difference between journal and research articles

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Understanding the Differences Between a Research Paper and a Journal

When it comes to academic writing, one of the most important distinctions that must be made is between a research paper and a journal. A research paper is an in-depth exploration of a specific topic; while journals are collections of articles on various topics relating to the same subject or field. Understanding these differences can help researchers ensure they’re using the right tools for their particular project. This article will outline key differences between a research paper and journal, as well as discuss how each type contributes to academia. Furthermore, it will provide examples of both types of work from several different fields in order to further explain how they differ in format, content and purpose.

I. Introduction

Ii. what is a research paper, iii. what is a journal, iv. types of journals and their purpose, v. differences between a research paper and journal, vi. benefits of publishing in both mediums, vii. conclusion.

As the ever-increasing population of researchers continues to generate vast amounts of knowledge and data, there is a growing need for reliable storage solutions. The research paper , which has been used as an effective means of disseminating information since its emergence in the 19th century, provides a particularly pertinent solution. In essence, it allows scientists from all over the world to store their findings without having to worry about preserving physical copies.

• A research paper acts as an online repository that ensures critical data is not lost or misappropriated; instead it can be referred back to by any interested parties at any given time.

A research paper is a form of academic writing that presents an argument or analysis based on the author’s original research. It typically follows a particular format and structure, which is designed to help readers locate specific pieces of information quickly. The main sections are often titled Introduction, Literature Review, Methodology, Results and Discussion.

Research papers can be written about virtually any topic imaginable but they generally center around literature reviews that include other scholarly work in the field such as journal articles or books. These documents also analyze data collected from surveys and experiments conducted by the author in order to provide evidence for their thesis statement. Additionally, some research papers may incorporate theoretical elements into their discussion section where philosophical concepts are discussed in relation to the findings presented earlier in the document.

• Is Research Paper A Journal?

No – while both types of documents aim to present knowledge within certain subject areas, journals tend towards shorter length content with more broad-reaching themes while research papers usually contain longer lengths with deeper levels of analysis pertaining to a specific area or topic. Furthermore, most journals do not require authorship credit whereas research papers almost always list authors’ names along with references at the end since its contents will serve as primary sources used by future researchers studying similar topics

A journal is an invaluable tool for academic research, allowing scholars to keep track of their work in a systematic and organized way. Journals are typically composed of multiple volumes or issues that each contain different articles related to the same subject matter.

• Periodicals : These journals may be published monthly, quarterly or annually depending on the type of content they focus on. They often cover topics such as news, politics and culture.
• Scholarly/Peer-Reviewed Journals : These publications specialize in scientific literature and other areas requiring advanced degrees. Authors have to submit their papers for peer review before publication.

Scholarly journals are a key resource for researchers to understand and share their findings. Journals come in many shapes and sizes, each with its own purpose.

• Peer-reviewed: These publications have gone through the scrutiny of academics who check the validity of content before it is published. They range from scientific research papers to essays or reviews on topics like literature or philosophy.

The goal of peer-reviewing journals is to keep information accurate and trustworthy by eliminating errors as much as possible. It also helps ensure that readers can rely on the material found within these types of journals.

• Non-peer reviewed: These publications may not be subject to an academic review process, but they do provide valuable perspectives related to specific fields such as history, economics, technology, etc. Some examples include magazines and trade publications containing interviews with experts in various industries.

Is a research paper considered a journal? Yes! Research papers often undergo some form of peer review before being accepted for publication – whether via online submission systems or traditional print publishing models – thus meeting the criteria necessary for them to be classified as scholarly journals. .

Exploring the Nuances

When it comes to academic writing, there are some distinctions between a research paper and a journal. To start with, while they both involve researching an issue in depth, their ultimate purpose differs. A research paper is meant to present original findings on a particular topic that have been gathered from different sources of information; its goal is usually to make new contributions or expand upon existing knowledge within its field of study. On the other hand, journals are intended for publishing comprehensive reviews on topics covered by experts in the field that summarise what has already been established so far – as such, they focus more heavily on disseminating current trends and developments than expanding them further.

The Details

In addition to this general divergence in overall aims and purposes between these two genres of writing, several structural differences can be identified. Generally speaking, research papers tend to be shorter than journals; moreover, unlike published articles which may feature sections such as introduction/background material & methodology before leading into conclusions about their central hypotheses or theories — most research papers will go straight into presenting evidence-based discussion followed by conclusion section without any referenceable materials throughout body content apart from cited works used previously in referencing mentioned ideas. Lastly it should also be noted here that ‘is research paper a journal?’ does not quite fit contextually either since even though traditionally both refer largely towards same domain viz., academics but generally differing levels of complexity across specific aspects definitely exist therein!

Publishing in both a research paper and journal has its advantages. First, publishing in either medium provides an opportunity to make one’s work accessible , allowing it to be seen by other academics and experts within the field. Additionally, publishing can create an avenue for dialogue among peers and colleagues about relevant topics.

Research papers serve as more comprehensive resources than journals . They typically provide authors with greater space for exploration of their ideas, so they are better suited to cover complex topics or those that require a deeper level of explanation. Journals on the other hand offer readers concise information—summarizing current theories or practices related to certain fields—which allows busy professionals quick access when researching new developments.

In conclusion, the research presented in this paper has determined that journaling is a useful and effective tool for dealing with negative emotions. Through self-reflection, individuals can better understand their feelings and learn to manage them more effectively. Journaling also provides an opportunity to engage in positive thought patterns, which leads to increased emotional stability and improved mental health outcomes.

The findings of this study suggest that those who use journals are likely to experience greater psychological well-being than those who do not. By engaging in reflective writing activities on a regular basis, people have access to powerful insights into their own thoughts and behaviors that they may otherwise miss out on if they rely solely on verbal communication or other traditional forms of therapy. Furthermore, since journaling is an inexpensive activity requiring no special training or equipment aside from pen/paper (or digital devices), it is accessible for all individuals regardless of resources available.

