peer reviewed primary research article

Finding Scholarly Articles: Home

What's a Scholarly Article?

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

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

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

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

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

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

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

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

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

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

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

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

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Peer-Reviewed Literature: Peer-Reviewed Research: Primary vs. Secondary

• Peer-Reviewed Research: Primary vs. Secondary
• Types of Peer Review
• Identifying Peer-Reviewed Research

Peer Reviewed Research

Published literature can be either peer-reviewed or non-peer-reviewed. Official research reports are almost always peer reviewed while a journal's other content is usually not. In the health sciences, official research can be primary, secondary, or even tertiary. It can be an original experiment or investigation (primary), an analysis or evaluation of primary research (secondary), or findings that compile secondary research (tertiary). If you are doing research yourself, then primary or secondary sources can reveal more in-depth information.

Primary Research

Primary research is information presented in its original form without interpretation by other researchers. While it may acknowledge previous studies or sources, it always presents original thinking, reports on discoveries, or new information about a topic.

Health sciences research that is primary includes both experimental trials and observational studies where subjects may be tested for outcomes or investigated to gain relevant insight.  Randomized Controlled Trials are the most prominent experimental design because randomized subjects offer the most compelling evidence for the effectiveness of an intervention. See the below graphic and below powerpoint for further information on primary research studies.

• Research Design

Secondary Research

Secondary research is an account of original events or facts. It is secondary to and retrospective of the actual findings from an experiment or trial. These studies may be appraised summaries, reviews, or interpretations of primary sources and often exclude the original researcher(s). In the health sciences, meta-analysis and systematic reviews are the most frequent types of secondary research. 

• A meta-analysis is a quantitative method of combining the results of primary research. In analyzing the relevant data and statistical findings from experimental trials or observational studies, it can more accurately calculate effective resolutions regarding certain health topics.
• A systematic review is a summary of research that addresses a focused clinical question in a systematic, reproducible manner. In order to provide the single best estimate of effect in clinical decision making, primary research studies are pooled together and then filtered through an inclusion/exclusion process. The relevant data and findings are then compiled and synthesized to arrive at a more accurate conclusion about a specific health topic. Only peer-reviewed publications are used and analyzed in a methodology which may or may not include a meta-analysis.

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Characteristics of a Primary Research Article

• Goal is to present the result of original research that makes a new contribution to the body of knowledge
• Sometimes referred to as an empirical research article
• Typically organized into sections that include:  Abstract, Introduction, Methods, Results, Discussion/Conclusion, and References.

Example of a Primary Research Article:

Flockhart, D.T.T., Fitz-gerald, B., Brower, L.P., Derbyshire, R., Altizer, S., Hobson, K.A., … Norris, D.R., (2017). Migration distance as a selective episode for wing morphology in a migratory insect. Movement Ecology , 5(1), 1-9. doi: doi.org/10.1186/s40462-017-0098-9

Characteristics of a Review Article

• Goal is to summarize important research on a particular topic and to represent the current body of knowledge about that topic.
• Not intended to provide original research but to help draw connections between research studies that have previously been published.  
• Help the reader understand how current understanding of a topic has developed over time and identify gaps or inconsistencies that need further exploration.

Example of a Review Article:

https://www-sciencedirect-com.ezproxy.oswego.edu/science/article/pii/S0960982218302537

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Articles: Finding (and Identifying) Peer-Reviewed Articles: What is Peer Review?

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

Peer Review in 3 Minutes

What is "Peer-Review"?

What are they.

Scholarly articles are papers that describe a research study. 

Why are scholarly articles useful?

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

How do you identify scholarly or peer-reviewed articles?

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

How do you find them? 

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

Google Scholar is another option for searching for scholarly articles. 

Know the Difference Between Scholarly and Popular Journals/Magazines

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

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

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• Last Updated: May 21, 2024 8:45 AM
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Distinguishing Scholarly Articles

• What Is a Scholarly Article?
• Where Can I Find Scholarly Articles?
• Types of Scholarly Articles

Source Provenance

• Glossary of Specialized Terms

For preliminary assessment of reliability or authenticity, academics frequently distinguish between Primary and Secondary sources of information.  Note that this distinction is based on content, and not format.

Primary sources are those that adhere most closely to the original experience or evidence being presented.

In history and the humanities, a primary source is a person, document or account relating direct experience from the time period under study (for example an eyewitness report to an event) or a later recapitulation of events from someone with direct experience (for example an oral history, autobiography or memoir).  Historical artifacts such as letters, diaries, interviews, or photographs are all considered primary sources, as are government documents presenting original work, e.g. legislation, hearings, speeches, reports, etc.  Creative works such as films, plays, music, poetry and art works can also be considered primary.

In the sciences, a primary source is the original publication of new data, research or theories by the individual(s) producing the data, conducting the research, or formulating the theory.  Examples of primary scientific sources include experimental studies, opinion surveys, clinical trials, and data sets.  Typically, primary research articles are published in peer-reviewed journal articles with standardized sections, often including a Literature Review , description of Methods , tables of Data , and a summary of Results or formal Conclusion .

Secondary sources are those that summarize, critique or comment on events, data or research presented previously.  Since they are one or more steps removed from the event, these sources are considered less reliable in terms of evidence.

Examples of secondary sources include textbooks, review articles, magazine articles, histories, news reports, encyclopedias and other reference books.  There can be significant variation in how strictly the terms "primary" and "secondary" are applied by academics, e.g. history professors may consider news articles that were published in the same time period as an historical event to be primary, for purposes of instruction.  If in doubt, a student should consult the classroom instructor for guidance.

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• Last Updated: Sep 5, 2024 8:40 AM
• URL: https://research.ewu.edu/scholarly_articles

Understanding research and critical appraisal

• Introduction
• Secondary research

What is primary research?

Quantitative research study designs, qualitative research study designs, mixed methods research study designs.

• Critical appraisal of research papers
• Useful terminology
• Further reading and helpful resources

Primary research articles provide a report of individual, original research studies, which constitute the majority of articles published in peer-reviewed journals. All primary research studies are conducted according to a specified methodology, which will be partly determined by the aims and objectives of the research.

The following sections offer brief summaries of some of the common quantitative, qualitative, and mixed-methods study designs you may encounter. 

Randomised Controlled Trial

A randomised controlled trial (RCT) is a study where participants are randomly allocated to two or more groups. One group receives the treatment that is being tested by the study (treatment or experimental group), and the other group(s) receive an alternative, which is often the current standard treatment or a placebo (control or comparison group). The nature of the control used should always be specified.

An RCT is a good study choice for determining the effectiveness of an intervention or treatment, or for comparing the relative effectiveness of different interventions or treatments. If well implemented, the randomisation of participants in RCTs should ensure that the groups differ only in their exposure to treatment, and that differences in outcomes between the groups are probably attributable to the treatment being studied.

In crossover randomised controlled trials, participants receive all of the treatments and controls being tested in a random order. This means that participants receive one treatment, the effect of which is measured, and then "cross over" into the other treatment group, where the effect of the second treatment (or control) is measured.

RCTs are generally considered to be the most rigorous experimental study design, as the randomisation of participants helps to minimise confounding and other sources of bias.

Cohort study

A cohort study identifies a group of people and follows them over a period of time to see who develops the outcome of interest to the study. This type of study is normally used to look at the effect of suspected risk factors that cannot be controlled experimentally – for example, the effect of smoking on lung cancer.

Also sometimes called longitudinal studies, cohort studies can be either prospective, that is, exposure factors are identified at the beginning of a study and the study population is followed into the future, or retrospective, that is, medical records for the study population are used to identify past exposure factors.

Cohort studies are useful in answering questions about disease causation or progression, or studying the effects of harmful exposures.

Cohort studies are generally considered to be the most reliable observational study design. They are not as reliable as RCTs, as the study groups may differ in ways other than the variable being studied.

Other problems with cohort studies are that they require a large sample size, are inefficient for rare outcomes, and can take long periods of time.

Case-Control Study

A case-control study compares a group of people with a disease or condition, against a control population without the disease or condition, in order to investigate the causes of particular outcomes. The study looks back at the two groups over time to see which risk factors for the disease or condition they have been exposed to.

Case-control studies can be useful in identifying which risk factors may predict a disease, or how a disease progresses over time. They can be especially useful for investigating the causes of rare outcomes.

Case-control studies can be done quickly, and do not require large groups of subjects. However, their reliance on retrospective data which may be incomplete or unreliable (owing to subject ability to accurately recall information such as the appearance of a symptom) can be a difficulty.

Cross-Sectional Study

A cross-sectional study collects data from the study population at one point in time, and considers the relationships between characteristics. Also  sometimes called surveys or prevalence studies.

Cross-sectional studies are generally used to study the prevalence of a risk factor, disease or outcome in a chosen population.

Because cross-sectional studies do not look at trends or changes over time, they cannot establish cause and effect between exposures and outcomes.

Case Series / Case Reports

A case series is a descriptive study of a group of people, who have either received the same treatment or have the same disease, in order to identify characteristics or outcomes in a particular group of people.

Case series are useful for studying rare diseases or adverse outcomes, for illustrating particular aspects of a condition, identifying treatment approaches, and for generating hypotheses for further study.

A case report provides a study of an individual, rather than a group.

Case series and case reports have no comparative control groups, and are prone to bias and chance association.

Expert opinion

Expert opinion draws upon the clinical experience and recommendations of those with established expertise on a topic.

Grounded theory

Grounded theory studies aim to generate theory in order to explain social processes, interactions or issues. This explanatory theory is grounded in, and generated from, the research participant data collected.

Research data typically takes the form of interviews, observations or documents. Data is analysed as it is collected, and is coded and organised into categories which inform the further collection of data, and the construction of theory. This cycle helps to refine the theory, which evolves as more data is gathered.

Phenomenology

A phenomenological study aims to describe the meaning(s) of the lived experience of a phenomenon. Research participants will have some common experience of the phenomenon under examination, but will differ in their precise individual experience, and in other personal or social characteristics.

Research data is typically in the form of observations, interviews or written records, and its analysis sets out to identify common themes in the participants' experience, while also highlighting variations and unique themes.

Ethnography

Ethnography is the study of a specific culture or cultural group, where the researcher seeks an insider perspective by placing themselves as a participant observer within the group under study.

Data is typically formed of observations, interviews and conversation. Ethnography aims to offer direct insight into the lives and the experiences of the group or the culture under study, examining its beliefs, values, practices and behaviours.

A case study offers a detailed description of the experience of an individual, a family, a community or an organisation, often with the aim of highlighting a particular issue. Research data may include documents, interviews and observations.

Content analysis

Content analysis is used to explore the occurrence, meanings and relationships of words, themes or concepts within a set of textual data. Research data might be drawn from any type of written document(s). Data is coded and categorised, with the aim of revealing and examining the patterns and the intentions of language use within the data set.

Narrative inquiry

A narrative inquiry offers in depth detail of a situation or experience from the perspective of an individual or small groups. Research data usually consists of interviews or recordings, which is presented as a structured, chronological narrative. Narrative inquiry studies often seek to give voice to individuals or populations whose perspective is less well established, or not commonly sought.

Action research

Action research is a form of research, commonly used with groups, where the participants take a more active, collaborative role in producing the research. Studies incorporate the lived experiences of the individuals, groups or communities under study, drawing on data which might include observation, interviews, questionnaires or workshops.

Action research is generally aimed at changing or improving a particular context, or a specific practice, alongside the generation of theory.

Explanatory sequential design

In an explanatory sequential study, emphasis is given to the collection and analysis of quantitative data, which occurs during the first phase of the study. The results of this quantitative phase inform the subsequent collection of qualitative data in the next phase.

Analysis of the resultant qualitative data is then used to 'explain' the quantitative results, usually serving to contextualise these, or to otherwise enhance or enrich the initial findings.

Exploratory sequential design

In an exploratory sequential study, the opposite sequence to that outlined above is used. In this case, qualitative data is emphasised, with this being collected and analysed during the first phase of the study. The results of this qualitative phase inform the subsequent collection of quantitative data in the next phase.

The quantitative data can then be used to define or to generalise the qualitative results, or to test these results on the basis of theory emerging from the initial findings.

Convergent design

In a convergent study, qualitative and quantitative data sets are collected and analysed simultaneously and independently of one another.

Results from analysis of both sets of data are brought together to provide one overall interpretation; this combination of data types can be handled in various ways, but the objective is always to provide a fuller understanding of the phenomena under study. Equal emphasis is given to both qualitative and quantitative data in a convergent study.

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• Last Updated: Mar 26, 2024 4:38 PM
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Peer Reviewed and Primary Research

• Peer Review--What is it?
• Scholarly Journal vs. Magazine
• Finding Peer-Reviewed Articles
• Databases for finding Articles with Primary Research

How to Identify Peer-Reviewed Journal Content

The terms "Academic," "Scholarly," "Peer-Reviewed" and "Refereed" are often used interchangeably.  However, although all Peer-Reviewed Journals ARE Scholarly/Academic, NOT ALL academic or scholarly journals are peer-reviewed or refereed!   As discussed in the previous page, "Peer Review" is something quite specific.  A quarterly journal in a particular field may be written for academic use but the editorial process for selecting articles may not include peer review.  So how do you determine whether a journal is peer-reviewed?  One way is to let the database help you select such journals.  Some databases like JSTOR ( http://www.jstor.org/ ) or  Project Muse ( http://muse.jhu.edu/index.html )  should only contain peer-reviewed journals.  But most general databases include journals (peer-reviewed and not) as well as other non-peer-reviewed materials like magazines, newspapers, conference papers, book chapters and reports.  Here are some tips for limiting to peer reviewed in Academic Search Complete (This works for the EBSCO ERIC database vendor product.)

EbscoHost Databases

You can simply check off the "Limit" box below the search box(es)--even before you do your search--and eliminate all magazine articles, newspaper stories...ANYTHING that is not defined by Ebsco as a Peer-Reviewed Journal:

Or, you may "Refine" your search after you produce an initial results list, by limiting the search from the left frame:

Additional Ways to Determine if a Journal is Peer-Reviewed

•  The webpage for a journal may state this fact.  For example, the homepage for the journal Evolutionary Psychology  includes a statement in the first paragraph that it is "an open-access peer-reviewed journal that aims to foster communication between experimental and theoretical work on the one hand and historical, conceptual and interdisciplinary writings across the whole range of the biological and human sciences on the other."

IMPORTANT NOTE :  When an instructor says that you must use Peer-Reviewed Literature, they often MEAN that the articles must be "Research Articles" or "Primary Articles."   If this is the case, then extra care must be taken in judging the articles you retrieve.  A peer-reviewed or refereed journal usually contains content besides original research articles.  This additional content may include letters, editorials, commentary, book reviews and more.  Generally, your professor does NOT WANT YOU TO USE THIS CONTENT.   They want you to use primary sources.  Look at the next tabbed page for more on this.

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Peer Review and Primary Literature: An Introduction: Primary Journal Literature

• Scholarly Journal vs. Magazine
• Peer Review: What is it?
• Finding Peer-Reviewed Articles
• Primary Journal Literature
• Is it Primary Research? How Do I Know?

What is a "Primary" Article, Study or Research Study?

What is a primary study.

When an author does do original research in a clinic or laboratory or out in the field, and then writes a detailed article about this research, this is a "primary study."  Other related terms are "original research" or "research study." 

By contrast, a secondary article is like most of your term papers.  You are basing your arguments and conclusions on research materials that were produced and written by other people. You did not personally collect the water samples in the marsh or compute the data on drug treatment outcomes or figure out how many juvenile offenders who went through a particular outreach program ended up being arrested again, so the resulting paper or article that you produce is secondary. Likewise, journalism or reportage may be considered secondary (or tertiary). For an article in Science News , for example, a writer calls up several university researchers on the phone and gets information from them about the latest developments in a particular field. Then the science journalist writes an article summarizing all the latest research findings, but they themselves did not actually do the research, so Science News could be a secondary resource.

Empirical Study?

A professor may also use the term "empirical" to describe a study or research article.  In many cases, the term empirical is used to mean the exact same thing as a "primary study" or "original research" article.  However, specifically, an empirical study is one that reports research based on direct observations or experiments. It often seeks to answer a specific question or to test a hypothesis. The research may use quantitative research methods, generating numerical data which attempts to establish causal relationships between two or more variables. Also, empirical research articles may use qualitative research methodology, in which the author objectively and critically analyzes beliefs or behaviors (etc.) without the analysis of numerical data.

Finding an empirical study can be tricky.  The word empirical might be used in describing the study. In a few cases, the subject term "EMPIRICAL research" might even be assigned to a record in a database. Other terms like quantitative data might also be used in the summary.  You can try searching for these words --for example, family violence and empirical -- but otherwise you will need to read and evaluate the article to decide whether that particular research article could be termed an empirical study.

An Additional Note on "Primary Sources" or "Primary Documents"

Historians often refer to "primary documents" or "primary sources".  This is different.  A primary document is an original work, but it is not a research study .  A letter, a diary or a speech are examples of a primary document.   Generally speaking, a primary document is a way to get a first-person view of an event or period.  They are either created during the time period being studied or are created at some later time by someone who participated in the events under study.  One such example would be a memoir or autobiography. If you are in a History or English course, you may need to find some primary documents for your paper, but if you are in a Sociology or Psychology or Communication or Biology class, chances are the instructor is looking for primary research studies and not primary documents.  Ask a reference librarian for clarification!

Subject Guide

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Explore millions of high-quality primary sources and images from around the world, including artworks, maps, photographs, and more.

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Finding Primary Research Articles in the Sciences: Home

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

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

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

Recommended Databases

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

• Link to all Polk State College Library databases

Login Required

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

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

You can also get help from Ask a Librarian . 

Search Tips

Keep your search terms simple.

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

Use the "Advanced Search" feature of the database.

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

Re-read the assignment guidelines often

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

Not finding what you are looking for?

• Ask a Librarian!

Search and Find a Primary Research Article

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

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

The following is _not_ primary research:

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

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

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

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

Other sections in a journal: 

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

• Conference Proceedings 
• Symposium Publications

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

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

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

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

How do I know if this article is primary?

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

Look for these sections: (terminology may vary)

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

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

Questions? Use Ask a Librarian

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• What Is Peer Review? | Types & Examples

What Is Peer Review? | Types & Examples

Published on December 17, 2021 by Tegan George . Revised on June 22, 2023.

Peer review, sometimes referred to as refereeing , is the process of evaluating submissions to an academic journal. Using strict criteria, a panel of reviewers in the same subject area decides whether to accept each submission for publication.

Peer-reviewed articles are considered a highly credible source due to the stringent process they go through before publication.

There are various types of peer review. The main difference between them is to what extent the authors, reviewers, and editors know each other’s identities. The most common types are:

• Single-blind review
• Double-blind review
• Triple-blind review

Collaborative review

Open review.

Relatedly, peer assessment is a process where your peers provide you with feedback on something you’ve written, based on a set of criteria or benchmarks from an instructor. They then give constructive feedback, compliments, or guidance to help you improve your draft.

Table of contents

What is the purpose of peer review, types of peer review, the peer review process, providing feedback to your peers, peer review example, advantages of peer review, criticisms of peer review, other interesting articles, frequently asked questions about peer reviews.

Many academic fields use peer review, largely to determine whether a manuscript is suitable for publication. Peer review enhances the credibility of the manuscript. For this reason, academic journals are among the most credible sources you can refer to.

However, peer review is also common in non-academic settings. The United Nations, the European Union, and many individual nations use peer review to evaluate grant applications. It is also widely used in medical and health-related fields as a teaching or quality-of-care measure.

Peer assessment is often used in the classroom as a pedagogical tool. Both receiving feedback and providing it are thought to enhance the learning process, helping students think critically and collaboratively.

Prevent plagiarism. Run a free check.

Depending on the journal, there are several types of peer review.

Single-blind peer review

The most common type of peer review is single-blind (or single anonymized) review . Here, the names of the reviewers are not known by the author.

While this gives the reviewers the ability to give feedback without the possibility of interference from the author, there has been substantial criticism of this method in the last few years. Many argue that single-blind reviewing can lead to poaching or intellectual theft or that anonymized comments cause reviewers to be too harsh.

Double-blind peer review

In double-blind (or double anonymized) review , both the author and the reviewers are anonymous.

Arguments for double-blind review highlight that this mitigates any risk of prejudice on the side of the reviewer, while protecting the nature of the process. In theory, it also leads to manuscripts being published on merit rather than on the reputation of the author.

Triple-blind peer review

While triple-blind (or triple anonymized) review —where the identities of the author, reviewers, and editors are all anonymized—does exist, it is difficult to carry out in practice.

Proponents of adopting triple-blind review for journal submissions argue that it minimizes potential conflicts of interest and biases. However, ensuring anonymity is logistically challenging, and current editing software is not always able to fully anonymize everyone involved in the process.

In collaborative review , authors and reviewers interact with each other directly throughout the process. However, the identity of the reviewer is not known to the author. This gives all parties the opportunity to resolve any inconsistencies or contradictions in real time, and provides them a rich forum for discussion. It can mitigate the need for multiple rounds of editing and minimize back-and-forth.

Collaborative review can be time- and resource-intensive for the journal, however. For these collaborations to occur, there has to be a set system in place, often a technological platform, with staff monitoring and fixing any bugs or glitches.

Lastly, in open review , all parties know each other’s identities throughout the process. Often, open review can also include feedback from a larger audience, such as an online forum, or reviewer feedback included as part of the final published product.

While many argue that greater transparency prevents plagiarism or unnecessary harshness, there is also concern about the quality of future scholarship if reviewers feel they have to censor their comments.

In general, the peer review process includes the following steps:

• First, the author submits the manuscript to the editor.
• Reject the manuscript and send it back to the author, or
• Send it onward to the selected peer reviewer(s)
• Next, the peer review process occurs. The reviewer provides feedback, addressing any major or minor issues with the manuscript, and gives their advice regarding what edits should be made.
• Lastly, the edited manuscript is sent back to the author. They input the edits and resubmit it to the editor for publication.

In an effort to be transparent, many journals are now disclosing who reviewed each article in the published product. There are also increasing opportunities for collaboration and feedback, with some journals allowing open communication between reviewers and authors.

It can seem daunting at first to conduct a peer review or peer assessment. If you’re not sure where to start, there are several best practices you can use.

Summarize the argument in your own words

Summarizing the main argument helps the author see how their argument is interpreted by readers, and gives you a jumping-off point for providing feedback. If you’re having trouble doing this, it’s a sign that the argument needs to be clearer, more concise, or worded differently.

If the author sees that you’ve interpreted their argument differently than they intended, they have an opportunity to address any misunderstandings when they get the manuscript back.

Separate your feedback into major and minor issues

It can be challenging to keep feedback organized. One strategy is to start out with any major issues and then flow into the more minor points. It’s often helpful to keep your feedback in a numbered list, so the author has concrete points to refer back to.

Major issues typically consist of any problems with the style, flow, or key points of the manuscript. Minor issues include spelling errors, citation errors, or other smaller, easy-to-apply feedback.

Tip: Try not to focus too much on the minor issues. If the manuscript has a lot of typos, consider making a note that the author should address spelling and grammar issues, rather than going through and fixing each one.

The best feedback you can provide is anything that helps them strengthen their argument or resolve major stylistic issues.

Give the type of feedback that you would like to receive

No one likes being criticized, and it can be difficult to give honest feedback without sounding overly harsh or critical. One strategy you can use here is the “compliment sandwich,” where you “sandwich” your constructive criticism between two compliments.

Be sure you are giving concrete, actionable feedback that will help the author submit a successful final draft. While you shouldn’t tell them exactly what they should do, your feedback should help them resolve any issues they may have overlooked.

As a rule of thumb, your feedback should be:

• Easy to understand
• Constructive

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Below is a brief annotated research example. You can view examples of peer feedback by hovering over the highlighted sections.

Influence of phone use on sleep

Studies show that teens from the US are getting less sleep than they were a decade ago (Johnson, 2019) . On average, teens only slept for 6 hours a night in 2021, compared to 8 hours a night in 2011. Johnson mentions several potential causes, such as increased anxiety, changed diets, and increased phone use.

The current study focuses on the effect phone use before bedtime has on the number of hours of sleep teens are getting.

For this study, a sample of 300 teens was recruited using social media, such as Facebook, Instagram, and Snapchat. The first week, all teens were allowed to use their phone the way they normally would, in order to obtain a baseline.

The sample was then divided into 3 groups:

• Group 1 was not allowed to use their phone before bedtime.
• Group 2 used their phone for 1 hour before bedtime.
• Group 3 used their phone for 3 hours before bedtime.

All participants were asked to go to sleep around 10 p.m. to control for variation in bedtime . In the morning, their Fitbit showed the number of hours they’d slept. They kept track of these numbers themselves for 1 week.

