribution of research in the field of older adults’ technology acceptance. The frequent occurrence of the keywords “TAM” and “UTAUT” indicates that the applicability and theoretical extension of existing technology acceptance models among older adults remain a focal point in academia. This phenomenon underscores the enduring influence of the studies by Davis ( 1989 ) and Venkatesh et al. ( 2003 ), whose models provide a robust theoretical framework for explaining and predicting older adults’ acceptance and usage of emerging technologies. With the widespread application of artificial intelligence (AI) and big data technologies, these theoretical models have incorporated new variables such as perceived risk, trust, and privacy issues (Amin et al. 2024 ; Chen et al. 2024 ; Jing et al. 2024b ; Seibert et al. 2021 ; Wang et al. 2024b ), advancing the theoretical depth and empirical research in this field.

Keyword co-occurrence cluster analysis has revealed multiple research hotspots in the field, including factors influencing technology adoption, interactive experiences between older adults and assistive technologies, the application of mobile health technology in health management, and technology-assisted home care. These studies primarily focus on enhancing the quality of life and health management of older adults through emerging technologies, particularly in the areas of ambient assisted living, smart health monitoring, and intelligent medical care. In these domains, the role of AI technology is increasingly significant (Qian et al. 2021 ; Ho 2020 ). With the evolution of next-generation information technologies, AI is increasingly integrated into elder care systems, offering intelligent, efficient, and personalized service solutions by analyzing the lifestyles and health conditions of older adults. This integration aims to enhance older adults’ quality of life in aspects such as health monitoring and alerts, rehabilitation assistance, daily health management, and emotional support (Lee et al. 2023 ). A survey indicates that 83% of older adults prefer AI-driven solutions when selecting smart products, demonstrating the increasing acceptance of AI in elder care (Zhao and Li 2024 ). Integrating AI into elder care presents both opportunities and challenges, particularly in terms of user acceptance, trust, and long-term usage effects, which warrant further exploration (Mhlanga 2023 ). These studies will help better understand the profound impact of AI technology on the lifestyles of older adults and provide critical references for optimizing AI-driven elder care services.

The Time-zone evolution mapping and burst keyword analysis further reveal the evolutionary trends of research hotspots. Early studies focused on basic technology acceptance models and user perceptions, later expanding to include quality of life and health management. In recent years, research has increasingly focused on cutting-edge technologies such as virtual reality, telehealth, and human-robot interaction, with a concurrent emphasis on the user experience of older adults. This evolutionary process demonstrates a deepening shift from theoretical models to practical applications, underscoring the significant role of technology in enhancing the quality of life for older adults. Furthermore, the strategic coordinate mapping analysis clearly demonstrates the development and mutual influence of different research themes. High centrality and density in the themes of Usage Experience and Assisted Living Technology indicate their mature research status and significant impact on other themes. The themes of Smart Devices, Theoretical Models, and Mobile Health Applications demonstrate self-contained research trends. The themes of Human-Robot Interaction, Characteristics of the Elderly, and Research Methods are not yet mature, but they hold potential for development. Themes of Digital Healthcare Technology, Psychological Factors, and Socio-Cultural Factors are closely related to other themes, displaying core immaturity but significant potential.

In summary, the research hotspots in the field of older adults’ technology acceptance are diverse and dynamic, demonstrating the academic community’s profound understanding of how older adults interact with technology across various life contexts and needs. Under the influence of AI and big data, research should continue to focus on the application of emerging technologies among older adults, exploring in depth how they adapt to and effectively use these technologies. This not only enhances the quality of life and healthcare experiences for older adults but also drives ongoing innovation and development in this field.

Research agenda

Based on the above research findings, to further understand and promote technology acceptance and usage among older adults, we recommend future studies focus on refining theoretical models, exploring long-term usage, and assessing user experience in the following detailed aspects:

Refinement and validation of specific technology acceptance models for older adults: Future research should focus on developing and validating technology acceptance models based on individual characteristics, particularly considering variations in technology acceptance among older adults across different educational levels and cultural backgrounds. This includes factors such as age, gender, educational background, and cultural differences. Additionally, research should examine how well specific technologies, such as wearable devices and mobile health applications, meet the needs of older adults. Building on existing theoretical models, this research should integrate insights from multiple disciplines such as psychology, sociology, design, and engineering through interdisciplinary collaboration to create more accurate and comprehensive models, which should then be validated in relevant contexts.

Deepening the exploration of the relationship between long-term technology use and quality of life among older adults: The acceptance and use of technology by users is a complex and dynamic process (Seuwou et al. 2016 ). Existing research predominantly focuses on older adults’ initial acceptance or short-term use of new technologies; however, the impact of long-term use on their quality of life and health is more significant. Future research should focus on the evolution of older adults’ experiences and needs during long-term technology usage, and the enduring effects of technology on their social interactions, mental health, and life satisfaction. Through longitudinal studies and qualitative analysis, this research reveals the specific needs and challenges of older adults in long-term technology use, providing a basis for developing technologies and strategies that better meet their requirements. This understanding aids in comprehensively assessing the impact of technology on older adults’ quality of life and guiding the optimization and improvement of technological products.

Evaluating the Importance of User Experience in Research on Older Adults’ Technology Acceptance: Understanding the mechanisms of information technology acceptance and use is central to human-computer interaction research. Although technology acceptance models and user experience models differ in objectives, they share many potential intersections. Technology acceptance research focuses on structured prediction and assessment, while user experience research concentrates on interpreting design impacts and new frameworks. Integrating user experience to assess older adults’ acceptance of technology products and systems is crucial (Codfrey et al. 2022 ; Wang et al. 2019 ), particularly for older users, where specific product designs should emphasize practicality and usability (Fisk et al. 2020 ). Researchers need to explore innovative age-appropriate design methods to enhance older adults’ usage experience. This includes studying older users’ actual usage preferences and behaviors, optimizing user interfaces, and interaction designs. Integrating feedback from older adults to tailor products to their needs can further promote their acceptance and continued use of technology products.

Conclusions

This study conducted a systematic review of the literature on older adults’ technology acceptance over the past decade through bibliometric analysis, focusing on the distribution power, research power, knowledge base and theme progress, research hotspots, evolutionary trends, and quality distribution. Using a combination of quantitative and qualitative methods, this study has reached the following conclusions:

Technology acceptance among older adults has become a hot topic in the international academic community, involving the integration of knowledge across multiple disciplines, including Medical Informatics, Health Care Sciences Services, and Ergonomics. In terms of journals, “PSYCHOLOGY, EDUCATION, HEALTH” represents a leading field, with key publications including Computers in Human Behavior , Journal of Medical Internet Research , and International Journal of Human-Computer Interaction . These journals possess significant academic authority and extensive influence in the field.

Research on technology acceptance among older adults is particularly active in developed countries, with China and USA publishing significantly more than other nations. The Netherlands leads in high average citation rates, indicating the depth and impact of its research. Meanwhile, the UK stands out in terms of international collaboration. At the institutional level, City University of Hong Kong and The University of Hong Kong in China are in leading positions. Tilburg University in the Netherlands demonstrates exceptional research quality through its high average citation count. At the author level, Chen from China has the highest number of publications, while Peek from the Netherlands has the highest average citation count.

Co-citation analysis of references indicates that the knowledge base in this field is divided into three main categories: theoretical model deepening, emerging technology applications, and research methods and evaluation. Seminal literature focuses on four areas: specific technology use by older adults, expansion of theoretical models of technology acceptance, information technology adoption behavior, and research perspectives. Research themes have evolved from initial theoretical deepening and analysis of influencing factors to empirical studies on individual factors and emerging technologies.

Keyword analysis indicates that TAM and UTAUT are the most frequently occurring terms, while “assistive technology” and “virtual reality” are focal points with high frequency and centrality. Keyword clustering analysis reveals that research hotspots are concentrated on the influencing factors of technology adoption, human-robot interaction experiences, mobile health management, and technology for aging in place. Time-zone evolution mapping and burst keyword analysis have revealed the research evolution from preliminary exploration of influencing factors, to enhancements in quality of life and health management, and onto advanced technology applications and deepening of theoretical models. Furthermore, analysis of research quality distribution indicates that Usage Experience and Assisted Living Technology have become core topics, while Smart Devices, Theoretical Models, and Mobile Health Applications point towards future research directions.

Through this study, we have systematically reviewed the dynamics, core issues, and evolutionary trends in the field of older adults’ technology acceptance, constructing a comprehensive Knowledge Mapping of the domain and presenting a clear framework of existing research. This not only lays the foundation for subsequent theoretical discussions and innovative applications in the field but also provides an important reference for relevant scholars.

Limitations

To our knowledge, this is the first bibliometric analysis concerning technology acceptance among older adults, and we adhered strictly to bibliometric standards throughout our research. However, this study relies on the Web of Science Core Collection, and while its authority and breadth are widely recognized, this choice may have missed relevant literature published in other significant databases such as PubMed, Scopus, and Google Scholar, potentially overlooking some critical academic contributions. Moreover, given that our analysis was confined to literature in English, it may not reflect studies published in other languages, somewhat limiting the global representativeness of our data sample.

It is noteworthy that with the rapid development of AI technology, its increasingly widespread application in elderly care services is significantly transforming traditional care models. AI is profoundly altering the lifestyles of the elderly, from health monitoring and smart diagnostics to intelligent home systems and personalized care, significantly enhancing their quality of life and health care standards. The potential for AI technology within the elderly population is immense, and research in this area is rapidly expanding. However, due to the restrictive nature of the search terms used in this study, it did not fully cover research in this critical area, particularly in addressing key issues such as trust, privacy, and ethics.

Consequently, future research should not only expand data sources, incorporating multilingual and multidatabase literature, but also particularly focus on exploring older adults’ acceptance of AI technology and its applications, in order to construct a more comprehensive academic landscape of older adults’ technology acceptance, thereby enriching and extending the knowledge system and academic trends in this field.

Data availability

The datasets analyzed during the current study are available in the Dataverse repository: https://doi.org/10.7910/DVN/6K0GJH .

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Acknowledgements

This research was supported by the Social Science Foundation of Shaanxi Province in China (Grant No. 2023J014).

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Xianru Shang, Zijian Liu, Chen Gong, Zhigang Hu & Yuexuan Wu

Department of Education Information Technology, Faculty of Education, East China Normal University, Shanghai, China

Chengliang Wang

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Conceptualization, XS, YW, CW; methodology, XS, ZL, CG, CW; software, XS, CG, YW; writing-original draft preparation, XS, CW; writing-review and editing, XS, CG, ZH, CW; supervision, ZL, ZH, CW; project administration, ZL, ZH, CW; funding acquisition, XS, CG. All authors read and approved the final manuscript. All authors have read and approved the re-submission of the manuscript.

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Shang, X., Liu, Z., Gong, C. et al. Knowledge mapping and evolution of research on older adults’ technology acceptance: a bibliometric study from 2013 to 2023. Humanit Soc Sci Commun 11 , 1115 (2024). https://doi.org/10.1057/s41599-024-03658-2

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The right care in the right place: a scoping review of digital health education and training for rural healthcare workers

• Leanna Woods 1 , 2 ,
• Priya Martin 3 ,
• Johnson Khor 1 , 4 ,
• Lauren Guthrie 1 &
• Clair Sullivan 1 , 2 , 5  

BMC Health Services Research volume  24 , Article number:  1011 ( 2024 ) Cite this article

Metrics details

Digital health offers unprecedented opportunities to enhance health service delivery across vast geographic regions. However, these benefits can only be realized with effective capabilities and clinical leadership of the rural healthcare workforce. Little is known about how rural healthcare workers acquire skills in digital health, how digital health education or training programs are evaluated and the barriers and enablers for high quality digital health education and training.

To conduct a scoping review to identify and synthesize existing evidence on digital health education and training of the rural healthcare workforce.

Inclusion criteria

Sources that reported digital health and education or training in the healthcare workforce in any healthcare setting outside metropolitan areas.

We searched for published and unpublished studies written in English in the last decade to August 2023. The databases searched were PubMed, Embase, Scopus, CINAHL and Education Resources Information Centre. We also searched the grey literature (Google, Google Scholar), conducted citation searching and stakeholder engagement. The JBI Scoping Review methodology and PRISMA guidelines for scoping reviews were used.

Five articles met the eligibility criteria. Two case studies, one feasibility study, one micro-credential and one fellowship were described. The mode of delivery was commonly modular online learning. Only one article described an evaluation, and findings showed the train-the-trainer model was technically and pedagogically feasible and well received. A limited number of barriers and enablers for high quality education or training of the rural healthcare workforce were reported across macro (legal, regulatory, economic), meso (local health service and community) and micro (day-to-day practice) levels.

Conclusions

Upskilling rural healthcare workers in digital health appears rare. Current best practice points to flexible, blended training programs that are suitably embedded with interdisciplinary and collaborative rural healthcare improvement initiatives. Future work to advance the field could define rural health informatician career pathways, address concurrent rural workforce issues, and conduct training implementation evaluations.

Review registration number

Open Science Framework: https://doi.org/10.17605/OSF.IO/N2RMX .

Peer Review reports

Introduction

Globally, healthcare workers (HCWs) face multiple pressures simultaneously: increasing demand for care, co-morbidities and condition complexity, budget pressures, and rapid digital disruption [ 1 ]. The digital disruption in healthcare promises an unprecedented circumstance to improve outcomes and strengthen health systems [ 2 ]. However, this opportunity depends on a capable healthcare workforce with adequate skills and knowledge in data and emerging technologies [ 3 ]. HCW capability in digital health and clinical informatics is increasingly acknowledged as an essential component to the delivery of high-quality patient care [ 4 ]. Universities do not yet routinely teach these curricula in clinical degrees, and the capability gap in the current workforce is often filled by brief, reactive, and on-the-job training [ 5 ]. Sustainability of healthcare includes developing a skilled healthcare workforce educated and competent in digital health [ 6 ].

The rural healthcare workforce is faced with the location-based issues of resource constraints, workforce shortages, high staff turnover rates, stress, burnout, and an ageing workforce [ 7 ]. The World Health Organization has acknowledged in a recent report (2021) the complex challenge of shortage of healthcare workers globally in rural areas [ 7 ]. This report has acknowledged that the workforce density is lower than national averages in most of these areas. In places where there isn’t a national shortage, maldistribution of the workforce has been noted [ 7 ]. Digitally enabled models of care are well placed to enhance health service delivery across vast and distributed geographic regions. However, rural health service organizations require uplift to align with their metropolitan counterparts in workforce digital readiness [ 8 ]. Building digital health capability in rural settings is critical because higher digital health capability is associated with better outcomes, including the ability to maintain an accurate patient health record, track patient experience data, track the patient journey, and mitigate clinical risks [ 9 ]. Rurality is contributing to widening digital health inequities [ 10 ] with significant efforts required to adequately manage the rural digital divide [ 11 , 12 ]. Building digital capabilities of healthcare providers in rural and remote settings through education, training and support is needed [ 13 ].

Existing evidence on the education and training the rural healthcare workforce is limited. Firstly, while health science faculties are progressively integrating digital health into the undergraduate curricula for the future workforce [ 14 , 15 , 16 ], it is unclear how the education of current HCW is approached [ 14 ]. Despite global exemplars such as fellowship training for physicians [ 17 ], certification for nurses [ 18 ], and advanced education for clinical and non-clinical professionals [ 19 ], limited evidence of successful workforce programs to build digital health skills exist [ 4 ]. None focus on the rural healthcare setting.

Secondly, in literature reporting digital health in rural settings, there is a notable scarcity on workforce training programs. Existing studies focus on efficacy of delivered healthcare [ 20 , 21 ], workforce perceptions of digital health tool implementation [ 22 , 23 ] or are limited to training of specific interventions (e.g., clinical telehealth [ 24 ]). This review sought to explore the literature where these two gaps coexist, the intersection of digital health education and training and the rural healthcare workforce, and synthesize the available evidence on digital health education and training for the rural healthcare workforce.

Review question

The research questions for this review were:

What are the existing practices and approaches to digital health education and training for rural HCWs?

How has digital health education and training been evaluated following implementation?

What are the barriers and enablers for high quality digital health education and training in the rural healthcare workforce?

Participants

The review considered studies and reports on any members of the workforce in healthcare settings outside of metropolitan areas. The healthcare workforce refers to ‘all individuals who deliver or assist in the delivery of health services or support the operation of health care facilities’ [ 3 ]. All clinical (e.g., medical doctors, nurses, allied health professionals, pharmacists, Indigenous HCWs, pre-registration/qualification students undertaking placements in health care facilities) and non-clinical workers (e.g., administration, executive and management, clinical support, and volunteers) were considered regardless of professional body or government registration status. Patients, healthcare consumers, and the public were excluded.

The core concepts of digital health and training were combined in this review. Digital health and clinical informatics are often used interchangeably, and both were considered in this review. While digital health refers to the use of digital technologies for health [ 25 ], clinical informatics refers to more specialized practice of analyzing, designing, implementing and evaluating information and communication systems [ 26 ]. Specific digital health systems (e.g., IT infrastructure, telehealth, electronic medical records) were included. Training relates to the education or training initiatives (e.g., programs, curriculum, course) that build an individuals’ digital health capability to confidently use technologies to respond to the needs of consumers now and into the future [ 1 ]. Both education and training activities were considered. Education often refers to theoretical learning (e.g., by an academic institution, qualification), and training often teaches practical skills (e.g., employer-provided professional development, ‘just-in-time’ training) [ 3 , 24 ]. This review did not consider HCW education delivered at a distance through technologies (e.g., telesupervision for clinical skills training).