English: This article provided a detailed comparison between research papers and journals, presenting their respective characteristics, writing conventions, and importance in academia. Understanding these differences is essential for any student looking to hone their skills as an academic writer. With this knowledge at hand, students can approach any assignment with confidence in knowing how best to structure and compose the text for maximum effect.

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Types of journal articles

It is helpful to familiarise yourself with the different types of articles published by journals. Although it may appear there are a large number of types of articles published due to the wide variety of names they are published under, most articles published are one of the following types; Original Research, Review Articles, Short reports or Letters, Case Studies, Methodologies.

Original Research:

This is the most common type of journal manuscript used to publish full reports of data from research. It may be called an  Original Article, Research Article, Research, or just  Article, depending on the journal. The Original Research format is suitable for many different fields and different types of studies. It includes full Introduction, Methods, Results, and Discussion sections.

Short reports or Letters:

These papers communicate brief reports of data from original research that editors believe will be interesting to many researchers, and that will likely stimulate further research in the field. As they are relatively short the format is useful for scientists with results that are time sensitive (for example, those in highly competitive or quickly-changing disciplines). This format often has strict length limits, so some experimental details may not be published until the authors write a full Original Research manuscript. These papers are also sometimes called Brief communications .

Review Articles:

Review Articles provide a comprehensive summary of research on a certain topic, and a perspective on the state of the field and where it is heading. They are often written by leaders in a particular discipline after invitation from the editors of a journal. Reviews are often widely read (for example, by researchers looking for a full introduction to a field) and highly cited. Reviews commonly cite approximately 100 primary research articles.

TIP: If you would like to write a Review but have not been invited by a journal, be sure to check the journal website as some journals to not consider unsolicited Reviews. If the website does not mention whether Reviews are commissioned it is wise to send a pre-submission enquiry letter to the journal editor to propose your Review manuscript before you spend time writing it.  

Case Studies:

These articles report specific instances of interesting phenomena. A goal of Case Studies is to make other researchers aware of the possibility that a specific phenomenon might occur. This type of study is often used in medicine to report the occurrence of previously unknown or emerging pathologies.

Methodologies or Methods

These articles present a new experimental method, test or procedure. The method described may either be completely new, or may offer a better version of an existing method. The article should describe a demonstrable advance on what is currently available.

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Journal Article vs Research Paper: Difference and Comparison

A journal article presents original research findings in a concise format, focusing on a specific topic within a broader field. It undergoes peer review before publication, ensuring quality and validity. On the other hand, a research paper is a comprehensive document that may include multiple experiments, analyses, and discussions, aimed at contributing to the advancement of scientific knowledge.

Key Takeaways A journal article is a shorter scholarly writing published in a specific academic journal. A research paper is a more extended, comprehensive academic writing presenting original research. Journal articles are more focused and present specific findings, while research papers are broader and present a more comprehensive study.

Journal Article vs Research Paper

A journal article is a piece of published work that presents the research findings and may include analysis, remark, or discussion. A research paper is a detailed account of the research that may be published or unpublished and includes an introduction, literature review, methods, results, and conclusion.

Comparison Table

What is journal article.

A journal article is a scholarly publication that presents the findings of original research, analysis, or review within a particular academic field. These articles serve as fundamental units of scholarly communication, disseminating new knowledge, theories, and insights to the academic community and beyond. Here’s a detailed breakdown:

Content and Structure

1 Abstract: A journal article begins with an abstract, a concise summary of the study’s objectives, methods, results, and conclusions. The abstract provides readers with a quick overview of the article’s content and findings.

2 Introduction: Following the abstract, the introduction sets the context for the study by reviewing relevant literature, identifying gaps or controversies in existing knowledge, and stating the research objectives or hypotheses.

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3 Methods: The methods section outlines the procedures, materials, and techniques used to conduct the study. It should provide sufficient detail to enable replication of the experiment or analysis by other researchers.

4 Results: This section presents the findings of the study, using tables, figures, or graphs to illustrate data. Authors describe the results objectively, without interpretation or speculation.

5 Discussion: In the discussion section, authors interpret the results in light of the study’s objectives and existing literature. They may address the implications of their findings, suggest future research directions, and discuss limitations or potential sources of bias.

6 Conclusion: The conclusion summarizes the main findings of the study and highlights their significance. It may also reiterate the study’s contribution to the field and offer final reflections or recommendations.

Peer Review Process:

1 Submission: Authors submit their articles to scholarly journals for publication consideration, adhering to the journal’s guidelines and formatting requirements.

2 Peer Review: Upon submission, the journal’s editor assigns the manuscript to peer reviewers—experts in the field—who evaluate the article’s quality, originality, methodology, and significance. Peer review helps ensure the rigor and credibility of the research.

3 Revision: Based on the reviewers’ feedback, authors may revise their article to address any concerns or criticisms raised. This iterative process of revision and reevaluation continues until the article meets the journal’s standards for publication.

4 Acceptance and Publication: If the article meets the journal’s criteria, it is accepted for publication and undergoes final editing and formatting. Once published, the article becomes part of the journal’s archive and is accessible to readers worldwide.

What is Research Paper?

A research paper is a comprehensive document that presents the findings, analysis, and interpretations of original research conducted by the author(s) within a specific academic discipline. These papers serve as a means for scholars to contribute new knowledge, theories, and insights to their respective fields. Here’s a detailed breakdown:

1. Content and Structure

1 Introduction: The introduction of a research paper provides background information on the topic, reviews relevant literature, and outlines the research objectives or hypotheses. It establishes the context for the study and justifies its significance.

2 Methods: The methods section describes the procedures, materials, and techniques employed in the research. It should provide sufficient detail to enable other researchers to replicate the study and verify its results.