Two independent t tests were used in order to compare Group 1 and Group 2, and Group 1 and Group 3. The first t test showed no significant difference ( p > .05) between the number of hours for Group 1 ( M = 7.8, SD = 0.6) and Group 2 ( M = 7.0, SD = 0.8). The second t test showed a significant difference ( p < .01) between the average difference for Group 1 ( M = 7.8, SD = 0.6) and Group 3 ( M = 6.1, SD = 1.5).

This shows that teens sleep fewer hours a night if they use their phone for over an hour before bedtime, compared to teens who use their phone for 0 to 1 hours.

Peer review is an established and hallowed process in academia, dating back hundreds of years. It provides various fields of study with metrics, expectations, and guidance to ensure published work is consistent with predetermined standards.

• Protects the quality of published research

Peer review can stop obviously problematic, falsified, or otherwise untrustworthy research from being published. Any content that raises red flags for reviewers can be closely examined in the review stage, preventing plagiarized or duplicated research from being published.

• Gives you access to feedback from experts in your field

Peer review represents an excellent opportunity to get feedback from renowned experts in your field and to improve your writing through their feedback and guidance. Experts with knowledge about your subject matter can give you feedback on both style and content, and they may also suggest avenues for further research that you hadn’t yet considered.

• Helps you identify any weaknesses in your argument

Peer review acts as a first defense, helping you ensure your argument is clear and that there are no gaps, vague terms, or unanswered questions for readers who weren’t involved in the research process. This way, you’ll end up with a more robust, more cohesive article.

While peer review is a widely accepted metric for credibility, it’s not without its drawbacks.

• Reviewer bias

The more transparent double-blind system is not yet very common, which can lead to bias in reviewing. A common criticism is that an excellent paper by a new researcher may be declined, while an objectively lower-quality submission by an established researcher would be accepted.

• Delays in publication

The thoroughness of the peer review process can lead to significant delays in publishing time. Research that was current at the time of submission may not be as current by the time it’s published. There is also high risk of publication bias , where journals are more likely to publish studies with positive findings than studies with negative findings.

• Risk of human error

By its very nature, peer review carries a risk of human error. In particular, falsification often cannot be detected, given that reviewers would have to replicate entire experiments to ensure the validity of results.

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

• Normal distribution
• Measures of central tendency
• Chi square tests
• Confidence interval
• Quartiles & Quantiles
• Cluster sampling
• Stratified sampling
• Thematic analysis
• Discourse analysis
• Cohort study
• Ethnography

Research bias

• Implicit bias
• Cognitive bias
• Conformity bias
• Hawthorne effect
• Availability heuristic
• Attrition bias
• Social desirability bias

Peer review is a process of evaluating submissions to an academic journal. Utilizing rigorous criteria, a panel of reviewers in the same subject area decide whether to accept each submission for publication. For this reason, academic journals are often considered among the most credible sources you can use in a research project– provided that the journal itself is trustworthy and well-regarded.

In general, the peer review process follows the following steps: 

• Reject the manuscript and send it back to author, or 
• Send it onward to the selected peer reviewer(s) 
• Next, the peer review process occurs. The reviewer provides feedback, addressing any major or minor issues with the manuscript, and gives their advice regarding what edits should be made. 
• Lastly, the edited manuscript is sent back to the author. They input the edits, and resubmit it to the editor for publication.

Peer review can stop obviously problematic, falsified, or otherwise untrustworthy research from being published. It also represents an excellent opportunity to get feedback from renowned experts in your field. It acts as a first defense, helping you ensure your argument is clear and that there are no gaps, vague terms, or unanswered questions for readers who weren’t involved in the research process.

Peer-reviewed articles are considered a highly credible source due to this stringent process they go through before publication.

Many academic fields use peer review , largely to determine whether a manuscript is suitable for publication. Peer review enhances the credibility of the published manuscript.

However, peer review is also common in non-academic settings. The United Nations, the European Union, and many individual nations use peer review to evaluate grant applications. It is also widely used in medical and health-related fields as a teaching or quality-of-care measure. 

A credible source should pass the CRAAP test  and follow these guidelines:

• The information should be up to date and current.
• The author and publication should be a trusted authority on the subject you are researching.
• The sources the author cited should be easy to find, clear, and unbiased.
• For a web source, the URL and layout should signify that it is trustworthy.

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George, T. (2023, June 22). What Is Peer Review? | Types & Examples. Scribbr. Retrieved September 3, 2024, from https://www.scribbr.com/methodology/peer-review/

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Q. How do I know if an article is a primary or secondary research article?

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Answered By: Jay Trask Last Updated: Oct 21, 2020     Views: 241140

A primary research article reports on an empirical research study conducted by the authors. It is almost always published in a peer-reviewed journal. This type of article:

• Asks a research question or states a hypothesis or hypotheses
• Identifies a research population
• Describes a specific research method
• Tests or measures something
• Includes a section called "method" or "methodology." This may only appear in the article, not the abstract.
• Includes a section called "results."

Words to look for as clues include: analysis, study, investigation, examination, experiment, numbers of people or objects analyzed, content analysis, or surveys.

To contrast, the following are not primary research articles (i.e., they are secondary sources):

• Literature reviews
• Meta-Analyses/Review articles (These are studies that arrive at conclusions based on research from many other studies.)
• Chapters in books
• Encyclopedia articles
• Speeches and interviews

Please note: if you are seeking information about primary and secondary sources for historical research, please find information here: https://libguides.unco.edu/history-primary-resources

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CRIM 1208: Research Methods

• About this guide
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Which of these is an ORIGINAL (PRIMARY) research article?

What are original (primary) research articles.

• Primary & secondary research

Structure of a primary research article

Primary and secondary research articles.

Once researchers complete a project, they will usually (try to) publish their findings in a peer-reviewed journal. These are often called PRIMARY or ORIGINAL research articles because they are the first-publication of new research findings and are written by the researchers themselves. They may also be called EMPIRICAL articles.

Secondary sources of information describe, explain, interpret or summarize primary sources. These include encyclopedias, book reviews, commentaries, literature reviews, and any books or journal articles that simply discuss the original (previously-published) work of others . Although these can be very helpful sources for identifying primary research articles, they are not primary studies themselves.

VIDEO: What is Original (Primary) Research in Criminology? (19:38)

Describes the typical structure of an original research article, with a particular focus on the Methods section. It shows examples of several types of original research articles (qualitative and quantitative, including articles using secondary data, and meta-analyses), as well as several types of secondary articles (book reviews, editorial essays, theoretical analyses and literature reviews). The emphasis is on learning to read the abstract for indications of original research, and checking for a Methods section in the article. Part 1 of the Finding Original Research Articles in Criminology video series.

• Video (Kaltura)
• Video transcript (text file)

• VIDEO: What is Empirical Research? (2:59)
• Finding Peer-Reviewed, Primary Research Articles in Criminology 4-page KPU Library guide.

A primary (original) research article will usually be divided into several labeled sections. The screenshot above is from the video " What is Original (Primary) Research in Criminology? ". You can jump to the 3:10 timestamp to watch the " Sections of an original research article " segment of the video.

• Introduction (which usually includes a literature review)
• Method (often called Methodology or Methods) -- always found in an empirical research article
• Findings or Results
• Conclusions

The names of the parts may vary, but a primary research article will always include a methodology section explaining how the research was conducted (i.e. what type of empirical method was used). Most secondary journal articles do not include a methods section.

• << Previous: What are scholarly articles?
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• Last Updated: May 22, 2024 12:51 PM
• URL: https://libguides.kpu.ca/crim/1208

Tutorial: Evaluating Information: Primary vs. Secondary Articles

• Evaluating Information
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• Peer Review
• Systematic Reviews & Meta-Analysis
• Gray Literature
• Evaluating Like a Boss
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Primary vs. Secondary Research Articles

In the sciences,  primary (or empirical) research articles :

• are original scientific reports of new research findings (Please note that an original scientific article does not include review articles, which summarize the research literature on a particular subject, or articles using meta-analyses, which analyze pre-published data.)
• usually include the following sections: Introduction , Methods , Results , Discussion, References
• are usually  peer-reviewed (examined by expert(s) in the field before publication). Please note that a peer-reviewed article is not the same as a review article, which summarizes the research literature on a particular subject

You may also choose to use some secondary sources (summaries or interpretations of original research) such as books (find these through the library catalog) or review articles (articles which organize and critically analyze the research of others on a topic). These secondary sources, particularly review articles, are often useful and easier-to-read summaries of research in an area. Additionally, you can use the listed references to find useful primary research articles.

Anatomy of a Scholarly Article

from NCSU Libraries' Anatomy of a Scholarly Article

Types of health studies

In the sciences, particularly the health sciences, there are a number of types of primary articles (the gold standard being randomized controlled trials ) and secondary articles (the gold standard being systematic reviews and meta-analysis ). The chart below summarizes their differences and the linked article gives more information.

Searching for Primary vs. Secondary Articles

Some scholarly databases will allow you to specific what kind of scholarly literature you're looking for.  However, be careful! Sometimes, depending on the database, the Review article type may mean book review instead of or as well as review article. You may also have to look under more or custom options to find these choices.

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Guide to Articles: Peer Reviewed, Reference, Popular Issues, & Primary Resources

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Primary Sources

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Primary Resource Databases

Primary sources examined.

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• Searching Tips

Step 1. What are you looking for?

Identify what would be considered a primary resource in the subject you are searching for..

By Discipline, Each field of study has its own sources, conventions, and vocabularies.  This list will help you to identify primary sources in your own discipline. 

In general, personal correspondence and diaries or journals are considered to be primary sources by all disciplines. If you are unsure that a source is considered primary by your discipline, ask your professor or a reference librarian for assistance.

• Archeology/Anthropology : an artifact or object that provides evidence of a society, such as clothing, farming tools, household items, and buildings.
• Arts and Literature : the original artistic or literary work that forms the basis for a criticism or review, such as feature films, musical compositions, sound recordings, paintings, novels, plays, and poems.
• Biology : research or lab notes, genetic evidence, plant specimens, technical reports, and other reports of original research or discoveries (e.g., conference papers and proceedings, dissertations, scholarly articles).
• Business : market research or surveys, anything that documents a corporation's activities, such as annual reports, meeting minutes, legal documents, marketing materials, and financial records.
• Communication : websites, blogs, broadcast recordings and transcripts, advertisements and commercials, public opinion polls, and magazines (e.g., Rolling Stone).
• Engineering : design notes, patents, conference proceedings, technical reports, and field surveys.
• Geography : field notes, census data, maps, satellite images, and aerial photographs.
• History : government documents (e.g., treaty, birth certificate), photographs, store account books, artifacts (such as those listed for archeology/anthropology), maps, legal and financial documents, and census records.
• Law : court decisions, trial transcripts, and law codes.

Step 2. Where do you search?

Choose a database, archive, public library, or repository to search..

On the left side of this page, scroll through the list of "Primary Resource Databases". Try searching for your time period, location, or topic within these databases. 

Search Tip: Start Broad then Narrow

Alternatively, use one of the databases below to search by topic. You can browse by collections, time periods, or geographic location.

"Disciplines" Source: David Kupas's "Finding Primary Sources" libguide:  http://pitt.libguides.com/primarysources

• Digital Public Library of America This online database includes image, text, and audiovisual content aggregated from digital collections across the United States. There are over 21 million resources in this database.
• HathiTrust Digital Library HathiTrust is a partnership of academic and research institutions, offering a collection of millions of titles digitized from libraries around the world.
• Library of Congress: Digital Collections The Library of Congress is the largest library in the world, with millions of books, recordings, photographs, newspapers, maps and manuscripts in its collections.

• World Digital Library The materials collected by the WDL make it possible to discover, study, and enjoy cultural treasures and significant historical documents including books, manuscripts, maps, newspapers, journals, prints and photographs, sound recordings, and films.
• Original materials that provide direct evidence or first-hand testimony concerning a topic or event.
• Contemporary sources created at the time when the event occurred (e.g., letters and newspaper articles--as long as the writer is a first-hand witness) or later (e.g., memoirs and oral history interviews).
• Primary sources may be published or unpublished.  Unpublished sources are unique materials (e.g., family papers) often referred to as archives and manuscripts.
• Primary sources vary by discipline. How the researcher uses the source generally determines whether it is a primary source or not.

Secondary Sources

• Works that interpret, analyze, and discuss the evidence provided by primary sources (e.g., scholarly books and articles).
• Secondary sources are generally a second-hand account or observation at least one step removed from the event.
• Secondary sources can be considered to be primary sources depending on the context of their use. For example, Ken Burns' documentary of the Civil War is a secondary source for Civil War researchers, but a primary source for those studying documentary filmmaking.

Tertiary Sources

• Books or articles that synthesize or distill primary and secondary sources--for example dictionaries, encyclopedias, indexes, and textbooks.  (Sometimes these are lumped in with the secondary sources category.) 
• Keep in mind that a secondary or tertiary source can lead you to a primary source by either referencing it, including it in a footnote or reproducing it in its entirety.  For example, at first glance, a source like “World War I: Encyclopedia” would not seem to be a primary source but if you look at the contents, volume five of this encyclopedia is entirely devoted to transcripts of documents of the war. Many subject encyclopedias like this one will turn out to be a rich source of primary source materials.

The Historian researching World War I might utilize:           

• Primary Sources : Newspaper articles, weekly/monthly news magazines, diaries, correspondence, and diplomatic records from the time period.
• Secondary Sources : Articles in scholarly journals analyzing the war, possibly footnoting primary documents; books analyzing the war.

The Literary Critic researching literature written during World War I might utilize:

• Primary Sources : Novels, poems, plays, diaries, and correspondence of the time period.
• Secondary Sources : Published articles in scholarly journals providing analysis and criticism of the literature; books analyzing the literature; formal biographies of writers from the era.

The Psychologist researching trench warfare and post-traumatic stress disorder in World War I veterans might utilize:

• Primary Sources : Original research reports on the topic or research notes taken by a clinical psychologist working with World War I veterans.           
• Secondary Sources : Articles in scholarly publications synthesizing results of original research; books analyzing results of original research.

The Scientist researching long term medical effects of chemical warfare on exposed veterans might utilize:      

• Primary Sources : Published articles in scholarly journals reporting on a medical research study and its methodology.    
• Secondary Sources : Published articles in scholarly journals analyzing results of an original research study; books doing the same.

Source:  David Kupas's "Finding  Primary Sources" libguide:  http://pitt.libguides.com/primarysources

Each field of study has its own sources, conventions, and vocabularies.  This list will help you to identify primary sources in your own discipline. 

Source: 

David Kupas's "Finding Primary Sources" libguide: http://pitt.libguides.com/primarysources

Library Catalogs

• Search FIU Catalog to find primary source materials at the FIU libraries.
• Search WorldCat to find collections at thousands of libraries worldwide. Use the Advanced Search feature to limit by format or publication date.

Finding Aids

Use finding aids to locate processed archival collections in archives, libraries, and museums. Finding aids are increasingly available online and freely accessible.

• Repositories of Primary Sources - An online listing of over 5,000 websites describing holdings of manuscripts, archives, rare books, historical photographs, and other primary sources.
• ArchiveGrid - Finding aids/collection descriptions from thousands of libraries, museums, and archives. Researchers searching ArchiveGrid can learn about the many items in each of these collections, contact archives to arrange a visit to examine materials, and order copies.

Reference & Other Print Sources

Make use of the many excellent print resources that are available to find primary source materials.  These include:

• Bibliographies
• Film, Literature, and Periodical Indexes
• Biographical Resources
• Encyclopedias, Dictionaries, Handbooks
• Secondary Sources (search the text, footnotes, and bibliographies for references to primary sources used)

Internet Search Engines

• Use the Internet to find primary source materials by adding primary source specific terms to a Search Engine search. For example, "Civil War +soldiers + diaries."

Keyword/Subject Searching

Adding keywords to a catalog search will help you to locate primary source materials. For example, if you need primary sources about the French Revolution, perform a keyword search by entering the terms "france revolution correspondence"

You may also pair an appropriate heading with additional subject terms that identify materials as primary sources. Some of these terms are

• correspondence
• personal narratives
• pictorial works
• songs and music
• manuscripts
• letters (use as keyword)
• self-portraits
• fiction (written during the historical time period you are researching.)

Note: these subject terms will not retrieve all possible primary sources but they are a good way to start.

Restricting by Date of Publication or Format

• You may also narrow a search by limiting the results by date of publication or format.
• Limiting sources to a particular date of publication will help you to locate contemporary sources published at the time of an event. For example, if you are studying British Literature during WWII, refine your search results by using the publication date limiters to retrieve novels published only during the years 1939 to 1945.
• To limit a search by format, go to the Advanced Search mode and select from the format list as appropriate to your needs.

Collections

Hathi Trust

Digital Public Library of America

Library of Congress Digital Collections

Internet Archive

Smithsonian Libraries Digital Libraries

NYPL Digital Collections

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Peer-review and primary research.

• Getting Started With Peer-Reviewed Literature
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Finding Peer-Reviewed Journal Articles

Finding peer-reviewed literature in primo, finding peer-reviewed literature in databases.

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Finding Peer Reviewed Journals

• Use a discipline-specific database (Education Full Text, Applied Science and Technology, APA PsycInfo, etc.). While this strategy will help you find peer-reviewed journal articles, you should be aware that not all citations in such indexes are from peer-reviewed journals. 
• Use special features of online databases. Many allow you to limit your search results to peer-reviewed journals.
• Check the Cabell's Directory , available from the Databases A-Z List, to see if it characterizes the journal in question as “peer-reviewed.”
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• PMC11367301

Nurse-delivered sleep restriction therapy to improve insomnia disorder in primary care: the HABIT RCT.

Insomnia is a prevalent and distressing sleep disorder. Multicomponent cognitive-behavioural therapy is the recommended first-line treatment, but access remains extremely limited, particularly in primary care where insomnia is managed. One principal component of cognitive-behavioural therapy is a behavioural treatment called sleep restriction therapy, which could potentially be delivered as a brief single-component intervention by generalists in primary care.

The primary objective of the Health-professional Administered Brief Insomnia Therapy trial was to establish whether nurse-delivered sleep restriction therapy in primary care improves insomnia relative to sleep hygiene. Secondary objectives were to establish whether nurse-delivered sleep restriction therapy was cost-effective, and to undertake a process evaluation to understand intervention delivery, fidelity and acceptability.

Pragmatic, multicentre, individually randomised, parallel-group, superiority trial with embedded process evaluation.

National Health Service general practice in three regions of England.

PARTICIPANTS

Adults aged ≥ 18 years with insomnia disorder were randomised using a validated web-based randomisation programme.

INTERVENTIONS

Participants in the intervention group were offered a brief four-session nurse-delivered behavioural treatment involving two in-person sessions and two by phone. Participants were supported to follow a prescribed sleep schedule with the aim of restricting and standardising time in bed. Participants were also provided with a sleep hygiene leaflet. The control group received the same sleep hygiene leaflet by e-mail or post. There was no restriction on usual care.

MAIN OUTCOME MEASURES

Outcomes were assessed at 3, 6 and 12 months. Participants were included in the primary analysis if they contributed at least one post-randomisation outcome. The primary end point was self-reported insomnia severity with the Insomnia Severity Index at 6 months. Secondary outcomes were health-related and sleep-related quality of life, depressive symptoms, work productivity and activity impairment, self-reported and actigraphy-defined sleep, and hypnotic medication use. Cost-effectiveness was evaluated using the incremental cost per quality-adjusted life-year. For the process evaluation, semistructured interviews were carried out with participants, nurses and practice managers or general practitioners. Due to the nature of the intervention, both participants and nurses were aware of group allocation.

We recruited 642 participants (n = 321 for sleep restriction therapy; n = 321 for sleep hygiene) between 29 August 2018 and 23 March 2020. Five hundred and eighty participants (90.3%) provided data at a minimum of one follow-up time point; 257 (80.1%) participants in the sleep restriction therapy arm and 291 (90.7%) participants in the sleep hygiene arm provided primary outcome data at 6 months. The estimated adjusted mean difference on the Insomnia Severity Index was -3.05 (95% confidence interval -3.83 to -2.28; p < 0.001, Cohen's d = -0.74), indicating that participants in the sleep restriction therapy arm [mean (standard deviation) Insomnia Severity Index = 10.9 (5.5)] reported lower insomnia severity compared to sleep hygiene [mean (standard deviation) Insomnia Severity Index = 13.9 (5.2)]. Large treatment effects were also found at 3 (d = -0.95) and 12 months (d = -0.72). Superiority of sleep restriction therapy over sleep hygiene was evident at 3, 6 and 12 months for self-reported sleep, mental health-related quality of life, depressive symptoms, work productivity impairment and sleep-related quality of life. Eight participants in each group experienced serious adverse events but none were judged to be related to the intervention. The incremental cost per quality-adjusted life-year gained was £2075.71, giving a 95.3% probability that the intervention is cost-effective at a cost-effectiveness threshold of £20,000. The process evaluation found that sleep restriction therapy was acceptable to both nurses and patients, and delivered with high fidelity.

LIMITATIONS

While we recruited a clinical sample, 97% were of white ethnic background and 50% had a university degree, which may limit generalisability to the insomnia population in England.

CONCLUSIONS

Brief nurse-delivered sleep restriction therapy in primary care is clinically effective for insomnia disorder, safe, and likely to be cost-effective.

FUTURE WORK

Future work should examine the place of sleep restriction therapy in the insomnia treatment pathway, assess generalisability across diverse primary care patients with insomnia, and consider additional methods to enhance patient engagement with treatment.

TRIAL REGISTRATION

This trial is registered as ISRCTN42499563.

The award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/84/01) and is published in full in Health Technology Assessment; Vol. 28, No. 36. See the NIHR Funding and Awards website for further award information.

Plain language summary

Insomnia refers to problems with falling asleep or staying asleep, which affects 10% of the adult population. The recommended treatment for insomnia is a psychological treatment called cognitive–behavioural therapy. Research shows this to be a very effective and long-lasting treatment, but there are not enough trained therapists to support the large number of poor sleepers in the United Kingdom. We have developed a brief version of cognitive–behavioural therapy, called sleep restriction therapy, which involves supporting the patient to follow a new sleep–wake pattern. We carried out this study to see if sleep restriction therapy, given by nurses working in general practice, can improve insomnia and quality of life. We searched general practice records and invited people with insomnia to take part. Six hundred and forty-two participants were assigned, by chance, to either sleep restriction therapy or a comparison treatment, called sleep hygiene. Sleep restriction therapy involved meeting with a nurse on four occasions and following a prescribed sleep schedule. Sleep hygiene involved receiving a leaflet of sleep ‘do’s and dont’s’. Those receiving sleep restriction therapy were also provided with the same sleep hygiene leaflet so that the difference between the two groups was whether or not they received nurse treatment. We measured sleep, quality of life, daytime functioning and use of sleep medication through questionnaires, before and after treatment. We calculated the cost to deliver the treatment, as well as the cost of other National Health Service treatments that participants accessed during the study. We also interviewed participants and nurses to understand their views of the treatment. We found that participants in the sleep restriction therapy group experienced greater reduction in their insomnia symptoms compared to sleep hygiene. They also experienced improved sleep, mental health, quality of life and work productivity. The two groups did not differ in their use of prescribed sleep medication. Our results suggest that the treatment is likely to represent good value for money for the National Health Service. Both nurses and participants considered the treatment to be acceptable and beneficial, and they suggested some potential refinements. The study shows that nurse-delivered sleep restriction therapy is likely to be a clinically effective approach to the treatment of insomnia, and good value for money for the National Health Service.

Full text of this article can be found in Bookshelf .

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• Systematic Review
• Open access
• Published: 05 September 2024

Factors associated with frailty in older people: an umbrella review

• Mouna Boucham   ORCID: orcid.org/0009-0005-2035-2366 1 , 2 ,
• Amal Salhi 3 ,
• Naoual El Hajji 2 ,
• Gloria Yawavi Gbenonsi 2 ,
• Lahcen Belyamani 4 , 5 &
• Mohamed Khalis 1 , 2 , 6 , 7  

BMC Geriatrics volume  24 , Article number:  737 ( 2024 ) Cite this article

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The number of frail older people is increasing worldwide, and all countries will be confronted with their growing needs for healthcare and social support. The aim of this umbrella review was to summarize the evidence on the factors associated with frailty in older people, using a socioecological approach.

PubMed (MEDLINE), Scopus, Web of Science, ScienceDirect, Hinari (research4life), and the Trip database were systematically searched up to April 2023. Systematic reviews of observational studies that explored factors associated with frailty in older adults aged 60 years and over were considered for inclusion. No language, geographical or setting restrictions were applied. However, we excluded systematic reviews that investigated frailty factors in the context of specific diseases. The Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses and the ROBIS tool were used to assess the quality and risk of bias in the included studies.