This review considered studies and reports from rural healthcare settings defined as outside metropolitan cities, inclusive of regional, rural, remote, and very remote settings. When the term ‘rural’ is used in this review, it refers to all areas outside major metropolitan cities as described by authors of individual studies and reports. All healthcare facilities across primary, secondary, and tertiary care settings were included in any country.

Types of sources

All research studies, irrespective of the study design, were considered. Reviews, conference abstracts and non-research sources (e.g., policy documents, program or course curriculum) were considered. The grey literature was included to capture reactionary training developed by rural health services that were not published as peer-reviewed research studies.

This review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews [ 27 ] and reported as per the Preferred Reporting of Systematic Reviews and Meta-analyses for scoping reviews (PRISMA-ScR) [ 28 ] (Additional file 1 ). The review protocol was registered in Open Science Framework [ https://doi.org/10.17605/OSF.IO/N2RMX ].

A scoping review approach was chosen over a systematic review to address a general, formative review question on this topic that is emerging in the literature and where the literature is complex and heterogenous [ 29 ]. An initial preliminary search of the topic in the academic databases, Cochrane Library, Open Science Framework and Prospero registry resulted in a very small number of relevant articles. It was determined that a broader search strategy and inclusion of non-research sources was required, consistent with the scoping review methodology [ 29 ]. Scoping review format is also well suited to the vast, diverse healthcare education topic across different disciplines, interventions and outcomes realised [ 30 ]. Mapping and synthesis across sources in this scoping review aims to inform research agendas and identify implications for policy and practice [ 31 ].

Deviations from the protocol

There were no deviations to the protocol.

Search strategy

The three phase JBI search process was followed. An initial limited search of PubMed was performed to identify keywords on the topic, followed by an analysis of the text words and index terms contained in the title and abstract. A subsequent preliminary search in Prospero registry, Cochrane Library and Open Science Framework informed the development of a full search strategy in PubMed. The search strategy, including all identified keyworks and index terms, was adapted for each included database and information source after refining the strategy with an information specialist. The reference lists of all included sources of evidence were screened for additional studies.

The review included only studies and reports in English (due to translation resourcing limitations) in the last 10 years (due to the relative novelty of the digital transformation of healthcare). The search was conducted in August 2023. The databases searched included PubMed, Scopus, Cumulative Index for Nursing and Allied Health Literature (CINAHL), Embase, and Education Resources Information Center (ERIC). Scopus was chosen over Web of Science as it provides 20% more coverage and the relative recency of articles indexed (publish date after 1995 [ 32 ]) was not a concern for our research question. The search for unpublished studies and grey literature included Google and Google Scholar, using a modified search strategy as required. In addition, national and international stakeholders ( n  = 29) from Asia, the Pacific Islands, Australia, USA and the UK known to have subject matter expertise on the topic were contacted via direct email. Stakeholders were asked to share any relevant work underway or otherwise undiscoverable using our scoping review methods. The full search strategy for each information source is provided in Additional file 2 .

Study selection

Following the search, identified articles were collated and uploaded into Covidence review software (Veritas Health Innovation Ltd; Melbourne, Australia) and duplicates removed. Two reviewers (among LW, JK and LG) then independently screened the title and abstract of each citation and selected studies that met the inclusion criteria. The full text articles were retrieved and uploaded into Covidence. These studies and reports were assessed independently by two reviewers (listed previously) for full assessment against the inclusion criteria. Any disagreements that arose between the reviewers at each stage of the selection process were resolved through discussion or with an additional reviewer (among LG and PM). Three meetings occurred to discuss any voting conflicts that occurred during title and abstract screening and full-text screening. Articles that did not satisfy the criteria were excluded with reasons for exclusion recorded. Search results and study selection process is presented in accordance to the PRISMA-ScR flow diagram (Fig. 1 ) [ 28 ]. Quality appraisal of selected studies was not conducted, consistent with scoping reviews methods [ 33 ].

Search results and source selection and inclusion process

Data extraction

Extracted data included the specific details about the participants, concept, context, study methods and key findings relevant to each review question. Data was extracted by one reviewer (JK) and checked by a second reviewer (LW). Data were extracted using the data extraction tool developed and piloted by the team (Additional file 3 ).

Data synthesis and presentation

The characteristics of the included studies were analyzed and organized in tabular format, accompanied by a narrative summary. Results of each research question was presented under separate headings. The data analysis for research question three (barriers and enablers of high-quality digital health education and training) was enhanced. We adopted the socio-institutional framework described by Smith et al [ 34 ] and used in education research [ 35 ] to classify macro, meso, micro level enablers and barriers to help improve the generalizability of the synthesized insights and identify stakeholders that are able to influence change. Gaps and limitations of the current literature were discovered from the evidence with recommendations for policy, practice and future research provided.

Study inclusion

Database searching yielded 1005 articles and stakeholder engagement yielded two articles. After removing duplicates, 660 articles were screened for title and abstract, after which 29 articles underwent full text review. Of the 29 articles, 24 articles were excluded: the setting was metropolitan or otherwise inadequately described as non-metropolitan ( n  = 6); the intervention was not a training or education initiative for digital health or clinical informatics ( n  = 16), or the population was not rural healthcare workers ( n  = 2). In total, following full-text screening, five articles were included in the final review (Fig.  1 ).

Characteristics of included studies

Of the five included articles, three were academic publications including two case studies [ 36 , 37 ] and one feasibility study [ 38 ] (Table 1 ). The two articles identified through stakeholder engagement presented course summaries [ 39 , 40 ] where one described a micro-credential [ 40 ] and the other described a fellowship [ 39 ]. Most articles ( n  = 3) were published recently between 2021 and 2023 [ 38 , 39 , 40 ]. Healthcare workforce settings were distributed across the continents of the United States of America [ 36 ], Asia [ 37 ], Africa [ 38 ] and Australia [ 39 , 40 ], with no articles reporting a setting in the European continent. Further study characteristics are available in Table 1 .

Review findings

What are the existing approaches to digital health education and training for rural hcws.

Training and education programs were needed due to identified gaps in knowledge, skills and expertise to support healthcare delivery in rural contexts with digital health [ 36 , 37 , 38 ], [ 40 ]. One article reported the target learners as village doctors, who may have “limited training and inadequate medical knowledge, yet they are generally the mainstay of health services” [ 37 ]. The mode of teaching in the included studies were four modular online learning courses [ 36 , 37 , 38 ], [ 40 ] and one fellowship [ 39 ]. Of the four modular online learning courses, one was supplemented by a facilitator-led train-the-trainer model [ 38 ], informed by an academic framework [ 41 ], with cohort-based discussion via a social media platform. The second was a certification in the form of a self-paced micro-credential completed individually [ 40 ]. Of the four modular online learning courses, the number of modules ranged from three to eight and covered a variety of digital health topics including innovation, commercialization, bioinformatics, technology use, data and information, professionalism, implementation and evaluation. One had a particular focus on information and communication technology tool use [ 37 ] while another focused on remote consulting [ 38 ]. The mode of delivery of the fellowship was not reported in the article.

Four [ 36 , 37 , 39 , 40 ] of the five included articles did not report an evaluation. One article in rural Tanzania described the evaluation of the train-the-trainer digital health training program using a mixed-method design [ 38 ]: (1) questionnaire informed by Kirkpatrick’s model of evaluation to capture knowledge gained and perceived behavior change on a Likert scale, (2) qualitative interviews to explore training experiences and views of remote consulting, and (3) document analysis from texts, emails and training reports [ 38 ]. Of the tier 1 trainees (senior medical figure trainers who were trained to educate their peers) that completed the questionnaire ( n  = 10, 83%), nine (90%) recommended the training program and reported receiving relevant skills and applying learning to daily work, demonstrating satisfaction, learning and perceived behavior change [ 38 ]. Overall, the feasibility study confirmed that remotely delivered training supported by cascade training was technically and pedagogically feasible and well received in rural Tanzania [ 38 ].

What are the barriers and enablers for high quality digital health education and training of the rural healthcare workforce?

Reported enablers and barriers are presented using the macro, meso, micro framework [ 34 ] (Table 2 ).

This scoping review reflects the scarcity of reported digital health education and training programs in existence for rural HCWs globally. This review responds to the World Health Organization (WHO) recommendation to design and enable access to continuing education and professional development programs that meet the needs of rural HCWs [ 7 ], and the Sustainable Development Goal for inclusive and equitable quality education [ 42 ].

Concurrent challenges of people (workforce), setting (rural) and content (digital health) are reported in included articles alongside enablers and barriers to education and training programs. Included studies reported a shortage of doctors and specialists [ 36 ], lack of technical knowledge [ 36 ] (people); higher cost of delivering rural healthcare, high burden of illness [ 40 ], medically underserved population due to rural hospital closures [ 36 ] (setting); and limited use of digital health tools due to coordination challenges among non-government organisations [ 37 ] (content). These additional macro, meso and micro level factors are described by authors firstly as influencing the need for digital health programs in rural settings, and secondly, as contributing to the challenges of implementing effective programs. The rural health workforce challenges in digital health education and training reflect the broader workforce development issues experienced globally [ 7 ]. While this review sought to identify workforce development programs, the WHO model indicates the need for attractiveness, recruitment and retention to enable workforce performance (i.e., appropriate and competent multidisciplinary teams providing care) and health system performance (i.e., improving universal health coverage) [ 7 ].

In low-resource settings such as rural areas, education and training may not be prioritized among other competing workload demands. As the value of digital health transformations are realized for strengthening healthcare systems [ 25 , 43 ], the value of digital health education or training programs may become realized. This value was evidenced in the implementation of the teleconsulting training intervention in rural Tanzania [ 38 ] in rapid response to supporting care delivery during the COVID-19 pandemic period. With evaluations of programs largely absent from an already small number of programs globally, it will be important for future research to focus on implementation evaluation studies. As Table 2 presents only limited enablers and barriers, more evidence is needed to build on the findings from this scoping review to inform strategies for policy and practice.

The interdisciplinarity of digital health presents challenges and opportunities for nurturing digital health expertise across the rural healthcare workforce. Included articles largely described the target learners of education and training programs as clinicians, practitioners and healthcare workforce. Walden et al. further indicated that users of online content may extend beyond rural health clinicians to healthcare administrators, researchers and providers relevant to address the regulatory factors of clinical validation and implementation [ 36 ]. Therefore, for their program of work, the University of Arkansas for Medical Sciences identified and fostered collaboration with an interprofessional team of clinicians, researchers, informaticists, a bioethicist, lawyers, technology investment experts, and educators [ 36 ]. No articles in the review described education or training health informaticians or similar digital health leadership role types, yet building defined career pathways for health informaticians is recommended [ 4 ]. Existing pedagogy shows that the learning principles of interprofessional practice is grounded in understanding one’s own practice as well as the practice of other health professionals and remains aligned to the educational needs of specific professions [ 44 ] (i.e., medicine, nursing, pharmacy). Defining new career pathways for interdisciplinary leaders in digital health within a specific clinical context, like the ‘rural health informatician’, will be important to identify or define the (hidden) specialized workforce.

Local, informal organizational initiatives for digital health learning were discovered alongside formal education or training programs in included studies. Programs were often reported in articles alongside concurrent digital health implementation or healthcare improvement programs, sometimes referred to as ‘outreach’ [ 36 ] activities. These informal initiatives included special interest groups, in-person conferences, networking events, working groups [ 36 ] and seminars [ 37 ]. Current evidence from this scoping review suggests that the efficacy and sustainability of education or training programs are reliant on integrated approaches, like the train-the-trainer [ 38 ] or academic organization approach [ 36 ], that foster translational research for rural healthcare improvement. As illustrated by Walden et al., success in digital health is likely to require a foundational environment where technologies can be discussed, developed and deployed [ 36 ]. Success in rural digital health skills acquisition likely requires a similar, longitudinal and collaborative approach beyond the confines of an online course completed individually. Previous research shows us that blended learning, which merges face-to-face with online learning, translates to better knowledge outcomes [ 44 ]. Blended learning can also overcome the barrier of rural HCWs travelling large distances to attend face-to-face training that comes at a great cost to themselves and the work unit. A key recommendation to improve the digital health training program described by Downie et al. was more face-to-face time with trainers, from the perspective of both trainee and facilitator [ 38 ]. This, however, can only be realized with targeted planning and budgeting of such offerings by involved rural healthcare organizations.

The opportunities to advance digital health education and training for rural HCWs are presented across the macro, meso and micro levels in the socio-institutional framework, with suggested relevant stakeholders suited to actioning the recommendations (Table  3 ). While the context for this is likely to vary across the globe, these recommendations and stakeholders are expected to provide a starting point to initiate a dialogue that can influence change. These recommendations are not meant to be prescriptive or rigid, but rather meant to flag actionable solutions that can be contextualized for any given setting.

Strengths and limitations

It is possible that there is a greater number of published educational and training programs than those reported in this review (i.e., publication bias). To mitigate this, we used a scoping review methodology and stakeholder engagement activity to identify unpublished or emerging programs that answer the review question but may not be discoverable in the academic databases. The review is limited to articles available in the English language. The small number of programs, heterogeneity of programs and limited evaluation of programs significantly limit generalizability of findings. Due to data availability, the barriers and enablers findings summary contain an overrepresentation from a small number of studies limiting conclusions that can be drawn.

Digital health offers the best opportunity for innovative sustainable change to address critical issues in health and care in rural settings. Workforce education and training initiatives in rural healthcare settings are scarce, largely delivered via online training, and are rarely evaluated. Current best practice points to flexible, blended (online and face-to-face) training programs that are suitably embedded with interdisciplinary, collaborative rural healthcare improvement initiatives. More research will expand the evidence base to deliver high-quality digital health education to strengthen rural healthcare delivery. Future work to advance the field could define rural health informatician career pathways, address concurrent rural workforce issues, and conduct implementation evaluations.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

Cumulative Index for Nursing and Allied Health Literature

Education Resources Information Centre

Healthcare worker

Joanna Briggs Institute

Preferred Reporting of Systematic Reviews and Meta-analyses for scoping reviews

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Dizon JMR. Educating future health professionals to keep pace with changing times. LWW, 2021, p. 2904–2905.

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Woods, L., Martin, P., Khor, J. et al. The right care in the right place: a scoping review of digital health education and training for rural healthcare workers. BMC Health Serv Res 24 , 1011 (2024). https://doi.org/10.1186/s12913-024-11313-4

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Hyperuricemia and its related diseases: mechanisms and advances in therapy

1 Sports Medicine Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041 China

2 Institute of Sports Medicine, Shantou University Medical College, Shantou, 515041 China

3 Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA 6009 Australia

4 Department of Orthopaedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China

Changqing Zhang

Zhigang zhong.

Hyperuricemia, characterized by elevated levels of serum uric acid (SUA), is linked to a spectrum of commodities such as gout, cardiovascular diseases, renal disorders, metabolic syndrome, and diabetes, etc. Significantly impairing the quality of life for those affected, the prevalence of hyperuricemia is an upward trend globally, especially in most developed countries. UA possesses a multifaceted role, such as antioxidant, pro-oxidative, pro-inflammatory, nitric oxide modulating, anti-aging, and immune effects, which are significant in both physiological and pathological contexts. The equilibrium of circulating urate levels hinges on the interplay between production and excretion, a delicate balance orchestrated by urate transporter functions across various epithelial tissues and cell types. While existing research has identified hyperuricemia involvement in numerous biological processes and signaling pathways, the precise mechanisms connecting elevated UA levels to disease etiology remain to be fully elucidated. In addition, the influence of genetic susceptibilities and environmental determinants on hyperuricemia calls for a detailed and nuanced examination. This review compiles data from global epidemiological studies and clinical practices, exploring the physiological processes and the genetic foundations of urate transporters in depth. Furthermore, we uncover the complex mechanisms by which the UA induced inflammation influences metabolic processes in individuals with hyperuricemia and the association with its relative disease, offering a foundation for innovative therapeutic approaches and advanced pharmacological strategies.