3 Results: This section presents the empirical findings of the research, using tables, figures, or graphs to illustrate data. Authors report their observations or measurements objectively, without interpretation or speculation.

4 Discussion: In the discussion section, authors interpret the results in light of the research questions or hypotheses, comparing them to previous studies and addressing their implications. They may also explore alternative explanations, limitations of the study, and avenues for future research.

5 Conclusion: The conclusion summarizes the main findings of the research and highlights their significance. It may reiterate the study’s contribution to the field, offer final reflections, and suggest directions for further inquiry.

Characteristics and Scope

1 Original Research: Unlike review papers or essays, research papers are based on original research conducted by the authors. They contribute new data, insights, or interpretations to the academic discourse.

2 Rigorous Methodology: Research papers adhere to rigorous scientific or scholarly methodologies, employing systematic approaches to data collection, analysis, and interpretation. They prioritize objectivity, validity, and reliability in their findings.

3 Length and Complexity: Research papers vary in length and complexity, depending on the scope of the study and the requirements of the target publication venue. They may range from concise reports of preliminary findings to comprehensive analyses of multi-year research projects.

4 Contribution to Knowledge: Research papers aim to advance knowledge within their respective fields by addressing research gaps, testing hypotheses, or generating new theories. They contribute to the cumulative growth of scholarship through the dissemination of original research findings.

Main Differences Between Journal Article and Research Paper

• Journal articles focus on a specific aspect or finding within a broader topic.
• Research papers provide a comprehensive analysis of a research project, including multiple experiments, analyses, and discussions.
• Journal articles are concise, containing essential findings, methods, and interpretations in a limited space.
• Research papers tend to be longer and more detailed, offering exhaustive exploration of the research topic, methodology, results, and implications.
• Journal articles undergo peer review by experts in the field before publication, ensuring quality and validity.
• Research papers may or may not undergo formal peer review, depending on the publication venue or academic requirements.
• Journal articles present findings objectively, without extensive interpretation or speculation.
• Research papers include in-depth interpretation of results, discussion of implications, and exploration of potential limitations or biases.
• Journal articles contribute to the scholarly conversation by presenting new findings, analyses, or reviews within a specific topic area.
• Research papers advance knowledge within a field by offering comprehensive analyses, testing hypotheses, or generating new theories through original research.

• https://gssrr.org/index.php/gssrr/How-to-Publish-Research-Paper
• https://www.springer.com/gp/authors-editors/journal-author/types-of-journal-manuscripts/1356
• https://owl.purdue.edu/owl/general_writing/common_writing_assignments/research_papers/index.html

Last Updated : 05 March, 2024

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21 thoughts on “journal article vs research paper: difference and comparison”.

The characteristics of a journal article outlined in the article shed light on the structured nature of these scholarly publications. It’s important to understand the components that make up a journal article to effectively communicate research findings.

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Articles, Books and . . . ? Understanding the Many Types of Information Found in Libraries

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Academic Journals

Magazines and trade journals, conference papers, technical reports, anthologies.

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Because of their short length, articles often exclude background info and explanations, so they're usually the last stop in your research process, after you've narrowed down your topic and need to find very specific information.

The main thing to remember about articles is that they're almost always published in some larger work , like a journal, a newspaper, or an anthology. It's those "article containers" that define the types of articles, how you use them, and how you find them.

Articles are also the main reason we have so many databases . The Library Catalog lists everything we own, but only at the level of whole books and journals. It will tell you we have the New York Times, and for what dates, but it doesn't know what articles are in it. Search in UC Library Search using the "Articles, books, and more" scope will search all the databases we subscribe to and some we don't. If you find something we do not own, you can request it on Interlibrary Loan.

Physical Media

While newer journals and magazines are usually online, many older issues are still only available in paper. In addition, many of our online subscriptions explicitly don't include the latest material, specifically to encourage sales of print subscriptions. Older newspapers are usually transferred to microfilm.

Scholarly Sources

The terms academic or scholarly journal are usually synonymous with peer-reviewed , but check the journal's publishing policies to be sure. Trade journals, magazines, and newspapers are rarely peer-reviewed.

Primary or Secondary Sources

In the social sciences and humanities, articles are usually secondary sources; the exceptions are articles reporting original research findings from field studies. Primary source articles are more common in the physical and life sciences, where many articles are reporting primary research results from experiments, case studies, and clinical trials.

Clues that you're reading an academic article

• Footnotes or endnotes
• Bilbliography or list of references

Articles in academic (peer-reviewed) journals are the primary forum for scholarly communication, where scholars introduce and debate new ideas and research. They're usually not written for laymen, and assume familiarity with other recent work in the field. Journal articles also tend to be narrowly focused, concentrating on analysis of one or two creative works or studies, though they may also contain review articles or literature reviews which summarize recent published work in a field.

In addition to regular articles, academic journals often include book reviews (of scholarly books ) and letters from readers commenting on recent articles.

Clues that you're reading a non -academic article

• Decorative photos
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Unlike scholarly journals, magazines are written for a mainstream audience and are not peer-reviewed. A handful of academic journals (like Science and Nature ) blur the line between these two categories; they publish peer-reviewed articles, but combine them with news, opinions, and full-color photos in a magazine-style presentation.

Trade journals are targeted toward a specific profession or industry. Despite the name, they are usually not peer-reviewed. However, they sometimes represent a gray area between popular magazines and scholarly journals. When in doubt, ask your professor or TA whether a specific source is acceptable.

Newspapers as Primary Sources

Though usually written by journalists who were not direct witnesses to events, newspapers and news broadcasts may include quotes or interviews from people who were. In the absence of first-person accounts, contemporary news reports may be the closest thing to a primary source available.

Of all the content types listed here, newspapers are the fastest to publish. Use newspaper articles to find information about recent events and contemporary reports of/reactions to historic events.