Forty-four systematic reviews were included, covering 1,150 primary studies with approximately 2,687,911 participants overall. Several risk factors, protective factors and biomarkers were found to be associated with frailty, especially in community-dwelling older people, including 67 significant associations from meta-analyses. The certainty of the evidence was rated as moderate or reached moderate levels for seven factors relevant to older people. These factors include depression (OR 4.66, 95% CI 4.07 to 5.34), loneliness (OR 3.51, 95% CI 2.70 to 4.56), limitations in activities of daily living (OR 2.59, 95% CI 1.71 to 3.48), risk of malnutrition (OR 3.52, 95% CI 2.96 to 4.17), Dietary Inflammatory Index score (OR 1.24, 95% CI 1.16 to 1.33), maximal walking speed (Standardized Mean Difference (SMD) -0.97, 95% CI -1.25 to -0.68), and self-reported masticatory dysfunction (OR 1.83, 95% CI 1.55 to 2.18). Additionally, only greater adherence to a Mediterranean diet showed a high level of evidence (OR 0.44, 95% CI 0.31 to 0.64).

Conclusions

This umbrella review will provide guidance for prevention strategies and clinical practice by promoting healthy lifestyles and addressing all modifiable risk factors associated with frailty. Future systematic reviews should consider heterogeneity and publication bias, as these were the main reasons for downgrading the level of evidence in our review.

Registration

PROSPERO 2022, CRD42022328902.

Peer Review reports

With the gradual ageing of the population [ 1 ], the number of older people becoming frail is increasing worldwide [ 2 , 3 , 4 , 5 , 6 ]. The World Health Organization defines frailty as "a clinically recognizable state in which the ability of older people to cope with everyday or acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems" [ 7 ].

The identification of frailty, pre-frailty and robustness status has often been done by considering the biological model of frailty known as Fried's physical phenotype or physical frailty [ 8 , 9 ]. It is generally recognized by the presence of at least three of the following five criteria: unintentional weight loss, muscle weakness, self-reported exhaustion, slowness and low physical activity [ 8 ].

A recent systematic review found that 13.6% of non-frail (robust or pre-frail) people became frail, with a global incidence rate of frailty of 43.4 cases per 1000 person-years [ 2 ]. The prevalence of frailty varies considerably between countries and regions, and also according to the assessment tool used [ 4 , 5 ]. The authors of a systematic review conducted in the context of low- and middle-income countries, showed that the prevalence of frailty and pre-frailty ranged from 3.9% to 59.4% and from 13.4% to 71.6%, respectively [ 4 ]. In a more recent systematic review of 62 countries around the world, the pooled prevalence of frailty was 12% using physical frailty and 24% using the deficit accumulation model [ 5 ].

As conceptual models of frailty have evolved, several authors have been interested in the multidimensional approach to frailty, taking into account all its domains: biological, psychological, and social [ 10 , 11 ].

Given the diversity of theoretical definitions of frailty in older persons [ 12 , 13 ], and despite the lack of consensus on an operational definition, it is crucial to identify frailty earlier in order to limit its negative consequences. Numerous studies have shown that frail older people have an increased risk of falls, fractures, disabilities, hospitalizations, institutionalization, and even death [ 14 , 15 , 16 , 17 , 18 ]. It is also important to note that frailty is considered a dynamic syndrome that can be reversed by addressing modifiable factors [ 19 , 20 , 21 ].

Frailty in the older population is influenced by multiple factors, and it is essential to approach it holistically by considering all the determinants related to the individuals, their relationships, and their living environment. The use of a socioecological approach will help to uncover the different levels of influence involved in the development of frailty and guide preventive interventions. According to commonly used models of application of this approach [ 22 , 23 ], it is possible to examine frailty factors at various levels: the individual or intrapersonal level, including demographic characteristics, lifestyle factors, and health-related factors of the older person; the relationship or interpersonal level, involving the older individual's social network, such as family relationships and friendships; the community level, encompassing the physical and social environment; and the societal or policy level, which includes local cultures, laws, and policies.

Over the past decade, there has been a gradual increase in the number of systematic reviews addressing factors related to frailty in older people. However, most of these studies have focused on only one or a few determinants of frailty in older individuals [ 24 , 25 , 26 , 27 , 28 ]. In addition, other systematic reviews have been limited to frailty associated with specific diseases, countries, regions or contexts, and very few studies have examined a wide range of determinants of frailty [ 29 , 30 ]. Therefore, the aim of this umbrella review was to summarize the best available evidence on the determinants and factors associated with frailty in older people from published systematic reviews, with or without meta-analysis, to guide clinical practice and health policies.

This umbrella review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Update guidelines [ 31 ] and the recommendations of the Joanna Briggs Institute (JBI) for conducting umbrella reviews [ 32 ].

Registration and protocol

The review protocol was registered on the international prospective register of systematic reviews (PROSPERO) on May 10, 2022, under the number CRD42022328902 and is available from the following link:  https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=328902 .

Data sources and search strategy

A comprehensive search strategy was developed and a systematic search was conducted on September 29, 2022, in the following databases: PubMed (MEDLINE), Scopus, Web of Science, ScienceDirect, Hinari (research4life), and the Trip database.

The keywords and MeSH terms used were guided by our preliminary research and included older people as our population of interest, the factors associated with different levels of influence of the socioecological approach as the exposure, and the concept of frailty as the outcome. There were no predefined interventions or comparisons in this review, and the research was conducted without limitation of geographical area or setting. The keywords were linked using the Boolean operators "AND", "OR" and "NOT" and our search equations were adjusted for each database. Details of these equations and the filters used can be found in the supplementary material (Additional file 1).

We have completed by hand searching reference lists and citations of the articles included in this review. Subsequently, an additional search in Google Scholar was performed on December 30, 2022, with a continuous check of the alerts generated in three main databases (Scopus, Web of Science, and ScienceDirect). As planned in our protocol, a re-run of the search strategy was performed on April 16, 2023, before completing our final analysis to retrieve any eligible articles. For those articles that were not available in full text, a request was made to the authors.

Eligibility criteria

Systematic reviews of observational studies, with or without meta-analysis, published from 2011 to 2023 that explored factors associated with frailty in older adults aged 60 years and over were considered for inclusion in this umbrella review.

The chosen age limit remains a reference for talking about older people [ 1 ] and allows us to cover a wider population in our study than if we had considered only people aged 65 years and over by convention.

For exposure, we considered all the determinants or factors associated with frailty that belong to different levels of influence as defined by the socioecological approach. These factors include those at the individual or intrapersonal level (e.g., age, gender, education, income, lifestyle factors or behaviors, biological and health-related factors), the relationship or interpersonal level (e.g., marital status, social support, family income), the community level (e.g., physical environment, neighborhood, social interactions), and the societal or policy level (e.g., public policies, cultural norms, legislation) [ 22 , 23 ]. Regarding the main outcomes, the studies to be included should address frailty as measured by any valid frailty assessment tool, and the nature of its association with the factor(s) studied.

In addition, systematic reviews that examined multiple factors associated with frailty with available and sufficient data in their qualitative synthesis, separated by age or study design, were also considered for inclusion.

We excluded systematic reviews that studied frailty factors in the context of specific diseases, included a population group under 60 years of age in their meta-analyses, or had no full text available. However, we did not apply any language, geographical or setting restrictions and no reviews were excluded after quality assessment.

Study selection process

The PRISMA 2020 flowchart was used to report our review process and the selection of studies. Records retrieved from all databases were transferred to a library created on the reference management software Zotero. This allowed two reviewers (MB and AS) to manually identify and remove duplicates. Subsequently, these reviewers independently screened all titles and abstracts of the remaining articles, making initial exclusions based on our eligibility criteria. The full texts of the articles were then assessed for inclusion.

Any disagreements between the two reviewers were resolved through discussion and, if necessary, the opinion of a third author (MK) was sought.

The combination of these results with those from the additional search helped determine which articles were retained and which were excluded at the end of the process.

Data collection process and data items

Data collection from eligible articles was conducted independently by two reviewers (MB and NEH) and with reference to the JBI Data Extraction Form for Review for Systematic Reviews and Research Syntheses [ 32 ]. The following data were extracted for each included systematic review: study details (title and reference; authors and year of publication; type of review; objective(s); participants; setting; factors explored), search details (number of databases and sources searched; date range of included studies; number of studies included; type of studies included; country of origin of included studies), quality appraisal (appraisal instruments used; appraisal rating), frailty assessment (frailty assessment tools used; result of the assessment), main findings (factors associated with frailty; significance/direction/ effect size), heterogeneity (if applicable) and limitations reported by the authors. To address missing data related to study or research details, we used information from the primary studies and also contacted some authors for supplementary material. Any discrepancies between the two reviewers were resolved through discussion and rechecking the data.

Quality and risk of bias assessment

The quality assessment of the reviews included in our umbrella review was independently performed by two reviewers (MB and AS) using the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses [ 32 ]. This appraisal tool consists of 11 questions, each with four possible answers: yes, no, unclear, or not applicable. The overall score is calculated by considering only the "yes" answers, which receive one point each, while all other answers receive zero points.

According to the final assessment score, the quality of the systematic reviews was rated as “high” (9–11), “moderate” (5–8) or “low” (0–4).

An additional assessment of the risk of bias in the included reviews was conducted using the ROBIS tool [ 33 ]. This tool is specifically designed to evaluate the risk of bias in systematic reviews and consists of three phases. The first phase, relevance assessment, is optional. The other required phases, 2 and 3, involve the identification of concerns with the review process and judging the risk of bias, respectively. It is important to note that phase 2 is composed of four domains: study eligibility criteria, identification and selection of studies, data collection and study appraisal, and synthesis and findings. Each domain includes questions that can be answered with "Yes", "Probably Yes", "Probably No", "No", or "No Information", with "Yes" indicating low concerns. The judgment for each domain, as well as for the final phase of risk of bias assessment, will be classified as "Low", "High" or "Unclear".

Data synthesis and certainty assessment

We conducted a qualitative synthesis, which included narrative tables of the main factors associated with frailty among older people. Additionally, we have developed an illustrative socio-ecological model of these factors.

The results obtained from the reviews were based on various effect measures, such as Relative Risk (RR), Odds Ratio (OR), Mean Difference (MD) or Standardized Mean Difference (SMD), with significance determined by a p -value < 0.05.

The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach [ 34 , 35 ] was then used to assess the certainty of the evidence in the systematic reviews for our patient-relevant outcomes. These factors were selected based on their relevance to clinical practice, the potential for making recommendations or implementing public health actions, and the availability of data. The quality of evidence for each outcome initially started as "Low" because it was based on observational studies. Risk of bias, inconsistency, indirectness, imprecision, and publication bias were the five reasons that could downgrade the quality of the evidence. However, there were three other considerations that could upgrade the quality of evidence: large effect size, dose response, and all plausible residual confounding factors or biases. The quality of a body of evidence will be rated as "High", "Moderate", "Low" or "Very Low".

Study selection

A total of 11,975 studies were identified by searching all databases. After removing duplicates, the remaining 3,689 articles were screened by title and abstract according to our inclusion criteria. Of these, 3,545 were excluded and only 144 full-text articles were assessed for eligibility. Subsequently, 103 studies were also excluded, leaving 41 studies. The additional search retrieved four studies and only one was selected after assessment for inclusion. No additional articles were found in the alerts of the databases, while two additional studies were retrieved by re-running our search strategy. Also, checking the reference lists of the last two included articles as well as a final checking of the citations of all included papers did not generate any new eligible articles. Thus, a total of 44 studies were retained in our umbrella review [ 28 , 29 , 30 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. Full details of the selection process for the systematic reviews included in our qualitative synthesis are presented in the PRISMA flow diagram (Fig.  1 ). Additionally, the list of full-texts that were excluded after evaluation is provided in the supplementary material (Additional file 2), along with the reasons for their exclusion.

PRISMA flow diagram for study selection. * Integration of two studies from the re-run of the research strategy

Study characteristics

The main characteristics of the included systematic reviews are summarized in Table  1 .

Of the 44 studies included in our review, 27 were systematic reviews with meta-analysis and 17 had only qualitative synthesis. The publication dates of these reviews ranged from 2014 to 2023, with the highest number of publications in 2022, with 11 studies (25%). It is worth noting that the two studies considered in 2023 were already first published online in 2022.

Regarding the number of databases searched it varied from one to eight databases with PubMed, Embase and MEDLINE as the main data sources. A total of 1,150 primary studies were included in our systematic reviews, with a range of three to 342 studies published from 1994 to 2022. The total number of participants per review ranged from 1,757 to 889,880 with approximately 2,687,911 participants overall. Cross-sectional studies or data dominated in comparison to longitudinal studies and in some papers, they have been combined.

Most primary studies collected information from both sexes and depending on the available data, the proportion of females ranged from 15.3% to 88.3%. Some studies involved only women while a few studies included only men.

The study setting was primarily at the community level and in terms of the countries of origin of included primary studies, 61 countries were reported, distributed as follows: 29 countries in Europe (47%); 17 countries in Asia (28%); 10 countries in the Americas (16%); four countries in Africa (7%) and one country in Oceania (2%). Furthermore, the countries of origin were not specified in eight cases.

As for the distribution of the primary studies around the world, the European continent was also leading, followed by the American continent, especially North America, and by Asia, Oceania and Africa respectively. In addition, seven countries accounted for more than 65% of the studies, namely the United States of America (USA), China, Japan, Spain, the United Kingdom (UK), Italy and Brazil.

Frailty assessment

Several tools have been used to assess frailty, and some of them have been adapted for specific countries, settings or components of frailty.

The Fried frailty phenotype [ 8 ] was the most commonly used tool in the included systematic reviews, whether used alone, in combination or in a modified version. It was followed by the Frailty Index [ 77 , 78 ] and the FRAIL scale [ 79 , 80 ], respectively.

According to the available data, the prevalence of frailty in older people ranged from 0.9% (Germany) using Fried’s criteria [ 75 ] to 88.4% (China) with Comprehensive Geriatric Assessment (CGA) combined with the Frailty Index [ 36 ].

Only two reviews have examined the factors associated with frailty and cognitive impairment or cognitive frailty [ 38 , 71 ]. However, cognitive function or cognitive impairment has been explored as factors associated with frailty in several reviews [ 29 , 30 , 36 , 50 , 66 , 69 ].

Quality appraisal and risk of bias in the included systematic reviews

Using the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses, the overall score ranged from seven to 11 out of 11 (Table  2 ). Therefore, 30 studies (68%) were rated as "high" quality, including 19 systematic reviews with meta-analyses and 11 systematic reviews with qualitative synthesis. There were no studies of low quality, and the remaining studies were rated as "moderate", with eight systematic reviews with meta-analyses and six systematic reviews with qualitative synthesis.

Based on the ROBIS tool [ 33 ] for assessing the risk of bias in systematic reviews, the final judgment of the risk of bias in the reviews was rated as "Low" for 25 studies (57%). This corresponds to 14 systematic reviews with meta-analyses and 11 systematic reviews with qualitative synthesis. The remaining 19 studies were rated as having a "High" risk of bias, including 13 systematic reviews with meta-analyses and six systematic reviews with qualitative synthesis. Table 3  presents the details of the assessment of the four domains of the second phase of the ROBIS tool and the final judgment of the risk of bias in the reviews.

Main factors associated with frailty in older people

Several factors were considered in the reviews, corresponding to different levels of influence in the adopted socio-ecological model. These factors mainly included individual factors that were explored in all reviews, including demographic and personal factors (11 reviews), clinical and health-related factors (30 reviews), lifestyle factors (13 reviews) and biological factors or biomarkers (11 reviews). Relationship and community factors were explored in ten and four reviews, respectively. Only ten reviews have combined the previous levels of influence in the socio-ecological model, and there were no reviews that addressed the societal or policy level. However, six reviews associated the individual and relational levels and four reviews combined the three levels explored. In addition, 24 reviews (55%) were able to explore multiple factors or parameters related to frailty, while the remaining 20 reviews focused only on one or two factors. In total, 75 factors were explored in several specific meta-analyses, revealing 67 significant associations with frailty in the older population, with 49 positive associations and 18 negative associations.

A summary of the main factors identified by the level of influence of the socio-ecological model and their associations with frailty is available in the Additional files (Additional file 4).

Individual level

Demographic factors and personal characteristics.

Older age [ 29 , 30 , 36 , 38 , 60 , 65 , 66 , 69 ] and female gender [ 29 , 30 , 36 , 65 , 69 , 70 ] were the most frequently identified risk factors for frailty in the older population, according to various systematic reviews and meta-analyses.

A lower level of education was often found to be significantly associated with frailty status [ 30 , 36 , 50 , 60 ], but non-significant associations were also reported [ 30 ]. The number of years of education was inversely associated with frailty [ 29 ], while the association between higher education level and frailty was controversial based on the results of meta-analyses [ 69 ]. Income was found to be inversely associated with frailty [ 29 , 30 ], and a consistent inverse association was identified between frailty and quality of life [ 45 ]. Ethnic background was reported to be associated with frailty in a few studies [ 29 , 30 ].

Clinical and health-related factors

Among the clinical and health-related factors explored, seventeen factors were identified as risk factors for frailty based on the results of meta-analyses. These factors included pain [ 69 ], loneliness [ 51 ], having three or more chronic diseases [ 65 ], metabolic syndrome [ 75 ], incontinence [ 36 ], respiratory disease [ 69 ], arterial stiffness indices [ 43 ] and sleep parameters [ 47 , 69 , 72 ] such as insomnia [ 47 ], difficulty falling asleep [ 47 ], difficulty in maintaining sleep [ 47 ], non-restorative sleep [ 47 ], poor sleep [ 69 ], short sleep duration (< 6 h) [ 72 ], long sleep duration (> 8 h) [ 72 ], daytime drowsiness [ 72 ], sleep-disordered breathing [ 72 ], and prolonged sleep latency [ 72 ].

According to both qualitative syntheses and meta-analyses, significant positive associations with frailty were also found with the following factors: poor self-perceived health [ 29 , 30 , 36 , 66 ], polypharmacy [ 36 , 69 ], history of falls [ 29 , 36 , 38 , 69 ], cognitive impairment [ 30 , 36 , 50 , 66 , 69 ], risk of malnutrition [ 29 , 36 , 63 , 66 ], malnutrition [ 29 , 59 , 63 , 69 ], masticatory dysfunction [ 53 , 64 ], limitations in activities of daily living (ADL) [ 36 , 60 , 65 , 66 ], abdominal obesity [ 29 , 40 , 60 ], obesity [ 30 , 40 , 60 ], underweight [ 29 , 40 ], comorbidities [ 29 , 36 , 69 ], diabetes [ 29 , 36 , 60 , 69 ], hypertension [ 36 , 60 ], arthritis [ 29 , 36 , 60 ], stroke [ 29 , 36 ], chronic obstructive pulmonary diseases (COPD) [ 29 , 36 ], hearing dysfunction [ 60 , 69 ], depression [ 28 , 29 , 36 , 60 , 69 ], and depressive symptoms [ 29 , 30 , 50 , 60 , 66 ]. However, non-significant associations with frailty were reported from quantitative analyses, particularly for early morning awakening [ 47 ], overweight [ 40 ], stroke [ 69 ], cardiovascular diseases [ 69 ], vision dysfunction [ 69 ], and human herpes virus seropositivity [ 46 ]. The five components of physical fitness [ 56 ] and the body mass index (BMI) [ 69 ] were found to have a significant negative association with frailty in the older adults.

Abdominal obesity, hyperglycemia and multiple concomitant cardiometabolic risk factors have been associated with an increased likelihood of frailty in older people with inconsistency between studies concerning the associations between dyslipidemia, elevated blood pressure, and frailty [ 74 ].

Oral health characteristics were specifically addressed in four systematic reviews [ 37 , 48 , 57 , 64 ]. The first review, published in 2015 [ 57 ], suggested a possible association between poor oral health and frailty. However, this review was not strongly conclusive due to limitations and concerns related to the included studies, and it also presented a high risk of bias. The most recent reviews with high quality and low risk of bias have identified different oral health indicators [ 37 , 48 , 64 ], which have been classified into four categories: "oral health status deterioration; deterioration of oral motor skills; chewing, swallowing, and saliva disorders; and oral pain" [ 64 ]. These factors include the number of teeth, decreased masticatory function, difficulty chewing, deterioration of oral health, oral diadochokinesis, reduced occlusal force, reduced tongue pressure, dry mouth, periodontal disease, difficulty swallowing, oral dysbiosis, and tooth or mouth pain [ 64 ]. In addition, non-use of dental services, the need for dentures, the need for preventive dental care, and worse self-perceived or self-reported oral health factors have also been associated with frailty in older persons [ 37 ]. Thus, oral frailty and the accumulation of oral health problems have been found to be associated with an increased incidence of frailty, while good oral health and good oral hygiene have been identified as protective factors [ 37 , 48 , 64 ].

Despite indicating positive associations with frailty, the exploration of anemia [ 42 ], sleep and wake disturbances [ 76 ], and cardiac autonomic nervous system impairment [ 68 ] were inconclusive or should be interpreted with caution.

Other factors that have been cited as contributing to frailty in systematic reviews include the number of falls in the last 12 months [ 30 , 60 ], fear of falling [ 44 ], a history of hospitalization [ 36 ], functional incapacity [ 29 ], and limitations in instrumental activities of daily living (IADL) [ 36 ].

Lifestyle factors and behaviors

Greater adherence to a Mediterranean diet [ 30 , 41 ], consumption of fruits and vegetables [ 30 , 58 ], higher protein intake [ 30 , 61 , 63 , 67 ], better diet quality and higher intake of α-carotene, β-carotene equivalent, vitamin D, α-tocopherol, vitamin B6, folate and vitamin C were found to be inversely associated with frailty [ 63 ]. Additionally, a higher Dietary Inflammatory Index score [ 55 ] and a low intake of specific micronutrients (vitamin D, E, C, folate, carotenoids, α-tocopherol) [ 63 ] showed a significant increased risk of frailty.

Sedentary behavior [ 60 ], a low level of physical exercise [ 36 , 69 ] and smoking [ 29 , 30 , 60 , 69 ] were considered to be significantly associated with the risk of frailty in many reviews. However, there was some inconsistency regarding alcohol consumption [ 29 , 30 , 36 , 60 ], with one meta-analysis showing a significant inverse association with frailty [ 69 ].

Biological factors

When considering biological factors, C-reactive protein (CRP) [ 30 , 39 , 49 , 50 , 54 , 60 , 71 ], Interleukin-6 (IL-6) [ 39 , 49 , 50 , 54 , 71 ], and Tumor necrosis factor alpha (TNF-α) [ 39 , 54 , 71 ] have been frequently studied and often found to have a positive and significant association with frailty. Low levels of vitamin D (25(OH)D) have also commonly been found in frail older people [ 30 , 39 , 50 , 62 , 69 , 71 ]. Various inflammatory, hematological, protein, endocrine, and nutritional markers have been explored, but with a limited number of primary studies [ 30 , 38 , 39 , 71 ]. Indeed, some reviews have suggested that frailty is associated with high levels of glycated hemoglobin [ 60 , 71 ], fibrinogen [ 39 , 71 ], and low levels of albumin [ 50 , 54 , 71 ], hemoglobin [ 50 , 54 , 71 ] and circulating insulin-like growth factor 1 (IGF-1) [ 54 ].

However, several genetic factors have been identified as associated with the frailty phenotype and, 13 correlations have been identified between serum and genetic markers [ 71 ]. For serum biomarkers, they included: myostatin, Klotho and IL-18, which were associated with frailty; vitamin D, cystatin C, IL-6, TNF-alpha, IL-6R, CRP and IL-1 βeta were related to frailty associated with cognitive decline; and chemokine receptor 2, IL-12p70, and brain-derived neurotrophic factor were associated with cognitive decline only [ 71 ]. In addition, the following genes, specified by their "single nucleotide polymorphism", were associated with the frailty phenotype: IL-18 rs360722, IL-6 rs1800796, COMT (catechol-O-methyltransferase) rs464316, TNF rs1800629 linked to chromosomes 11, 7, 22, and 6, respectively [ 71 ].

As for the association between frailty and telomere length, frail older people had shorter telomeres and this appears to be ethnic dependent [ 73 ].

Relationship level

Living alone [ 29 , 36 , 60 , 69 ] and marital status (single or widowed) [ 29 , 36 ] have been identified as risk factors for frailty in older adults, based on qualitative and quantitative syntheses. Lower family income [ 36 , 60 ], abuse [ 29 ], and spouse’s depression [ 30 ] were also cited as having a significant positive association with frailty in some systematic reviews based on a few primary studies. Living conditions during childhood, monthly family income and being married appear to be associated with a decreased risk of frailty [ 29 ]. One systematic review also suggested a possible association between pet ownership and a lower risk of frailty [ 52 ]. Older people taking care of their grandchildren or pets had a 40% lower risk of being frail [ 52 ].