Introduction

Hyperuricemia is a metabolic disorder marked by elevated serum uric acid concentrations in both extracellular fluids and tissues, coupled with impaired uric acid excretion. 1 The definition of hyperuricemia is SUA level ≥ 7.0 mg/dl (416.0 μmol/L) in males or ≥ 6.0 mg/dl (357.0 μmol/L) in females. 2 Hyperuricemia is associated with various risk factors, including a high-purine diet, alcohol consumption, medication usage, hypertension, hypothyroidism, and obesity. Additionally, social factors such as higher socioeconomic status, as well as a history of smoking and alcohol use, further contribute to the heightened risk of developing this condition. 1 , 3 , 4 UA plays a double-edged sword role in humans. 5 Uric acid possesses antioxidant capabilities that combat free radicals and reactive oxygen species, thus preventing oxidative stress. 6 – 8 The antioxidant effect of uric acid can be manifested in the inhibition of cell death to protect nerves as well as profile support of NO-mediated vasodilation. 9 However, uric acid will be transformed into a pro-oxidant and pro-inflammatory molecule that exacerbates oxidative stress when the UA levels are increased. 10 – 12 UA, mediates the innate immune response, which can release inflammatory mediators and activate the renin-angiotensin system, 13 inflammatory responses, oxidative stress, vascular endothelial dysfunction and insulin resistance. 14 – 16 Mendelian randomization studies have demonstrated no causal relationship between elevated uric acid levels and the risks of diabetes, coronary heart disease, ischemic stroke, heart failure, body mass index, bone mineral density, coronary artery disease, blood pressure, metabolic syndrome, blood glucose levels, triglyceride levels, diabetes mellitus, serum creatinine levels, glomerular filtration rate, and Parkinson’s disease. 17 – 21 The only phenotypes that were causally associated with HU were gout and kidney disease. 22 However, epidemiological and clinical studies have linked hyperuricemia to the development of various conditions, including chronic kidney disease, fatty liver, metabolic syndrome, hypertension, insulin resistance, obesity, type 2 diabetes, and cardiovascular and cerebrovascular disorders. 1 , 23 – 25 In this article, we review the complex physiological roles and metabolism of uric acid and the interconnections of mechanisms between hyperuricemia and potential diseases. Furthermore, we summarize the novel therapeutic interventions for hyperuricemia by examining its common comorbidities, underlying mechanisms, phenotypes, and pathogenesis.

The timescale and prevalence of hyperuricemia

Among history, Podagra first developed and identified by Hippocrates, which called “unwalkable illness” in 400 BC. with the definition podagra as a style called “arthritis of the rich.” Over 2000 years ago, Colchicine, initially used as a purgative in ancient Greece, which was later recognized by Alexander of Tralles in the sixth century AD for its specific therapeutic effects on arthritis. 26 By 1200, gout was dubbed the ‘disease of kings’ due to its association with a luxurious lifestyle. In 1679, Antonie van Leeuwenhoek, a pioneer in microbiology, first observed crystals from tophi in gout patients. The chemical composition of uric acid was identified by a Swedish chemist in 1797, and by 1940, the understanding of uric acid metabolism, including its excretion and overproduction was established. 27 – 30 The role of genetic factors in hyperuricemia prevalence was discovered in the 1960s. In 1963, the introduction of Allopurinol, an inhibitor of xanthine oxidase, marked a significant advancement in treating hyperuricemia. More recently, in 2010, uricase enzymes like Pegloticase and Rasburicase were approved for the management of persistent arthritis in patients with comorbidities and joint deformities. 31 – 33 Currently, the emerging drugs and some advanced treatments such as uricosuric compounds, antidyslipidemic drugs or gut microbiota, can reduce the concentration of serum uric acid to address resistant hyperuricemia (Fig. ​ (Fig.1 1 ).

The timescale and historical development of hyperuricemia (depicted in light red) and hyperuricemia treatment (depicted in dark red) from 1944 to June 2024, along with the volume of published literature, have been analyzed using data extracted from PubMed. The search criteria included “hyperuricemia*“ in conjunction with terms such as “history”, “medicine”, “treatment”, “therapy”, “drug”, “mechanism”, “genetic”, and “uric acid”

Hyperuricemia is a globally prevalent condition, particularly in high- and middle-income countries. Its prevalence varies significantly due to factors such as geographic location, regional differences, ethnicity, dietary habits, and economic conditions. Recent trends indicate an increase in the prevalence of hyperuricemia. 2 , 3 The global prevalence rate has been reported to be ranging from 2.6% to 36% in different populations. 34 The U.S. National Health and Nutrition Examination Survey (NHANES) indicates that approximately 21% of adults, or 43 million individuals, have been diagnosed with hyperuricemia. 35 Comparative prevalence rates are as follows: 16.6% in Australia, 36 48% in Finland with a gender-specific breakdown of 60% in males and 31% in females, 37 17.0% in New Zealand with 27.8% in males and 8.8% in females, 38 24.5% in Ireland with 25.0% in males and 24.1% in females, 39 9.9% in Croatia, 40 16.8% in Russia, 41 12.1% in Turkey with 19.0% in male and 5.8% in female, 42 21.2% in Qatar. 43 Likewise, among developing countries, the Korea NHANES reported that the prevalence of hyperuricemia in Korea was 11.4% with 17.0% in male and 5.9% in female. 44 In addition, it is 20.6% in Mexico, 45 17.2% in Niger with 25.0% in male and 13.7% in female, 46 71.6% in French Polynesia, 47 9.9% in Croatia, 40 44.6% in India, 48 28.1% in Jordan, 49 31.8% in sub-Saharan African, 50 10.6% in Thailand with 18.4% in male and 7.8% in female, 51 8.4% in Saudi Arabia 52 and approximately 9.3% in Bangladesh. 53 (Table ​ (Table1) 1 ) As expected, the prevalence of hyperuricemia found in our study is higher in most developed countries. Interestingly, the prevalence of hyperuricemia is higher in coastal areas and countries than in landlocked countries, especially for countries surrounded by sea and in developing. China, with its large population, exhibits significant demographic diversity and regional differences. The prevalence of hyperuricemia was 6.4% in Chinese adults according to a study covering 13 provinces. 2 Geographically, the prevalence of hyperuricemia is highest in southern China (9.1%) and lowest in northern China (3.2%). The majority of affected individuals (71.0%) reside in urban areas, with a substantial proportion (44.7%) living in coastal cities. The prevalence is notably higher in urban regions (8.0%) compared to rural areas (5.0%). By 2014, the overall prevalence of hyperuricemia in mainland China had reached 13.3%, 54 and this gradually increased to 17.7% in 2017. The prevalence was higher in the elderly population, and the rate was higher in male (23.5%) than in female (11.7%). 55

Diagnostic criteria and prevalence for hyperuricemia in each country/area

/, the country without an exact criteria

Physiological role of uric acid

Uric acid is the final product of the catabolism of purine nucleotides. UA is a weak diprotic acid with one dis-sociable H + at physiologic pH values. The concentrations of UA range from 3.5 to 7.2 mg/dL (210–430 μmol/L) in males and 2.6–6.0 mg/dL (155–360 μmol/L) in premenopausal females. 2 , 35 In addition to its role as a byproduct of purine metabolism, uric acid is recognized for its multifaceted effects, which include antioxidant, pro-oxidant, pro-inflammatory, nitric oxide regulation, immune system interactions, and anti-aging properties. 7 , 56

Antioxidant and Pro-oxidant

Uric acid is a natural byproduct of purine metabolism, arising from the enzymatic degradation of hypoxanthine to xanthine, which is subsequently converted by xanthine oxidase. 57 In the process in which uric acid is produced, ROS, particularly superoxide anions and hydrogen peroxide (H 2 O 2 ), are generated as byproducts. 58 – 61 Uric acid functions as a powerful antioxidant, effectively neutralizing singlet oxygen molecules, oxygen radicals, and peroxynitrite (ONOO-) molecules, due to its ability to provide electrons and act as a powerful reducing agent. 27 – 29 , 62 – 65 It can easily provide a hydrogen atom to free radicals, thereby stabilizing them and preventing further oxidative damage. 66 Therefore, uric acid has remarkable antioxidant properties that effectively combat oxidative stress induced by free radicals and reactive oxygen species (ROS). 7 Free radicals are highly reactive entities that can cause oxidative stress and cellular damage and contribute to the development of various diseases. 67 Nevertheless, uric acid has a highly reducing structure that effectively neutralizes free radicals and mitigates their harmful effects. Additionally, uric acid acts as an inhibitor of the oxidative chain reaction through a dual mechanism. 68 , 69 It captures and neutralizes free radicals, forming stable intermediates and thereby impeding the transmission of the oxidative reaction. 66 Furthermore, the complex formed by uric acid and free iron ions acts as a chelating agent, effectively inhibiting the formation of free radicals from iron ions and enhancing the antioxidant effect. 67 Uric acid regulates the inflammatory response by inhibiting the production of inflammatory mediators, which significantly reduces the formation of free radicals. 57 One of the most interesting aspects of the antioxidant function of uric acid is its potential role in neuroprotection. 60 – 62 Uric acid and purines, including adenosine and adenosine triphosphate, have been implicated in regulating central nervous system functions such as convulsive threshold, memory, cognition, sleep, activity, appetite, mood, social interaction, drive, impulsivity, and intelligence. 70 – 72 Some studies have found that patients with neurodegenerative diseases, like Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS), tend to have lower serum uric acid levels, suggesting a potential neuroprotective effect of uric acid. 73 Patients with major depression and anxiety disorders had lower plasma uric acid levels and increased UA levels after treatment, further suggesting that UA may have a neuroprotective effect. 70 The antioxidant properties of UA and its ability to inhibit oxidative stress may attenuate inflammatory damage to the nervous system and contribute to the maintenance of neuron number and function by inhibiting programmed apoptosis of neuronal cells, which protects against excessive neuronal cell damage. The capacity of uric acid to neutralize reactive oxygen species (ROS) and shield neurons from oxidative damage may underlie its observed neuroprotective effects. Furthermore, the antioxidant properties of uric acid have significant implications for cardiovascular health. 66 The ability of uric acid to scavenge ROS and reduce oxidative stress may have protective effects on the cardiovascular system. Studies illustrated that uric acid may indirectly support NO-mediated vasodilation by preventing nitric oxide degradation by superoxide radicals. This finding implies that uric acid may play a role in maintaining vascular health and regulating blood pressure. 74 The antioxidant function of serum uric acid reflects the multifaceted and complex nature of its physiological role. The ability of uric acid to neutralize free radicals and protect against oxidative stress has implications for all aspects of health. 67 , 75 Interestingly, a level of uric acid that is either too high or too low disrupts the delicate balance of oxidative stress regulation and may lead to excessive oxidative damage or impaired antioxidant defense. At higher intracellular concentrations, uric acid can function as a pro-oxidant molecule. 76 Studies have shown that within various cell types, including vascular smooth muscle cells, endothelial cells, adipocytes, hepatocytes, pancreatic islet cells, and renal tubular cells, uric acid can activate NADPH oxidase, a crucial enzyme involved in the generation of reactive oxygen species. 57 , 76 Moreover, in certain cell types, NADPH oxidase may translocate to the mitochondria, further exacerbating oxidative stress. 77 , 78 The effects of soluble urate on mononuclear cells are multifaceted. Some studies suggest that priming peripheral blood mononuclear cells (PBMCs) with urate enhances the release of interleukin-1β (IL-1β) in response to lipopolysaccharide (LPS), indicating a potential pro-inflammatory effect. 79 While it was found no significant effects of urate on IL-1β release, superoxide dismutase 2 (SOD2) gene transcription, or the total antioxidant capacity of the cell. 80

Pro-inflammatory

Uric acid acts as a danger signal, being naturally released by necrotic cells and subsequently initiating adaptive immune responses. Studies have indicated that uric acid crystals can engage with Toll-like receptors (TLRs), which are membrane-bound receptors integral to innate immunity, thereby inducing inflammation. 10 , 11 , 81 , 82 Specifically, TLR-2, TLR-4, and the myeloid differentiation primary response protein 88 (MyD88) are crucial to the inflammatory reaction of macrophages to uric acid crystals. These crystals can directly interact with these receptors, initiating signal transduction pathways that ultimately activate NF-κB. 83 – 87 NF-κB is a transcription factor responsible for improving the transcription of various inflammation-associated proteins, including pro-interleukin-1 (pro-IL-1), when secreted in the extracellular space. 88 In recent years, studies have revealed that UA activates the TLR4-NLRP3 inflammatory complex, which is a multi-protein complex that plays a pivotal role in initiating the innate immune response to various danger signals, including MSU crystals. Upon recognition of MSU crystals, the NLRP3 inflammasome is activated, leading to the cleavage of pro-inflammatory cytokines, specifically interleukin-1β (IL-1β) and interleukin-18 (IL-18). 89 – 93 These cytokines play a central role in orchestrating the inflammatory response by recruiting additional immune cells and amplifying the proinflammatory cascade. 57 UA exerts its influence on the renin-angiotensin system through dual mechanisms involving the stimulation of plasma renin activity and renal renin expression. Additionally, UA contributes to the activation of the intrarenal angiotensin system. 94 These immune inflammatory pathways, particularly those involving monocytes and macrophages, are upregulated in the presence of hyperuricemia. 95 , 96 The pro-inflammatory function of uric acid is critical for revealing its role in various inflammatory conditions, such as gout, cardiovascular disease, and metabolic syndrome. 82 UA was observed to reduce reactive oxygen species (ROS) and interleukin-6 (IL-6) production in macrophages while enhancing fatty acid oxidation (FAO) under inflammatory and hypoxic conditions in vitro. 95 Although the antioxidant properties of uric acid have long been recognized, its pro-inflammatory effects complicate its physiological significance and clinical relevance.

Nitric oxide regulation

Nitric oxide (NO) is a vital signaling molecule produced by endothelial nitric oxide synthase (eNOS) within endothelial cells. It serves as a powerful vasodilator, modulating blood pressure by inducing relaxation in the smooth muscle cells of blood vessel walls. 97 Hyperuricemia, by inducing oxidative stress and inflammation, diminishes the expression of eNOS and the synthesis of NO, while elevating levels of inflammatory cytokines such as IL-6 and TNF- α , ultimately impairing endothelial function. 98 , 99 In addition, NO is involved in inhibiting platelet aggregation, leukocyte adhesion, and inflammation. It also contributes to various signaling pathways that affect cardiac function, nerve conduction, and the immune response. 100 The interaction between uric acid and NO is bidirectional. When concentrations are low, uric acid acts as a natural antioxidant that scavenges free radicals and prevents oxidative damage. Specifically, uric acid neutralizes peroxynitrite, a harmful molecule formed from the reaction between nitric oxide and superoxide radicals. 101 , 102 This antioxidant effect of uric acid protects nitric oxide from degradation by superoxide radicals, thereby indirectly supporting nitric oxide bioavailability and potentially enhancing nitric oxide-mediated vasodilation. 61 , 103 However, at higher concentrations, uric acid reduces NO bioavailability, impairs eNOS function, reduces NO production, and further exacerbates endothelial cell dysfunction. These complex interactions have important implications for cardiovascular health, renal function, and treatment of NO-related diseases. 97 , 104 , 105 Uric acid has a protective effect against dementia and cognitive impairment related to senescence. 72 , 106 – 110 UA endowed with hydrophilic antioxidant properties which can exert a protective influence against Alzheimer’s disease and Parkinson’s disease, while hyperuricemia could potentially worsen vascular dementia, encompassing conditions such as stroke and small vessel cerebrovascular disease. 111

Aging and Anti-aging effects

Uric acid can influence cellular activities, such as cell proliferation, by modulating EGF/EGFR bioactivity. Hyperuricemia can downregulate the expression of cell cycle proteins including D1, p-Rb, Ki67, and CDK4, inducing cellular senescence and consequently diminishing EGF/EGFR signaling. Increased levels of uric acid result in inflammation and oxidative stress, which serve as potential risk factors for cellular senescence, apoptosis, and disruptions in the cell cycle. Conversely, physiological concentrations of uric acid (5 mg/dl) exhibit anti-aging effects by enhancing growth factor activity in aging cells. However, at higher concentrations (10 mg/dl), uric acid promotes cellular senescence and downregulates EGF/EGFR signaling. 112

Immune system interaction effects

The interaction of uric acid with the immune system involves the formation of monosodium urate (MSU) crystals. These uric acid crystals activate pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors, and the NLRP3 inflammasome. 113 – 116 Activation of these receptors initiates an inflammatory signaling cascade resulting in the secretion of pro-inflammatory cytokines and chemokines. These needle-shaped crystals can accumulate in diverse tissues, particularly in joints, eliciting an innate immune response. Consequently, immune cells, notably neutrophils and macrophages, are recruited to sites of crystal deposition. 10 Moreover, neutrophils can phagocytose uric acid crystals and release various inflammatory mediators, such as interleukin-1β and ROS, further activating inflammation and amplifying the local inflammatory response. 113 Studies have shown that UA also affects both T-cell populations and regulatory T-cell populations. 117 UA-induced inflammation leads to the recruitment and activation of effector T cells at the site of crystal deposition, thereby exacerbating local inflammation. 113 , 117

The physiology of Hyperuricemia

Hyperuricemia is characterized by an elevated level of uric acid in the bloodstream, often surpassing the normal physiological threshold. This metabolic state arises from a dysregulation between uric acid production and elimination, culminating in its accumulation in the bloodstream. 118 The etiology of hyperuricemia is multifaceted and involves genetic predispositions, environmental factors, and complex metabolic pathways governing urate homeostasis.

Factors influencing uric acid

The risk of developing hyperuricemia is influenced by a combination of inherited genetic variants, environmental factors, gene-environment interactions, and intrinsic factors such as age, sex, and body weight. 119 Research indicates that factors such as age, diet, alcohol consumption, fructose-rich intake, pharmacologic interventions and diseases, such as obesity, insulin resistance, Down syndrome, and kidney disease, contribute to the development of hyperuricemia 120 – 124 (Fig. ​ (Fig.2 2 ).