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Reviews are a type of article that can appear in any of the categories above. The type of publication will usually determine the type of review. Newspapers and magazines review movies, plays, general interest books, and consumer products. Academic journals review scholarly books.

Note that a review is not the same as scholarly analysis and criticism! Book reviews, even in scholarly journals, are usually not peer-reviewed.

Conference papers aren't always published and can be tricky to find . Recent conference papers are often online, along with the PowerPoint files or other materials used in the actual presentation. However, access may be limited to conference participants and/or members of the academic organization which sponsored the conference.

In paper formats, all of the papers from a certain conference may be re-printed in the conference proceedings . Search for Proceedings of the [name of conference] to find what's available, or ask for help from a librarian. But be aware that published proceedings may only include abstracts or even just the name of the presenter and the title of the presentation. This is especially true of poster presentations , which really are large graphic posters (which don't translate well to either printed books or computer monitors).

As the name implies, most technical reports are about research in the physical sciences or engineering. However, there are also technical reports produced in the life and social sciences,

Like conference papers , some technical reports are eventually transformed into academic journal articles , but they may also be released after a journal article to provide supplementary data that didn't fit within the article. Also like conference papers, technical reports can be hard to find , especially older reports which may only be available in microfiche . Ask for help from a librarian!

Anthologies are a cross-over example. They're books that contain articles (chapters). Anthologies may be collections of articles by a single author, or collections of articles on a theme from different authors chosen by an editor. Many anthologies reprint articles already published elsewhere, but some contain original works.

Anthologies are rarely peer-reviewed, but they still may be considered scholarly works, depending on the reputation of the authors and editors. Use the same criteria listed for scholarly books .

Of course, reprints of articles originally published in peer-reviewed journals retain their "scholarly" status. (Note that most style manuals have special rules for citing reprinted works.)

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Article Types: What's the Difference Between Newspapers, Magazines, and Journals?

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Article : Much shorter than a book, an article can be as short as a paragraph or two or as long as several dozen pages. Articles can address any topic that the author decides to explore and can reflect opinion, news, research, reviews, instruction, nearly any focus. Articles appear in newspapers, magazines, trade publication, journals, and even in books. Because of their relative brevity, articles typically are used to provide up-to-date information on a wide variety of topics.

Book Review : A usually brief article that provides an evaluation and appreciation of a book. A review might assess the importance of a book's contributions to a particular field of study or might make recommendations to potential readers of the book. Reviews of fiction will usually comment on originality, style, and readability. While an important tool for helping a researcher assess the value of a book to his or her research topic, a book review, by itself, is usually not sufficient for use as a source in a research project.

Issue : A single, regular publication of a journal, magazine, newspaper, newsletter, or trade publication. A magazine or journal that publishes monthly will have twelve issues in a year. News magazines like Time and Newsweek publish weekly and will have 52 issues in a year. Newspapers might publish daily or weekly. A daily will have 365 issues in a year. Issues are usually numbered, so a journal that publishes twelve issues in a year starting with January will number each issue sequentially (issue 1, January; issue 2, February; issue 3, March; etc.).

Journal : A regularly published collection of articles that focus on topics specific to a particular academic discipline or profession. Journals might be published monthly, bi-monthly, quarterly, semi-annually, or even annually. Probably the most common publication frequency is monthly and quarterly. Journal articles are typically of substantial length (often more than 10 pages) and usually reflect research, whether it be surveys of existing research or discussions of original research. Most journal articles will be prefaced with an abstract and will include extensive documentation within the article or at the end of the article. Most research begins with a survey of existing literature on a topic and proceeds with the development of new ideas or new research into a topic. Articles are usually written by experts in their fields, although journals might also publish letters from their readership commenting on articles that have been published in previous issues. Journals might also include opinion articles or editorials. Examples of journals include Journal of the American Medical Association, American Sociological Review, Psychological Reports, Publications of the Modern Language Association, Educational Research Quarterly, and Evolutionary Biology.

Literature Review : An important part of nearly any research project, a literature review consists of a survey of previously published or non-published materials that focus on a particular subject under investigation. For example, a researcher looking into whether there is a relationship between musical aptitude and academic achievement in elementary age students would begin by looking for articles, books, and other materials that reflected previous research into this topic. The function of the review is to identify what is already known about the topic and to provide a knowledge foundation for the current study.

Magazine : A regularly published collection of articles that might focus on any topic in general or on topics of interest to a specific group, such as sports fans or music fans or home decorators. Magazines might be published weekly, monthly, semi-monthly or only several times a year. More commonly, magazines are published weekly or monthly. Articles in magazines are typically written for the general reading public and don't reflect in-depth research (an exception might be an investigative report written in a news magazine that involved weeks or months of research and interviews to complete). Most magazine articles do not list references and are written by the magazine's own staff writers. In general, magazine articles are easy to read, are fairly brief in length, and may include illustrations or photographs. Magazines also rely heavily on advertisements targeted to consumers as a source of revenue. Examples of magazines include Time, Newsweek, Rolling Stone, Popular Mechanics, Car and Driver, Interview, Good Housekeeping, Elle, GQ, and Sports Illustrated.

Newsletter : A regularly published collection of brief news articles of interest to members of a particular community. Professional associations might issue newsletters to keep their membership up to date. Businesses and schools might issue newsletters to keep their constituents up to date. Nearly any type of organization or society might have its own newsletter. Articles in newsletters are typically brief, and the entire newsletter itself might be only half a dozen pages in length. These are usually internal publications that have interest mainly to people who participate in the activities of the issuing body. They are frequently used to inform members of an organization of upcoming events. Examples of newsletters include 401(k) Advisor, Adult Day Services Letter, Black History News & Notes, Credit Card Weekly, Education Business Weekly, Music Critics Association Newsletter, and Student Aid News.