Community and society levels

While no societal-level factors were studied, very few community-level factors were addressed or identified. It was reported that neighborhood conditions [ 30 ], rural residence [ 38 ], and low social support [ 38 ] were associated with higher frailty in older people. Additionally, social interaction was mentioned to have an inverse effect on frailty in older individuals [ 29 ].

An illustrative socio-ecological model of the main factors contributing to frailty in older people is provided in Fig.  2 .

Socio-ecological model of the main factors associated with frailty in older people

Certainty of the evidence

A total of 37 relevant factors for older people were assessed for certainty of the evidence using the GRADE approach. According to 18 systematic reviews with meta-analyses [ 28 , 36 , 38 , 40 , 41 , 47 , 51 , 53 , 55 , 56 , 58 , 61 , 62 , 65 , 66 , 69 , 72 , 75 ] and 51 specific evaluations, the certainty of the evidence was rated as "Very low" or "Low" for 15 and 12 factors, respectively. Additionally, seven factors were rated as moderate or reached a moderate level of evidence. These include the Dietary Inflammatory Index score (OR 1.24, 95% CI 1.16 to 1.33) [ 55 ], maximum walking speed (SMD -0.97, 95% CI -1.25 to -0.68) [ 56 ], self-reported masticatory dysfunction (OR 1.83, 95% CI 1.55 to 2.18) [ 53 ], depression (OR 4.66, 95% CI 4.07 to 5.34) [ 36 ], loneliness (OR 3.51, 95% CI 2.70 to 4.56) [ 51 ], ADL limitations (OR 2.59, 95% CI 1.71 to 3.48) [ 66 ], and risk of malnutrition (OR 3.52, 95% CI 2.96 to 4.17) [ 36 ]. For the three remaining factors, adherence to a Mediterranean diet showed a "High" level of evidence, while the certainty of evidence varied for vitamin D levels and diabetes with "Very low" and "Low" ratings.

The main reasons for downgrading the level of evidence were inconsistency with significant heterogeneity (31 evaluations) and publication bias (20 evaluations). However, all plausible residual confounding or bias and large effect allowed us to upgrade the level of evidence in 27 and 20 evaluations, respectively. Details of these assessments are provided in the Additional files (Additional file 5).

The aim of this umbrella review was to identify factors associated with frailty in the older population, using a socioecological approach. Several risk factors, protective factors and biomarkers were found to be related to frailty, especially in community-dwelling older people, with 67 significant associations from meta-analyses. Individual-level factors were predominant, followed by relationship and community factors, while no society-level factors were explored in the included systematic reviews.

Our umbrella review highlighted the wide variability in frailty prevalence reported in the literature [ 3 , 4 , 5 , 6 , 81 , 82 ]. This variability can be attributed to a number of factors, including the frailty assessment tool used, differences between countries, regions, and study settings, as well as age and gender. Frailty increases with age [ 3 , 4 , 6 ], and although women are more frail than men [ 2 , 4 , 5 , 6 ], they paradoxically experience a lower mortality rate [ 83 ]. Some authors have identified biological, behavioral, and social hypotheses that could explain sex differences in mortality, morbidity, and frailty, and have consequently suggested specific interventions for frailty prevention [ 84 ].

The majority of our relevant factors for the older population showed very low or low levels of evidence, with little or limited confidence in the effect estimate. Among these factors, co-morbidities, having three or more chronic diseases, diabetes, hypertension, and metabolic syndrome were identified as risk factors for frailty in older people. All of these conditions lead to multiple drug prescriptions and polypharmacy was also identified as a factor that increases the probability of becoming frail in our review. According to a recent overview, medication reviews can reduce inappropriate use of medications, but there is insufficient evidence to improve frailty [ 85 ]. Despite the lack of hindsight, a new and more comprehensive model, "the polypharmacy stewardship model", has recently been proposed to promote the appropriate use of medicines, particularly in frail older people with multimorbidity and polymedication [ 86 ]. This model is based on five stages: patient identification, medication review, personalized deprescribing, support and engagement with patient-centered intervention, and collaboration between all stakeholders.

When considering relevant nutritional, lifestyle, behavioral and psychosocial factors, our review has identified several factors significantly associated with frailty, namely: malnutrition, risk of malnutrition, high Dietary Inflammatory Index score, low vitamin D levels, protein intake, fruit and vegetable consumption, adherence to Mediterranean diet, abdominal obesity, obesity, underweight, sleep parameters, smoking, alcohol use, low level of physical exercise, physical fitness components, ADL limitations, depression or depressive symptoms, cognitive impairment, loneliness, and living alone. Of note, some of these factors achieved a moderate certainty of evidence (depression, ADL limitations, loneliness, risk of malnutrition, dietary inflammatory index score, maximal walking speed), while only greater adherence to a Mediterranean diet showed a high level of evidence for its protective effect against frailty.

In addition, systematic reviews, mainly based on randomized controlled trials (RCTs) support our findings by revealing the benefits of physical activity and nutrition-based interventions on frailty and its related risk factors or components [ 87 , 88 , 89 , 90 , 91 ]. There is moderate certainty of evidence that physical activity interventions have significant effects on mobility, ADL, cognitive function, quality of life and frailty [ 87 ]. Also, interventions based on a combined approach, including physical activity and a nutritional intervention with protein and vitamin D supplementation, dietary counseling, education or cooking classes showed significant effects on physical function, mobility and measures of frailty [ 88 ]. Another recently published overview suggested that diets, physical activity and digital technologies can also improve loneliness, social isolation and frailty among older people [ 92 ]. Resistance training alone or multi-component exercise interventions have been recommended for frail and pre-frail older persons to improve their muscle strength, walking speed, balance, and physical performance [ 93 ]. The average frequency of exercise reported was two to three times a week, for ten to 90 min per session, with a total duration of five to 72 weeks, and a minimum of 2.5 months for the majority [ 93 ].

It is important to report that there is limited but interesting evidence of the anti-inflammatory effect of physical activity, diet supplementation and the Mediterranean diet, with a reduction in inflammatory biomarkers, which may contribute to the effect on frailty [ 94 , 95 , 96 ].

According to our findings, self-reported masticatory dysfunction is another relevant factor associated with frailty, with moderate certainty of evidence. Poor oral health status is associated with the onset of frailty in the older population, with nutritional, inflammatory, psychological and neuronal mechanisms suggested to explain this relationship [ 97 ].

Even with low certainty of evidence, a history of falls is also an important factor related to frailty in our review. It is one of the major risk factors for falls in older people, along with balance and gait disorders, polypharmacy, female gender, fear of falling, visual impairment, cognitive decline, depression, and environmental factors [ 98 , 99 ]. Among older adults living in the community, multifactorial interventions, including exercise, may decrease the falls rate [ 100 ], and with high certainty of evidence, home fall-hazard interventions were also effective in reducing falls in high-risk individuals [ 101 ].

Strengths and limitations of this umbrella review

To our knowledge, there is no previous umbrella review summarizing the evidence from published systematic reviews and meta-analyses on factors associated with frailty in older persons. Our current review followed the PRISMA 2020 guidelines and the Joanna Briggs Institute recommendations with a pre-registered protocol on PROSPERO.

A comprehensive search strategy was adopted and all details on study selection and data collection were provided. The quality and risk of bias assessment of the included systematic reviews were conducted using two relevant tools. In addition, the GRADE approach was used to assess the certainty of the evidence for outcomes relevant to older people.

However, our review has certain limitations. Some of these limitations are common to umbrella reviews, namely: the influence of possible errors in the conduct of the included systematic reviews or meta-analyses; the reliance on syntheses of the results of systematic reviews, which are based on the primary studies included in these reviews; and the coverage of existing systematic reviews, which means that several factors are not exploited or have not yet been addressed by systematic reviews. Although the quality of the included reviews was rated as high or moderate, some reviews had a high risk of bias. Furthermore, inconsistency with significant heterogeneity and publication bias were the main reasons for downgrading the level of certainty of the evidence for outcomes relevant to older people. Finally, since the included systematic reviews were solely based on observational studies, only associations, rather than causations, can be identified.

Implications for practice, policy and future research

Various clinical practice guidelines have focused on the identification and management of frailty, providing recommendations primarily in one or more of the following areas: prevention, frailty screening, comprehensive assessment, physical activity, nutrition, medication management and fall prevention [ 102 , 103 , 104 , 105 , 106 ]. These recommendations were often based on scientific evidence or expert consensus, but some gaps have been identified. These gaps include a lack of evidence-building and detailed strategies for effective implementation and monitoring of these recommendations.

Our umbrella review will help to update these clinical practice guidelines and guide health policies and research towards the importance of adopting a holistic approach that considers all the influences of the different levels of the socio-ecological model and also considers the individual as a whole with a person-centered approach. There is a need to involve older people in the whole process, from identifying their needs to studying the feasibility, acceptability and cost-effectiveness of the actions.

Existing primary research data on factors associated with frailty in older people should be better exploited in future systematic reviews and meta-analyses. In addition to examining the individual level, future research should also consider other relational, community, and societal or policy levels. It is important to promote community-based research in order to tailor interventions to local specificities and resources, in collaboration with all stakeholders.

Frailty in older individuals is a dynamic and multifactorial syndrome that requires a holistic approach to its prevention and management. Our umbrella review highlighted several factors that are associated with frailty, particularly in community-dwelling older people. These factors seem to interact to either increase or decrease the likelihood of the occurrence of frailty. Individual factors were predominant, followed by relationship and community factors, suggesting the possibility of interventions on all modifiable factors at the different levels of influence of the socio-ecological model. Currently, lifestyle interventions based on physical activity and nutrition are the most effective in reducing frailty and a number of its risk factors or components, while other interventions remain promising, particularly those based on digital health and innovation.

Availability of data and materials

All data relevant to our review are included in the article and also available as additional files.

Abbreviations

Activities of daily living

Body mass index

C-reactive protein

Grading of Recommendations, Assessment, Development and Evaluations

Instrumental activities of daily living limitations

Interleukin-6

Joanna Briggs Institute

Mean Difference

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

International prospective register of systematic reviews

Risk of bias in systematic reviews

Relative Risk

Standardized Mean Difference

Tumor necrosis factor alpha

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MB and MK: conceptualization and design. MB and GYG: preliminary research. MB and MK: methodology and search strategy. MB and AS: study selection and quality assessment. MB and NEH: data extraction. MB: assessment of risk of bias and certainty of evidence. MB: writing the first draft of the manuscript. LB and MK: review and supervision.  All authors reviewed and approved the manuscript.

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Additional file 1. detailed research strategy., additional file 2. list of excluded full-text articles and reasons for exclusion., additional file 3. detailed narrative table of data from systematic reviews included in the umbrella review., 12877_2024_5288_moesm4_esm.docx.

Additional file 4. Summary of the Main Factors Identified by Level of Influence of the Socio-Ecological Model and Their Associations with Frailty.

12877_2024_5288_MOESM5_ESM.docx

Additional file 5. Grading of Recommendations, Assessment, Development, and Evaluations for Frailty-Related Factors Relevant to the Patient.

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Boucham, M., Salhi, A., El Hajji, N. et al. Factors associated with frailty in older people: an umbrella review. BMC Geriatr 24 , 737 (2024). https://doi.org/10.1186/s12877-024-05288-4

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Comprehensive analysis of POLH-AS1 as a prognostic biomarker in hepatocellular carcinoma

• Yan Dong 1   na1 ,
• Xinyi Chen 2   na1 ,
• Shen Yang 3   na1 ,
• Yilong Fu 3 ,
• Liangyu Wang 3 ,
• Xueping Gao 4 ,
• Di Chen 5 &
• Lixia Xu 3  

BMC Cancer volume  24 , Article number:  1112 ( 2024 ) Cite this article

Metrics details

Hepatocellular carcinoma (HCC), a prevalent primary malignant tumor, is notorious for its high mortality rate. Despite advancements in HCC treatment, patient outcomes remain suboptimal. This study endeavors to assess the potential prognostic significance of POLH-AS1 in HCC.

In this research, we gathered RNA-Seq information from individuals with HCC in The Cancer Genome Atlas (TCGA). We analyzed the levels of POLH-AS1 expression in both HCC cells and tissues using statistical tests. Additionally, we examined various prognostic factors in HCC using advanced methodologies. Furthermore, we employed Spearman’s rank correlation analysis to examine the association between POLH-AS1 expression and the tumor’s immune microenvironment. Finally, the functional roles of POLH-AS1 in HCC were validated in two HCC cell lines (HEP3B and HEPG2).

Our analysis revealed elevated POLH-AS1 expression across various cancers, including HCC, with heightened expression correlating with HCC progression. Notably, POLH-AS1 expression emerged as a potential biomarker for HCC patient survival and prognosis. Mechanistically, we identified the involvement of POLH-AS1 in tumorigenesis pathways such as herpes simplex virus 1 infection, interactions with neuroactive receptors, and the cAMP signaling pathway. Lastly, inhibition of POLH-AS1 was discovered to hinder the proliferation, invasion and migration of HEP3B and HEPG2 HCC cells.

Conclusions

POLH-AS1 emerges as a promising prognostic biomarker and therapeutic target for HCC, offering potential avenues for enhanced patient management and treatment strategies.

Peer Review reports

Hepatocellular carcinoma (HCC) is a significant malignant tumor originating from liver cells and ranks as one of the most lethal cancers globally [ 1 , 2 ]. In 2020, approximately 906,000 individuals were diagnosed with HCC worldwide, making it the third leading cause of cancer-related deaths. The prognosis remains grim, with a five-year relative survival rate of around 18% [ 3 ]. Currently, early surgical resection remains the foremost therapeutic strategy, aiming to curtail mortality rates associated with HCC [ 4 ]. Despite advancements in medical science, the anticipated therapeutic efficacy for patients with HCC has not yet achieved optimal levels. The challenges are attributed to the highly invasive, heterogeneous, and drug-resistant nature of HCC, resulting in a poor prognosis [ 4 , 5 , 6 ]. Understanding the molecular mechanisms underlying HCC initiation and progression is crucial for improving clinical interventions and patient outcomes. Therefore, a deeper exploration of these molecular processes is essential to develop more effective treatment strategies and enhance survival rates in HCC patients.

Long non-coding RNAs (lncRNAs) have emerged as critical players in cancer biology, influencing six key characteristics: cell growth, motility, immortality, angiogenesis, and survival [ 7 ]. Various studies have highlighted the dualistic role of lncRNAs, acting as either tumor promoters or suppressors within the tumor microenvironment [ 8 ]. Their significant role in cancer-related pathways suggests their potential as biomarkers for tumor diagnosis, treatment, and prognosis [ 9 ]. Consequently, the exploration of lncRNAs as biomarkers has become a prominent area of research in oncology.

POLH antisense RNA1 (POLH-AS1) is a long non-coding RNA derived from the reverse transcription of the POLH gene. Recent studies have illuminated its pivotal role as a master regulator in HCC, significantly impacting patient prognosis by modulating various emerging cell death pathways, including necroptosis, ferroptosis, and cuproptosis [ 10 , 11 , 12 ]. Furthermore, a set of necrosis-associated lncRNAs, including POLH-AS1, has been proposed to guide the prognosis of HCC and inform immunotherapeutic approaches [ 13 ]. However, the precise regulatory mechanisms through which POLH-AS1 affects HCC progression remain largely unexplored.

In this study, we spotlight a promising lncRNA, POLH-AS1, demonstrating its potential to forecast prognosis and guide the choice of immunotherapy for HCC patients. Furthermore, we tentatively examined the expression levels of POLH-AS1 across HCC cell lines and human normal liver cell lines. Finally, we delved into the functional relevance of POLH-AS1 in HCC progression, unveiling that its inhibition resulted in attenuated cell proliferation, migration, and invasion. In aggregate, our findings underscore POLH-AS1 as a noteworthy prognostic biomarker and a viable target for tailored HCC treatment.

Data acquisition and processing

Data on hepatocellular carcinoma and transcriptome data obtained from RNA sequencing were extracted from The Cancer Genome Atlas (TCGA) database. 374 HCC samples and 50 samples of normal tissue were included in the research after individuals with missing clinical data were eliminated. Following this, research was carried out to explore the relationship between the levels of POLH-AS1 expression and the survival rate of individuals diagnosed with HCC.

Tumor samples collection

Between Oct 2021 and Mar 2022, 8 HCC tissue samples and 8 normal liver tissues were gathered from patients at the First Affiliated Hospital of Zhengzhou University, Henan, China. The clinicopathological characteristics of the patients with HCC were summarized in supplementary table S1 . HCC tissue samples were stored with liquid nitrogen after resection, and mRNA expression levels were evaluated using quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Prognostic model development and evaluation

Univariate and multivariate Cox regression analyses were carried out to evaluate the potential of POLH-AS1 as an independent prognostic indicator at a significance level of p  < 0.05. The analyses incorporated clinicopathological variables such as age, gender, histologic grade, histologic type, pathologic stage and alpha-fetoprotein (AFP). Time-dependent receiver operating characteristic (ROC) curve analysis was performed using the survivor ROC software [ 14 ]. Further, we developed the nomogram for the prediction of clinical outcomes for HCC patients [ 15 ].

Functional enrichment analysis

Functional enrichment analysis was performed as described in our previous study [ 16 , 17 ]. All HCC samples in the TCGA dataset were categorized into high and low expression groups based on the median expression level of POLH-AS1 as the cutoff value. The ‘edgeR’ software was utilized to detect differentially expressed genes (DEGs) in HCC tissue with low and high POLH-AS1 expression levels, meeting the adjusted criteria ( p  < 0.05 and |log2fold-change (FC)| > 1). Next, the DEGs underwent Gene Ontology (GO) analyses to identify the most significantly enriched biological functions. To determine the enriched signaling pathways, the DEGs underwent Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis [ 16 ].

Immune infiltration and immune checkpoint analysis

Immune infiltration and immune checkpoint analysis were conducted as described previously [ 16 , 17 ]. The Gene Set Enrichment Analysis (GSEA) was utilized to evaluate the immune infiltration cells linked to POLH-AS1. A study on immunity revealed marker genes for 24 distinct types of immune cells [ 18 ]. Using Spearman’s rank correlation, the relationships between POLH-AS1 and these 24 cell types were investigated [ 17 ]. Subsequent analysis of the relationship between POLH-AS1 and immunological checkpoints produced a statistically significant result ( p  < 0.05).

Cell culture

For the cell culture, we used a previously published protocol [ 16 , 17 ]. The Chinese Academy of Sciences (Shanghai, China) provided the HEP3B and HEPG2 human HCC cell lines, along with normal human liver cells (NCs). These cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 2 mM L-glutamine at 37 °C in an incubator with 5% CO 2 .

RNA extraction and RT-qPCR

The RNA extraction and RT-qPCR were administered as described previously [ 16 , 17 ]. RNA extraction from the specified cell lines and tissue samples was conducted using the RNA easy mini kit (QIAGEN, USA). GAPDH mRNA levels were utilized for data normalization, and the 2^(-ΔΔCT) method was employed for outcome quantification. The primer sequences are shown in table S2 .

Cell transfection

Small interfering RNA (siRNA) plasmid of POLH-AS1 and the negative control (si-NC) were packed from GenePharma (Shanghai, China). The full length of POLH-AS1 synthesized by GenePharma was subcloned into a lentivirus vector. HEP3B and HEPG2 cells were transfected using Lipofectamine ® 3000 (Invitrogen, USA) according to our previously published article and the manufacturer’s protocol [ 16 ]. The sequences of siRNA are shown in table S3 .

Cell counting kit-8 (CCK-8) assay

CCK-8 assay was performed to detect cell proliferation as previously reported [ 16 , 19 ]. In 96-well plates, the HCC cells were planted at a density of 3 × 10 3 cells per well. Next, 10 µL of CCK-8 solution was applied to the medium at 0, 24, 48, and 72 h, and it was then incubated for two hours. At 450 nm in wavelength, the optical density (OD) was measured with a SpectraMax i3x device. Then, a proliferation curve was produced using the absorbance values that were discovered at the 72-hour mark.

Transwell migration and invasion assays

Transwell assays were used to evaluate the migratory and invasive potential of HCC cells, as previously described [ 16 , 19 ]. The bottom chambers of the migration experiment were filled with 500 µL of culture media that contained 10% FBS. In the top chamber, 3 × 10 4 HCC cells were seeded per well using 250 µL of serum-free media. Swabs were used to extract the cells from the top compartment after 48 h. Using an Olympus microscope (Tokyo, Japan), the remaining cells were preserved with 95% ethanol, dyed with a 0.5% crystal violet solution, photographed, and the number of moving cells was counted. Before cell seeding, the filter for the invasion experiment was pre-coated with Matrigel (BD Biosciences, San Jose, CA, USA). The next steps were the same as for the migration test.

Wound healing assay

An assay of wound healing was conducted based on previous studies [ 16 ]. In 6-well plates, cells were seeded and cultured until reaching confluence. A wound was then made in the center of the plate using pipette tips, followed by a switch to a serum-free medium. After 48 h, images were captured, and the closure of the wound was subsequently assessed.

Statistical analysis

Statistical data analysis was conducted using R software version 3.6.3. A comparison of the variations in POLH-AS1 levels among the two groups was performed utilizing Fisher’s exact test, Mann-Whitney test, and Chi-square test. The Wilcox or Kruskal test was utilized to evaluate the relationship between POLH-AS1 levels in patients with HCC and their clinical information. The Kaplan-Meier technique was used to analyze survival. p  < 0.05 was deemed as the statistically significant threshold.

Features of HCC patients

The TCGA databases provided 374 RNAseq data sets of HCC patients with clinical resources including their age, histologic grade, histological type, pathologic stage, AFP, and vascular invasion. Clinical data is displayed in Table  1 .

The high expression level of POLH-AS1 in HCC tissues

Initially, we examined the expression levels of POLH-AS1 in various tumor tissues, utilizing data from TCGA. The analysis revealed that POLH-AS1 expression was elevated in several malignancies, with HCC showing particularly high levels compared to corresponding normal tissues (Fig.  1 A). As shown in Fig.  1 B and C, the RNA levels of POLH-AS1 in HCC tissues were consistently higher than those in normal liver tissues. Furthermore, we performed RT-qPCR on POLH-AS1 levels in eight individual HCC cases and their corresponding normal liver tissues. The qPCR results confirmed that POLH-AS1 expression was significantly higher in HCC tissues than in the matched normal tissues (Fig.  1 D).

The expression level of POLH-AS1 in different types of tumors. ( A ) The expression of POLH-AS1 between normal tissues and cancer samples in TCGA database. ( B ) The expression of POLH-AS1 in normal tissues and HCC tissues in TCGA database. ( C ) The expression of POLH-AS1 in 50 pairs of HCC tissues and non-cancerous adjacent tissues in TCGA database. ( D ) The expression of POLH-AS1 was assessed in 8 HCC tissues and 8 normal liver tissues by RT‑qPCR assay. * p  < 0.05, ** p  < 0.01, *** p  < 0.001

The expression of POLH-AS1 correlates with clinicopathological characteristics of HCC

Utilizing data from the TCGA cohort, we explored the association between POLH-AS1 levels and various clinical factors, including histologic grade, histologic type, pathological stage, and AFP concentration. The analysis revealed that POLH-AS1 expression was significantly elevated in G3&G4 HCC compared to G1&G2 HCC (Fig.  2 A). Additionally, POLH-AS1 expression was higher in hepatocholangio carcinoma (mixed type) than in fibrolamellar carcinoma and hepatocellular carcinoma (Fig.  2 B). Furthermore, elevated expression of POLH-AS1 was observed in Stage III&IV compared to Stage I&II (Fig.  2 C). A positive correlation between POLH-AS1 expression and AFP concentration was also established, with higher POLH-AS1 expression observed in patients with elevated serum AFP levels (Fig.  2 D).

The correlations between POLH-AS1 expression and clinicopathological characteristics of HCC. ( A )-( D ) The relationship between the POLH-AS1 expression and the histological grade ( A ), histological type ( B ), pathological stage ( C ), AFP ( D ). ( E ) ROC analysis of POLH-AS1 expression shows promising discrimination power between normal samples and HCC tissues. ( F ) Time-dependent ROC curves and AUC values for 1-year, 3-year, and 5-year OS prediction. * p  < 0.05, *** p  < 0.001

Moreover, ROC curve analysis was performed to evaluate the diagnostic potential of POLH-AS1 in HCC patients. The findings demonstrated that POLH-AS1 possesses significant diagnostic value for HCC, as evidenced by an AUC value of 0.864 (95% CI = 0.823–0.906) (Fig.  2 E). Additionally, time-dependent ROC curve analysis revealed AUC values of 0.677, 0.624, and 0.608 for predicting 1-year, 3-year, and 5-year survival rates in HCC patients, respectively (Fig.  2 F), indicating that POLH-AS1 serves as a reliable prognostic marker for HCC survival.