Consumption of purine-rich meats such as beef, pork, lamb, and seafood like oysters, shrimp, and tuna, as well as dietary fructose, are known to elevate uric acid (UA) production. Additionally, alcohol metabolism from beer and distilled spirits, along with certain medical conditions such as tumor lysis syndrome and obesity, pose increased risks for hyperuricemia. Hepatic metabolism of uric acid involves the sequential processing of purine nucleotides, including adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine monophosphate (IMP). 66 IMP plays a pivotal role as a key intermediate in purine nucleotide biosynthesis, serving as a precursor for the synthesis of both adenosine monophosphate (AMP) and guanosine monophosphate (GMP). Moreover, IMP can be enzymatically deaminated by IMP dehydrogenase, leading to the formation of inosine. Inosine, in turn, can undergo phosphorylation to become hypoxanthine. Hypoxanthine undergoes oxidative reactions catalyzed by xanthine oxidase (XOD), resulting in the production of xanthine. Xanthine can further undergo oxidation reactions, also catalyzed by XOD, ultimately leading to the formation of uric acid from xanthine. 118 However, xanthine oxidase inhibitors, such as allopurinol, febuxostat, and topiroxostat, serve as first-line therapies by effectively reducing the production of uric acid from both endogenous and dietary purine sources. In the final step of purine metabolism, the enzyme uricase converts uric acid into allantoin, a highly soluble compound. While humans lack the uricase enzyme, animals naturally possess it. The therapeutic agents pegloticase and rasburicase are recombinant forms of uricase, designed to facilitate the breakdown of uric acid in humans

Dietary selections abundant in purine, particularly nucleic acids, notably contribute to the production of uric acid. Beverages like beer, which contains purine-rich yeast, along with the consumption of foods such as bacon, beef, lamb, turkey, veal, venison, organ meats, and certain types of fish and shellfish (including anchovies, cod, tuna, sardines, shrimp, scallops, trout, and haddock), are implicated in elevating uric acid levels. 101 , 125 Beer contains high amounts of guanosine, and ethanol increases the degradation of ATP. Alcohol and dietary purines (meat, seafood) may be risk factors for gout, which has traditionally been considered a disease of affluence. Sugar (sucrose) is a disaccharide composed of glucose and fructose. 126 Among middle-aged Chinese men, a direct and notable association exists between seafood consumption and the occurrence of hyperuricemia. Conversely, protein intake from either animal or plant sources demonstrated a contrasting impact on the prevalence of hyperuricemia. Nevertheless, comprehensive data on the precise purine content of foods remains limited, primarily due to various factors such as food processing techniques, which can influence purine levels. 121 According to the NHANES, dietary folate intake reduces the risk of hyperuricemia in female, while vitamin B12 and folate intake are associated with a reduced risk of hyperuricemia in men. 127

Fructose metabolism

Fructose metabolism, particularly through the aldolase reductase pathway in the liver, results in increased UA levels. 128 Fructose is transported into cells via SLC2A5 (Glut5) and undergoes metabolism to fructose 1-phosphate catalyzed by ketohexokinase (KHK), a process requiring ATP. This metabolic pathway primarily occurs in the liver, leading to a transient reduction in intracellular ATP and phosphate levels. Subsequently, activation of adenosine monophosphate (AMP) deaminase occurs, with AMP generated from fructose metabolism entering the purine catabolic pathway, ultimately resulting in the production of uric acid. 129

Purine metabolism

Uric acid originates from the breakdown of purines catalyzed by the oxidized and reduced forms of xanthine oxidoreductase (XOR) and xanthine dehydrogenase (XDH). Purines are essential nucleotide components of DNA and RNA, crucial for cell division and metabolism. 101 Both endogenous purine metabolism and dietary intake contribute to uric acid production. Increased cellular catabolism, heightened endogenous purine synthesis, and a diet rich in purines can elevate urate levels. Although basal XOR expression is typically low in humans, various factors such as hypoxia, ischemia-reperfusion injury, interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and corticosteroid treatment can markedly enhance XOR transcription. Additionally, the conversion of XDH to XO is expedited under hypoxic conditions. 101 Purine metabolism occurs primarily in the liver and in tissues where xanthine oxidase is widely distributed. Approximately 65% of uric acid is excreted from the kidneys, and the rest is excreted mainly into the intestine. 130 Due to the absence of the uricase enzyme responsible for converting uric acid into allantoin and allantoic acid, UA remains the terminal metabolic product in humans. The majority of uric acid is filtered in its free form, with approximately 90% of the filtered UA being reabsorbed. 131 Hyperuricemia can be triggered by inadequate excretion due to reduced glomerular filtration, impaired tubular secretion and improved tubular reabsorption. 39 , 40 Elevated phosphoribosyl pyrophosphate (PRPP) synthetase activity and deficiency in hypoxanthine phosphoribosyl transferase (HPRT) not only enhance endogenous purine synthesis but also result in excessive production and buildup of uric acid. 132 , 133

Cellular turnover processes like tumor lysis, rhabdomyolysis, and hemolysis contribute to increased urate production. Additionally, various transporters in the intestinal mucosa and salivary glands, diverse medications, extracellular fluid volume depletion, and organic acids that facilitate transport can influence uric acid metabolism. Thus, both intrinsic and extrinsic factors play roles in urate production. 134

Uric acid regulation

UA levels are contingent on the dynamic equilibrium among purine-rich food intake, endogenous urate synthesis, and urate excretion through various routes, including urine and the gastrointestinal tract. Disruptions to this balance can impact serum uric acid (SUA) levels. 135 – 137 The transport of uric acid entails multiple genes and proteins, collectively participating in the complex mechanisms of uric acid reabsorption and secretion. At a genome-wide significant level, three loci (ABCG2, SLC2A9, and CUX2) have been identified in association with renal urate overload, whereas four loci (ABCG2, SLC2A9, CUX2, and GCKR) have been linked to renal urate underexcretion. 138 , 139 The main transporter genes are SLC22A12 (URAT1), SLC2A9 (GLUT9), and ABCG2 (BCRP). 140 (Table ​ (Table2) 2 ) It is increasingly recognized that disturbances in urate transport, both in the gastrointestinal tract and kidneys, are pivotal in the pathogenesis of diseases associated with hyperuricemia. Investigating these transporters and their genetic loci is essential for regulating and achieving target serum urate levels. Moreover, alterations in gut microbiota structure or imbalance can contribute to metabolic disorders, influencing the synthesis of purine-metabolizing enzymes and the release of inflammatory cytokines. This relationship is closely linked to the onset and progression of hyperuricemia and gout, which are metabolic immune disorders. 141 , 142

Urate transporters and their characteristics related to launched therapies for hyperuricemia

Gut microbiota

UA serves as both an antioxidant and an immune modulator, exerting significant influence on the composition of the gut microbiota. Notably, the gastrointestinal tract plays a pivotal role as a pathway for uric acid excretion, with the microbial ecosystem within the gut intricately involved in this metabolic process. 143 Transporters for uric acid located in intestinal epithelial cells facilitate the translocation of uric acid from the bloodstream into the intestinal lumen. 144 – 152 Once in the intestinal lumen, UA can either be directly excreted or metabolized by the gut microbiota. 153 Specific bacteria, such as Lactobacillus and Pseudomonas, participate in the degradation and elimination of uric acid in the intestine through the production of short-chain fatty acids (SCFAs). 154 Moreover, the activities of enzymes involved in uric acid metabolism are intricately connected to the gut microbiota. 155 – 157 Uricase, an enzyme responsible for converting UA into allantoin and urea, is found in various bacterial species including Bacillus pasteurii, Proteus mirabilis, and E. coli. Certain strains of Lactobacillus, such as Lactobacillus sp. OL-5, Lactobacillus plantarum Mut-7, and Lactobacillus plantarum Dad-13, have been found to exhibit higher intracellular uricase activity, further emphasizing the role of gut microbiota in UA metabolism. 143 , 149 , 154 An imbalance in the gut microbiota can elevate uric acid concentrations, thereby exacerbating the chronic deposition of UA crystals in joints, characteristic of gout. This dysbiosis typically involves a proliferation of opportunistic pathogens alongside a reduction in beneficial bacteria known to stimulate the synthesis of anti-inflammatory cytokines. 145 , 158 , 159 The exploration of intestinal flora metabolism represents a promising frontier in clinical research pertaining to hyperuricemia and gout. Metabolic research has established a correlation between hyperuricemia and disruptions in the primary bile acid pathway or intestinal metabolism, suggested that targeting the gut microbiome could offer innovative therapeutic approaches for managing hyperuricemia and its associated complications. Future studies will concentrate on unraveling the intricate mechanisms through which gut microbiota modulates metabolic processes in these patient populations.

Genetics of urate control

Hyperuricemia and hyperuricosuria have been shown to cluster in families, indicating a familial transmission pattern. Studies in South American ethnic groups have demonstrated heritability rates ranging from 39% to 45%. 160 – 165 Both adults and children have been found to exhibit genetic mutations that affect baseline renal urate excretion levels. In a genome-wide association study (GWAS) involving more than 140,000 individuals of European descent, uric acid receptors encoded by twenty-eight chromosomal genes were discovered to impact plasma uric acid levels. Genetic variants associated with uric acid levels mainly include purine metabolism (e.g., XDH, HPRT1), urate transporters (e.g., SLC2A9, SLC22A12), and renal urate processing regulators (e.g., ABCG2). 119 , 166 , 167 Single nucleotide polymorphisms (SNPs) within or near these genes have consistently shown associations with variations in uric acid levels across diverse populations. 168 Genome-wide association studies (GWAS) have identified key loci housing urate transporters crucial for uric acid excretion in both renal and gastrointestinal pathways. 167 , 169 Through functional insights and expression quantitative trait loci (eQTL) analyses, several loci have identified probable causal genes, such as SLC2A9, ABCG2, PDKZ1, SLC22A11 (OAT4), and INHBB. 166 Additionally, numerous other loci have strong candidate genes identified, including GCKR, RREB1, SLC17A1 to SLC17A4, SLC22A12, MAF, MLXIPL, PRKAG2, HNF4G, A1CF, IGFR1, and HLF. 166 , 170 (Fig. ​ (Fig.3) 3 ) The primary physiological regulation of serum uric acid levels occurs through renal excretion. 171 GWAS in major populations consistently highlight urate transporter genes as pivotal loci influencing serum uric acid levels, 138 , 139 notably SLC2A9 (GLUT9) and SLC22A12 (URAT1), involved in urate reabsorption from urinary filtrates. 172 , 173 For instance, the primary effect of SLC2A9 (rs12498742) explains 2% to 3% of serum uric acid level variance in Europeans, which is substantial for a complex phenotype. 174 , 175 Variation in ABCG2 (BCRP) is also noteworthy across European and East Asian populations. 176 – 178 Notably, in individuals of European ancestry, the genetic control of SLC2A9a and SLC2A9b isoforms, situated at basolateral and apical membranes respectively, constitutes a prominent genetic signal. 172 , 174 Thus, we concluded several key genes have been identified with significant associations with SUA levels. Among these genes, ABCG2 stands out as one of the most crucial and strongly linked to SU levels to the risk of hyperuricemia. 167 , 171 , 179 , 180 A specific polymorphism (rs2231142) within ABCG2 has been identified, which reduces urate efflux activity and increases the susceptibility to both HU and gout. 181 Notably, this variant is more prevalent in Asian populations compared to Europeans. 180 , 182 Another important gene, SLC2A9, encodes a urate transporter and exerts a significant influence on SUA levels. A specific polymorphism (rs734553) within SLC2A9 has been associated with an elevated risk of hyperuricemia. 119 , 166 Interestingly, the prevalence of this variant varies among different populations, with higher frequencies observed in Asian populations. Research indicates that the rs1967017 variant in PDZK1 creates a binding site for the transcription factor hepatocyte nuclear factor 4α (HNF4α) within an enhancer region upstream of the PDZK1 transcription start site. 170 This binding increases PDZK1 expression, potentially leading to reduced urate excretion. Another prominent genetic variant associated with serum urate levels is rs1263026 at GCKR. 183 The Leu allele of this variant induces relaxation of glucokinase inhibition, resulting in heightened glucose phosphorylation. This process diminishes the ATP pool and augments urate production through ADP catabolism. 184 However, other loci with more modest effects have not consistently replicated in subsequent studies examining their correlation with serum urate levels.

In East Asian populations, four loci have demonstrated a significant association with serum urate levels: SLC2A9, ABCG2, SLC22A12, and MAF. Similarly, in African American populations, three loci have been identified: SLC2A9, SLC22A12, and SLC2A12. In contrast, the European population predominantly shows an association with only one locus, SLC2A9. Australian studies have identified 28 loci, encompassing all but one (SLC2A12) of those found in African American and East Asian populations. Among these diverse populations, certain loci, such as SLC2A9, ABCG2, GCKR, and SLC17A1-SLC17A4 (also known as NPT1-NPT4), exhibit stronger effects and have been consistently replicated in multiple studies

URAT1, located in the membrane of renal tubular epithelial cells, serves as a uric acid transporter protein. It plays a crucial role in mediating UA reabsorption, a process in which approximately 90% of uric acid is typically reabsorbed following glomerular filtration. 175 URAT1 belongs to the organic anion transporter (OAT) subgroup within the broader gene family. Other subcategories within this family include organic cation transporters, as well as novel type/carnitine transporters. Moreover, additional genetic alterations in hyperuricemia and gout associated with PDZK1 likely occurs through its modulation of the apical membrane localization of URAT1. 55 Research has shown that individuals with renal hypouricemia and loss-of-function mutations in URAT1 demonstrate incomplete responses to both pyrazinamide and uricosurics, resulting in average concentrations reaching 0.93 mg/dL. 185

GLUT9 functions as the principal transporter for urate efflux across the basolateral membrane of the proximal tubule in the kidney, facilitating transepithelial urate absorption. 186 The pronounced lack of renal reabsorption of filtered urate in hypouricemic patients with GLUT9 loss-of-function mutations provides compelling evidence of the critical role this protein plays in renal tubular urate reabsorption. In these individuals, the fractional excretion of urate approaches 150%, highlighting the predominant mechanism of tubular urate secretion in the absence of reabsorption. 134

BCRP is an efflux pump that is driven by ATP on the apical membrane proximal renal tubule and intestinal epithelial cells and is critical for UA excretion. Mutated or dysfunctional ABCG2 may lead to significantly reduced excretion, moderate hyperuricemia and metabolic syndrome. 139 Initially, it was hypothesized that the loss or reduction of ABCG2-mediated renal urate secretion would result in increased renal urate reabsorption, as diminished renal excretion is typically considered the primary mechanism of hyperuricemia in most gout patients. However, hyperuricemic patients with varying degrees of ABCG2 dysfunction, categorized by genotypes of dysfunctional SNPs, exhibit hyperuricemia characterized by urate overproduction. This is evidenced by elevated urinary urate excretion and a fractional excretion exceeding 5.5%. Additionally, ABCG2 dysfunction appears to contribute to renal underexcretion of urate in patients with milder functional impairments, also classified by genotype. 136

OAT1, OAT3 and OAT4

OAT1 and OAT3, located on the basolateral membrane of the proximal tubule, function as urate/dicarboxylate exchangers responsible for uric acid excretion. Additionally, OAT4 participates in the transport of high-affinity binding steroids such as estrone sulfate (ES). 187 This transporter operates as a chloride-ion-dependent exchanger for both ES and uric acid. Physiologically, OAT4 facilitates uric acid excretion in the proximal tubule by orchestrating ion exchange processes such as PAH/Cl-, PAH/ES, and potentially PAH/UA interactions. Its interplay with NHE3 and sodium dicarboxylate transporter 1 contributes to the regulation of intracellular α-ketoglutarate levels. 134

NPT1 and NPT4

NPT1, which exhibits a weak to moderate correlation with altered uric acid levels, facilitates both the absorption and efflux of urate. It functions as a chloride-dependent urate transporter, which is involved in sodium/phosphate cotransport activities. 188 NPT4 is crucial in urate excretion, working synergistically with basolateral organic anion transporters 1 and 3 (OAT1/OAT3). Uric acid was absorbed by OAT1 and OAT3 into tubular cells, which is subsequently transported into the urinary lumen by NPT4. 189

Polyvalent PDZ domain 1 (PDZK1) is a multidomain protein with four PDZ domains, primarily located at the apical membrane of kidney proximal tubule cells. It is abundantly expressed in this region and engages directly with several apical transporters, such as URAT1 and NPT1. 134 As a scaffold protein, PDZK1 significantly regulates the activity of various transport proteins within the proximal tubules. Additionally, PDZK1 is proposed as a potential upstream regulator of ABCG2, impacting its function in the small intestine. Specifically, the upregulation of ABCG2 expression and function in response to soluble uric acid in intestinal cell lines is dependent on PDZK1 at the transcriptional level. 188

These genes are specifically expressed on the apical membrane of renal proximal tubule cells, which are crucial for the secretion of uric acid into the glomerular filtrate, as depicted in Fig. ​ Fig.4. 4 . Beyond the genes that encode for these transporter proteins, over a hundred genetic loci have been associated with hyperuricemia. Genome-wide association studies provide a comprehensive and unbiased method for pinpointing genetic factors linked to urate regulation and metabolism. 190

Uric acid undergoes a dynamic process of elimination and reabsorption, primarily orchestrated by the kidneys (two-thirds) and the intestines (one-third). In the nephron, filtration of water and solutes occurs within the glomerular capsule, followed by tubular reabsorption, predominantly mediated by the proximal convoluted tubule. Concurrently, tubular secretions extract uric acid from peritubular capillaries, secreting it into the tubular fluid for urinary excretion. Urate transporters in renal proximal tubule epithelial cells actively mediate the secretion and reabsorption of urate, thus determining the net excretion levels from the kidney. In the renal proximal tubule, SLC22A12 (URAT1), SLC17A1 (NPT1), and SLC22A11 (OAT4) located on the apical membrane facilitate reabsorption. SLC2A9 (GLUT9), found in both the apical and basolateral membrane tubules, is a long isoform that mediates the basolateral efflux of urate back into circulation. For excretion, SLC22A6 (OAT1) and SLC22A8 (OAT3) on the basolateral membrane facilitate urate entry into the renal tubules. ABCG2 (BCRP) and SLC17A3 (NPT4), positioned on the apical side, contribute to the secretory transport of urate into the tubule lumen for urinary excretion. In intestinal metabolism, uric acid is actively secreted into the intestinal lumen primarily by the transporter ABCG2, underscoring the role of the intestines in urate homeostasis

Hyperuricemia and diseases

An elevated uric acid concentration above physiological levels can pose a potential risk factor for several diseases closely associated with metabolic disorders. Numerous epidemiological studies have suggested that hyperuricemia may correlate with hypertension, metabolic syndrome, insulin resistance, dyslipidemia, type II diabetes, kidney disease, and cardiovascular events including coronary heart disease and cerebrovascular disease. 191 – 199 Studies have demonstrated that serum uric acid levels can also predict the onset of hypertension, diabetes, obesity, and renal disorders 74 , 200 , 201 (Table ​ (Table3 3 ).