Newspaper : A regularly published collection of fairly brief articles that provide updates on current events and interests. Newspapers are generally published daily, weekly, and bi-weekly, although they may have less regular publication schedules. Most major newspapers publish daily, with expanded coverage on the weekends. Newspapers can be national or international in focus or might be targeted strictly to a particular community or locality. Newspaper articles are written largely by newspaper staff and editors and often do not provide authors' names. Many of the articles appearing in national, international, and regional papers are written by various wire service writers and are nationally or internationally syndicated. Examples of wire services are Reuters and the Associated Press. Newspapers rely on advertising for a part of their income and might also include photographs and even full color illustrations of photos. A common feature of most newspapers is its editorial page, where the editors express opinions on timely topics and invite their readers to submit their opinions. Examples of newspapers include New York Times, Times of London, Florida Times-Union, Tampa Tribune, Denver Post, Guardian, and USA Today.

Peer Reviewed/Refereed Journal : Most academic/scholarly journals use subject experts or "peers" to review articles being considered for publication. Reviewers will carefully examine articles to ensure that they meet journal criteria for subject matter and style. The process ensures that articles are appropriate to a particular journal and that they are of the highest quality.

Trade Journal : A regularly published collection of articles that address topics of interest to members of a particular profession, such as law enforcement or advertising or banking. Articles tend to be brief and often report on developments and news within a field and might summarize current research being done in a particular area. Trade journals might also include editorials, letters to the editor, photo essays, and advertisements that target members of the profession. While trade journal articles might include references, the reference lists tend to be brief and don't reflect thorough reviews of the literature. Articles are usually written with the particular profession in mind, but are generally pretty accessible so that a person wishing to learn more about the profession would still be able to understand the articles. Examples of trade journals include Police Chief, Education Digest, Energy Weekly News, Aviation Week and Space Technology, Engineering News Record, Design News, and Traffic World.

Volume : Most journals and many magazines, newsletters, newspapers, and trade publications assign volume numbers to a year's worth or half a year's worth of issues. For example, a journal that publishes four times a year (quarterly) might assign each yearly collection of four issues a volume number to help identify which issues of the journal were published during a particular year. Publications that publish more frequently than monthly might also assign volume numbers, but they might change volume numbers mid year, so that there may be two volumes in any one publishing year.

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• Key Differences

Know the Differences & Comparisons

Difference Between Article and Journal

On the contrary, Journal is a periodical publication in a specific field of study, which is often reviewed by experts in the concerned area. Journal publications are regarded as one of the highly honoured forms of publications, because of its high standards in reviewing and publishing.

Come let’s discuss the differences between article and journal.

Content: Article Vs Journal

Comparison chart, definition of article.

The article implies an independently written composition, usually short and precise, which is traditionally included in the newspaper, magazines, websites, journals, etc. It is written for a large audience in an entertaining manner, so as to grab and retain their interest and attention. The name of the person who wrote the article is always mentioned.

An article not just integrates facts, but the thoughts and opinions of the writer and experts, and balanced arguments are also included. A well-drafted article often brings out topics of interest into the limelight.

An article may cover fascinating stories, reported speech, information, suggestions and other descriptions. It can also describe any event, experience, person or anything else. Articles are classified on the basis of need or preference:

• News Articles : Articles containing breaking news, information, happenings, events of public interest, what will happen in the near future or a trending topic. It may contain photographs, charts, interviews, debates, etc. Its objective is to report on when, how, where and why the event took place and who is involved in it.
• Feature Articles : One that is written creatively and descriptively so as to entertain, engage and influence the reader. The article can be based on anything, i.e. from people to place or from event to experience.
• Editorial Articles : These are commonly found in newspapers and magazines, which often showcase a new outlook or opinion, on a current issue. It often expresses a distinctive angle or approach about someone or something and provokes the reader to think that way.
• How-to Articles : Such articles are instructional in the sense that they offer complete guidelines on how-to-do something.
• Marketing Articles : A short piece of writing, which is actually an advertisement, written to catch the attention of the reader towards the company’s product or service.
• Question-Answer Articles : As the name suggest, these articles are in question-answer format, based upon an interview with the famous personality. It does not contain an introductory paragraph.
• Profile Articles : Profile articles are all about a specific person, which requires research and interview, to gather relevant information about that person.

Definition of Journal

Journal can be defined as a professional or academic publication, which features a number of educational articles, written by researchers, experts or someone having academic qualifications in the concerned subject, which presents original and new research, book reviews, feedback, review articles and so forth. It includes references and targets academic audience only.

A journal is always on a specific discipline, that targets a particular group of people, typically students pursuing that discipline and not the general public. It must be noted, the journals are usually peer-reviewed (refereed) and so they undergo an extensive editorial process. However, all the journals are not peer-reviewed.

They focus on current developments in the field of study. It is available in both offline (printed form) and online mode. One can use journal articles for the purpose of research as they are authoritative, up to date, topic-specific and understandable.

Journals are published periodically, i.e. weekly, bi-monthly, monthly, quarterly, semi-annually or annually. Each copy is termed as an issue, and a set of issues are called volume.

Key Differences Between Article and Journal

The points given below are noteworthy so far as the difference between article and journal is concerned:

• An article is a written composition on a topic of interest, which forms a separate part of a book, magazine or newspaper. On the other hand, Journal is a type of magazine which contains articles and other descriptions on a particular discipline or professional activities.
• While the article is a work of literature, the journal is a form of publication.
• An article is non-fictional and informative in nature. As against, the journal is educational and academic.
• The article can include news, stories, information, facts or writer’s experience, opinion, suggestion, facts, etc. Conversely, a journal contains articles, book reviews, editorial content, achievements, feedback, recent developments in the field of study and many more.
• An article is written on the topic of interest of the writer or any burning issue. In contrast, a journal is all about the specific field of study or professional course and developments thereon.
• The main objective of writing an article is to influence the reader and urging them to think. On the flip side, a journal aims to provide relevant information relating to the professional course.