High POLH-AS1 expression indicated poor prognosis in HCC patients

The prognostic value of POLH-AS1 in HCC was assessed using Kaplan-Meier survival analysis with RNA-seq data from TCGA. The findings revealed a significant inverse correlation between POLH-AS1 expression levels and overall survival ( p  = 0.005), disease-specific survival (DSS, p  = 0.011), and progression-free interval (PFI, p  = 0.015) (Fig.  3 A-C). Further univariate and multivariate analyses confirmed that POLH-AS1 upregulation is an independent prognostic factor in HCC (Fig. S1 A-B and table S4 ).

The relationship between POLH-AS1 and the survival of patients with HCC. ( A )-( C ) K-M survival analysis showing the effect of POLH-AS1 expression level on OS ( A ), DSS ( B ), and PFI ( C ) in patients with HCC in TCGA cohort. ( D ) Nomogram for predicting the probability of 1-, 3-, and 5-year OS for patients with HCC. ( E ) The calibration curves showing the concordance between the prediction by nomogram and actual survival

A nomogram model incorporating clinical characteristics was developed to predict overall survival rates for HCC patients at 1, 3, and 5 years (Fig.  3 D). Calibration curves were then used to evaluate the accuracy of the nomogram’s predictions, showing a strong concordance between the predicted survival rates and actual outcomes (Fig.  3 E).

Identification of DEGs and functional enrichment analysis

To explore the potential mechanisms of POLH-AS1 in HCC, we categorized HCC patients into high- and low-POLH-AS1 expression groups based on the median expression level of POLH-AS1. We identified 2,183 upregulated and 682 downregulated genes, applying the criteria of |log2FC| > 1 and adjusted p  < 0.05 (Fig.  4 A). The relative expression levels of the top 30 DEGs between the two groups are depicted in Fig.  4 B.

Identification of DEGs and functional enrichment analysis of POLH-AS1 in HCC. ( A ) Volcano plot of differentially expressed genes. Red and green indicated up-regulated and down-regulated genes, respectively (|log2 fold change (FC)| > 1 and p  < 0.05). ( B ) Heatmap showing the top 30 co-expressed differential genes in the POLH-AS1 low and high expression groups. ( C ) The bubble plot showing the GO functional enrichment analysis results (BP, biological process; CC, cellular component; MF, molecular function). ( D ) The bubble plot showing the results of KEGG enrichment analysis

To assess the functional significance of these DEGs in HCC, we conducted KEGG and GO enrichment analyses. GO analysis highlighted significant enrichment in processes such as organelle fission, ion channel complex formation, and passive transmembrane transporter activity (Fig.  4 C). KEGG analysis revealed enrichment in pathways linked to carcinogenesis, including herpes simplex virus 1 infection, neuroactive ligand-receptor interaction, cAMP signaling pathway, and proteoglycans in cancer (Fig.  4 D). These findings strongly suggest the involvement of these DEGs in the development and progression of HCC.

Examination of the relationship between POLH-AS1 and immune infiltration in HCC

Immune infiltration plays a crucial role in HCC progression and provides valuable insights for potential immunotherapies [ 20 ]. Utilizing the ssGSEA technique, we explored the correlation between POLH-AS1 levels and the presence of 24 unique immune cell populations within HCC. The results demonstrated that POLH-AS1 expression was significantly positively correlated with Th2 cells ( R  = 0.276, p  < 0.001) and T helper cells ( R  = 0.192, p  < 0.001). Conversely, POLH-AS1 expression was negatively associated with DCs ( R  = − 0.383, p  < 0.001), neutrophils ( R = -0.300, p  < 0.001), pDCs ( R  = − 0.286, p  < 0.001), and cytotoxic cells ( R = -0.285, p  < 0.001) (Fig.  5 A-B and Fig. S2 A-F). Additionally, we explored the relationship between POLH-AS1 and immune checkpoints. The analysis revealed a significant positive correlation between POLH-AS1 expression and several immune checkpoint molecules, including CD276 ( R  = 0.4, p  < 0.001), TNFSF4 ( R  = 0.37, p  < 0.001), TNFSF15 ( R  = 0.3, p  < 0.001), and NRP1 ( R  = 0.27, p  < 0.001) (Fig.  5 C and Fig. S2 G). Collectively, these findings suggested that POLH-AS1 expression is closely related to the immune microenvironment in HCC, potentially influencing tumor immune cell infiltration and the expression of immune checkpoints, which could hold significant implications for immunotherapy strategies in HCC.

The association between POLH-AS1 expression and immune infiltration in HCC. ( A ) The infiltrating levels of 24 subtypes immune cells in high and low POLH-AS1 expression groups. ( B ) The correlation between the 24 subtypes immune cells and POLH-AS1 expression level. ( C ) The correlation between POLH-AS1 and immune checkpoint genes. * p  < 0.05, ** p  < 0.01, *** p  < 0.001

Inhibition of POLH-AS1 impeded cell proliferation in HCC

To further investigate the role of POLH-AS1 in the initiation and progression of HCC, we examined its expression in HEP3B and HEPG2 cell lines. RT-qPCR analysis revealed a significantly elevated expression of POLH-AS1 in both HEP3B and HEPG2 cell lines compared to the negative control (NC) cells (Fig.  6 A). Subsequently, POLH-AS1 expression in HEP3B and HEPG2 cells was downregulated using small interfering RNA (siRNA), effectively silencing POLH-AS1, as confirmed by RT-qPCR analysis (Fig.  6 B-C). The results of CCK8 assays demonstrated that knockdown of POLH-AS1 significantly inhibited the proliferation of HEP3B and HEPG2 cells (Fig.  6 D-E), whereas overexpression of POLH-AS1 markedly promoted these cellular behaviors (Fig. S3 A-C).

Inhibition of POLH-AS1 impeded cell proliferation in HCC. ( A ) RT-qPCR analysis showing the expression of POLH-AS1 in two HCC cell lines (HEP3B and HEPG2) and a normal liver cell (NC). ( B )-( C ) RT-qPCR analysis showing the efficiency of si-POLH-AS1 transfection in HEP3B and HEPG2 cells. ( D )-( E ) CCK8 assays showing proliferation of HEP3B ( D ) and HEPG2 ( E ) cells transfected with control (si-NC) or si-POLH-AS1. Data are presented as the mean ± SDs. *** p  < 0.001

Suppression of POLH-AS1 hindered migration and invasion of HCC

Our study extended beyond the effects of POLH-AS1 on HCC cell growth to examine its role in cell migration and invasion. Transwell assays demonstrated that knockdown of POLH-AS1 significantly impaired the migration and invasion capabilities of HEP3B and HEPG2 cells (Fig.  7 A-D), while overexpression of POLH-AS1 markedly enhanced these cellular behaviors (Fig. S3 D-G). Additionally, wound healing assays revealed that knockdown of POLH-AS1 significantly reduced the wound closure rate in HCC cells (Fig.  7 E-H). Collectively, these findings provide compelling evidence that suppression of POLH-AS1 hinders the migration and invasion of HCC cells, suggesting that targeting POLH-AS1 may offer therapeutic benefits for HCC.

Knockdown of POLH-AS1 inhibited cell migration and invasion in HCC. ( A )-( D ) Transwell migration and invasion assays showing the migratory and invasive ability of POLH-AS1-deficient HEP3B ( A, B ) and HEPG2 ( C, D ) cells. Scales bar, 100 µM. The data are the means ± SDs. ( E )-( H ) Wound healing migration assays showing HEP3B ( E, F ) and HEPG2 ( G, H ) cell migration of control cells compared to POLH-AS1-depleted cells. Scales bar, 100 µM. Data are presented as the mean ± SDs. *** p  < 0.001

HCC is a common yet highly aggressive malignant tumor, often progressing silently and resulting in a grim prognosis for patients. Despite the availability of various treatment modalities, including radiation, chemotherapy, and surgery, each approach has its inherent limitations. Although multiple therapeutic options exist for HCC, the overall prognosis remains poor, with a 5-year survival rate of just 18% [ 21 ]. The urgent need for novel therapeutic strategies is underscored by the unfavorable prognosis, emerging drug resistance, and significant side effects associated with current treatments.

Recent research has revealed a significant correlation between altered lncRNA expression levels and poor prognosis in HCC, underscoring the potential of these biomarkers in predicting both diagnosis and prognosis [ 11 ]. These pioneering discoveries offer renewed hope for advanced HCC patients by opening new avenues for treatment. LncRNAs are crucial regulatory elements that influence cancer aggressiveness by modulating its progression, particularly in HCC. The depletion of oncogenic lncRNAs has been shown to induce apoptotic cell death and cause cell cycle arrest in HCC [ 22 ], whereas their overexpression substantially increases the proliferation of cancer cells [ 23 ]. For instance, researchers exploring immunotherapy for HCC have identified several lncRNAs that can predict patient prognosis [ 24 , 25 ]. From a selection of potentially significant lncRNAs, we have focused on POLH-AS1 to investigate its relationship with HCC and to assess its potential utility in predicting outcomes and guiding treatment strategies for HCC patients.

In our research, we found that POLH-AS1 was highly expressed in HCC and that this elevated expression was associated with more advanced clinicopathological features. Further investigation into the relationship between POLH-AS1 expression and the prognosis of HCC patients revealed that increased POLH-AS1 expression may be linked to poorer outcomes. Additionally, the results from univariate and multivariate analyses, ROC curve analysis, and Kaplan-Meier survival analysis all support the notion that POLH-AS1 can serve as an independent prognostic marker in HCC. Finally, we explored the functional relevance of POLH-AS1 in HCC progression, unveiling that its inhibition resulted in attenuated cell proliferation, migration, and invasion. In aggregate, our finding suggested that POLH-AS1 might be used as a potential prognostic factor that affected the prognosis of patients with HCC. However, the mechanism by which POLH-AS1 leads to poor prognosis of HCC is unclear and needs further investigation.

To explore the role of POLH-AS1 in the malignant progression of HCC, we performed a GSEA using RNA-Seq data from TCGA. GSEA is widely used to reliably uncover potential molecular mechanisms underlying specific genes involved in disease pathology [ 26 ]. Our analysis revealed significant enrichment of POLH-AS1 in pathways related to herpes simplex virus 1 infection, neuroactive ligand-receptor interaction, and cAMP signaling, all of which are known to impact the prognosis and treatment of HCC patients. Emerging evidence suggests that these pathways are critically involved in HCC tumorigenesis and progression [ 27 , 28 , 29 ]. For example, Lam et al. identified an efficient and safe herpes simplex virus type 1 amplicon vector for transcriptionally targeted therapy in human hepatocellular carcinomas [ 28 ]. Similarly, neuroactive ligand-receptor interaction has been shown to play a pivotal role in HCC cell proliferation and invasion [ 29 ]. Moreover, vasoactive intestinal peptide was found to induce apoptosis in hepatocellular carcinoma by inhibiting the cAMP/Bcl-xL signaling pathway [ 27 ]. These findings collectively indicate that POLH-AS1 may influence the prognosis of HCC through its involvement in these cancer-related signaling pathways.

A growing body of research has highlighted that immune infiltration, a key component of the tumor microenvironment, plays a crucial role in oncogenesis and tumor progression, as well as influencing the response to immunotherapy [ 30 ]. However, no studies had previously reported a correlation between POLH-AS1 and immune infiltration in HCC. In our study, we identified a negative association between POLH-AS1 expression and dendritic cells (DCs) in HCC. Previous research has shown that local ablation of hepatocellular carcinoma can activate dendritic cells, thereby inducing sustained anti-tumor immune responses and ultimately reducing tumor progression and recurrence [ 31 , 32 ]. This suggests that POLH-AS1 may promote HCC progression by impairing DC function. Moreover, we explored the relationship between POLH-AS1 expression and immune checkpoints, including CD276, TNFSF4, TNFSF15, and NRP1, discovering a significant positive co-expression correlation between POLH-AS1 and these immune checkpoints. Immune checkpoints are known as a class of immunosuppressive molecules that enhance the immune response against HCC [ 30 ]. These findings suggest that POLH-AS1 plays a role in the tumor immune microenvironment primarily by regulating DCs function and immune checkpoints, and that POLH-AS1 may influence patient prognosis by modulating the immune microenvironment in HCC.

Nevertheless, our study has certain limitations. Firstly, the sample data were exclusively sourced from TCGA databases, with no clinical information from external cohorts to validate the findings. Additionally, the molecular mechanisms through which POLH-AS1 affects HCC growth, migration, and invasion remain inadequately elucidated. Further investigation into the regulatory mechanisms of POLH-AS1 will be pursued both in vivo and in vitro.

Our investigation showcased the potential of POLH-AS1 as both a prognostic determinant and a viable target for therapeutic intervention in HCC patients. A deeper comprehension of its impact on cell growth regulation could pave the way for clinical innovations aimed at enhancing the prognostic outlook for individuals with HCC.

Data availability

Data information from this research is available in the TCGA repositories (http://cancergenome.nih.gov) and UCSC Xena (http://xenabrowser.net/datapages/) platform.

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Acknowledgements

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This work was funded by the Henan Medical Science and Technology Joint Building Program (no. LHGJ20190255).

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Yan Dong, Xinyi Chen and Shen Yang contributed equally to this work.

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Department of Hepatobiliary Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

Department of Gynecological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China

Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

Shen Yang, Yilong Fu, Liangyu Wang & Lixia Xu

Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Xueping Gao

Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

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LXX, YD, and XYC were responsible for designing the project and writing the manuscript. SY, DC and XPG downloaded and analyzed the data. YLF and LYW collected samples and processed the data. The final manuscript was reviewed and approved by all writers.

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Correspondence to Xueping Gao , Di Chen or Lixia Xu .

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Dong, Y., Chen, X., Yang, S. et al. Comprehensive analysis of POLH-AS1 as a prognostic biomarker in hepatocellular carcinoma. BMC Cancer 24 , 1112 (2024). https://doi.org/10.1186/s12885-024-12857-8

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Clinical and scientific review of severe and enduring anorexia nervosa in intensive care settings: introducing an innovative treatment paradigm

• Joseph A Wonderlich 1 , 2 ,
• Dorian R Dodd 1 , 2 ,
• Cindy Sondag 2 ,
• Michelle Jorgensen 2 ,
• Candice Blumhardt 2 ,
• Alexandra N Evanson 2 ,
• Casey Bjoralt 2 &
• Stephen A Wonderlich 1  

Journal of Eating Disorders volume  12 , Article number:  131 ( 2024 ) Cite this article

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Anorexia nervosa is a serious and potentially lethal psychiatric disorder. Furthermore, there is significant evidence that some individuals develop a very long-standing form of the illness that requires a variety of different treatment interventions over time.

The primary goal of this paper was to provide a review of treatment strategies for severe and enduring anorexia nervosa (SE-AN) with the particular focus on treatments involving hospital care. Additionally, we wish to highlight a contemporary approach to such care and provide qualitative reactions to this model from both staff and patients.

A selective and strategic review of the treatment literature for SE-AN was conducted for the current paper. Emphasis was placed on clinical or scientific papers related to hospital-based care. Additionally, staff who work on a specific inpatient eating disorder unit with a substantial treatment program for SE-AN, along with a number of SE-AN patients were surveyed regarding their experiences working on, or receiving treatment on the unit. Importantly, the staff of this unit created a specific treatment protocol for individuals receiving hospital care. The results of the highlight both advantages and challenges of a hospital-based protocol oriented toward emphasizing quality of life, medical stability, and a health-promoting meal plan.

While there is general inconsistency with the type of treatment that is best suited to individuals with SE-AN, this is particularly true for higher levels of care that rely on inpatient hospital units or residential treatment settings. This is a highly significant clinical topic in need of further clinical and scientific examination.

Plain English summary

Anorexia nervosa is a serious illness which often persists for decades. Treatments for persistent anorexia nervosa are not well defined and there is considerable debate in the field about appropriate types of treatment strategies for these individuals. Such clinical uncertainty is particularly noteworthy in terms of the most appropriate types of care for these patients when they are hospitalized, which happens relatively frequently. Greater efforts are needed to develop inpatient programs for SE-AN that take into consideration their unique clinical needs.

Anorexia Nervosa (AN) is a serious and potentially lethal psychiatric disorder that is most typically seen in girls and young women, with a lifetime prevalence of 2–4% [ 1 , 2 ]. While AN is rare in some countries (e.g., Africa and Latin America) it is most prevalent in Europe, North America, and Australasia. AN is considered one of the most lethal psychiatric disorders with a crude mortality rate of 5% per decade and a standardized mortality ratio of around 6 [ 2 , 3 ].

Prospective longitudinal studies have consistently identified a subset of AN patients who have long-standing eating disorders, characterized by minimal improvement and significant impairment over decades (e.g. [ 4 , 5 ]). However, there has been significant variability across studies in terms of rates of remission and recovery from AN. Eddy and colleagues [ 5 ], suggested that the longer the duration of follow up in such prospective longitudinal designs, the greater the rates of recovery. Steinhausen [ 6 ] reported that in studies with follow up to four years since index diagnosis, recovery was approximately 33%, while studies with follow-ups ranging from 4 to 10 years average 47% recovered, and studies longer than 10 years in duration revealed recovery rates over 70%. Robinson [ 7 ] examined the same literature and concluded that rates of recovery after 10 years seemed to be declining compared to follow-ups ranging from 4 to 10 years. Eddy et al., [ 5 ] suggest that studies beyond 20 years of follow-up are not only limited, but the findings are even more inconsistent. For example, Theander [ 8 ] reported outcomes over 33 years of follow-up with 76% achieving recovery. However, two other studies [ 9 , 10 ] found that approximately 20 years after an initial hospitalization, around 50% of the sample of AN individuals was recovered. Ratnasuriya [ 11 ] reported that 20 years after hospitalization only 30% of the patients had a good outcome. Similarly, a study with a large sample of individuals treated for AN revealed that the longer the duration of the eating disorder, the lower the chance of recovery [ 12 ]. These findings are further supported by a recent systematic review on the treatment of eating disorders that showed that 40% of AN cases had partial or no remission of symptoms [ 13 ].

However, another important longitudinal study, by Eddy et al., [ 5 ] relied on a well-characterized and regularly assessed sample of both individuals with AN and bulimia nervosa (BN) over 22 years. In this study, the authors found that at the end of the first decade of illness, approximately 31% of the individuals with AN and 68% of the individuals with BN were recovered. Thus, BN appeared to be a much more remitting illness than AN. However, approximately two decades after the initial diagnosis, there was significant proportional change. At this point, approximately 63% of the individuals with AN and 68% of the individuals with BN had recovered. Approximately half of those with AN who had not recovered in the first decade did recover in the second decade. Interestingly, the recovery rate of BN did not change significantly over that decade. Thus, the study by Eddy and colleagues [ 5 ] suggests that recovery from AN may continue for decades after onset, but importantly, well over a third of the AN sample continued to have very significant AN moving into the third decade of the illness.

During the timeframe when many of these longitudinal studies were being conducted, clinicians were actively attempting to outline treatment strategies for long-term, persistent, and minimally remitting AN. Wonderlich and colleagues [ 14 ] summarized these clinical strategies, which were wide ranging and infrequently tested empirically. Overall, the collection of strategies reflected the informed experience of clinicians who had treated numerous patients with long-standing AN and served as a repository of clinical wisdom accrued largely during the 80s and 90s. Numerous recommendations and suggestions from these individuals still inform contemporary treatment strategies for SE-AN, such as establishing clear guidelines, the value of a team-oriented approach, the importance of meaningful treatment collaboration, inclusion of the patient’s family, avoidance of aggressive change-oriented techniques, and the potential value of psychiatric rehabilitation models of intervention. Additionally, Williams and colleagues [ 15 ] described an integrated treatment program which included staff from hospital-based eating disorder program along with a community-based mental health rehabilitation team and demonstrated some degree of efficacy.

An important point in the treatment literature for long-standing AN was the randomized controlled trial conducted by Touyz and colleagues [ 16 ]. This study compared the efficacy of 30 outpatient sessions of an adapted form of cognitive behavioral therapy (CBT) to an adapted form of specialist supportive clinical management (SSCM). Both treatments had a modified primary focus on enhancing quality of life and promoting harm reduction, rather than weight gain and symptom reduction. Both treatments had excellent retention of participants, with attrition rates under 15%. Comparisons between the two treatments revealed minimal differences in outcome. Furthermore, secondary analyses found a series of meaningful predictors of good response and revealed that quality of the therapeutic alliance was associated with positive responses, broadly [ 17 ]. Thus, this study offers support for the treatment of SE-AN and developing treatments that optimize patient engagement.

Several other empirical studies preliminarily have examined the impact of evidence-based, shorter-term treatments on SE-AN. Some of these studies suggested that treatments, such as CBT appear equally effective when delivered to individuals with AN versus individuals with SE-AN [ 18 ]. Similarly, two studies found that duration of illness was not a significant predictor of the outcome in structured treatment such as CBT and MANTRA [ 19 , 20 ]. However, in another study, which relied on practice guideline-based treatments, there was a significant difference in outcome between early stage versus SE-AN patients. Specifically, the SE-AN patients were less likely to improve in areas of work and social adjustment than the early stage patients and the SE-AN patients were more likely to access intensive services following treatment [ 21 ]. There are an increasing number of empirical studies with SE-AN patients which could ultimately impact effective treatment deliveries, however at this point in time, the number of these studies remains relatively limited and frequently constrained by sample size issues. Thus, there is a significant need for additional strategies to be tested with individuals, displaying long-standing and serious forms of AN.

Wonderlich and colleagues [ 22 ] outline a number of innovative treatment strategies which have been tested, at least preliminarily, in individuals with long-standing SE-AN. They highlight that there are new behavioral strategies (e.g., exposure paradigms [ 23 ], habit-oriented interventions [ 24 ], cognitive remediation therapy [ 25 ]), along with novel pharmacologic interventions, (e.g., ketamine [ 26 ], and dronabinol [ 27 ]) which may have potential value in treating longer standing forms of AN. Additionally, there are brain stimulation interventions (e.g., rTMS [ 28 ], DBS [ 29 ]) which continue to be tested in individuals with SE-AN and show either reasonable tolerability or preliminary efficacy. Also, there are system-oriented strategies that are being looked at, such as stepped-care treatment models [ 30 ] and novel “self-admission” approaches [ 31 ] to inpatient care. Again, preliminary data suggests these strategies may have value.

However, despite these newer developments, we agree with the general idea that the lack of understanding of SE-AN and the associated dearth of treatments represent a serious deficit in the eating disorder field. Moreover, we believe that this dearth of empirically supported treatments for SE-AN patients is even more of an urgent situation for higher levels of care in hospital based and residential treatment settings as many of these patients repeatedly utilize a higher level of care. The primary aim of this paper is to highlight that empirically informed treatments for SE-AN patients are particularly limited in higher levels of care, such as inpatient units, partial hospitals, and residential treatment centers. Furthermore, we want to highlight the significance of this dilemma and the impact it has on SE-AN patients, and the clinical teams who attempt to treat them in these environments. In the next section, we will provide an overview of this situation and describe an innovative program, which has recently been developed based on clinical need and expertise, to provide quality care for SE-AN patients and also support the treatment teams who are attempting to provide the intervention.

Higher levels of care and SE-AN

Historically, there has been some debate about the most preferred treatment setting for patients with SE-AN. Some individuals clearly suggest that outpatient treatment is appropriate if medical stability is maintained [ 32 ]. However, Strober [ 33 ] advocates for inpatient hospitalization for SE-AN and suggests that comprehensive coordinated care is best provided in such a setting. Woodside [ 34 ] provides broad strategy for SE-AN patients when hospitalized, which happens relatively frequently. He notes that many SE-AN patients cannot realistically conceive of recovery but are interested in incremental improvements in their eating disorder. Others are interested in pursuing enhanced quality of life or improving their overall condition. He highlights the importance of collaborative goal setting that is realistic and tailored to each individual patient. There are no minimum standards for goals, virtually any change is promoted. Woodside does not provide high levels of detail about the operations of the program over the course of a hospital stay, but does conclude that there is an urgent need for increased dialogue about the issues regarding inpatient care and SE-AN.

Banford et al. [ 35 ] offer comments about the idea that eating disorder treatment programs, both outpatient and inpatient, often pursue treatment goals that are inconsistent with SE-AN patient motivation. Furthermore, many of these programs are oriented toward more acute cases of AN, often of younger ages than many of the SE-AN patients. Thus, the authors highlight the possible problems for SE-AN patients when they are in traditional eating disorder programs. They emphasize that when SE-AN patients are integrated into recovery focused partial hospital programs with younger, more acute patients, problems may emerge and they recommend that SE-AN patients are best treated in a separate program with individualized goals and interventions. They highlight that there are very few descriptions of SE-AN specific hospital units in the eating disorder literature, but note that such patients are frequently admitted. They highlight that in an ideal SE-AN hospital unit, goals might include harm reduction, improved quality of life, achieving stabilization, reducing medical risk and decreasing crisis hospital dependency. Overall, they highlight an approach that is characterized by clinical flexibility, creativity, and adaptability for higher levels of care for SE-AN.