The mechanisms of conditions caused by hyperuricemia

Mendelian randomized studies

A significant biomedical question is whether hyperuricemia is causally associated with related comorbid conditions such as gout, hypertension, cardiac and kidney disease, etc. 202 – 209 Utilizing data from observational epidemiologic studies in conjunction with experimental evidence from in vitro and animal model investigations, elevated serum urate levels have been suggested as being potentially linked to concurrent metabolic disorders. 210 The principles of Mendelian randomization, which leverages genetic variants influencing exposures (e.g., UA levels), can serve as a natural randomization method to study the causal effects of these exposures on disease outcomes. 21 , 211 , 212 To investigate the association between elevated serum urate concentrations and comorbid metabolic conditions, Mendelian randomized studies were conducted using genetic variants linked to increased serum urate levels. 213 – 215 These genetic variants act as proxies for prolonged urate exposure, assuming they remain unconfounded by other factors. 18 , 22 , 206 , 216 The pioneering Mendelian randomization studies leveraged specific genetic variants with substantial impacts on serum uric acid levels as instrumental variables. The objective of their research was to investigate the associations between uric acid concentrations and various health conditions, including body mass index, bone mineral density, coronary artery disease, blood pressure, metabolic syndrome, blood glucose levels, triglyceride levels, diabetes mellitus, serum creatinine levels, estimated glomerular filtration rate, Parkinson’s disease, memory, and gout. 207 , 212 , 217 – 220 However, over the past three years, Mendelian randomization studies have utilized genetic variants associated with serum uric acid levels, identified through genome-wide association studies (GWAS), to construct genetic risk scores. These investigations consistently indicate a lack of evidence supporting a causal relationship between elevated serum urate levels and the risk of developing type 2 diabetes mellitus, coronary heart disease, ischemic stroke, and heart failure. 17 , 221 – 223 Li et al. 22 , 169 conducted a comprehensive analysis of 107 Mendelian randomization studies, included a median of 7,158 participants and 2,225 cases, with serum uric acid level as the exposure variable for various health outcomes. The instrumental variables utilized in these studies explained 2% to 6% of the variability in serum uric acid levels. The results indicated a significant association between serum uric acid levels and four health outcomes: diabetic macrovascular disease, arterial stiffness, renal events, and gout. Particularly noteworthy was the robust association observed with gout. However, the study did not find significant associations with several common cardiac and metabolic disorders, including type 2 diabetes, hypertension, chronic kidney disease, ischemic heart disease, and congestive heart failure. 224 – 238 These findings suggest that while elevated serum uric acid levels may be associated with certain health outcomes such as gout and renal diseases, the evidence does not strongly support a causal relationship with other metabolic disorders. Additional analyses have shown consistent results across most outcomes examined, which included a variety of cardiovascular diseases, such as incidence of atrial fibrillation, 239 coronary heart disease, incidence of hypertension, 216 and incidence of stroke, 71 diabetes, 240 chronic kidney disease, 222 mild cognitive impairment, Parkinson’s disease, 241 and multiple sclerosis. 21 However, statistical significance was inconsistent in the two outcomes of diabetic neuropathy 5 , 218 and Alzheimer’s disease. 242 In particular, the role of genetic variants, such as those within the SLC2A9 gene, in influencing cardiovascular and metabolic outcomes remains subject to debate. 6 , 191 , 223 , 243 , 244 Recent research has delved into the causal relationship between variants of the URAT1 transporter gene (SLC22A12) and obesity and metabolic syndrome. 245 , 246 In a randomized controlled trial involving patients with essential hypertension, specific SLC22A12 single nucleotide polymorphisms (SNPs), such as rs11602903, were associated with higher body mass index (BMI), larger waist circumference, higher HDL cholesterol levels, and the presence of metabolic syndrome in individuals of European descent. 247 – 249 However, these associations were not observed in non-European populations, underscoring potential ethnic differences in genetic susceptibility to hyperuricemia-related metabolic abnormalities. 250 – 252

UA induced inflammation and relative mechanism

Uric acid signaling triggers the activation of several transcription factors, such as NF-κB or AP-1, through the activation of MAPK p38 and ERK pathways, resulting in the production of reactive oxygen species (ROS) under the conditions of hyperuricemia. 78 The NLRP3 inflammasome, part of the nucleotide-binding domain and leucine-rich repeat protein family complex, is essential in the development of numerous infections and inflammatory disorders. 116 , 253 – 256 The expression of NLRP3 is induced by NF-κB activation, leading to the assembly of a complex with the adaptor protein ASC and procaspase-1. 85 , 91 , 114 , 257 Subsequently, procaspase-1 transforms into its mature form, caspase-1. This enzyme then activates pro-IL-1β and pro-IL-18, converting them into their mature forms, IL-1β and IL-18, respectively. This process coincides with the initiation of pyroptosis, facilitating the release of IL-1β into the extracellular environment. 258 , 259 In gout, the activation of the NLRP3 inflammasome by monosodium urate (MSU) crystals stimulates the release of IL-1β, which contributes to the progression of arthritis. This activation mechanism involves phagocytic cells such as macrophages and neutrophils. 260 – 264 This cascade of events leads to enhanced transcription of innate cytokines in various cell types including vascular endothelial cells, smooth muscle cells, and adipocytes. The activation is linked to the generation of vasoconstrictive agents, including MCP-1, (pro)renin receptor, endothelin, and angiotensin II, while concomitantly diminishing vasodilatory compounds like nitric oxide, which may contribute to the development of hypertension and lead to decreased viability of cardiomyocytes and myocardial damage. 94 , 265 – 267 Moreover, in vascular cells, upregulation of growth factors like PDGF has been noted, which can promote smooth muscle cell proliferation and atherosclerosis. 268 In vascular smooth muscle cells, uric acid-induced activation of MAPKs promotes the expression of MCP-1, an important chemokine involved in atherosclerosis progression. In pancreatic β-cells, uric acid triggers ERK activation, resulting in reduced cell viability, apoptosis, and the production of reactive oxygen species. 78 , 269 , 270 Treatment with a URAT1 inhibitor suppresses the ERK pathway and mitigates uric acid-induced cell damage, underscoring the involvement of intracellular uric acid in MAPK activity. 271 – 274 Additionally, uric acid regulates MAPK through phosphatase activity that inhibits the MAPK pathway. 275 , 276 Monosodium urate crystals are ingested by monocytes via phagocytosis, engaging Toll-like receptors (TLRs) such as TLR2 and TLR4. This interaction prompts the recruitment of the adaptor protein ASC to the NLRP3 inflammasome complex. Subsequently, caspase-1 is drawn to the ASC assembly, where it oligomerizes along the ASC filaments. This oligomerization triggers the autoproteolytic maturation of caspase-1, activating its inflammatory caspase function. 183 , 277 Active caspase-1 then catalyzes the proteolytic cleavage and maturation of proIL-1β into the biologically active IL-1β, which leads to acute flares of gouty arthritis. 183 In neutrophils, uric acid activates the ERK/p38 signaling pathway while inhibiting the Nrf2 pathway. Additionally, monosodium urate crystals induce the translocation of Nrf2 into the nucleus and modulate intracellular reactive oxygen species levels, thereby promoting the activation of the NLRP3 inflammasome. This ROS-induced injury can lead to apoptosis, disruptions in ion regulation, and mitochondrial dysfunction, further exacerbating the inflammatory response and tissue damage. 67 , 278 Furthermore, resolution of gout flares involves the formation of neutrophil extracellular traps, which capture monosodium urate crystals. Uric acid can modulate cytokine production and inflammatory outcomes through various pathways. 253 , 279 , 280 Uric acid can enhance AKT phosphorylation, which subsequently leads to PRAS40 phosphorylation with the activation of mTOR, 281 resulting in the inhibition of autophagy, as well as inhibiting AMPK phosphorylation. 282 When UA levels are elevated, RAGE signaling is stimulated, leading to the activation of nuclear factor-kappa B (NF-κB). NF-κB activation triggers the transcription and release of pro-inflammatory cytokines within endothelial cells. Additionally, UA-induced activation of RAGE promotes the expression and extracellular release of high mobility group box 1 protein (HMGB1) by endothelial cells, lymphocytes, monocyte-derived macrophages, and vascular smooth muscle cells. 87 , 283 , 284 The interaction between HMGB1 and RAGE amplifies the inflammatory cascade, contributing to cell apoptosis and endothelial dysfunction, resulted to CVD or CKD. 277 , 285 This dysregulation of the HMGB1-RAGE pathway further diminishes NO availability, exacerbating inflammation. Moreover, UA-induced inflammation and oxidative stress can also trigger endoplasmic reticulum (ER) stress, decreased nitric oxide bioavailability and produce peroxynitrite (ONOO-), a very powerful radical, which contributing to cellular dysfunction and apoptosis. 61 , 103 , 270 , 282 Uric acid diminishes nitric oxide levels through several mechanisms, including the consumption of NO due to excessive reactive oxygen species production and direct inhibition of NO synthesis. UA-induced dephosphorylation of endothelial NO synthase (eNOS) via uric acid transporters reduces NO production in human umbilical vein endothelial cells. Moreover, the HMGB1-receptor for advanced glycation end products pathway regulates eNOS production 14 , 98 , 286 , 287 (Fig. ​ (Fig.5 5 ).

The role of uric acid in the pathogenesis of hyperuricemia and its associated diseases involves complex intracellular signaling mechanisms. Elevated intracellular uric acid levels stimulate the production of reactive oxygen species and activate multiple inflammatory signaling pathways. XO xanthine oxidase, eNOS endothelial nitric oxide synthase, MSU monosodium urate, Nrf2 Nuclear factor-erythroid 2-related factor 2, mTOR mammalian target of rapamycin complex, ERK extracellular signal-regulated kinase, AMPK AMP-activated protein kinase, IL-1β interleukin-1β, MAPK mitogen-activated protein kinases, PRAS40 Proline-Rich AKT Substrate, NF-κB nuclear factor κB, TLR Toll-like receptors, NLRP3, NOD-, LRR- and pyrin domain-containing 3, PKC Protein Kinase C, RAGE Receptor for Advanced Glycation End Products pathway

Biomarkers of hyperurceimia and its relative disease

Recent advances in proteomics have shed light on the biochemical underpinnings of hyperuricemia. Notably, Liu’s 288 research indicated elevated serum levels of complement C3, haptoglobin, complement C4, and apolipoprotein A1 (apo A1) in Uyghur patients with hyperuricemia. This suggests a correlation between hyperuricemia and high-density lipoprotein (HDL) components, with apo A-I implicated in cholesterol transport and anti-atherosclerotic properties. 289 – 291 Furthermore, HDL’s role in lipid metabolism regulation and its influence on cardiovascular disease and diabetes development cannot be overlooked. 292 The inhibition of apo A-I may be linked to atherosclerosis progression through chronic inflammation pathways. Moreover, the complement system’s activation in response to hyperuricemia has been implicated in the pathogenesis of various inflammatory conditions, including gout, renal injury, and type 2 diabetes (T2DM). 144 The NLRP3 inflammasome’s activation and its interplay with the complement and coagulation systems are of particular interest. Component C5a of the complement system, recognized for its potent pro-inflammatory effects, can amplify monocyte and neutrophil activation. MSU crystals have been shown to trigger IL-1β production and inflammatory cytokine release through C5a activation, highlighting the potential of complement antagonists in managing gout inflammation. In the realm of urine proteomics, Huo et al. 293 conducted a comparative study between healthy individuals and those with hyperuricemia, revealing differentially expressed proteins that hint at pathways involved in insulin receptor recycling and lipid metabolism. The study pinpointed the V-type proton ATPase subunit B kidney isoform and Complex Factor D (CFAD or adipsin) as key factors impacting insulin regulation in hyperuricemia patients.

Cardiovascular metabolic mechanisms and diseases

In recent years, numerous studies have reinforced the strong association between hyperuricemia and cardiovascular events. Research has demonstrated that serum uric acid levels are positively correlated with hypertension. 265 , 294 , 295 The proposed mechanisms involve the activation of the renin-angiotensin system, inflammatory responses, oxidative stress, vascular smooth muscle cell proliferation, and insulin resistance. 57 , 69 , 78 , 94 , 296 The ONATA study showed a negative correlation between serum uric acid levels and insulin sensitivity, suggesting a potential link between uric acid, insulin sensitivity, and the risk of developing hypertension. 105 , 212 Hyperuricemia frequently coexists with insulin resistance, which can elevate the activity of the renin-angiotensin-aldosterone system and the sympathetic nervous system. This interaction leads to sodium retention, increased blood volume, and subsequent hypertension. 297 , 298 In patients with hyperuricemia, elevated serum levels of high-sensitivity C-reactive protein (hs-CRP) are closely linked to inflammation and oxidative stress, which may exacerbate hypertension. 299 Soluble urate may further exacerbate vascular inflammation and oxidative stress by promoting LDL oxidation, lipid peroxidation, and elevating hs-CRP levels. Moreover, hs-CRP can contribute to vascular endothelial injury by activating the complement system. 99 , 287 Furthermore, elevated uric acid levels have been implicated in causing inflammation in endothelial cells via the activation of the receptor for advanced glycation end products (RAGE) signaling pathway. 285 When UA levels are increased, RAGE signaling becomes activated, that ultimately lead to endothelial dysfunction, is a key feature of various cardiovascular diseases. Specifically, the activation of RAGE triggers the nuclear factor-kappa B pathway, resulting in the transcription and release of proinflammatory cytokines within endothelial cells. 277 , 285 To mitigate UA-induced endothelial dysfunction and inflammation, targeting the RAGE signaling pathway offers a promising therapeutic strategy. Employing anti-RAGE antibodies to inhibit RAGE activity can suppress the HMGB1/RAGE signaling axis, thereby alleviating endothelial dysfunction and diminishing inflammation within endothelial cells. 285 , 300 , 301 (Fig. ​ (Fig.5) 5 ) By modulating this pathway, it may be possible to alleviate the detrimental effects of elevated UA levels on endothelial function and reduce associated cardiovascular risks. 105 , 265 , 302

Elevated serum uric acid levels heighten the risk of cardiovascular disease (CVD) mortality, potentially due to mechanisms by which hyperuricemia activates the renin-angiotensin system and induces hypertension. Additionally, uric acid has been detected in atherosclerotic plaques. 102 , 201 A recent study conducted in the Japanese revealed that even among healthy, lean, normotensive individuals, the presence of hyperuricemia is associated with an elevated risk of cardiometabolic disease. 191 Kleber et al. reported a significant association between each 1 mg/dL increase in genetically predicted uric acid concentration and the risk of cardiovascular death and sudden cardiac death. 207 Emerging evidence has linked elevated serum uric acid levels to cardiovascular diseases, particularly atherosclerosis and hypertension. Chronic low-grade inflammation is a hallmark of atherosclerosis, and UA-induced IL-1β release may contribute to this inflammatory milieu. 69 , 90 , 239 , 303 Additionally, uric acid has been associated with endothelial dysfunction, which further exacerbates vascular inflammation and contributes to hypertension. 237 , 304 – 308 Endothelial dysfunction characterized by impaired nitrogen oxide-mediated vasodilatation is a key event in the development of atherosclerosis. 94 Experimental and clinical research has substantiated that elevated uric acid levels exert detrimental effects on cardiovascular health, with increased oxidative stress being a key mechanism implicated in these adverse outcomes, 6 , 66 decreased nitric oxide availability, endothelial dysfunction, the promotion of local and systemic inflammation, vasoconstriction, vascular smooth muscle cell proliferation, insulin resistance 309 and metabolic disorder. 51 , 124 Additionally, endothelial dysfunction associated with elevated serum uric acid levels leads to a low-grade inflammatory state and vascular activation of the angiotensin system. As estrogen production declines with age in females, its cardio-protective effects may diminish, thereby increasing susceptibility to elevated uric acid levels. 307