In a nutshell, an article differs from a journal in the sense that an article is a written composition, which is just a small part of the journal, while the journal is itself a publication containing a number of articles and other relevant material.

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Q. What's the difference between a research article (or research study) and a review article?

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Answered By: Priscilla Coulter Last Updated: Jul 29, 2022     Views: 232151

A research paper is a primary source ...that is, it reports the methods and results of an original study performed by the authors . The kind of study may vary (it could have been an experiment, survey, interview, etc.), but in all cases, raw data have been collected and analyzed by the authors , and conclusions drawn from the results of that analysis.

Research papers follow a particular format.  Look for:

• A brief introduction will often include a review of the existing literature on the topic studied, and explain the rationale of the author's study.  This is important because it demonstrates that the authors are aware of existing studies, and are planning to contribute to this existing body of research in a meaningful way (that is, they're not just doing what others have already done).
• A methods section, where authors describe how they collected and analyzed data.  Statistical analyses are included.  This section is quite detailed, as it's important that other researchers be able to verify and/or replicate these methods.
• A results section describes the outcomes of the data analysis.  Charts and graphs illustrating the results are typically included.
• In the discussion , authors will explain their interpretation of their results and theorize on their importance to existing and future research.
• References or works cited are always included.  These are the articles and books that the authors drew upon to plan their study and to support their discussion.

You can use the library's article databases to search for research articles:

• A research article will nearly always be published in a peer-reviewed journal; click here for instructions on limiting your searches to peer-reviewed articles.  
• If you have a particular type of study in mind, you can include keywords to describe it in your search .  For instance, if you would like to see studies that used surveys to collect data, you can add "survey" to your topic in the database's search box. See this example search in our EBSCO databases: " bullying and survey ".   
• Several of our databases have special limiting options that allow you to select specific methodologies.  See, for instance, the " Methodology " box in ProQuest's PsycARTICLES Advanced Search (scroll down a bit to see it).  It includes options like "Empirical Study" and "Qualitative Study", among many others.  

A review article is a secondary source ...it is written about other articles, and does not report original research of its own.  Review articles are very important, as they draw upon the articles that they review to suggest new research directions, to strengthen support for existing theories and/or identify patterns among exising research studies.  For student researchers, review articles provide a great overview of the existing literature on a topic.    If you find a literature review that fits your topic, take a look at its references/works cited list for leads on other relevant articles and books!

You can use the library's article databases to find literature reviews as well!  Click here for tips.

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Answered By: Elizabeth Galoozis (she/her) Last Updated: Sep 27, 2019     Views: 74423

In assignments, or on the library website, you’ve probably seen the three words “article,” “journal,” and “database.” How do they relate to each other, and how do they relate to searching for sources?

When you search in the libraries’ home page, you’re searching across several databases , including collections of books, e-books, and films, along with individual databases  - for example, JSTOR or ProQuest Research Library. Each database includes sources such as articles, government documents, and many more. You can search for databases by name using the “Databases” search on the libraries’ home page.

One of the most common types of sources is a journal . This word may be used interchangeably in some places with periodical or serial , but basically a journal is a publication that comes out in issues on a regular basis - for example, four times a year. An example is Feminist Economics:

An issue of a journal contains individual articles . These are probably what you’re used to finding when you search for sources in the libraries or online, but you usually find them detached from their particular journal issue.

You can search for journals by title using the “Journals” search on the libraries’ home page.

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When writing a paper or conducting academic research, you’ll come across many different types of sources, including periodical articles. Periodical articles can be comprised of news accounts, opinion, commentary, scholarly analysis, and/or reports of research findings. There are three main types of periodicals that you will encounter: scholarly/academic, trade, and popular.  The chart below will help you identify which type of periodical your article comes from.

Text and chart adapted from the WSU University Libraries' How to Distinguish Between Types of Periodicals  and Types of Periodicals guides

What makes information peer-reviewed vs. scholarly vs. non-scholarly? Which type of source should I use?

• What makes information peer-reviewed vs. scholarly vs. non-scholarly?
• Which type of source should I use?

There is a nuanced distinction between peer-review and scholarship, which typically doesn't matter when evaluating sources for possible citation in your own work.  Peer-review is a process through which editors of a journal have other experts in the field evaluate articles submitted to the journal for possible publication.  Different journals have different ways of defining an expert in the field.  Scholarly works, by contrast have an editorial process, but this process does not involve expert peer-reviewers.  Rather, one or more editors, who are themselves often highly decorated scholars in a field, evaluate submissions for possible publication.  This editorial process can be more economically driven than a peer-review process, with a greater emphasis on marketing and selling the published material, but as a general rule this distinction is trivial with regard to evaluating information for possible citation in your own work.

What is perhaps a more salient way of thinking about the peer-review / scholarship distinction is to recognize that while peer-reviewed information is typically highly authoritative, and is generally considered "good" information, the absence of a peer-review process doesn't automatically make information "bad."  More specifically, the only thing the absence of a peer-review process means is that information published in this manner is not peer-reviewed.  Nothing more.  Information that falls into this category is sometimes referred to as "non-scholarly" information -- but again, that doesn't mean this information is somehow necessarily problematic.

Where does that leave you in terms of deciding what type of information to use in producing your own work?  That is a highly individual decision that you must make.  The Which type of source should I use?  tab in this box offers further guidance on answering this question, though it is important to be aware that many WSU instructors will only consider peer-reviewed sources to be acceptable in the coursework you turn in .  You can ask your instructor for his or her thoughts on the types of sources s/he will accept in student work.

Image:  Martin Grater. (2017, Nov. 1). Deep Thought. Retrieved from https://www.flickr.com/photos/152721954@N05/24304490568/. Used under the Creative Commons License.