A recent systematic review of treatment interventions for SE-AN suggests that hospital-based care for SE-AN is not well understood and varies significantly across studies [ 36 ]. The evidence suggests that inpatient treatment for SE-AN may have a beneficial impact on eating disorder symptoms, but the evidence is unclear about whether or not such gains are maintained. Importantly, however, the five trials that are included in this review relied on a heterogenous collection of treatment strategies for these patients. Some programs were clearly oriented around cognitive behavioral therapy (CBT) while others were only partly based on CBT. Some programs included well defined nutrition plans, while others did not. Some programs relied on antidepressants while others did not. The length of the programs varied significantly, ranging from 3 to 5 months, which is a substantial variation. We would suggest that the clinical variability reported across the hospital-based programs in this review is representative of hospital programs broadly that treat individuals with SE-AN. In fact, this review provides support for the fundamental argument in the present paper, that there is a need for increased scientific and clinical attention to treatment protocols for SE-AN at higher levels of care.

Considerations for developing a treatment of SE-AN in higher levels of care

The Sanford Eating Disorders Unit in Fargo, North Dakota, is one of a declining number of hospital-based eating disorder programs with inpatient, partial hospital and intensive outpatient programming in the United States. In this program, we provide care annually to approximately 250 patients ranging in age from early adolescence throughout the life span. Additionally, we are one of a limited number of programs that openly accepts public insurance in the U.S. As such, we regularly provide care to individuals turned away from other treatment centers due to high medical complexity or insurance policies not covered by other programs. Typically, these individuals display SE-AN. Over time, the unit has attempted to develop a humane and effective approach to care for these individuals. In the hospital setting, we were forced to grapple with several ethical questions, such as whether we should provide care focused on full-weight restoration for a given SE-AN patient, when there is evidence to suggest that this approach has not worked well with the patient previously. Alternatively, should SE-AN patients be allowed to be admitted to the hospital without an active weight restoration based treatment plan, given the long-term risks of premature death in SE-AN? Thus, we sought to develop a treatment program that provides medical stabilization, promotes quality of life, and retains the possibility that one could, in fact, recover after years or decades of serious SE-AN [ 5 ].

In developing a standardized treatment approach for individuals with SE-AN, addressing the challenges associated with hospital-based care for individuals who vary significantly in terms of their desire or ability to restore weight was crucial. The heterogeneity of individuals with eating disorders is a significant issue in general but is even more significant in the shared space afforded by hospital treatment units. Thus, the typical hospital program for eating disorders must try to develop clinical programming to accommodate a wide variety of individuals. This may become particularly challenging when we consider that there is marked variability in the age of patients, the number of previous inpatient treatment episodes, and the total length of time they have been treated. In the case of AN, hospital programs must provide treatment programming for first-episode patients who are often adolescents and have significant family involvement, as well as long-standing patients with AN who may be significantly older, without family support.

Furthermore, there may be significant differences among SE-AN patients in terms of the degree to which the primary focus should be on weight-based recovery, or one that prioritizes a goal of maintaining medical stability and promoting quality of life. Importantly, these significant differences may, at times, be complicated for treatment teams in the hospital who are actively promoting weight-based recovery in one patient and maintaining medical stability and quality of life, or palliative or hospice care in another. Clearly, the complexity of patient experiences in a hospital environment with shared treatment programming and physical space limitations between patients is noteworthy, and a significant challenge for clinicians.

Another challenge for hospital-based programs is the impact of such diversity of patient characteristics on the distribution of valuable clinical resources. Hospital staff must repeatedly, and frequently, make decisions about who will be admitted when there is an opening for care. Should the opening be allocated to more acute, recent onset cases of AN in teenagers versus individuals with long-standing AN who have been hospitalized multiple times and not established significant weight restoration?

Furthermore, as we have noted previously, all of this clinical diversity and complexity in the hospital environment is increased because there is no well-defined, structured intervention for individuals with SE-AN in the hospital setting. As a result, there is often confusion about whether treatment goals for such individuals should focus on weight-based recovery versus medical stabilization with enhancement of quality of life. There is also uncertainty about what treatment approaches may be beneficial to SE-AN patients. For example, in the hospital, what type of psychological intervention may be most beneficial for individuals with SE-AN? Should dietary interventions be modified for such individuals? What is the role of pharmacotherapy in the treatment of SE-AN?

Given these challenges, and the lack of any clear guidance in the literature, we created an active treatment program track for hospitalized individuals with SE-AN. Due to the need to capitalize on existing resources, the SE-AN track was developed entirely integrated within our traditional eating disorder inpatient program. This means that all patients, regardless of whether they are on the SE-AN track, take part in group therapy and eat in the dining room together. In an effort to reduce potential conflicts arising in treatment as a result of a mixed milieu, some adjustments to therapeutics and dining room rules were implemented. These are described in more detail below.

When developing the SE-AN track, our primary goal was to help our SE-AN patients improve their quality of life, primarily by reducing the duration and frequency of hospitalizations and creating a more personalized treatment approach. Second, we aimed to provide transparency between patients and clinical staff regarding the rationale and procedures for treating individuals with SE-AN. Third, we sought to establish a highly collaborative agreement early in treatment between a patient and clinical staff regarding structured goals to reduce future long-term hospitalizations. Fourth, we aim to actively engage with the patient regarding discharge planning at the start of treatment. The primary objectives of the program are to maintain gains established during the hospital stay, develop an outpatient treatment plan with explicit targets, and provide a clear understanding of the procedures utilized in the long-term treatment plan (which may include repeated short-term, return hospital visits).

A description of a SE-AN treatment program at a higher level of care

In deciding to change treatment outcomes for SE-AN patients in the hospital, it became crucial to re-examine the treatment approaches generally used on the unit, given that they were designed for traditional treatment targets (e.g., full weight restoration). Changes were made across almost all therapeutic modalities (e.g., psychotherapy, psychiatric interventions, and nutritional rehabilitation). For example, our goal was no longer primarily focusing on three to four pounds of weight restoration a week in the hospital. We wondered what this would mean for dietitians working with SE-AN patients or when determining the length of hospitalization. Furthermore, in a patient’s psychotherapy, if quality of life is the outcome being measured, what should a therapist focus on in a session? Though specific quality of life interventions were not clear in the existing literature, what became clear to our team was the need to reduce the length and frequency of hospitalizations. We did not believe that a high-quality life could be achieved moving from hospital admission to hospital admission. However, SE-AN patients also often require significant time and support from providers at higher levels of care due to their high medical acuity arising from complications of their SE-AN. Thus, any quality of life focused treatment for individuals with SE-AN at higher levels of care must find a way to reduce time spent in the hospital by the patients, while also providing them significant ongoing support. This perspective (i.e., reducing frequency and length of hospitalizations while supporting the patients) became an overarching goal across all aspects of the SE-AN program. Below, we outline the fundamental procedures for the program.

Admission procedures and initiation of SE-AN treatment

As previously stated, one of the primary goals of the SE-AN program is to provide transparency and collaborative goal setting between patients and clinical staff. As such, discussing the SE-AN program goals should be started immediately, but not prescriptively. We believe the best approach for goal-setting is through collaborative formulation process among the treatment team and the patient, as this is one of the best ways to ensure adherence to treatment and improve clinical outcomes. Upon intake, patients are assessed as to whether they meet SE-AN criteria (e.g., duration of illness over seven years and multiple failed empirically supported treatment attempts) and their personal treatment goals are identified. Patients who meet these SE-AN criteria and express goals in line with improved quality of life and medical stability are informed of the SE-AN program. All new SE-AN patients are informed that their initial stay will be considered a brief evaluation stay of 2–4 weeks to achieve medical stability and assess readiness for the SE-AN program. During the first few days of the admission, patients meet with the provider to start an ongoing conversation about their therapeutic goals and receive psychoeducational materials about the SE-AN program. Patients are informed about the program’s guidelines, including working towards specific goals, SE-AN-specific interventions, length of stay, and discharge planning, all of which are presented below. If, at the end of the evaluation stay, the patient and team decide that the SE-AN program is suitable for the patient, the “ongoing admission” process is discussed. The details of the ongoing admission process will be described below. In short, this process ultimately allows the patient to return to the hospital on the SE-AN track for brief goal-oriented stabilization stays if they have adhered to their treatment plan for at least three months.

Treatment contract and goal setting

As noted by Woodside [ 34 ] collaborative goal setting that is realistic and tailored to each individual patient is crucial for treating individuals with SE-AN. While Woodside suggests that no goal is too small, we believe that at higher levels of care, goals must actively move the patient toward improved quality of life. Therefore, all patients with SE-AN in our program must set goals in three domains: quality of life improvement, ongoing medical stability, and maintaining a meal plan tailored to work with the patient’s goals (e.g., weight maintenance or varying degrees of weight restoration). Patients are asked to work with their treatment team in each domain to establish 2–3 measurable objectives that will help them move their lives forward. For example, a quality of life goal might be “going to get coffee once a week with a friend,” while an example of a goal to help a patient meet their meal plan requirements might be “establish appointments with an outpatient dietitian twice a month.” The treatment team retains measurable objectives created collaboratively to measure future progress and decide the suitability of continuing specific SE-AN programming for future admissions.

Furthermore, individuals with SE-AN often carry comorbidities that may be treatment-interfering (e.g., substance use, obsessive-compulsive disorder, post-traumatic stress disorder). If the treatment team, or patient, determine a patient’s comorbidities interfere with the SE-AN approach during the initial evaluation stay, additional goals must be set to address these ongoing issues either at the outpatient level of care or in a different treatment facility. For example, if a patient with SE-AN also experiences obsessive-compulsive behaviors, the patient and team must think through achievable goals (e.g., exposure and response prevention therapy or medication management) to reduce the impact on SE-AN treatment. These goals should be established with the treatment team and may range from traditional therapeutic interventions (e.g., exposure therapy or substance use treatment) to potentially more experimental approaches (e.g., repetitive transcranial magnetic stimulation [rTMS] or psychedelic-assisted psychotherapy) when indicated. The primary objectives regarding setting goals around comorbidities is to reduce treatment-interfering symptoms not directly related to the eating disorder outside the hospital and increase the likelihood an individual will be able to adhere to the treatment plan.

Another goal-related issue often pertains to step down and discharge planning. Following an inpatient admission on the SE-AN track, individuals may have the desire to step-down their level of care to a partial hospitalization program (PHP) or intensive outpatient program (IOP) to ensure a higher degree of aftercare compared to stepping down to outpatient therapy. As our primary goal is to improve quality of life outside of the hospital, our program has taken the stance that this is acceptable as long as there are specific, and clear goals that have been identified to work on while in the PHP or IOP. Additionally, we have occasionally utilized both PHP and IOP as the primary level of care for our SE-AN protocol; however, only for individuals who come to the hospital medically stable.

Specific interventions for SE-AN

Medical stability.

One of the immediate priorities of a SE-AN approach at a higher level of care is addressing the patients’ physical health and stabilizing any medical complications resulting from SE-AN. This includes addressing the various physical consequences of prolonged inadequate nutrition. Most crucially, medical experts should address issues such as cardiovascular complications, hypoglycemia, organ damage, electrolyte imbalances, and gastrointestinal distress that interferes with the ability to eat. While medication management of psychiatric comorbidities may also be necessary, the initial goal is to stabilize physical health so that there is a life remaining to improve.

Nutritional rehabilitation

An essential consideration for nutritional rehabilitation for individuals with SE-AN is the role of dietitians in the care team and developing simple, and achievable menu plans. While traditional goals, like improved diet variety, have been linked to sustained recovery following weight restoration treatments [ 37 ], the SE-AN program shifts away from what or how these patients eat, prioritizing only that they eat a sufficient amount. Thus, in collaboration with a dietitian, the SE-AN patient creates a meal plan based on foods they are already eating, described as “simple and doable.” While the dietitian works to ensure the patient meets their macronutrient targets (within what is possible given what the patient is willing and able to eat),, there is initially less concern about various food or meal challenges. Over time, if patients successfully adhere to their meal plan, they may choose to increase variety or do meal exposures during future SE-AN admissions. As has been discussed among our team while developing this program, some of these recommendations may challenge the traditional treatment targets utilized by dietitians in treating eating disorders. However, the concept of helping a patient find a meal plan to stabilize their weight and stop weight loss is a skill dietitians most likely already possess. Thus, this does not require extensive additional training. However, we encourage collaborative, and ongoing, discussions among the medical providers and the dietitians in determining various nutritional rehabilitation interventions, such as determining rate of increase in calories to stop weight loss while not destabilize the patient and potentially changes to the macronutrient breakdown of the diet to address medicals needs like treatment of edema. While many of the skills needed to treat SE-AN are already possessed by dietitians, specialized training for working with severely low-weighted, chronically-ill patients may want to be pursued by dietitians, or any of the team members, when it comes to how to best treat SE-AN patients nutritionally.

Another important consideration is how individuals with SE-AN utilize the dining room. Among providers, it has often been argued that the dining room is the most therapeutic intervention for individuals with eating disorders at a higher level of care. While this remains true for individuals with SE-AN, the dining room often serves a very different purpose. The primary function of the dining room is to support SE-AN patients who are trying a different eating model than what they have tried in previous treatments. For the treatment team, this might require changing the expectations in the dining room. For example, in our program, it is understood that patients with SE-AN may engage in some behaviors in the dining room that are often considered disordered. Rather than providing redirection for any eating disorder behavior (e.g., cutting food into small pieces, overuse of condiments), only behaviors that interfere with the patient’s ability to consume their expected nutritional goals (e.g., delaying the start of their meal until the last 5 min so that they are not able to finish their meal) receive redirection. Discussions between SE-AN patients and staff should be supportive, calming, and reassuring. Calm, kind, and reassuring non-verbal messages are also encouraged. Ideally, SE-AN patients should be able to complete their meal in food, given that the patient and dietitian agreed the meal was simple and doable, and that these patients are given only the amount of nutrition needed for medical stabilization and to support their own weight goals, which often means halting weight loss and stabilizing and maintaining current weight. However if a patient does not finish their meal in food, they are expected to consume the missed nutrition immediately following the meal via a liquid supplement. Repeated refusal of planned foods or supplements suggests that the patient is not able to utilize and benefit from the SE-AN program at this time, and calls into question the utility of future admissions under the SE-AN track. The team and the patient would collaboratively discuss expectations for treatment adherence and how nonadherence may decrease the likelihood of the patient being allowed to continue treatment in the SE-AN track.

As previously noted, one of the challenges of creating a hospital-based treatment for SE-AN is the potential interaction of these patients with other patients pursuing different treatment goals. While this might not be an issue in some settings, the dining room can often create a space of conflict between individuals on a traditional restoration plan and those on the SE-AN program. To reduce interference with patients on weight restoration programs, patients on the SE-AN program eat at a designated table within the dining room. These simple modifications are essential in dealing with the heterogeneity of the eating disorder patient population.

Psychotherapeutic interventions

Psychotherapeutic strategies for patients with eating disorders at higher levels of care, in general, are extremely varied, making decisions about psychotherapy interventions for individuals with SE-AN difficult [ 38 , 39 ]. Given that the goal of our SE-AN program is to promote quality of life and increase time outside of hospital units, we have shifted the programming towards values-oriented therapies [ 40 ] and skills-based distress tolerance interventions [ 41 ]. Acceptance and Commitment Therapy (ACT) techniques, like cognitive defusion and committed action, help patients deal with ruminative thinking, a hallmark of SE-AN, while pursuing valued goals following discharge from the hospital. Meanwhile, Dialectical Behavior Therapy (DBT) distress tolerance skills help SE-AN patients more effectively cope with the distress involved in changing eating disorder behaviors and resisting eating disorder urges, in order to approach valued personal goals, even when distressed. With these simple interventions, we hope to help patients increase their treatment motivation and adherence to the treatment plan. The hope is that this approach reduces the pressure on the patient and leads to greater hope and self-efficacy, as they take steps toward recovery in achievable ways, rather than having patients see recovery as an externally imposed goal that is also an insurmountable obstacle.

Additionally, conventional relapse prevention planning, consistent with Cognitive Behavioral Therapy (CBT), is also promoted to assist patients in adhering to clinical goals regarding relapse in the SE-AN program. An essential structural treatment issue is the need to strongly promote continued collaboration with the patient’s outpatient providers following discharge from the hospital program. Such ongoing collaboration is necessary for protecting gains made during the hospitalization.

Criteria for return visits and staying in the SE-AN program

Following discharge from a SE-AN hospital stay, patients are encouraged to immediately begin working towards the goals they set at intake to improve the quality of their life, adhere to their meal plan, and stay medically stable. If, after three months, the patient has been able to meet all of their goals, the patient should still be medically stable and have maintained their weight. Thus, SE-AN patients can return to treatment for 2–3 weeks to work on potential increases in their meal plan, maintaining their progress, or identify opportunities to enhance medical stability. However, patients who are meeting their goals and feel confident in their ability to continue doing so may choose to wait longer than three months before returning. If medically stable patients wait longer than three months, the expectation is still that they can return to treatment for short term stays if they have remained medically stable and have adhered to their individualized meal plan.

While the program aims to provide a more “doable” treatment option, it is necessary to recognize that there is less of a safety net with a maintenance intervention than a full-weight restoration treatment. The likelihood that there are slips, lapses, or relapses for individuals with SE-AN is still high. However, given the slower pace of treatment, getting back on track requires less effort than when relapse happens on traditional treatment approaches. Thus, the first step for any patient who slips on the SE-AN program is simply returning to their meal plan outlined at discharge. The patient-centered meal plan was created to be doable by the patient using foods they were already eating. Returning to the meal plan, the patient can maintain their current weight and potentially drift back to their discharge weight.

If a patient lapses and cannot maintain their weight, we may request that the patient delay return admission beyond three months and begin working to get back on track with their previous discharge plan to demonstrate that they can maintain their weight and stick to their meal plan outside the hospital. For patients unable to get back on track, we advise they seek treatment for medical stabilization. Once medically stable, if they can get back on track, the patient and treatment team must discuss whether it would be appropriate to return for continuation of the SE-AN program. Just as the creation of this program arose from the ethical considerations regarding continually trying unsuccessful full-weight restoration approaches with individuals with chronic anorexia nervosa, the SE-AN program must fall under the same scrutiny. For patients for whom the SE-AN program did not work, the treatment team and patient must carefully weigh the minimal potential for benefit of continuing in a treatment that has not proven to be effective, relative to the costs of continuing a treatment that is not working, as well as the missed opportunity of pursuing other potential treatments options. The treatment team needs to be willing to discuss all alternative options, including returning to weight restoration approaches or the initiation of palliative, or even hospice, care.

Staff and patient feedback

As reviewed above, there is a dearth of research on effective treatments at higher levels of care for patients with SE-AN. Furthermore, the heterogeneity of the limited existing research impedes the ability to meaningfully synthesize this work and translate it to clinical practice. Meanwhile, patients with SE-AN frequently request admissions for hospital care, and programs must decide, with little evidence to consult, how to best serve these patients. Absent empirical guidance or professional consensus on the best way to serve these patients, we believe that exposing higher levels of care treatment programs to professional scrutiny in order to prompt more in-depth discussion of treatment issues for this population would be beneficial. Additionally, without a generalizable understanding of hospital treatment for patients with SE-AN, program evaluations should be conducted within individual treatment programs to inform strengths and shortcomings of each specific program, from the perspective of the patients and staff. We recently began a quality assessment effort to elicit feedback on our program, in order to further refine and enhance the SE-AN treatment protocol. Below, we provide an overview of staff and patient feedback. Of note, this feedback was given as part of evaluation efforts for our particular program, rather than as part of a methodologically rigorous research protocol, and as such is not intended to create generalized knowledge about hospital treatment of SE-AN.

Staff feedback

Overall, staff feedback about the SE-AN treatment model has been quite positive. Staff responses consistently indicated that the SE-AN model seemed to give a sense of hopefulness for many patients, and provided a good opportunity for us to “meet patients where they’re at.” Staff acknowledged that this can be a last resort for patients without other options, who are deemed “too sick” or noncompliant and are thus turned away from many other programs. Staff also noted that the greater autonomy given to patients in SE-AN protocol is helpful for their treatment process and progress, and appears to contribute to an increase in effective collaboration between the patient and providers. Staff believe that patients find this approach to be more tolerable, which decreases patient resistance and defensiveness. Finally, staff appreciated being able to individualize treatment around identifying realistic goals for patients to achieve incremental change outside of the hospital, and felt that in this way they were helping to set the patients up for success rather than contributing to a treatment/relapse cycle.

Staff also noted challenging aspects of the SE-AN treatment model, and areas for improvement. Specifically, several staff noted that explaining this model can be difficult as some patients initially worry that providers are “giving up on them.” And although individualization of treatment is generally seen as a strength of the model (by staff and patients alike), staff note that this can also cause issues with consistency and clarity, and for some patients not in the SE-AN program, it can cause an increase in comparisons with others (e.g., patients questioning why other patients are allowed certain accommodations, but they are not). A third challenge noted was that some patients do not use the treatment model effectively. For example, doing it to placate family or outside providers by “doing treatment,” but without genuine collaborative intent, is inconsistent with the model. Finally, this model can lead to significant challenges when patients (and/or their families and outside providers) do not have a realistic understanding of the severity of and impairment from their disorder, which can cause disagreement between the patient and their team regarding what goals are realistic. For example, a patient who states they want to gain significant weight but is unable to adhere to even a maintenance meal plan while in the hospital, would be required to set a more realistic goal. Treatment staff indicated that patients can at times get fixated on the parameters of the SE-AN model, and consistently challenge the SE-AN model limits (e.g., on length of stay, being asked to set more realistic goals); working through this reactivity and conflict detracts from providers being able to more meaningfully work on the eating disorder itself and provide patients with the full benefit of this model.

Patient feedback

Overall, patient feedback has been positive, though somewhat more mixed than staff feedback. Generally, patient and staff feedback show good correspondence, with both groups noting similar strengths and weaknesses of the treatment model. On the positive side, patients voiced appreciation for the autonomy and individuality that this approach provided with regards to being able to tailor their goals to what is specific for them. Patients stated that they “felt heard” and that their team collaborated well with them. As one patient stated “I don’t need to have a 4-hour panic attack over…lasagna which I’m never going to eat outside treatment. It just made sense to me working on what I wanted to work on.” Patients described the program as “realistic” and “autonomy supporting” and “humane” because it is “not forcing something that’s not worked in the past. And it’s not forcing, like, the cookie cutter model on a person, because every person is unique.” One patient with a trauma history stated that being given autonomy over her own choices while being kept safe from her ED was like “nothing I’ve experienced before and I think so incredibly healing.” Another patient highlighted that “people with AN often desire a high need for control. This program helps give us some level of control while working on difficult recovery goals…. This is the first time where I feel like I am in control of my recovery. I’m no longer scared I am going to die. I am no longer going to the ER 1–2 times a week…. It really seems to be working.”

Some patients were conflicted on the theoretical approach to treatment. For example, one patient expressed appreciation that “skills are repeatedly used to help facilitate success on the outside” [outside the hospital], while another patient stated that “more of the process work could be utilized rather than skills over and over” because “if you’re on the SE-AN track you probably have learned that before and probably done those groups a million times.”

Patients struggled with the structure of the treatment model. Some stated that they “wish it was faster” though they know “this is the speed it has to be for me.” Patients also expressed a desire for even more individualization, though also acknowledged that it can be difficult to balance individualization and consistency. One patient stated that she has seen other patients “just messing around” and “not actually working…just doing your disorder in treatment.” So, while patients understand the need for structure and limitations, they tend to think those limits make sense in general and for other patients on the SE-AN model, but should be less rigid for themselves. Patients discussed feeling worried that they may not be allowed to return if they struggle and are unable to meet their goals in between hospital stays, which highlights the difficult balance between requiring patients to demonstrate that they are being helped by the treatment model (to ensure we are not enabling stagnation and continued disorder) while also making allowances for nonlinear recovery processes. Patients also expressed that the SE-AN model can feel limiting. One patient stated that as a result of the SE-AN treatment model she had “lower expectations for myself” and felt the “agenda for this stay was tainted by previous stays” and that “once labeled, no matter your willingness to move forward, regardless of want to go further, it’s shut down.” Several patients similarly commented that being “labeled” as SE-AN and being recommended to the SE-AN treatment model was originally hard as it made them feel hopeless and given up on, but that once the goals of this approach were more clearly communicated, they understood its value better. Finally, patients noted some concern about lack of community resources and understanding of this approach, with one patient stating “I am scared that other treatment programs won’t take an approach like this. It can also be hard to get my outpatient providers to understand the program.”