Renal metabolic mechanisms and diseases

Emerging evidence increasingly supports the pathogenic role of hyperuricemia in both the onset and progression of chronic kidney disease (CKD). Untreated hyperuricemia is notably acknowledged as a risk factor for the development of CKD. In China, the prevalence of hyperuricemia among CKD patients varies from 36.6% to 50%, with a notable rise observed as CKD progresses. 310 The mechanisms by which hyperuricemia contributes to chronic kidney disease include renal inflammation, endothelial dysfunction, and activation of the renin-angiotensin system. 13 Hyperuricemia is known to stimulate the renin-angiotensin system and impair endothelial nitric oxide release, which collectively lead to renal vasoconstriction and increased blood pressure. 100 Nitric oxide (NO) plays a crucial role in regulating vascular endothelial cell relaxation, maintaining stable renal vascular tone, and influencing renal blood flow, renin secretion, and tubuloglomerular feedback mechanisms. 105 , 311 However, hyperuricemia inhibits nitric oxide synthase, leading to reduced nitric oxide levels. 312 Furthermore, endothelial cells respond to hyperuricemia by upregulating angiotensin-converting enzyme activity, which enhances angiotensin II and superoxide anion production. This cascade promotes vasoconstriction and hypertension. 102 , 313 Uric acid directly affects endothelial cells by reducing nitric oxide levels, influencing processes such as vascular smooth muscle cell proliferation, extracellular matrix deposition, and the adhesion and migration of macrophages. 102 , 227 , 228 , 314 – 317 These effects lead to arterial resistance and remodeling, ultimately contributing to renal dysfunction and fibrosis. 6 , 318 However, the evidence supporting the treatment of asymptomatic hyperuricemia in hypertensive patients with chronic kidney disease is limited. Observational studies have produced inconsistent findings, and there is a notable absence of large-scale randomized controlled trials to validate the efficacy of lowering uric acid levels. Despite these limitations, the majority of existing studies suggest that therapies aimed at reducing uric acid levels may potentially attenuate the progression of CKD. 102 , 319 – 321 A single-center double-blind, randomized, parallel placebo-controlled study found that uric acid reduction slowed the decline of glomerular filtration rate in patients with stage 3 and 4 CKD. 322 Another study by Jeong et al. demonstrated that febuxostat treatment to reduce serum uric acid levels tended to reduce renal functional deterioration in patients with both CKD and hyperuricemia. 323 These findings suggest that reducing uric acid levels could potentially improve renal function. However, ongoing debate centers on whether the benefits of uric acid-lowering therapy stem from decreased uric acid levels or the inhibition of XO activity. 319 , 324 , 325 Further investigations have shown that medications like benzbromarone and febuxostat can mitigate the advancement of chronic kidney disease and decrease serum uric acid levels in CKD patients, highlighting the potential advantages of treatments aimed at lowering uric acid levels. 319 , 326 – 328

Increased uric acid levels are linked to kidney inflammation and the progression of kidney diseases, especially in the presence of hyperuricemia. Gout has been identified as an independent risk factor for chronic kidney disease, nephrolithiasis and acute kidney injury, wherein uric acid excretion by the kidneys participate in facilitating crystal-induced direct tubular toxicity. 310 This finding underscores the close interconnection between uric acid and nitric oxide regulation in this particular clinical context. 329 Kidney damage mediated by UA involves the stimulation of the renin-angiotensin-aldosterone system. In the medulla, an elevated UA concentration results in the deposition of urate precipitates and the activation of the Nod-like receptor protein 3 (NLRP3) inflammasome. 96 Activation of these pathways leads to chronic interstitial inflammation and tubular damage, ultimately contributing to kidney fibrosis. Additionally, in the renal cortex, hyperuricemia amplifies the activity of the renin-angiotensin-aldosterone (RAA) system, fostering sustained vasoconstriction of the afferent arterioles. 130 In turn, leads to glomerular damage and the development of glomerulosclerosis. 330 CKD is characterized by endothelial dysfunction and NO deficiency; thus, uric acid is a potential contributor to CKD progression. It is primarily driven by the development of hypertrophy in the afferent arteriole, which compromises autoregulation and facilitates heightened transmission of systemic blood pressure to the glomerulus. 310 The kidney’s susceptibility to oxidative stress stems from various sources including the mitochondrial respiratory complex, NADPH oxidases, endothelial nitric oxide synthase (eNOS), myeloperoxidase, and xanthine oxidoreductase (XOR), all of which contribute to the advancement of chronic kidney disease and its related complications. 331 Oxidative stress is a characteristic feature of chronic kidney disease, initiating inflammation and endothelial dysfunction, which accelerates arteriosclerosis. This sequence plays a role in glomerular injury, leading to albuminuria and eventual glomerulosclerosis. Hyperuricemia exacerbates oxidative stress, thereby intensifying inflammation and endothelial dysfunction within this context. 332

Gout and its mechanism

Gout is one of the most common forms of chronic degenerative disease of the joints. 333 , 334 It is defined by recurring episodes of inflammatory arthritis affecting joints and specific soft tissues, including cartilage, synovial bursae, and tendons, particularly in the lower extremities, due to the deposition of uric acid in the form of monosodium urate crystals. 34 The painful pathological state of gout is mainly induced by hyperuricemia with the concentration of more than 6.8 mg/dL under physiological conditions (37 ◦C, pH 7.4). 333 , 334 When uric acid levels increase to such concentration, crystals form in the joints, triggering an inflammatory response. MSU crystals display a triclinic structure composed of stacked sheets of purine rings, forming needle-shaped crystals observable under microscopy. The exposed, charged surfaces of these crystals are thought to promote interactions with phospholipid membranes and serum factors, thereby contributing to the inflammatory response mediated by these crystals. 335 MSUs serve as the primary stimuli for initiating, amplifying, and sustaining the innate immune response. They are phagocytosed by macrophages as foreign particles and recognized by Toll-like receptors 2 and 4 (TLR2/TLR4), which subsequently activate and oligomerize the NLRP3 complex. 336 The NLRP3 complex, a multiprotein assembly with proteolytic activity, facilitates the conversion of the pre-IL-1β into its active form, IL-1β. Subsequently, IL-1β is released into the extracellular milieu, initiating acute inflammation. 337 The MSU crystals are initially engulfed by macrophages, which then facilitate the assembly and activation of the NLRP3 inflammasome, preceded by priming through pathways that activate NF-κB, such as those initiated by the engagement of Toll-like receptors (TLRs) within the TLR family. 338 – 340 Inflammasomes are intracellular multiprotein complexes that trigger inflammatory responses. These structures emerge as intracellular pattern recognition receptors (PRRs) like NLRP3 detect signals that have infiltrated the cell’s cytosol. 341 The recognition triggers the PRR to oligomerize and associate with a complex comprising adaptor proteins and effector enzymes. 342 – 344 The formation of the NLRP3 inflammasome involves the recruitment of the adaptor protein ASC, which is then followed by the recruitment of caspase-1. 345 Following initial oligomerization within the inflammasome structure, ASC monomers can subsequently polymerize into high-molecular-weight aggregates. 341 , 346 The recruitment and oligomerization of caspase-1 by this complex initiate the activation and proteolytic cleavage of its substrates. Caspase-1 activates proinflammatory cytokines such as IL-1β by cleaving their respective precursor proteins and proIL-1β. 262 In gout, the release of IL-1β mediated by inflammasomes triggers a significant inflammatory response characterized by vasodilation and rapid recruitment of neutrophils to the site of crystal deposition, thereby driving acute inflammatory episodes. 347 – 349 Similarly, MSU promotes the expression of other cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon gamma (IFN-γ), and chemokines, such as monocyte chemotactic protein-1 (MCP-1). MCP-1 induces the recruitment of innate immune cells and indirectly affects gout progression. 214 Flare resolution involves the capture of MSU crystals by neutrophil extracellular traps. 350

Diabete and its mechanism

Chronic hyperuricemia is associated with pancreatic β-cell dysfunction, which is a critical component of type 2 diabetes. 4 Research indicates that the likelihood of developing diabetes rises by 6% with each 1 mg/dL increment in uric acid concentration. 240 Uric acid has been observed to adversely affect β-cells, resulting in impaired insulin secretion and decreased functional β-cell mass. This contributes to an insufficient compensatory response to insulin resistance and gluconeogenesis, mediated by the inhibition of hepatic AMP-activated protein kinase, thereby promoting the progression towards overt diabetes. 351 Uric acid can promote oxidative stress, generating reactive oxygen species that cause cellular damage. 122 Oxidative stress is closely associated with insulin resistance and β-cell dysfunction. The increased oxidative load in hyperuricemia may impair insulin sensitivity and exacerbate the metabolic disorders observed in diabetes. 309 Moreover, hyperuricemia frequently coincides with low-grade inflammation. Increased uric acid concentrations have been implicated in the release of inflammatory cytokines, thereby contributing to systemic inflammation. Inflammation is a well-recognized contributor to the pathogenesis of insulin resistance and type 2 diabetes. This inflammatory environment disrupts insulin signaling pathways and exacerbates glucose intolerance. Elevated insulin levels, stemming from insulin resistance and β-cell dysfunction, may enhance the renal reabsorption of uric acid. Consequently, this cycle potentially reinforces higher serum uric acid levels, establishing a feedback mechanism in the interplay between hyperinsulinemia and hyperuricemia. 352 Additionally, research has shown that elevated uric acid levels inhibit insulin-induced glucose uptake in cardiomyocytes. This effect is primarily mediated by an increase in the phosphorylation of insulin receptor substrate 1 (IRS1) and a concomitant inhibition of Akt phosphorylation, a crucial component of the insulin signaling pathway. 353 Moreover, clinical research has identified a correlation between hyperuricemia and diabetes, although the causal relationship remains controversial. While high UA may accelerate the development of diabetes and impair glucose tolerance, it is insufficient to solely induce diabetes. 19 , 351 , 354

Metabolic syndrome (MetS) and its mechanism

Metabolic syndrome is characterized by a cluster of conditions, including obesity, insulin resistance, and dyslipidemia, and is intimately linked to chronic inflammation. 355 The prevalence of metabolic syndrome rises by approximately 5% in men and 9% in female with each 1 mg/dL increase in serum uric acid concentration. 356 Elevated serum uric acid levels have been shown to impair insulin sensitivity, thereby contributing to the development of insulin resistance. In response to increased insulin resistance, the pancreas compensates by secreting higher levels of insulin, resulting in hyperinsulinemia. 357 The prevalence of metabolic syndrome components, including hyperglycemia, hypertriglyceridemia, low HDL cholesterol, and hypertension, shows a rising trend with increasing serum uric acid levels. Interestingly, central obesity appeared to decrease slightly in individuals with exceptionally high serum uric acid concentrations. 200 Uric acid is implicated in the pathogenesis of metabolic syndrome through its ability to induce insulin resistance and promote low-grade inflammation, underscoring its proinflammatory role. 51 In addition, hyperuricemia is frequently accompanied by dyslipidemia, another hallmark of metabolic syndrome. Studies have demonstrated an association between elevated serum uric acid levels and alterations in lipid profiles, including increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-C) levels. 358 These lipid abnormalities contribute to the dyslipidemia pattern often observed in individuals with metabolic syndrome. There is evidence to suggest that hyperuricemia may promote weight gain and central obesity, both of which are integral components of metabolic syndrome. Uric acid has been shown to influence adipogenesis and fat accumulation, potentially exacerbating obesity in individuals with MetS. 200

Hypertension and its mechanism

Hyperuricemia may acutely influence blood pressure through a renin-dependent pathophysiological mechanism. Additionally, it is postulated that hyperuricemia exacerbates hypertension by promoting systemic endothelial dysfunction and oxidative stress. 201 Epidemiological studies consistently demonstrate a robust association between hyperuricemia and the incidence of hypertension. Each 1 mg/dL rise in serum uric acid is linked to a 13–15% increase in hypertension risk. 299 Elevated serum uric acid levels constitute a substantial risk factor for both the onset and progression of hypertension. The precise mechanisms by which elevated uric acid concentrations lead to hypertension are not entirely understood but likely involve complex processes related to cardiovascular disease pathogenesis. The increase in blood pressure in hyperuricemic individuals is predominantly attributed to oxidative stress and intracellular urate activity, mediated chiefly by xanthine oxidoreductase (XOR). 299 Uric acid deposition-induced inflammation, resulting in endothelial dysfunction and vascular damage (referred to as vascular gout), can occur at serum uric acid levels exceeding 6.5 mg/dL. This threshold is notably higher than those typically linked with hypertension and cardiovascular disease. 201 Uric acid-lowering therapy effectively reduces both systolic and diastolic blood pressure in pediatric and adolescent patients newly diagnosed with essential hypertension, particularly in young individuals with a short duration of hypertension and preserved renal function. 200

Intervertebral degeneration (IVD) and its mechanism

Several studies have confirmed that the oxidative properties of physiological levels of UA can eliminate 60% of ROS in the body. 359 This reduction in ROS can inhibit autophagy in IVDs and reduce the apoptosis of myeloid cells caused by oxidative stress, maintaining the stability of the structure of IVD. 94 However, high concentrations of UA can promote oxidative stress and mitochondrial dysfunction. The induction of XO can promote the production of ROS, thus promoting oxidative stress in IVD and exacerbating IDD. Moreover, high osmolality induced by high uric acid levels may inhibit PDGF- and IGF-I-mediated DNA synthesis in the medulla oblongata. 268 Additionally, MSU crystals may accumulate in IVD under high uric acid conditions and cause damage to cone endplates. 360 MSU crystals cause cellular damage and mediate inflammatory responses, such as prostaglandin, bradykinin, IL-1, IL-6, and TNF-a. 337 The accumulation of inflammation and bone destruction affect the ability of cartilage endplates to provide nutrients to IVD, exacerbating IDD. 361

Therapy approaches for hyperuricemia

Hyperuricemia can manifest either asymptomatically or symptomatically, leading to distinct management approaches. 95 Thus, the management strategies for hyperuricemia typically involve two primary modalities: non-pharmacological interventions and pharmacological therapy. These approaches are tailored based on the clinical presentation and individual patient factors, aiming to mitigate the risk of complications. 362

Treatment of asymptomatic hyperuricemia

Non-pharmacological interventions play a crucial role in managing hyperuricemia, particularly in asymptomatic individuals. 363 , 364 Dietary modifications, such as adherence to a low-purine diet and avoidance of alcohol, particularly beer and spirits, sugar-sweetened beverages, heavy meals, and excessive intake of meat and seafood, have demonstrated efficacy in reducing uric acid levels by approximately 10-15%. 365 Furthermore, incorporating cherries, coffee, and low-fat dairy products into the diet can confer beneficial effects. Consumption of fructose-rich beverages should be minimized. Protein-rich vegetables like nuts, legumes, beans, spinach, cauliflower, and mushrooms can be consumed in moderation due to their low bioavailability of urate and high fiber content, which are less likely to elevate serum uric acid levels. 324 , 366 – 369 However, complete prohibition of purine intake is not recommended due to its limited effect on serum uric acid levels (approximately 1 mg/dL) and the significant burden it imposes on patients. 1 Instead, supplementation with vitamins such as ascorbic acid (vitamin C) and folic acid can help lower serum urate concentrations. Vitamin C, administered in doses ranging from 500 to 1000 mg/day, exhibits mild uricosuric properties and can complement dietary and lifestyle modifications. Similarly, folic acid supplementation has been shown to effectively reduce serum urate levels. 9 , 127 , 370 , 371 Of note, non-pharmacological interventions represent valuable adjunctive measures for all individuals with gout, encompassing weight management and avoidance of excessive consumption of purine-rich foods, alcoholic beverages, and fructose-rich beverages. However, complete elimination of purine intake is not recommended due to its limited impact on serum uric acid levels, typically resulting in a reduction of approximately 1 mg/dL. Nonetheless, exceptional cases may require pharmacotherapy even in asymptomatic individuals with elevated serum uric acid levels. 372 For instance, patients undergoing radiotherapy or chemotherapy for malignancies are at risk of uric acid nephropathy and may require preventive therapy with intravenous hydration and xanthine oxidase inhibitors. 330 , 373 , 374 Xanthine oxidase inhibitors are typically used in such case. In Japan, treatment of asymptomatic hyperuricemia is recommended to mitigate the risk of chronic diseases such as hypertension, coronary artery disease (CAD), and chronic kidney disease (CKD). 191 However, the decision to initiate pharmacotherapy for asymptomatic hyperuricemia remains debatable and should be based on individual risk factors and considerations. While recent studies suggest a potential association among hyperuricemia, cardiovascular and renal diseases, further research is needed to elucidate the mechanisms and clinical benefits of urate-lowering therapy in these populations. 102 , 320 , 375

Treatment of hyperuricemia with commodities

An analysis of twenty-two guidance documents revealed a consensus on target serum uric acid levels for long-term control, with 6.0 mg/dL (or 360 μmol/L) as the predominant recommendation. 362 Uric acid-lowering drugs can be broadly classified into three major groups: drugs that reduce uric acid synthesis (xanthine oxidase inhibitors), drugs that promote uric acid excretion (reabsorption inhibitors), and drugs that regulate uric acid metabolic hydrolysis (uricase inhibitors). 1 Irrespective of the specific urate-lowering therapy (ULT) selected, fundamental principles entail commencing treatment concurrently with prophylaxis and initiating with a conservative dosage, followed by systematic monitoring of serum uric acid levels and subsequent dose adjustment until the therapeutic target is attained. 310 For symptomatic hyperuricemia, the common pharmacological interventions for urate-lowering therapy (ULT) are illustrated in Fig. ​ Fig.4. 4 . Xanthine oxidase (XO) plays a central role in purine metabolism by catalyzing the conversion of hypoxanthine to xanthine and further to uric acid (UA). Concurrently, XO contributes to the production of reactive oxygen species (ROS). 372 Allopurinol, categorized as a purine-like XO inhibitor, and febuxostat and topiroxostat, classified as non-purine XO inhibitors, constitute the primary pharmacological approach for ULT. 326 , 376 , 377 By inhibiting XO activity, these agents demonstrate antioxidant properties by reducing ROS production associated with purine metabolism as well as remain the cornerstone of hyperuricemia treatment. 139 Uricosuric agents represent a secondary or alternative therapeutic option, with recent guidelines advocating their use in combination with XO inhibitors when monotherapy proves ineffective. 378 However, it is crucial to acknowledge that the predominant cause of hyperuricemia in most patients which is impaired renal clearance of uric acid. This impairment may be influenced by inherited renal transport factors or a reduced estimated glomerular filtration rate (eGFR). 102 , 189 , 320 , 330 In patients with lower eGFR levels, uricosuric agents may not be as effective, necessitating the use of alternative agents with different mechanisms of action. 379 – 381 Benzbromarone, another potent uricosuric drug, acts by inhibiting URAT1 and GLUT9. 328 , 382 Emerging evidence linking hyperuricemia to cardiovascular and metabolic comorbidities has spurred the development of novel agents. Lesinurad and arhalofenate, inhibitors of URAT1 and OAT4, respectively, offer promising therapeutic avenues. 383 , 384 Dotinurad, a selective urate reabsorption inhibitor available in Japan, inhibits URAT1 with high selectivity, demonstrating non-inferiority to febuxostat in lowering serum UA levels with no significant safety concerns 385 (Table ​ (Table4 4 ).