Your topic and research question or thesis statement will guide you on which resources are best.  Sources can be defined as primary, secondary and tertiary levels away from an event or original idea. Researchers may want to start with tertiary or secondary source for background information. Learning more about a topic will help most researchers make better use of primary sources.

While articles from scholarly journals are often the most prominent of the sources you will consider incorporating into your coursework, they are not the only sources available to you.  Which sources are most appropriate to your research is a direct consequence of they type of research question you decide to address.  In other words, while most university-level papers will require you to reference scholarly sources, not all will.  A student in an English course writing a paper analyzing Bob Dylan's lyrics, for example, may find an interview with Dylan published in Rolling Stone magazine a useful source to cite alongside other scholarly works of literary criticism.

The WSU University Libraries' What Sources Should I Use? handout, as well as the other sub-tabs under the  Evaluating information  section of this guide (which is indeed the section you are currently viewing) offer further guidance on understanding and identifying scholarly resources, and comparing them against different criteria to evaluate if they will be of value to your research.  How many non-scholarly works (if any) you are at liberty to cite alongside scholarly ones is often a question to ask of your professor.  Some may not want you to cite any, whereas others may be ok with some non-scholarly works cited alongside scholarly ones.

Image:  Brett Woods. (2006, Jan. 6). Deep Thoughts. Retrieved from https://www.flickr.com/photos/brettanicus/87653641/. Used under the Creative Commons License.

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Expert Commentary

White papers, working papers, preprints, journal articles: What’s the difference?

In this updated piece, we explain the most common types of research papers journalists will encounter, noting their strengths and weaknesses.

Republish this article

This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License .

by Denise-Marie Ordway, The Journalist's Resource February 25, 2022

This <a target="_blank" href="https://journalistsresource.org/media/working-papers-research-articles/">article</a> first appeared on <a target="_blank" href="https://journalistsresource.org">The Journalist's Resource</a> and is republished here under a Creative Commons license.<img src="https://journalistsresource.org/wp-content/uploads/2020/11/cropped-jr-favicon-150x150.png" style="width:1em;height:1em;margin-left:10px;">

This tip sheet, originally published in May 2018, has been updated to include preprint research, a type of research featured often in news coverage of the coronavirus pandemic.

Journalists rely most often on four types of research in their work. White papers, working papers, preprints and peer-reviewed journal articles.

How are they different? And which is best?

Below, we explain each, pointing out its strengths and weaknesses. As always, we urge journalists to use care in selecting any research to ground their coverage and fact-check claims.

Peer-reviewed article

Peer-reviewed research — the kind that appears in academic journals and that we highlight here at The Journalist’s Resource — has undergone a detailed critique by scholars with expertise in the field. While peer-reviewed research is generally the most reliable, journalists should keep in mind that publication in a prestigious journal is no guarantee of quality and that no single university or research organization always does the best research on a given topic.

It is safe to assume, however, that articles published in top-tier journals have been reviewed and given a stamp of approval by a number of accomplished scholars. For journalists who are uncertain, we’ve put together a list of 13 questions  to ask to gauge the quality of a research article.

Keep in mind that not everything that appears in a scholarly journal has been peer reviewed. Journals publish various types of content, including book reviews, editorials, letters to the editor and, sometimes, even poetry.

Working paper

This broad category describes research papers that have not been peer reviewed or published in a journal. Working papers can be in various stages of completion. One might be ready for publication in a prestigious journal while another requires significant editing and other changes that could actually alter its main findings. Sometimes, working paper findings are so preliminary, authors will advise against citing their work .

Even so, working papers are a great way for journalists to gain access to new research quickly. The peer-review and publication process can take months to a year or longer, which means that by the time studies get published, their findings are sometimes not as useful or the data are old.

In choosing working papers, journalists should communicate with scholars about the progress of their research and how confident they are in their findings. It’s a good idea to seek corroboration from peer-reviewed research and to ask other researchers for help assessing a study.

A preprint is similar to a working paper in that it has not been vetted through a formal peer-review process. However, preprints tend to be more complete . Also, preprints submitted to public servers such as the Social Science Research Network and the health sciences server medRxiv get a cursory screening before they’re published online for public view.

Preprints, like academic journal articles, are assigned a Digital Object Identifier , or DOI, and become a permanent part of the scientific record.

White paper

A white paper is a report, often compiled by government agencies, businesses and nonprofit organizations, that outlines an issue and often explores possible solutions to a problem. For example, in November 2021, the federal Office of Community Oriented Policing Services released a white paper looking at factors that help or hinder law enforcement recruitment of Black Americans. Earlier in the year, the Advanced Technology Academic Research Center published a white paper on the American Rescue Plan ‘s widespread implications for government agencies.

In the business world, white papers also are used for marketing purposes — to describe a new product or approach, for instance, or diagnose a problem.

While a white paper can help journalists get up to speed quickly on an issue, it’s important to note some white papers advocate a specific position or policy change. Some rely on incomplete research or research that has not been peer reviewed.

Looking for more guidance on writing about research? Check out our tip sheets on covering biomedical research preprints amid the coronavirus and what journalists should know about peer review .

The Journalist’s Resource would like to thank Matthew Baum , the Marvin Kalb professor of global communications and professor of public policy at Harvard Kennedy School, for his help preparing this tip sheet.

About The Author

Denise-Marie Ordway

International Journal of Research (IJR)

IJR Journal is Multidisciplinary, high impact and indexed journal for research publication. IJR is a monthly journal for research publication.

DIFFERENCE BETWEEN RESEARCH PAPER AND JOURNAL ARTICLE

Difference between research paper and journal article.

Research Paper

Argumentative Research Paper

Analytical research paper, journal article, the differences, research paper:, journal article:.

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Answered By: Sarah Naomi Campbell Last Updated: Sep 07, 2018     Views: 214548

Watch this short video to learn about types of scholarly articles, including research articles and literature reviews!