Staff and patient feedback takeaways

Overall, staff and patient feedback suggest that the SE-AN treatment protocol is beneficial in many ways, especially in providing a treatment option—one that has the potential to extend life and willingness to engage with treatment—for those who are “too sick” for other treatment or who feel they cannot tolerate or do not want full/traditional recovery. Areas for potential improvement have been highlighted. Specifically, further consideration should be given to balancing individualization with consistency and having clearer guidelines for when, and with whom, to hold rigid expectations and under what circumstances greater flexibility can be extended. It will be important to continue to develop better strategies to communicate clearly and collaboratively with patients around what being classified as SE-AN means and the potential benefits of the SE-AN model in a way that can instill hope rather than hopelessness. Also, greater attention should be paid to addressing patient dissatisfaction when they feel limited by the SE-AN model but may not be able or willing to do traditional treatment with full weight restoration. Finally, thorough integration of the SE-AN program with outpatient providers is critical, but it can be challenging to find outpatient providers who will accept patients with SE-AN and who will agree to work on the patient’s SE-AN goals rather than traditional recovery goals and weight restoration.

In summary, we have provided a brief overview of SE-AN both scientifically and clinically. We have also attempted to highlight the limited empirically supported treatment options for SE-AN, but wish to underscore that this dearth of treatment options is significantly pronounced at higher levels of care. Given the severity of SE-AN, it is a simple fact that these patients will often use hospital-based services, and thus, greater attention to this deficit is encouraged.

Our program developed a structured treatment program for SE-AN which highlights flexible goalsetting, high levels of collaboration between patient and clinical staff, and an emphasis on enhancing quality of life, medical stability, and adequate nutritional rehabilitation. Furthermore, the approach highlights the importance of tailoring treatment planning to a given patient and their collaboratively established goals. Explicit treatment contracts are developed with patients and include a shared understanding of targeted objectives. Additionally, there is a significant effort to develop a detailed plan for maintaining health and returning to treatment after discharge from the hospital. This may include future “booster” admissions for limited periods of time to assist patients in continuing to maintain, or incrementally advance, health related goal achievement. Presently, our survey of patients, and staff suggest that the program offers significant advantages for both the treatment team and the patient, but also the continued challenges that a program for SE-AN in a hospital environment must face. We would strongly recommend that clinicians and scientists work to establish empirically supported approaches to treating patients with SE-AN in a hospital environment. Given this is a necessary type of care for such patients and the very serious nature of this illness, it is worthy of such an investment.

Data availability

No datasets were generated or analysed during the current study.

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Wonderlich, J.A., Dodd, D.R., Sondag, C. et al. Clinical and scientific review of severe and enduring anorexia nervosa in intensive care settings: introducing an innovative treatment paradigm. J Eat Disord 12 , 131 (2024). https://doi.org/10.1186/s40337-024-01079-9

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Determining the minimum data set of geriatric assessment at the Iran primary health care referral system: shifting from fragmentation to integration care for older people

• Razieh Mirzaeian 1 , 2 ,
• Mohsen Shafiee 3 ,
• Mohammad Reza Afrash 4 , 5 &
• Hadi Kazemi-Arpanahi   ORCID: orcid.org/0000-0002-8882-5765 6  

BMC Health Services Research volume  24 , Article number:  1039 ( 2024 ) Cite this article

Metrics details

Geriatric assessment (GA) is a multidimensional process that disrupts the primary health care (PHC) referral system. Accessing consistent data is central to the provision of integrated geriatric care across multiple healthcare settings. However, due to poor-quality data and documentation of GA, developing an agreed minimum data set (MDS) is required. Therefore, this study aimed to develop a GA-MDS in the PHC referral system to improve data quality, data exchange, and continuum of care to address the multifaceted necessities of older people.

In our study, the items to be included within GA-MDS were determined in a three-stepwise process. First, an exploratory literature search was done to determine the related items. Then, we used a two-round Delphi survey to obtain an agreement view on items to be contained within GA-MDS. Finally, the validity of the GA-MDS content was evaluated.

Sixty specialists from different health geriatric care disciplines scored data items. After, the Delphi phase from the 230 selected items, 35 items were removed by calculating the content validity index (CVI), content validity ratio (CVR), and other statistical measures. Finally, GA-MDS was prepared with 195 items and four sections including administrative data, clinical, physiological, and psychological assessments.

Conclusions

The development of GA-MDS can serve as a platform to inform the geriatric referral system, standardize the GA process, and streamline their referral to specialized levels of care. We hope GA-MDS supports clinicians, researchers, and policymakers by providing aggregated data to inform medical practice and enhance patient-centered outcomes.

Peer Review reports

The aged population is growing faster than any other age group worldwide [ 1 ]. It’s estimated that by 2050, people aged 60 years or older will make up over 21.4% of the global population. This percentage is predicted to triple to more than 27.7% by the year 2100 [ 2 ]. This demographic shift is having a significant impact on developing countries, which are home to two-thirds of the world’s aging population. Iran is one such country where the population is shifting from youth to old age. Currently, 10% of Iran’s population is aged 60 or older, and projections indicate that by 2050, the number of people aged 65 and over will make up 31% of the country’s total population [ 3 , 4 ]. Population aging has negative impacts on the economy, society, and health fields [ 5 ]. This period of life closely contributes to a similar rise in the wide variety of chronic and costly diseases. Older people are hospitalized more frequently than other age groups, exposing them to iatrogenic diseases and leading to physical and psychological complications [ 6 , 7 ]. Declining health in older adults has been linked to functional disabilities, dependencies, and comorbidities. Additionally, psychosocial stressors such as loneliness, the loss of loved ones, loss of individuality, and changes in socioeconomic status can increase the risk of mental health issues in older people [ 8 ]. Therefore, it is crucial to address the health needs of this vulnerable group by considering their economic and social status and prioritizing the affordability of their healthcare should be the primary focus of health policymakers [ 9 , 10 ]. Given the high incidence of undiagnosed and untreated health conditions in older adults, it is necessary to establish an effective geriatric assessment (GA) plan [ 11 ]. GA involves identifying a list of health problems related to older people’s general health status, including comorbidities, functional, cognitive, social, nutritional, and psychological aspects [ 12 , 13 ].

Despite the broadly encouraged worth of preventive and promotive care, most healthcare systems still mainly focus on treating single diseases. This approach leads to inefficient, wasteful, and fragmented care for older adults, causing patient confusion, low participation in treatment, and even treatment faults [ 14 ]. Even within healing medicine, care for older people is facing a crisis, remarkable fragmentation, and aggressiveness of emergency care rather than thoughtful planning and effective care management. This fragmentation in service delivery impedes proactive, person-centered, and integrated care for older adults [ 15 , 16 ]. To overcome these problems, effective communication between primary health care (PHC) and specialist care is crucial [ 17 ].

PHC level serves as a gateway to providing healthcare services and has a determining effect on the economic and social progress of nations. Providing longitudinal, comprehensive, and coordinated care at the PHC level has a direct influence on public health and reduces the number of non-essential visits to healthcare settings [ 18 , 19 ]. However, PHC providers report a high volume of outpatient visits daily, making it impossible to allocate appropriate time for examining and performing a comprehensive assessment of older people’s health status [ 20 , 21 ]. Additionally, PHC providers are less equipped to manage complex clinical situations, so they need a system that simplifies the process of seeking help from experts or using higher-level resources for direction in the management of clinical events without shifting accountability [ 22 ].

In this regard, a referral system is a fundamental necessity for connecting primary care to specialty care [ 23 ]. The traditional referral system has several challenges that include the accumulation of errors in the next stages, the absence of a comprehensive and uniform referral system, the direct referral to medical centers by bypassing lower levels, which causes an increase in the burden of hospitals and disrupts service delivery, lack of expert and motivated workforce, failure to comply with the guidelines intended for an effective referral system, inadequate responsibility to control needless referrals at each level, and insufficient back referral system of trivial cases that come straight to the higher level [ 24 , 25 , 26 ].

These problems are partly due to the lack of a nationally agreed framework to guide the workforce to collect required data and perform documentation processes efficiently [ 27 , 28 ]. However, the current referral processes in Iran PHC are often paper-based and poorly documented. The data relating to older people has not been received by the next health settings [ 29 , 30 ]. Paper-based referrals are particularly difficult to track, information is regularly inadequate and does not encompass all important data required for the delivery of quality care. These referral methods are susceptible in the fragmented ambulatory environment where information is transferred between health centers physically [ 31 ]. To address these challenges, we developed a minimum data set (MDS) to standardize and improve the quality of GA data [ 32 , 33 , 34 ]. Having an agreed MDS enables the generation of nationally comparable and reliable data, regardless of how the data is gathered. It allows for consistent assessment across various authorities, organizations, and subdivisions, and encourages more efficient data gathering by reducing duplication of effort [ 35 ]. Hence, the objective of this study is to establish an MDS for this purpose. This MDS can serve as a foundation for developing a consistent referral system for older people throughout the primary healthcare system.

Study design

This study is a mixed-method investigation performed in 2023 in Iran. It utilized both quantitative and qualitative methods to design GA-MDS. First, a review of scientific and grey literature was conducted to extract potential data items related to GA. Then, a two-round Delphi survey was used to obtain the perspective of experts. Finally, two additional supplementary surveys were conducted to calculate the content validity ratio (CVR) and content validity index (CVI) of the final GA-MDS.

Literature review

As part of the literature review, scientific databases, including Web of Science, PubMed, Scopus, Google Scholar, Society for Information Display (SID), and MagIran, were searched to retrieve relevant data sources and data collection projects related to GA. The search utilized keywords such as “referral system”, “information system”, “primary care”, “registry system”, “data management”, “MDS”, “minimum data set”, “minimum dataset”, “required data set”, “core data items”, along with elderly-related terms (elderly, geriatric, aged, aging, senior, older age, older adults, older person, older people, older population, older individual, older patient) in individual or combined form. The search was conducted in English and Persian languages up until 2023, with no restrictions applied regarding the publication date. A systematic literature review was not conducted, and instead, a formative review was performed to extract possible data items. Additionally, grey literature, such as geriatric health websites and records, was reviewed until data saturation was achieved, where no new piece of data item emerged from the sources. Finally, relevant data points were extracted and compiled into a primary checklist, which was organized into four distinct sections: administrative, clinical assessment, body systems assessment, and psychology assessment items.

Delphi study

Following the preparation of the initial checklist in the previous step, a Delphi survey consisting of two rounds was conducted to identify the most significant data items among the primary extracted ones. The first and second rounds were held two months apart. During this period, the data collection tool was refined based on the feedback received from the experts. The same panel members participated in both rounds, and a 5-point Likert scale was used to evaluate responses. There is no standard agreement level for Delphi studies, but some suggest a threshold of ≥ 70% for each round [ 36 , 37 , 38 ]. In this study, an 80% agreement level was set for each item to be included in the GA-MDS. This means that items with an agreement level of less than 50% and a mean score of < 3.5 were excluded. Items with an agreement level of 50–79% and a mean score ranging from 3.5 to < 4, as well as any additional data items suggested by the expert panel, were evaluated in the second round. Any items with an agreement threshold of 80% or more were accepted in the first round [ 39 , 40 ]. In the second round of Delphi, the experts’ feedback and comments on the initial items from the first round were taken into consideration. The acceptance criteria for the data items remained the same as in the first round. Finally, the collected data was analyzed using SPSS 22 (SPSS Inc., Chicago, IL), and a statistical significance level of p -value < 0.05 was set.

Panel of experts

In Delphi surveys, a panel of 15–20 experts is typically used. However, we selected a sample of 60 experts to reduce errors [ 41 ]. The participants were selected using a purposive/non-random sampling method. The criteria for participation were as follows: (1) have sufficient expertise in the care and treatment of older people, (2) have more than three years of practical skill, and, if possible, have related scientific publications. The panel of experts comprised 60 participants, including psychiatrists, general physicians, gerontologists, geriatrics specialists, nursing geriatrics, community health nursing, cardiologists, urologists, neurologists, respiratory specialists, and epidemiologists was formed. The panel of experts used to develop and evaluate the MDS remained consistent across the Delphi phase and content evaluation. Specifically, the same group of experts participated in both stages of the process.

Evaluating the content validity of GA-MDS

To compute the ultimate multidimensional scaling MDS, we evaluated the temporal information of the initial MDS, utilizing the phases as the fundamental metric for analysis. During the Delphi phase of our study, we relied on the input of 60 panel experts to evaluate the MDS content. The data collection period for this phase lasted three months. Following the Delphi stage, a group of experts was tasked with assessing the content of the MDS using an initial checklist. To facilitate the evaluation process, the team enlisted the services of ten individuals, who were responsible for the collection of data in a blind manner. These individuals subsequently followed up on the return of the initial checklist to gather relevant information for further analysis. The MDS content validity was checked in the following steps:

The most commonly used way to measure an instrument’s content validity is the CVI calculation. The CVI can be calculated for each item on the instrument (known as item level-CVI or I-CVI) as well as for the instrument as a whole (known as the instrument level-CVI). To assess the CVI, experts rate each item based on its relevance or representativeness on a 4-point Likert scale ranging from 1 (not relevant or not representative) to 4 (extremely relevant or representative). The I-CVI is calculated by determining the proportion of experts who rated an item as 3 or 4, divided by the total number of experts. It is important to note that using the CVI as a measure of inter-rater agreement can lead to an inflation of agreement due to chance factors. To address this issue, Lynn has provided guidelines for the number of experts and the minimum number of experts who must agree with an item or instrument’s content to achieve an acceptable CVI, using the standard error of the proportion. So, the CVI evaluates the relevancy of the items to the main purpose of the instrument based on experts’ opinions. In the present study, the items selected from the Delphi survey were sent to the panel of experts, and they were asked to assign an importance value for the relevancy of items using a four-point Likert scale from not relevant to completely relevant. The CVI was calculated using Formula 1 . The acceptable value for CVI was considered 0.78% [ 42 , 43 , 44 , 45 ]. To eliminate this chance, Scale-CVI (universal agreement) and (average) were calculated. It is suggested that adequate S-CVI should be considered 0.8 to indicate content validity. (see formula 1 )

Kappa Statistic coefficient

The Kappa statistic is a widely recognized measure for evaluating inter-rater agreement. Yet, it does have its limitations, and the proportion of the agreement index is often deemed basic. In response to these shortcomings, the CVI was developed, which assesses inter-rater agreement based on relevance and non-relevance. The CVI has an edge over kappa and other inter-rater agreement measures that solely focus on relevance. To determine the CVI, one must first calculate the probability of chance agreement using a specific formula. The I-CVI is then calculated for each item, and the Kappa modified (k*) can be derived from the values of both the probability of chance agreement (Pc) (see formula 2 ) and the I-CVI. Several different standards have been proposed for evaluating kappa, including the Landis and Koch standard, which deems a value above 0.60 to be substantial, and the Fleiss Cicchttie and Sparrow standards, which suggest that a value of 0.75 or higher is excellent. The Kappa coefficient is an index that eliminates the possibility of chance agreement between several raters [ 46 ]. In our study, first, the likelihood of chance agreement was computed according to Formula 2 , where N indicates the number of experts and A is the number of experts who agreed that the item was relevant. Then, the Kappa coefficient was measured for each item according to Formula 3 . The evaluation for K* is that values greater than 0.74 indicate that the item was excellent; values between 0.6 and 0.74 mean good, and the K* values between 0.4 and 0.59 indicate that the item is fair.

One of the most reliable techniques for ensuring the content validity of an instrument is to gather a group of experts who can evaluate the relevance of each item. Among the many methods available for measuring content validity, the CVR developed by Lawshe in 1975 has gained widespread popularity. This approach involves asking experts to classify each item as “Essential,” “Useful, but not essential,” or “Not necessary.” The items that receive a critical mass of “Essential” ratings are retained in the final form, while those that fall short are eliminated. This process helps to ensure that the final instrument is both effective and reliable, providing accurate results. CVR shows the necessity of the items for operating a construct [ 47 ]. In our study, to measure the CVR, the experts were requested to score each item using a three-point Likert scale, where a score of 1 shows the non-necessity and a score of 3 shows the necessity of an individual item. CVR was calculated according to Formula 4 . In this formula Ne is the number of panelists representing “essential” and N is the total number of panelists.

Extracting potential data items related to the GA

After conducting an extensive search, a list of primary items was compiled under the guidance of a geriatric nurse and two HIM experts. These items were organized into a checklist and forwarded for validation through the Delphi survey. All the possible data items related to the GA process were extracted and a maximum of probable data items was determined. The initial set of items were classified into four classes in a checklist.

Participant characteristics

The panel of experts comprised 60 participants, including psychiatrists, general physicians, gerontologists, geriatrics specialists, nursing geriatrics, community health nursing, cardiologists, urologists, neurologists, respiratory specialists, and epidemiologists was formed. Table  1 shows the characteristics of the expert panel.

The present study employed a Delphi survey in two rounds to identify the important primary components of an initial checklist. The checklist comprised 256 items grouped into four categories. Panel experts kept 205 items in during the first round of the survey, while they rejected 51 items. They considered for inclusion but ultimately omitted, in the second round, five items. The outcome was a primary checklist of 200 essential items, as determined by the panel of experts. Table  2 provides an illustrative example of the Delphi survey results. After the completion of the Delphi phase, the MDS was formulated and made available for assessment. In the Delphi phase, the Wilcoxon test and Bonferroni correction were performed to reduce type I error and ensure the accuracy of the answer.

Checking validity

After the Delphi survey, selected items were sent to a panel of experts to calculate the CVI and 200 items were identified as relevant items. Table  3 shows the CVI of the cardiovascular examination items as a sample of GA-MDS. The S-CVI was also computed to remove the chances of agreement (Table  3 ).

CVR and modified kappa

CVR and kappa were computed for 200 items. Of them, 195 items remained and five items were removed. Table  4 demonstrates the CVR and kappa of each item of the cardiovascular examination class.

Final GA-MDS

After the literature review step, Delphi survey, and validation of content. The final platform of GA-MDS with 195 items was prepared. The MDS items in their final form can be referred to from Tables  5 , 6 , 7 , and 8 , which are presented in the appendix for reference.

In this study, the GA-MDS was developed with 195 items classified into four domains, including administrative, clinical (past medical history and vital signs), physiological, and psychological assessments. The administrative section contains socio-demographic data such as age, gender, residence status, economic level, and legal data, which can be used as a valued source to inform policy-making decisions about healthcare and other services demanded by the older population [ 48 , 49 ]. The clinical section of GA-MDS provides a comprehensive assessment of the older person’s body systems based on normal and abnormal changes. In the GA process, abnormal changes in the body are examined and the referral process of the older person to the next levels, i.e., medical specialists, is clarified. Studies have shown that chronic pain or discomfort, mobility impairments, and depression or anxiety significantly affect the well-being of older adults. Therefore, PHC providers must proactively address these concerns. To achieve this, PHC practitioners can conduct a comprehensive health assessment of older adults using the GA-MDS. With this thorough examination, PHC providers can accurately refer patients, administer appropriate treatments, and reduce the risk of disease-related complications in older adults [ 50 ]. The physical domain of GA-MDS contains data about overall physical assessment, nutrition status, independence status or activities of daily living (ADLs), malnutrition, and fall risk assessment. Frailty as an important syndrome of geriatrics is a state of clear vulnerability to stressful conditions such as diseases, etc., which leads to a gradual decrease in physiological functions during a lifetime. This syndrome increases the risk of mortality, morbidity, and falls. One of the most important ways to identify and reduce the amount of this syndrome in older people is GA [ 51 ]. In our developed MDS, it was tried to examine the degree of older adults’ dependence so that their referral can be done better. One of the most effective factors in the referral of older persons is cognitive problems and frail conditions [ 36 ]. Therefore, the developed MDS in our study contain such information, improve their referral, and on the other hand, help health policy making for better planning. Nutrition is another important factor that affects the aging process, the incidence of diseases related to old age, and the functional changes of the body in the aging process. Therefore, consistent collection and analysis of data related to the nutritional status of older adults can help improve and promote their health [ 52 ]. In the physiological section of GA-MDS, it is also possible to capture the data regarding nutritional status, the risk of falling, and dependency. In the referral process, older people depend on daily tasks that may disturb their correct referral [ 53 ]. Falling is the second cause of death and the first cause of trauma in the older adults and the primary cause of their hospitalizations. It causes irreparable complications such as mobility, mortality, and greatly increases costs [ 54 , 55 ]. So, using the present MDS developed in our study can assess the complications of falls in older people in the primary referral system.

In developing countries, mental disorders are common. For example, the rate of people with depression is 79–93% and the rate of people with anxiety is 85–95%. Many of these clients do not have access to proper treatment facilities. Therefore, WHO found it necessary to have an integrated program to assess patients in the primary referral system. However, there were some barriers to the implementation of this program such as the lack of an integrated information system and the lack of implementation in many areas of these countries [ 56 ]. So, the MDS designed in our study can provide a uniform system that assesses the physical and mental condition of the older adults at the primary level of referral in different regions of the country. Thus, it can solve the barriers to the implementation of the WHO program in developing countries to some extent.

So far, no MDS has been developed specifically for GA at the PHC level. However, some studies have developed MDS for other purposes for the older population. For instance, Lutomski et al. [ 57 ] developed an MDS survey for older persons and informal caregivers (TOPICS-MDS). This MDS has the advantage of gathering uniform data on a large sample of older persons and caregivers, and it also promotes data sharing between institutions. Abellan Van Kan et al. [ 58 ] developed an MDS for geriatric clinical trials. This MDS offers an opportunity for research in older people with appropriate outcome measures and significantly facilitates meta-analysis of relevant clinical trials. Soleimani et al. [ 32 ] developed an MDS for the information management system of aged care centers in Iran, which could be used to standardize data in aged care centers and improve the quality of care and services related to the older population. Massirfufulay et al. [ 59 ] and Jennifer et al. [ 60 ] also developed two MDSs for older people living in homecare centers. Our developed MDS represents the current scientific agreement view on GA across the PHC. It is a tool for capturing data related to the assessment of individuals aged 60 years and above. This instrument is designed to identify the key factors that influence their overall well-being. We envision that further development and use of this data set will foster collaboration between three levels of the care referral system, organizations involved in geriatric care, as well as researchers, and academic institutions. Significantly, the use of GA-MDS will contribute to streamlining the overall older adults referral process. It can address data requirements and furthermore enable data reporting purposes of the older adults referral system by lessening repetition of effort and enhancing data quality. It is expected that our developed MDS will show that standardization of clinical data and documentation will, in turn, have a great influence on providing geriatric care, clinical outcomes, and decrease older adults’ treatment costs and healthcare burden.

Globally, health policymakers, gerontologists, and other health authorities have long recognized the value of integrating minimal data gathering as part of routine management in healthcare organizations and hospitals as well as an instrument to reach standardized outcome measurements in clinical research [ 57 ]. Our developed MDS would not only have the inherent benefit of collecting consistent information on a large sample of older people but also promote data exchange between involved organizations. This MDS proposed specific patient data can then be shared to enable meta-analysis as well as serve as a source for external users. In this context, the GA-MDS was developed as a tool that not only collects information on older adults but also informs the decisions of policymakers and healthcare planners.

Our study has some limitations that need to be addressed. First, the primary literature search did not take a systematic method. However, we tried to review all the articles and documents available in the field of geriatric medicine to reach data saturation and find all the possible data items to enter into the GA-MDS. In addition, respondents were asked to suggest new data items that they felt were important but not included in the initial list. Second, although a multidisciplinary team, including physicians, allied health specialists, and pharmacists were requested to contribute, respondents were mainly geriatric nurses. In this study, to design MDS, various statistical methods and measures were taken to reduce the chance of error. In our study, GA-MDS was designed and developed because a standard core dataset is required to develop a uniform older adults’ referral information system. Therefore, in future studies, an external evaluation is suggested to refine some data categories.

The establishment of the MDS is a crucial first step in the development of an electronic referral system for GA in Iran. The proposed MDS will greatly simplify and standardize data capture in PHC settings, leading to higher data quality and streamlined referral processes. Health management professionals and policymakers will have access to this data set, which they can use to make informed decisions. The GA-MDS has been developed through a modified Delphi survey, specifically for geriatric medicine research. In the future, this MDS will enable the exchange and assembly of data across various organizations for individual patient data meta-analyses and secondary research analyses.

Data availability

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

Abbreviations

• Minimum data set
• Geriatric assessment

Content validly index

• Primary health care

Society for information display

Content validity ratio

Scale-level content validity indices

Universal agreement among experts

Primary Health Centers

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Acknowledgements

We thank the research deputy of the Abadan University of Medical Sciences for financially supporting this project. Also, we would like to thank all Experts who freely participated in this study.