Update on the therapies for the treatment of hyperuricemia

Xanthine oxidase inhibitors (XOIs)

Xanthine oxidase catalyzes the conversion of purine metabolites to uric acid (UA). Therefore, xanthine oxidase inhibitors reduce UA production from both endogenous and dietary purine sources, making them the first-line therapies for managing hyperuricemia. 23 , 55

Allopurinol

Allopurinol is an inhibitory agent that interferes with xanthine oxidase-mediated purine synthesis; allopurinol undergoes metabolic conversion to alloxanthine, which is a potent xanthine oxidase enzyme inhibitor. 386 The dual action of allopurinol and its metabolite, alloxanthine, inhibits xanthine oxidase, effectively catalyzing the conversion of hypoxanthine to xanthine and its subsequent conversion to uric acid. Allopurinol is crucial for promoting the secondary utilization of hypoxanthine and xanthine through a metabolic pathway intricately linked with hypoxanthine-guanine phosphoribosyl transferase. This metabolic cascade contributes to the synthesis of nucleic acids and nucleotides, elucidating the multifaceted impact of allopurinol on purine metabolism. 358 This metabolic process results in an increased concentration of nucleotides, triggering feedback mechanisms that suppress the synthesis of purines. Consequently, the reduced levels of uric acid in both urine and serum contribute to a reduction in the occurrence of hyperuricemia. 383 The initial dose of 50 mg was given 1 ~ 2 times a day, and each time, the dose was increased by 50 ~ 100 mg. The general dose was 200 ~ 300 mg/d, divided into 2 ~ 3 doses, for a maximum daily dose of 600 mg. 387 Notably, the CKD-FIX study and the PERL trials demonstrated that allopurinol did not significantly slow the deterioration of estimated glomerular filtration rate (eGFR) in chronic kidney disease patients compared to placebo, over a span of 2 and 3 years, respectively. 388 , 389 However, a contrasting outcome was observed in a pediatric study where allopurinol treatment over four months led to an improvement in renal function in children with CKD. 390 The ALL-HEART trial, which included patients over the age of 60 with ischemic heart disease but without a history of gout, found that allopurinol did not reduce the incidence of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death over an average follow-up period of 4.8 years when compared to standard care. 391 Conversely, a smaller study involving 82 heart failure patients indicated that long-term allopurinol administration was associated with an improvement in left ventricular function. 392 However, an algorithm was developed to theoretically mitigate the risk of allopurinol hypersensitivity syndrome (AHS), which occurs in 2–8% of patients. 393 Allopurinol can cause severe cutaneous adverse reactions (SCARs), which is a primary concern associated with allopurinol use. SCARs are strongly correlated with the HLA B*5801 allele and include drug rash accompanied by eosinophilia and systemic symptoms, Stevens–Johnson syndrome, and toxic epidermal necrosis. 394 In certain regions, a precautionary measure involves tailoring the allopurinol dosage based on creatinine clearance, aiming to mitigate the risk associated with SCARs, particularly considering renal failure as a predisposing factor for these adverse reactions. Notably, when allopurinol doses are less than 300 mg daily, less than half of patients achieve the therapeutic target of a serum uric acid (SU) concentration less than 6.0 mg/dL. 395 Intriguingly, even in instances where allopurinol is not adjusted according to the estimated glomerular filtration rate (eGFR), approximately one-third of patients fail to attain SU levels below the designated threshold of 6.0 mg/dL. Nonetheless, a significant portion of patients receiving allopurinol fail to reach the target serum urate concentrations. 396 Notably, the ABCG2 Arg141Lys variant has been consistently linked with poor response to allopurinol across multiple independent cohorts. 397

Febuxostat, a nonpurine xanthine oxidase inhibitor, effectively reduces serum uric acid levels without impeding the enzymes involved in pyrimidine and purine metabolism and synthesis. Its biotransformation is facilitated by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Notably, patients treated with febuxostat demonstrate a slightly reduced risk of heart failure exacerbation compared to those receiving allopurinol. 398 In China, febuxostat is recommended as a urate-lowering therapy and is prescribed at a daily dosage of 20–40 mg, contrasting with the global recommendation of 80-120 mg/day. In the United States, febuxostat is tolerated at doses of 40 and 80 mg per day, while in Europe it is 120 mg per day, and in Japan it is 10–60 mg per day. 336 The CONFIRMS trial provided evidence that a daily dosage of 80 mg of febuxostat is more efficacious in lowering serum uric acid levels than a 300 mg daily dose of allopurinol. 399 This nonpurine xanthine oxidase inhibitor is considered a viable alternative for individuals with allopurinol allergies. Notably, in scenarios of renal impairment, febuxostat is deemed more potent than allopurinol. 326 Approximately 65% of patients achieved serum uric acid levels less than 6.0 mg/dL, although concerns have been raised regarding the cardiac safety profile of febuxostat. 400 Common side effects of febuxostat encompass muscle pain, gastrointestinal discomfort, skin rashes, diarrhea, and a slight elevation in liver enzymes. Notably, the incidence of skin rashes is comparable to that observed with allopurinol. The manufacturer advises careful monitoring of liver function at the commencement of therapy and in the presence of any symptom’s indicative of liver injury. Importantly, the incidence of adverse effects associated with febuxostat remains low unless the daily dosage exceeds 120 mg. 376 In the PRIZE trial, a cohort of 483 individuals with asymptomatic hyperuricemia was randomly assigned to either a two-year treatment with febuxostat or a control group that received lifestyle modifications. The study found that febuxostat did not correlate with a slowed progression of carotid intima-media thickness. 401 However, a detailed sub-analysis revealed that the febuxostat group experienced a greater reduction in arterial stiffness parameters compared to the control group. 402 Additionally, another sub-analysis indicated that patients on febuxostat treatment exhibited improved diastolic function. 403 The FREED trial, involving 1070 elderly patients with hyperuricemia and cardiovascular risk factors, randomized participants to receive either febuxostat or non-febuxostat treatment. The results demonstrated that febuxostat was linked to a significantly reduced risk of the primary composite endpoint, encompassing cerebral, cardiovascular, renal events, and all-cause mortality. 404

Topiroxostat

Topiroxostat, a nonpurine xanthine oxidase inhibitor, interacts with multiple amino acid residues within the solvent channel and forms covalent bonds with the molybdenum ion. This interaction produces a hydroxylated 2-pyridine metabolite that effectively inhibits xanthine oxidase, a critical enzyme in uric acid metabolism. Additionally, topiroxostat inhibits the ATP-binding cassette transporter G2 (ABCG2), which plays a key role in renal uric acid reabsorption and the secretion of uric acid from the intestines. 394 However, topiroxostat has not received approval for use in the United States and Europe, although it is utilized in Japan. The medication is available in oral tablets of 20, 40, and 60 mg. The standard recommendation is to initiate treatment with a 20 mg dose administered twice daily, with a maximum approved dosage of 80 mg twice daily. 387 The literature on topiroxostat reports certain adverse effects, including polyarthritis, nasopharyngitis, and an increase in liver enzymes. Notably, the majority of these adverse effects are generally classified as mild to moderate in severity. 377 A study demonstrated a marked enhancement (≥150%) of warfarin activity in 32% of patients with cardiovascular disease and hyperuricemia who were treated with topiroxostat. 405 A prospective, randomized, blinded study compared the effects of topiroxostat with allopurinol and suggested that topiroxostat may lead to a reduction in left ventricular end-diastolic pressure, indicating a potential benefit for cardiac function. 406 Additionally, the study hinted at nephroprotective properties of topiroxostat compared to allopurinol. As for nephroprotection, an RCT on the use of febuxostat vs topiroxostat show none improvement in urinary protein/creatinine ratio. 407

Advanced therapy

Hyperuricemia can arise due to either overproduction or underexcretion of uric acid, with the latter being the predominant form as mentioned. The underexcretion of uric acid is primarily attributed to diminished renal clearance. 138 , 139 During renal filtration, uric acid is extensively handled by proximal tubular cells. Approximately 90% of the filtered uric acid is reabsorbed via the apical transporters URAT1 and OAT4, as well as the basolateral GLUT9. Conversely, a portion of uric acid is secreted back into the proximal tubular lumen through various apical transporters, including ABCG2, NPT1, NPT4, and GLUT9, along with the basolateral transporters OAT1 and OAT3. 138 , 139 Uricosuric agents act on the proximal tubule of the kidney by inhibiting the reabsorption of uric acid or enhancing its excretion. These medications are considered second-line treatments for hyperuricemia, particularly in cases unresponsive to standard therapies. They are often used in conjunction with xanthine oxidase (XO) inhibitors or prescribed for patients who cannot tolerate XO inhibitors. Additionally, certain antihypertensive and lipid-lowering drugs, such as losartan, simvastatin, atorvastatin, and fenofibrate, have been shown to reduce serum uric acid levels, potentially exhibiting a synergistic effect when used alongside standard hypouricemic treatments. 81 , 408

Probenecid is a quintessential uricosuric agent with multifaceted effects on renal function, significantly influencing the elimination of organic anions and tubular reabsorption of urate. Its therapeutic potential extends beyond managing hyperuricemia, demonstrating efficacy as a URAT1 and GLUT9 inhibitor, especially in cases of renal impairment. Probenecid exerts its uricosuric effects by inhibiting renal organic anion elimination and disrupting tubular urate reabsorption. This dual action enhances urinary uric acid excretion, thereby reducing serum urate concentrations. Additionally, probenecid may modulate urate binding by plasma proteins and influence uric acid secretion within the renal tubules. 397 The comprehensive use of probenecid is not without consideration of adverse reactions, as it spans various organ systems. Gastrointestinal, dermatologic, hematologic, renal, and immunologic manifestations have been reported. 409 Approximately 5% of users experience manifestations such as rash, gastrointestinal complaints, and hypersensitivity reactions. While serious toxicity is infrequently reported, a notable proportion of patients, approximately one-third, may exhibit intolerance, necessitating discontinuation of probenecid. 410

Benzbromarone

Benzbromarone, recognized as a uricosuric agent, exhibits notable in vitro inhibitory effects on urate transport facilitated by URAT1 and GLUT-9. Its approval for clinical use comes with cautious considerations, particularly in terms of dosing and associated hepatotoxicity. The recommended starting dosages of benzbromarone range from 12.5 mg to 50 mg daily, a regimen predominantly observed in Europe and Asia. 79 , 83 , 411 As novel URAT1 inhibitor uricosuric therapies gain momentum in clinical trials, particularly among Western populations, the application of benzbromarone warrants meticulous consideration. Patient selection for clinical trials should reflect the pathophysiologic subtype of hyperuricemia, existing comorbidities, and concurrent use of urine alkalization agents such as potassium citrate. This comprehensive approach facilitates a thorough evaluation of benzbromarone’s efficacy and safety across diverse patient cohorts, ultimately refining uricosuric therapy regimens. 55 The risk of hepatotoxicity is especially increased in individuals administered high doses of 300 mg daily of benzbromarone. However, findings from a comprehensive systematic review indicates that, when juxtaposed with probenecid, benzbromarone is associated with a reduced frequency of adverse effects. 378 Certain scholars posit that the removal of benzbromarone from the market may not align with the best interests of patients with gout, with the argument that conceivable toxicity could be mitigated through a cautious approach involving gradual dosage escalation coupled with vigilant monitoring of liver function. 327 Importantly, similar to those treated with febuxostat, patients on benzbromarone exhibited a significantly reduced risk of advancing to end-stage renal disease. 412 In an additional study, benzbromarone demonstrated a lower risk of experiencing the initial gout flare and developing type 2 diabetes when contrasted with allopurinol. 413 A randomized, open-label, crossover study comparing benzbromarone and febuxostat in hyperuricemia patients indicated that benzbromarone was associated with diminished endothelial dysfunction and an increase in adiponectin levels. 414

Emerging drugs and uricosuric compounds

Given the advancements in drug delivery systems and a deeper understanding of renal mechanisms and urate transporters, numerous novel therapeutic agents for managing hyperuricemia are currently in various stages of clinical development. 372 , 415 , 416 Emerging pharmacological agents for hyperuricemia management are currently undergoing various stages of clinical development, ranging from preclinical to early clinical trials. Notable candidates in Phase II/III trials include arhalofenate (MBX102), AC201, the RDEA group (including lesinurad), tranilast, and ulodesine (BCX4208). Additionally, Phase I trials are evaluating drugs such as levotofisopam and Marine Active. The primary goal of these innovative therapies is to improve serum uric acid control in patients with symptomatic hyperuricemia, particularly those with comorbid conditions. These new agents aim to offer enhanced tolerability and minimize adverse events compared to traditional treatments. However, it is important to acknowledge that uricosuric agents and emerging therapies that increase renal clearance of uric acid may also raise the risk of renal adverse events. 188

Lesinurad (RDEA594)

Lesinurad is a common URAT1 inhibitor that influences the serum uric acid concentration through the inhibition of URAT1 and OAT4. 394 Lesinurad is metabolized and eliminated predominantly by the liver (75%) and to a lesser extent by the kidneys (25%), with a half-life of approximately 9 to 10 h. The primary treatment-emergent adverse events reported with its use include serious cardiovascular events and potential nephrotoxicity. Nonetheless, clinical studies have demonstrated that lesinurad at a dosage of 200 mg once daily does not elevate the risk of renal, cardiovascular, or other adverse events beyond those associated with xanthine oxidase (XO) inhibitors alone, with the exception of transient increases in serum creatinine levels. 417 Nephrotoxicity emerges as the primary adverse effect associated with lesinurad, with its incidence being dose dependent. A recent Phase III clinical trial focused on gout patients who were intolerant or contraindicated to xanthine oxidase inhibitors (XOIs) revealed that lesinurad monotherapy at a dosage of 400 mg led to a significant incidence of elevated serum creatinine. Additionally, the trial reported renal-related adverse events, including serious adverse events, at a higher rate compared to the placebo group. 383 However, Lesinurad is a relatively new pharmaceutical agent, currently lacks data regarding its potential impact on cardiovascular and renal outcomes.