There was no funding for this research project.

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Razieh Mirzaeian

Department of Modeling in Health Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran

Department of Nursing, Abadan University of Medical Sciences, Abadan, Iran

Mohsen Shafiee

Department of Artificial Intelligence, Smart University of Medical Sciences, Tehran, Iran

Mohammad Reza Afrash

Artificial Intelligence in Medical Sciences Research Center, Smart University of Medical Sciences, Tehran, Iran

Department of Health Information Technology, Abadan University of Medical Sciences, Abadan, Iran

Hadi Kazemi-Arpanahi

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HKA, MSH: Conceptualization; Data curation; Formal analysis; Investigation; Software; Roles/Writing - original draft. HKA, RM: Funding acquisition; Methodology; Project administration; Resources; Supervision; Writing – review & editing. HKA, MSH, MRA: Methodology; Validation; Writing – review & editing.

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Mirzaeian, R., Shafiee, M., Afrash, M.R. et al. Determining the minimum data set of geriatric assessment at the Iran primary health care referral system: shifting from fragmentation to integration care for older people. BMC Health Serv Res 24 , 1039 (2024). https://doi.org/10.1186/s12913-024-11498-8

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Evaluating fentanyl test strips as a harm reduction strategy in rural and urban counties: study protocol for a randomized controlled trial

• Ashley Short Mejia 1 ,
• Gary A. Smith 1 , 2 ,
• Soledad A. Fernandez 1 , 3 ,
• Bridget Freisthler 1 , 4 ,
• Christine Grella 5 &
• Nichole L. Michaels   ORCID: orcid.org/0000-0003-2618-6440 1 , 2  

Trials volume  25 , Article number:  587 ( 2024 ) Cite this article

Metrics details

Opioid-related fatalities are a leading cause of death in Ohio and nationally, with an increasing number of overdoses attributable to fentanyl. Rapid fentanyl test strips can identify fentanyl and some fentanyl analogs in urine samples and are increasingly being used to check illicit drugs for fentanyl before they are used. Fentanyl test strips are a promising harm reduction strategy; however, little is known about the real-world acceptability and impact of fentanyl test strip use. This study investigates fentanyl test strip distribution and education as a harm reduction strategy to prevent overdoses among people who use drugs.

The research team will recruit 2400 individuals ≥ 18 years with self-reported use of illicit drugs or drugs purchased on the street within the past 6 months. Recruitment will occur at opioid overdose education and naloxone distribution programs in 16 urban and 12 rural Ohio counties. Participating sites will be randomized at the county level to the intervention or non-intervention study arm. A brief fentanyl test strip educational intervention and fentanyl test strips will be provided to participants recruited from sites in the intervention arm. These participants will be eligible to receive additional fentanyl test strips for 2 years post-enrollment. Participants recruited from sites in the non-intervention arm will not receive fentanyl test strip education or fentanyl test strips. All participants will be followed for 2 years post-enrollment using biweekly, quarterly, and 6-month surveys. Primary outcomes include (1) identification of perceived barriers and facilitating factors associated with incorporating fentanyl test strip education and distribution into opioid overdose education and naloxone distribution programs; (2) differences in knowledge and self-efficacy regarding how to test drugs for fentanyl and strategies for reducing overdose risk between the intervention and non-intervention groups; and (3) differences in non-fatal and fatal overdose rates between the intervention and non-intervention groups.

Findings from this cluster randomized controlled trial will contribute valuable information about the feasibility, acceptability, and impact of integrating fentanyl test strip drug checking in rural and urban communities in Ohio and help guide future overdose prevention interventions.

Trial registration

ClinicalTrials.gov NCT05463341. Registered on July 19, 2022. https://clinicaltrials.gov/study/NCT05463341

Peer Review reports

The United States (US) is experiencing an opioid-related public health crisis. In 2021, Ohio ranked 7th among all states for the highest age-adjusted drug overdose death rate, 48.1 per 100,000 population, which was 48.5% higher than that of the overall US (32.4 per 100,000 population) [ 1 , 2 ]. This drug overdose fatality rate is driven by the use of opioids [ 1 , 2 , 3 ]. An increasing number of opioid-related deaths in the US are attributable to fentanyl, a highly potent synthetic opioid pain medication [ 3 , 4 , 5 ]. Illicit fentanyl and its analogs may be manufactured and sold alone or added to other drugs, such as heroin, cocaine, and counterfeit prescription pills, with or without the user’s knowledge [ 3 , 4 , 5 ].

The increasing pervasiveness of highly lethal fentanyl and fentanyl analogs in the illicit drug supply in the US, including Ohio, has posed a substantial challenge for public health officials looking for strategies to reduce overdoses. While some effective harm reduction strategies, such as opioid overdose education and naloxone distribution (OEND) programs, are becoming more available and widely accepted, they may not be sufficient for preventing overdose deaths due to fentanyl.

Rapid fentanyl test strips (FTS), designed to test for the presence of fentanyl and some fentanyl analogs in urine samples, are increasingly being used off-label to test illicit drugs for fentanyl before they are consumed and are highly sensitive and specific in detecting fentanyl [ 6 , 7 , 8 , 9 ]. Research indicates that when people who use drugs (PWUD) receive a positive result from a fentanyl test strip, they are more likely to perform overdose risk reduction behaviors [ 9 ]. These behaviors (e.g., using less of the drug; using in the presence of someone else) may help to prevent an overdose, or ensure that assistance is nearby, if needed. In the US, access to FTS for home use is variable and is primarily being supported by public health departments and community-based harm reduction organizations. Because access to FTS is limited, little is known about (1) the feasibility and acceptability of this intervention among public health workers, community-based organizations, and PWUD and (2) how outcomes from this intervention compare with OEND-only programs.

This study protocol is designed to test an intervention to prevent drug overdoses among PWUD in rural and urban counties of Ohio. Rural populations are disproportionately burdened by the opioid crisis and face serious health disparities related to their ability to access substance use disorder treatment and emergency care, making them an important population for this research [ 10 , 11 ]. The proposed intervention will incorporate FTS education and distribution into a subset of OEND sites in Ohio. The long-term goal of this research is the reduction of overdose-related morbidity and mortality in Ohio and nationally.

Study objectives and aims

The research objectives of this study are:

Determine the feasibility and acceptability of providing FTS education and testing materials distribution in existing OEND programs.

Determine if adding FTS education and distribution to OEND programs decreases opioid overdose rates among PWUD.

Using a two-arm cluster-randomized trial design, we will answer the research objectives by testing the following specific aims:

Specific aim #1. Determine the perceived barriers and facilitating factors associated with incorporating FTS education and distribution in existing OEND programs in rural and urban counties.

Specific aim #2. Test the hypothesis that PWUD who receive FTS education and testing materials as part of an OEND program will have improved knowledge and self-efficacy regarding how to test drugs for fentanyl and strategies for lowering their risk of an opioid overdose.

Specific aim #3. Test the hypothesis that individuals who receive FTS education and testing materials as part of an OEND program will have a lower opioid overdose rate than individuals who receive OEND only (“usual practice”).

Methods/design

Study setting.

Ohio has an established infrastructure to streamline OEND that can aid in opioid overdose prevention. In an effort to prevent opioid overdose fatalities in the state, the Ohio Department of Health has partnered with local public health departments and community organizations in the state to establish a network of OEND sites. The initiative, called Project DAWN (Deaths Avoided With Naloxone), has more than 200 sites throughout the state, with many counties having multiple sites ( https://odh.ohio.gov/know-our-programs/project-dawn/project-dawn-programs ). Project DAWN sites use trained overdose prevention educators to provide OEND at no cost to clients. Recruitment for this study will occur at Project DAWN sites in Ohio.

Eligibility

Inclusion criteria for the study are (1) age 18 years or older; (2) visitor to a Project DAWN site in Ohio that has agreed to participate in the study; (3) self-reported use of illicit drugs or any drugs purchased on the street within the past 6 months; (4) has a phone number or email address to allow for follow-up contact; and (5) able to participate in study activities in English. Individuals will be excluded from the study if they are unwilling or unable to give informed consent due to altered mental status or other reasons or if they are currently incarcerated.

Study recruitment

Study recruitment will happen on a rolling basis. Periodically throughout the recruitment period, our study partner, Ohio Department of Health, will send recruitment invitations to Project DAWN sites on our behalf. A stratified sampling process will be used to select 12 rural and 16 urban counties from among those with Project DAWN sites that indicate interest in participating in the study and that are not distributing FTS at the time of study enrollment.

Participating counties will then be randomized into the intervention and non-intervention arms of the study, stratified by rural/urban status (Fig.  1 ). Randomization will occur at the county level, and all Project DAWN sites in the same county will be assigned to the same study arm (either intervention or non-intervention). Therefore, all participants enrolled in the same county will be in the same study arm. County randomization will be conducted by the biostatistician on the project (SAF), without influence by study principal investigators (PIs) or staff.

Method of assignment of counties to intervention and non-intervention study arms

To achieve our recruitment goal of 2400 participants, study staff will be on-site to enroll Project DAWN clients who wish to participate in the study. Informed written or e-consent and baseline data, contact information (i.e., locator form), and demographics will be obtained. Project DAWN sites vary in size and operate according to different schedules, but generally provide OEND at least once per week, and frequently see clients more than once. Research study staff will coordinate with each site to ensure rotating coverage of all study counties. Enrollment will begin upon Institutional Review Board (IRB) approval and follow-up will continue with each participant for 2 years. Six-month follow-up questionnaires will be administered to each participating client based on their date of enrollment. Clients who decline to participate will not be included in the study. Individuals who decline to participate but indicate they are interested in obtaining FTS will be offered a printed list of alternate sources of FTS.

Intervention

Fentanyl test strip intervention.

A brief 20-min FTS educational intervention will be provided by the study team to participants at Project DAWN sites in the intervention arm of the study following enrollment and collection of baseline data (Table  1 ). The education will be offered one-on-one with participants in the intervention arm using a curriculum developed by the study team. The curriculum contains the following components: education on the purpose, benefits, and limitations of FTS testing; a hands-on demonstration of how to use FTS for drug testing prior to consumption; diagrams explaining how to interpret FTS results; and what to do if the FTS is positive. Education will be provided on how to use FTS for different drug delivery methods (e.g., injection, snorted, pills). A brief video will be developed by the study team to demonstrate how to use and interpret the FTS. The video will be shown during the educational intervention and will also be accessible to participants in the intervention arm following enrollment. Participants will be advised of the possibility of false positive/negative results, as well as the possibility that their drugs could be mixed with other harmful and/or unanticipated substances not detectable with FTS. Participants will be encouraged to practice other harm reduction strategies (e.g., having someone with them when using drugs, keeping naloxone nearby).

Each study participant will be given 10 FTS upon enrollment. The strips will be packaged with instructions on how to use FTS, a QR code link to the video, harm reduction strategies, and contact information for the study team. Replacement FTS will be available to study participants in the intervention arm upon request throughout their 2-year follow-up period and participants will be asked if they need additional FTS during their biweekly surveys. Replacement FTS can be mailed to participants via US Postal Service or obtained from study staff during subsequent visits to the Project DAWN sites.

Non-intervention group

Participants in the non-intervention arm of the study will not receive FTS education or test strips upon enrollment, but will receive OEND from Project DAWN staff according to their usual practice. During the latter half of year 5, after data collection is complete, participants in the non-intervention arm will be offered the FTS educational intervention and a supply of FTS.

Data collection

Questionnaires.

Baseline and 6-month follow-up questionnaires will consist of true/false knowledge questions, 5-point Likert scale attitude and self-efficacy questions, and multiple-choice questions related to participant behaviors and characteristics. Participants will be asked to indicate their degree of interest in using or avoiding drugs containing fentanyl. Baseline questionnaires will be administered to Project DAWN clients who enroll in the study using iPads and the REDCap (Research Electronic Data Capture) data collection platform. Follow-up questionnaires will be administered at 6 months post-enrollment to study participants via email/text, in-person at Project DAWN sites, or via telephone. Data from paper questionnaires will be entered into REDCap by the research team upon completion and double-entry verification will be used.

Qualitative data

In the second quarter of year 5, qualitative data will be collected through interviews with Project DAWN personnel in the intervention arm to examine the feasibility and acceptability of offering FTS at Project DAWN sites. Topics of discussion will include (1) attitudes about the use of FTS; (2) perceptions of the FTS intervention that was offered at their Project DAWN site, including perceived benefits and harms; (3) barriers and enabling/reinforcing factors related to offering FTS at Project DAWN sites; and (4) interest in continuing to offer FTS at Project DAWN sites. Interviews will be conducted by study staff using an interview guide and will be audio recorded and transcribed. Coding and analysis of the transcripts will be conducted by the study team.

Statistical analyses

Study data will be analyzed using an intention-to-treat approach.

Specific aim #1: To determine the feasibility and acceptability of incorporating FTS education and distribution into existing OEND programs, a questionnaire will be administered to Project DAWN personnel, site supervisors, health commissioners, and other key intervention site personnel in year 5. Project DAWN clients in the intervention arm will be asked about the acceptability of the program as part of their 6-month follow-up questionnaire. Process measures will be collected throughout the study as another source of data on the feasibility and acceptability of the intervention. Quantitative data on process measures will include, but is not limited to, number of Project DAWN sites that express interest in participating in the study; number of Project DAWN sites that enroll; number of potential participants who request to enroll in the study; number of participants successfully enrolled; number of replacement FTS requested and distributed; proportion of participants who complete the brief biweekly surveys; and the proportion of participants who complete the 6-month follow-up questionnaire. Descriptive statistics will be calculated, including overall mean estimates with 95% confidence intervals. Analyses will also be performed by subgroups (e.g., rural/urban, Project DAWN site personnel/client, and demographic subgroups).

Specific aim #2: Measures will be taken at two time points (baseline and 6 months) to test specific aim #2. The instrument to test change in knowledge is composed of true/false items. Correct responses for each of the items will be assigned a value of 1, and incorrect responses will be given a value of 0. Total scores will be calculated. There are also items to test changes in attitudes and self-efficacy that use a 5-point Likert scale. We will also compute total scores for these items. We will fit a linear mixed model using total scores for knowledge as the response variable to test change in knowledge and will fit another linear mixed model using total scores for attitudes/self-efficacy as the response variable to test change in self-efficacy.

Random effects for county (rural/urban), Project DAWN site within county, and participant within county will be included, as well as fixed effects for time (baseline or 6 months) and treatment (intervention/non-intervention). A random variable for secular time will also be included to account for changes across time (e.g., new opioid overdose prevention initiatives, changes in drug supply). To test the hypothesis of change differences between the two time points between the two arms, we will include an interaction term “treatment × time (baseline, 6 months)” in the model. This model will include demographic variables (gender, age, and race) and other relevant covariates or confounding factors, such as education level completed, employment, previous receipt of FTS education and testing materials (Y/N), and previously experienced an overdose (Y/N). Other relevant interaction terms, such as “treatment × gender” and “treatment × race,” will be evaluated. Holm’s method will be used to adjust for ad hoc multiple comparisons. In addition, general linear mixed models (GLMM) with a logit link function will be used to study change differences for specific Y/N items or questions.

Specific aim #3: Non-fatal overdose measures will be taken every 2 weeks and fatal overdose measures will be taken quarterly to test specific aim #3. To study the odds of an experienced overdose (Y/N), a GLMM with logit function will be used. This model will include the same random and fixed effects as identified for the model used to test specific aim #2. At the end of the study period, the overall non-fatal overdose rate (with a 95% confidence interval) will be compared between intervention and non-intervention arms. The same comparison will be done separately for the overall fatal overdose rate (with a 95% confidence interval) between the intervention and non-intervention arms.

Missing data

The analyses will be conducted using an intention-to-treat approach. For the primary and secondary outcomes, every effort will be made to minimize missing data; however, in the event that data are missing, we will document the process that resulted in the missing data and consider model-based imputation methods to account for the missing data. Guidelines for handing missing data in clinical trials will be followed [ 12 ].

Sample size

We expect an enrollment rate of 65% of eligible participants and 30% attrition, a conservative estimate based on research with similar populations [ 13 ]. For the power calculations, we conservatively assumed one Project DAWN site per county. We also assumed that non-fatal overdose rates in the non-intervention and intervention groups are 20% and 10%, respectively, and the annual fatal overdose rate in the non-intervention group is 0.65% [ 14 ]. Based on our sample size calculations, we will enroll 1200 participants in each study arm for a total of 2400 participants. Assuming a 30% attrition rate, 840 participants in each arm will complete 2 years of follow-up, for a total of 1680 participants. This will permit detection of an effect size range of 0.3–0.4 for specific aim #2 and rate differences of 0.1 and 0.14, respectively, for non-fatal and fatal rates for specific aim #3, given the assumptions identified above.

Participant retention

Participant retention will be managed in a series of ongoing steps (Table  2 ). First, participants will receive “thank you” messages via email through an automated REDCap system or letter via US mail, if email is not available. Next, participants’ locator form contact information will be verified by the enrolling research assistant (RA) within 2 weeks of enrollment.

After this, participants will receive follow-up communication from the study team if they miss biweekly surveys or their 6-month survey. Participants receive automated reminders via REDCap every 3 days for up to four reminders for each biweekly survey via email or text, depending on the participant’s preference. Within 2 weeks of missing a second consecutive biweekly survey, RAs will send an email, call/voicemail, letter, and/or social media message depending on the participant’s preferences. Within 3 weeks of missing a second consecutive biweekly survey, the RAs will use the participant’s locator form to contact the participant’s friend or family. This process will be completed monthly until the individual has been successfully contacted or begins surveys. Participants also will receive automated reminders for the 6-month survey every 5 days with up to five reminders via their default survey delivery method through REDCap. Within 2 weeks of missing their 6-month survey, RAs will send an email, call/voicemail, letter, and/or message through social media. Within 3 weeks of missing the 6-month survey, RAs will use the participant’s locator form to contact the participant’s friends or family. This process will be completed for up to 2 months. Participants will also receive a participant newsletter and annual “New Year” and birthday cards.

Study timeline

We expect it will take approximately 24 months to enroll all study participants. After enrollment, study participants will complete follow-up activities for 2 years. Participants may choose to withdraw from the study at any time and will not receive further contact from the study team.

Data management

A Certificate of Confidentiality is in place for this study. Confidentiality will be promoted by assigning an identification number to each study participant. We will use only these identification numbers (and not participants' names) in the database used for study analyses. Study materials containing identifiers, including signed consent forms and gift card receipts, will be scanned and then paper copies will be shredded. Research records will be stored in a password protected computer file. Only study team members with a research need to view the data, appropriate research certifications, and IRB approval will have access. Identifiable data will be retained for 6 years after the research is complete. Upon acceptance of all study manuscripts, any electronic files with participant identifiers will be deleted.

The study team consists of two principal investigators who collaborate closely to oversee the day-to-day work of the study team and are responsible for all aspects of this research, as well as 3 co-investigators, a research coordinator, and 4 research associates. Study co-investigators assisted the principal investigators with the development of study protocols and processes in year 1 and contribute their expertise as needed throughout the study. The research coordinator oversees the implementation of participant recruitment, retention, and consent processes as well as data collection procedures conducted by the research associates. A principal investigator meets with the research coordinator at least weekly and meets with the research associates at least biweekly. The study also utilizes a community advisory board that consists of representatives from non-profit organizations active in the harm reduction community, representatives from government agencies, such as health departments and mental health services, and individuals with lived experience of drug use. The advisory committee meets approximately every 6 months.

Data safety and monitoring

A data safety and monitoring board (DSMB) will be used for this study. Collectively, the DSMB has expertise in medicine, harm reduction, behavioral science (including qualitative research expertise), biostatistics, and public health. The DSMB will review study protocols to identify whether appropriate safeguards are in place to prevent adverse events, such as fatal drug overdoses, and to determine whether the observed frequency and type of events exceed those expected in the study population. The DSMB will review the frequency of adverse events reported among intervention and non-intervention participants to identify any unanticipated problems that may increase the risk of harm among study participants or others and will make recommendations for additional safety measures, or in the case of severe unanticipated negative outcomes, stopping the trial. The DSMB will meet twice a year to review study progress and may convene additional meetings as necessary. Further details about the DSMB charter are available upon request.

Dissemination of study findings

Study findings will be shared with study participants and partnering Project DAWN sites. This study is registered on www.ClinicalTrials.gov , and summaries of study findings will be available on the website upon study completion. Study findings will also be shared through publication in peer-reviewed journals and presentation at scientific meetings and conferences. Publication authorship will be determined using International Committee of Medical Journal Editors guidelines.

Because opioid overdose is a tremendous problem in Ohio and nationally, more studies on the primary and secondary prevention of overdose are needed. Collaborating on this research project with public health officials at the state and local levels, as well as community-based harm reduction organizations, will give us insight into the real-world benefits, challenges, and unanswered questions associated with implementing FTS education and distribution programs and guide future studies.

We expect that the findings of this study will be used to inform decisions by public health leaders and policy makers on whether to support the continuation and expansion of fentanyl test strip education and distribution in Ohio. Using improved scientific rigor compared with previous research, the findings of this study will provide missing, fundamental information to our base of knowledge regarding the feasibility, acceptability, and associated benefits and harms of this emerging strategy for preventing opioid overdoses. In addition to Ohio, we believe that this program could serve as a model for other states.

Trial status

Protocol version 5, approved on October 11, 2023. Study recruitment began on September 9, 2022, and is ongoing. We anticipate study recruitment will be complete by December 31, 2024.

Availability of data and materials

The study PIs will oversee the management of all aspects of this research study and will determine access to the final trial dataset. Unique study resources and data will be made available for research purposes to qualified individuals within the scientific community after publication. Upon written request to the study contact PI (NLM), de-identified data used in publications will be made available to users under a data-sharing agreement. Along with the data, we also will make available the data instruments used to collect the data, methods of collection, variable definitions, and potential limitations for use.

Abbreviations

• Fentanyl test strips

Data safety and monitoring board

General linear mixed models

Institutional Review Board

Opioid overdose education and naloxone distribution

Principal investigator

Project Deaths Avoided With Naloxone

People who use drugs

Research assistant

Research Electronic Data Capture

United States

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Acknowledgements

We would like to thank our colleagues Alexandra Antonova, Aleah Cumberbatch, Jacob Holycross, and Spencer Long for their contributions to this research.

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number R01DA052580. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in the design of this study and will not have any role in the collection, management, analysis, and interpretation of data; writing of the report; or decision to submit the report for publication.

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Ashley Short Mejia, Gary A. Smith, Soledad A. Fernandez, Bridget Freisthler & Nichole L. Michaels

Department of Pediatrics, College of Medicine, The Ohio State University, 370 W. 9th Avenue, Columbus, OH, 43210, USA

Gary A. Smith & Nichole L. Michaels

Department of Biomedical Informatics and Center for Biostatistics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA

Soledad A. Fernandez

College of Social Work, The Ohio State University, Columbus, OH, 43210, USA

Bridget Freisthler

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ASM led manuscript preparation. The research was conceptualized and the original study protocol was developed by NLM, GAS, and SAF. All authors provided feedback on the manuscript and approved the final draft of the manuscript for publication.

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Correspondence to Nichole L. Michaels .

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Ethics approval and consent to participate.

The Nationwide Children’s Hospital Institutional Review Board has given ethical approval for this study (STUDY00001919). Any modifications to the study protocol are subject to approval by the IRB of record. Relevant modifications will be reported to the trial registry and other parties as necessary. Informed consent will be obtained from all study participants according to the IRB-approved study protocol. The consent process will take place on-site at the recruitment location and will be completed prior to any data collection. At the time of enrollment, a member of the research team will review the contents of the informed consent document with the potential participant and answer any questions they may have prior to obtaining written consent via e-signature or paper consent form. Consent will be documented in REDCap and a pdf file of the signed e-consent form will be emailed to the participant. If the participant does not have an email address, a paper copy will be signed and distributed to them. Paper consent forms will be used to obtain written consent in person at the time of enrollment only as necessary (e.g., due to technology failure). Participants will be able to leave the study or stop participating in study activities at any time.

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Competing interests

The authors declare that they have no competing interests.

As the primary organization conducting this study and associated data analysis, Nationwide Children’s Hospital is the sponsor of this research. They can be contacted at 700 Children’s Drive, Columbus, OH 43205, USA; phone number: 614–722-2000.

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Short Mejia, A., Smith, G.A., Fernandez, S.A. et al. Evaluating fentanyl test strips as a harm reduction strategy in rural and urban counties: study protocol for a randomized controlled trial. Trials 25 , 587 (2024). https://doi.org/10.1186/s13063-024-08440-y

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DOI : https://doi.org/10.1186/s13063-024-08440-y

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