Arhalofenate (MBX-102)

Arhalofenate (MBX-102) is a uricosuric compound that has been investigated for its potential in the treatment of gout and hyperuricemia. It acts as a dual-acting agent, combining the properties of a uricosuric and a nonsteroidal anti-inflammatory drug (NSAID). By inhibiting URAT1, arhalofenate promotes the excretion of uric acid in the urine, reducing serum uric acid levels. 384 Furthermore, arhalofenate has anti-inflammatory properties, which can be beneficial in the context of gout, where inflammation plays a significant role in joint symptoms. However, clinical trials of arhalofenate have been conducted to assess its efficacy and safety in the treatment of gout and hyperuricemia. These trials aimed to evaluate its ability to lower serum uric acid levels, reduce gout flares, and provide anti-inflammatory effects. 418 Arhalofenate is available for oral administration in daily dosages are 200, 400, or 600 mg once. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) respectively concurred with a pharmaceutical company on the efficacy endpoints for two distinct clinical indications of arhalofenate in 2017. Currently, three Phase III trials are in progress, designed to assess the comparative efficacy of a combination therapy consisting of arhalofenate plus febuxostat 40 mg versus febuxostat monotherapy at 80 mg. These trials aim to evaluate the reduction in serum uric acid levels and the incidence of gout flares. 419

Dotinurad represents a novel and selective urate reabsorption inhibitor that has received approval for clinical application in Japan. This medication potently inhibits the URAT1 transporter to a lesser extent, which also affects ABCG2, OAT1, and OAT3. 420 Phase III clinical trials have substantiated the non-inferiority of dotinurad in comparison to both febuxostat and benzbromaron. 421 Notably, dotinurad has demonstrated safety in patients with an estimated glomerular filtration rate (eGFR) between 60 ml/min and 30 ml/min, without necessitating any dosage adjustments. In terms of adverse drug reactions, aggregated data from phase II and III studies indicate that while dotinurad can potentially cause liver-related adverse reactions, such as hepatic steatosis and abnormal liver function tests, which the incidence is lower compared to benzbromarone. 420

Tranilast, is recognized as an anti-inflammatory agent initially designed for treating allergic conditions such as asthma and allergic rhinitist. 422 – 424 Recent research has shed light on its efficacy in lowering urate levels by inhibiting renal transporters URAT1 and Glucose Transporter 9 (GLUT9). 425 In two separate preclinical trials, tranilast exhibited promising urate-lowering effects along with a reduction in inflammation associated with urate crystal deposition. Following the administration of a single dose of tranilast, a mean reduction in serum uric acid levels of 0.17 mg/dL at 4 h and 0.24 mg/dL at 24 h was observed. Headache was notably identified as the predominant adverse effect associated with tranilast. Furthermore, tranilast has been investigated in Phase II clinical trials in combination with allopurinol for patients experiencing moderate-to-severe gouty arthritis. 418

Ulodesine (BCX4208)

Ulodesine, an inhibitor of purine nucleoside phosphorylase (PNP), operates upstream of xanthine oxidase (XO) in the purine metabolism pathway. By blocking PNP activity, ulodesine diminishes the substrates available for XO, thereby reducing uric acid production. 426 Currently, this drug is in development for managing hyperuricemia in chronic gout. Promising results have been observed in two Phase II clinical trials, evaluating ulodesine both as a monotherapy and in combination with allopurinol. In a 24-week extension study, the treatment response rates for 5 mg, 10 mg, and 20 mg doses were 40%, 50%, and 45%, respectively, compared to a 25% response rate for the placebo. 427 , 428 Interestingly, no significant adverse events were documented compared to the placebo group. Ulodesine displays no interactions with CYP450 isoforms and undergoes no hepatic metabolism, thereby minimizing anticipated drug interactions. However, there are concerns regarding its potential effects on T cells. Deficiency of purine nucleoside phosphorylase (PNP) has been linked to immunodeficiency and autoimmune disorders. 243

Uricase, facilitating enhanced uric acid excretion involves the administration of exogenous urate oxidase, is an enzyme which not endogenously expressed in humans. Uricases are employed in the treatment of refractory gout and are capable of achieving a rapid reduction in hyperuricemia, significant resolution of tophi, alleviation of chronic joint pain, and enhancement of overall quality of life. 387 Urate oxidase catalyzes the breakdown of uric acid into 5-hydroxyisourate, which subsequently undergoes spontaneous degradation to allantoin without enzymatic assistance. The heightened solubility of allantoin, surpassing that of uric acid by 5-10-fold, facilitates its more efficient renal excretion. 429 Addressing this constraint, the development of a recombinant urate oxidase, rasburicase and pegloticase has shown superior efficacy in rapidly reducing uric acid plasma concentrations compared to allopurinol. 387 Pegloticase, a recombinant urate oxidase conjugated to polyethylene glycol (PEG), has been introduced to reduce immunogenicity and extend the half-life of rasburicase. Nevertheless, recent concerns regarding the development of antibodies against PEG in healthy blood donors prompt further exploration of potential implications for the efficacy of PEGylated pharmaceuticals. However, the main side effects include serious cardiovascular events and infusion reactions. 1 Rasburicase is approved for managing hyperuricemia linked to chemotherapy in cancer patients. It is known for its immunogenicity and infusion-related reactions, like pegloticase. Unlike pegloticase, however, rasburicase is not PEGylated and has a shorter half-life of 8 hours. 430 Rasburicase is predominantly employed in the management of tumor lysis syndrome owing to its rapid onset of action and short treatment duration. However, it is associated with significant incidences of infusion reactions, anaphylaxis, methemoglobinemia, and hemolysis, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. 431 However, the application of uricases has been constrained by factors such as availability, cost, and immunogenicity. Despite these limitations, uricases have the potential to become a primary therapeutic option for severe and challenging cases of hyperuricemia. They may be utilized as induction or debulking therapy to lower the urate pool, followed by maintenance with urate-lowering therapy (ULT).

Therapy frame and future considerations

Per the 2020 American College of Rheumatology guidelines, allopurinol is recommended as the initial therapeutic approach for symptomatic hyperuricemia, aiming to achieve a target serum uric acid level below 6 mg/dl. 432 Epidemiological studies suggest that maintaining a serum uric acid level below 5.5 mg/dl may offer enhanced cardiovascular and renal protection compared to target levels of 6 mg/dl or higher. 433 Maintaining urate levels at or below 360 μmol/L through urate-lowering therapy is deemed safe and crucial for the prevention and reversal of joint, cardiovascular and renal damages. 308 , 362 , 363 , 372 , 434 – 436 Additionally, EULAR guidelines recommend losartan for patients with hypertension and fenofibrate for those with hyperlipidemia, both of which have mild uricosuric effects. 336 , 437 Additionally, the British Society for Rheumatology advocates for a lower target serum uric acid level of less than 5 mg/dl. 438 Similarly, the Japanese Society of Gout and Nucleic Acid Metabolism endorses allopurinol as the primary therapy for hyperuricemia, with a target serum uric acid level of less than 6 mg/dl. Furthermore, they suggest initiating treatment for hyperuricemia when the serum uric acid level exceeds 8 mg/dl with at least one complication, or above 9 mg/dl without any complications. 439 , 440 Concurrently, the development of novel uricosuric compounds aims to address resistant hyperuricemia while maintaining a favorable safety profile. The uricosuric agents targeting the URAT1 transporter, such as lesinurad and dotinurad, along with the formulation of oral combination therapies comprising xanthine oxidase inhibitors and uricosuric agents, is poised to improve the attainment of the target serum uric acid level of less than 6 mg/dL. 387 In conclusion, navigating the intricacies of hyperuricemia treatment requires a tailored approach. To mitigate acute arthritis attacks and associated complications, early initiation of pharmacotherapeutic interventions is advisable. The dynamic landscape, characterized by established agents and novel contenders, necessitates ongoing research to optimize therapeutic strategies, ensuring efficacy while mitigating potential risks. 441

Conclusion and perspective

Among the history of hyperuricemia development, uric acid accumulation in serum characterizes hyperuricemia, a condition with diverse physiological roles ranging from antioxidant processes, pro-oxidative activities, pro-inflammatory activities, nitric oxide regulation, anti-aging effects and innate immune response. 14 – 16 Understanding its multifaceted functions and mechanisms is crucial for deciphering its implications in health and disease. Furthermore, circulating urate levels are intricately regulated by the balance between urate production and excretion, and the kidney plays a pivotal role in maintaining this homeostasis. 186 , 187 Urate transporters contribute to this delicate equilibrium. Genetic factors, particularly variations in urate transporter genes, significantly influence individual susceptibility to hyperuricemia. 245 , 442 Altered urate transport mechanisms, both in the gastrointestinal tract and kidneys, are implicated in the pathogenesis of diseases associated with hyperuricemia.(Fig. ​ hyperuricemia.(Fig.4) 4 ) Future genome-wide association studies should aim to broaden their scope by encompassing diverse ethnic groups and varied patient populations. Furthermore, investigations into comorbidities linked with hyperuricemia need expansion to better elucidate the role of transporter gene mutations in disease pathogenesis. 303 , 443 In the meantime, by utilizing the results of GWAS studies, clinicians can identify individuals at risk for adverse drug reactions better, thereby improving safety and treatment compliance. 150 Furthermore, redefining hyperuricemia as a dynamic variable rather than a static biochemical parameter may offer novel perspectives on its role in disease progression. As our understanding advances, the intricate nature of hyperuricemia-related diseases necessitates ongoing exploration, emphasizing the importance of innovative personalized medicine approaches and a nuanced perspective to unravel these complexities. Dysmetabolic intestinal flora potentially contributes to gout-related metabolic and inflammatory symptoms by promoting Th17 infiltration. The identification of probiotic strains, such as DM9218, capable of lowering uric acid levels represents a novel therapeutic avenue. Currently, the modulation of intestinal microbiota through microecological therapies, including probiotics, prebiotics, and fecal microbiota transplantation, is a prominent area of clinical investigation for preventing and managing hyperuricemia and gout. These interventions aim to restore intestinal microecological balance, increasingly recognized as pivotal in the pathophysiology of these conditions. By targeting the gut microbiome, these therapies offer a novel and potentially effective strategy for mitigating the risks and progression of hyperuricemia and gout, thereby contributing to a more holistic and personalized treatment approach in clinical practice. 143 , 444 Furthermore, identifying the distinct phenotypes is crucial, as hyperuricemia stemming from increased XO activity may have a different correlation with cardiovascular disease compared to that caused by renal underexcretion. Moreover, patients with the underexcretion phenotype might respond more favorably to uricosuric agents than to XO inhibitors. We suspect that biases in patient population selection could account for the inconsistent findings regarding the cardio and nephroprotective effects of hypouricemic agents in clinical trials. Differentiating between gout and asymptomatic hyperuricemia can be challenging, as gouty nephropathy may occur even in the absence of clinically apparent gout or with serum uric acid levels below the solubility threshold. There is an urgent need for future studies to delineate the effects of different classes of hypouricemic drugs on each hyperuricemia phenotypes. 372

In addition, in terms of the major mechanism of hyperuricemia induced commodities, oxidative stress, inflammatory signaling pathway and immune response are involved in this process, which mainly lead to cell apoptosis and endothelial dysfunction. 105 , 270 , 287 (Fig. ​ (Fig.5) 5 ) While some associations have been observed, particularly with gout and renal diseases, evidence from Mendelian randomization studies did not consistently support a causal relationship between elevated serum urate levels and other metabolic or cardiovascular disorders. However, hyperuricemia plays a role in promoting inflammation, oxidative stress, and endothelial dysfunction underscores its potential contribution to disease pathogenesis. 249 , 445 – 449 Uric acid exerts multifaceted effects on endothelial function and vascular health through its interactions with NO, ROS, and inflammatory pathways, highlighting its potential role in the pathogenesis of cardiovascular diseases like atherosclerosis. 69 , 90 , 256 Targeting these pathways may offer therapeutic opportunities for mitigating the adverse vascular effects of hyperuricemia. However, the precise mechanisms by which NLRP3 is activated in response to monosodium urate crystals remain incompletely understood. 91 , 114 , 263 , 423 , 450 , 451 The caspase-1-independent pathways of IL-1 production, including the specific proteases involved and the stimuli for their activation, are still not well-defined. Clarifying the stages at which these pathways contribute to the inflammatory phenotype and identifying the cell types orchestrating this inflammasome-independent response are crucial areas for further investigation. 337 , 340 , 452 Moreover, a pivotal area of research concerns the mechanisms that precipitate gouty attacks in patients with sustained monosodium urate crystal deposits. It remains uncertain whether distinct initiation mechanisms trigger the inflammatory response by acting on priming signaling pathways, or if a reduction in the negative regulation of NLRP3 activation amplifies the inflammatory cascade. 15 , 453 , 454 Current therapeutic approaches for hyperuricemia focus on mitigating associated complications and reducing serum UA levels with non-pharmacological interventions include dietary modifications and some environment factors. 455 Besides, pharmacological interventions primarily involve urate-lowering drugs, uricosuric compounds and emerging agents. 55 Traditional XO inhibitors and newer uricosuric compounds provide additional options for personalized treatment approaches. Newer uricosuric compounds, such as probenecid, lesinurad and arhalofenate, target different aspects of uric acid metabolism, providing additional options for personalized treatment approaches. Compared with XOIs, uricase, rasburicase and pegloticase convert UA to allantoin in adults with gout resistant to conventional therapy. 429 Precision medicine guided by genetic insights holds promise for tailoring hyperuricemia management to individualized needs. 410 Efforts are underway to develop novel therapies addressing unmet needs, such as alternative agents for long-term management of hyperuricemia. 201 , 411 , 438 , 456 Integration of genetics into hyperuricemia research offers opportunities for advancing personalized medical approaches and improving patient outcomes. In the future, precision medicine, guided by genetic variants, represents a promising avenue for tailoring hyperuricemia management to individualized needs. Hyperuricemia continues to be inadequately managed, primarily due to factors such as ineffective dosing of urate-lowering therapy, patient noncompliance, and intolerance/adverse events associated with current treatment options. 23 , 321 , 325 , 415 , 455 These limitations highlight the urgent needs for the creation of alternative treatment options capable of safely and effectively reducing serum uric acid levels for the long-term management of hyperuricemia. Acknowledging the growing need for better control of hyperuricemia, considerable research has been dedicated to the discovery and development of innovative therapies designed to meet these clinical challenges.

Acknowledgements

This study was performed with the support of the National Natural Science Foundation of China (82002339, 81820108020), Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System (BJ1-9000-22-4002). BioRender ( https://www.biorender.com/ ) was used to create the Figs. ​ Figs.3 3 and ​ and5 5 .

Author contributions

L.D., Y.Z., H.L., and J.G. drafted and conceived the initial manuscript. J.G., C.Z. and Z.Z. provided the essential assistant for our final manuscript. L.D., H.L., J.G., Q.W., B.Y., L. X., Y.P. and Y.Z. drew the figures and arranged the tables, contributed to the review of the literature and preparation of the manuscript. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

These authors contributed equally: Lin Du, Yao Zong, Haorui Li.

Contributor Information

Changqing Zhang, Email: nc.ude.utjs@qcgnahz .

Zhigang Zhong, Email: moc.361@gzzts .

Junjie Gao, Email: moc.361@jjgniloc .

• DOI: 10.1108/jpmh-04-2024-0055
• Corpus ID: 272230078

Defining mental health literacy: a systematic literature review and educational inspiration

• Shengnan Zeng , Richard Bailey , +1 author Xiaohui Chen
• Published in Journal of Public Mental… 2 September 2024
• Psychology, Education

56 References

A systematic review of the limitations and associated opportunities of chatgpt, deductive qualitative analysis: evaluating, expanding, and refining theory, conceptualising and measuring positive mental health literacy: a systematic literature review, mental health education integration into the school curriculum needs to be implemented, review: school-based mental health literacy interventions to promote help-seeking - a systematic review., public opinion towards mental health (the case of the vologda region), quantifying the global burden of mental disorders and their economic value, mental health literacy: it is now time to put knowledge into practice, clarifying the concept of mental health literacy: protocol for a scoping review, positive mental health literacy: a concept analysis, related papers.

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• Lorna Hollowood 1 ,
• Calvin Moorley 2
• 1 University of Birmingham , Birmingham , UK
• 2 London South Bank University School of Health and Social Care , London , UK
• Correspondence to Lorna Hollowood; L.hollowood{at}bham.ac.uk

https://doi.org/10.1136/ebnurs-2024-104183

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Nursing is a profession that has always worked with diverse people and communities and has taken a social justice approach to care. Nursing has also undertaken research that includes diverse groups and communities. However, nurse researchers working with and undertaking research with diverse groups and communities may encounter problems in executing the research. This may be for reasons such as poor understanding of cultural and racial difference, not having an inclusive research team, for example, LGBTQIA+ researchers to help conduct LGBTQIA+ focused research or using an ableist approach, all of which can lead to exclusion, diminished trust and credibility. In this commentary, we draw on Hollowood’s doctoral journey and Moorley’s research experience, where both work with and research diverse communities’ health. Nurse researchers need to apply methodologies and approaches that are culturally sensitive and inclusive and here we offer essential tips, which have helped us by drawing on culturally specific and diversity-sensitive methods and frameworks to support inquiries which aim to improve the situation of the diverse communities nursing serves.

Choosing culturally sensitive theoretical frameworks and methodologies

Whiteness has dominated nursing, 1 and this also extends to nursing research where dominant western philosophies and methodologies are applied. Nurse researchers have not had many culturally and racially sensitive frameworks to choose from and so their research on, for example, race and culture has mainly used frameworks framed on whiteness and this can lead to health and care being interpreted, analysed and recommendations made based on white lens. One of the frameworks we advocate for is The Silences Framework. 2 It is a powerful tool to help uncover and understand marginalised discourses in research. This framework explicitly supports the researcher to identify and address the ‘silences’ which sit within a group and impact on their experiences and perspectives. ‘Silences’ refers to the areas of research that we know little about, …

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Commissioned; internally peer reviewed.

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