Not in the mood for a video? Read on!

What's the difference between a research article and a review article?

Research articles , sometimes referred to as empirical  or primary sources , report on original research. They will typically include sections such as an introduction, methods, results, and discussion.

Here is a more detailed explanation of research articles .

Review articles , sometimes called literature reviews  or secondary sources , synthesize or analyze research already conducted in primary sources. They generally summarize the current state of research on a given topic.

Here is a more detailed explanation of review articles .

The video above was created by the Virginia Commonwealth University Libraries .

The defintions, and the linked detailed explanations, are paraphrased from the Publication Manual of the American Psychological Association , 6th ed .

The linked explanations are provided by the Mohawk Valley Community College Libraries .

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Cultural Relativity and Acceptance of Embryonic Stem Cell Research

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There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities.

INTRODUCTION

Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve.

Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes. [1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research. [2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.” [3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops. [4]  Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture.

I.     Global Cultural Perspective of Embryonic Stem Cells

Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense, [5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research. [6] Consequently, global engagement in ESC research depends on social-cultural acceptability.

a.     US and Rights-Based Cultures

In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism, [7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.” [8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed. [9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field. [10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture. [11]

b.     Ubuntu and Collective Cultures

African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama , which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,” [12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth. [13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole . Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value. [14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society.

Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.” [15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail.

Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable. [16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus. [17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines. [18]

Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim. [19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research. [20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF.  Their use is conditioned on consent, and available only to married couples. [21] The community's receptiveness to stem cell research depends on including communitarian African ethics.

c.     Asia

Some Asian countries also have a collective model of ethics and decision making. [22] In China, the ethics model promotes a sincere respect for life or human dignity, [23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life. [25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research. [26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions. [27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency. [28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021. [29] However, issues still need to be addressed in implementing effective IRB review and approval procedures.

The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy, [30] research ethics should also adapt to ensure respect for the values of its represented peoples.

Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies. [31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells. [32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval, [33] and in another instance, the oocyte source was unclear and possibly violated ethical standards. [34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust.

d.     Middle East

Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells, [35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research. [36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors. [37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so. [38]

Jordan has a positive research ethics culture. [39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial. [40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation. [41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.” [42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes.

e.     Europe

In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected. [43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44]

For example, in Germany, Lebenzusammenhang , or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.” [45]  Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount. [46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007. [47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization. [48] Spain’s approach differs still, with a comprehensive regulatory framework. [49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility. [50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices. [51]

II.     Religious Perspectives on ESC

Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives.

The Qur'an states:

“And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.” [52]

Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception. [53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible. [54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research. [55]

In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided. [56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden. [57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all. [58] Acceptance varies on applied beliefs and interpretations.

Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero, [59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all. [60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime. [61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit. [62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets. [63]

Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life. [64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception: [65]

“If she is found pregnant, until the fortieth day it is mere fluid,” [66]

Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation. [67] Stem cell research is accepted due to application of these religious laws.

We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory , which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions. [68] We only wish to show that the interaction with morality varies between cultures and countries.

III.     A Flexible Ethical Approach

The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities.

While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe. [69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation.

For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent. [70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context, [71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders.  This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research.

Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values. [72]

An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions. [73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion.

IV.     Concerns

Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values. [74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions.

Other concerns include medical tourism, which may promote health inequities. [75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments. [76]

For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.” [77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices. [78]

The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.” [79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds. [80]

While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research.

For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society.

This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model.

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Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics , 23 (3), 260–268. https://doi.org/10.1111/dewb.12355 ; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know . Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know

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[43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France.  Biotechnology Law Report ,  32 (6), 349–356. https://doi.org/10.1089/blr.2013.9865

[45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[46] Tomuschat, C., Currie, D. P., Kommers, D. P., & Kerr, R. (Trans.). (1949, May 23). Basic law for the Federal Republic of Germany. https://www.btg-bestellservice.de/pdf/80201000.pdf

[47] Regulation of Stem Cell Research in Germany . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany

[48] Regulation of Stem Cell Research in Finland . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland

[49] Regulation of Stem Cell Research in Spain . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain

[50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered:

Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110.

Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ...  Revista do Colegio Brasileiro de Cirurgioes ,  41 (5), 374–377. https://doi.org/10.1590/0100-69912014005013

Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India . Routledge.

For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe   

[51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights.  Cultura (Iasi, Romania) ,  14 (2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent?  Research Ethics ,  13 (1), 23-41.  https://doi.org/10.1177/1747016116650235

[52] The Qur'an  (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23

[53] Lenfest, Y. (2017, December 8). Islam and the beginning of human life . Bill of Health. https://blog.petrieflom.law.harvard.edu/2017/12/08/islam-and-the-beginning-of-human-life/

[54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics , 31: 399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386

[55] Rashid, R. (2022). When does Ensoulment occur in the Human Foetus. Journal of the British Islamic Medical Association , 12 (4). ISSN 2634 8071. https://www.jbima.com/wp-content/uploads/2023/01/2-Ethics-3_-Ensoulment_Rafaqat.pdf.

[56] Sivaraman, M. & Noor, S. (2017). Ethics of embryonic stem cell research according to Buddhist, Hindu, Catholic, and Islamic religions: perspective from Malaysia. Asian Biomedicine,8(1) 43-52.  https://doi.org/10.5372/1905-7415.0801.260

[57] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation.  Journal of Religion and Health ,  30 (1), 35–41. http://www.jstor.org/stable/27510629 ; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva . A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm

[59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. (( King James Bible . (1999). Oxford University Press. (original work published 1769))

Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…”

In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David.

Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…”

These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth.

[60] It should be noted that abortion is not supported as well.

[61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day . Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html

[62] The Vatican. (2000, August 25). Declaration On the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells . Pontifical Academy for Life. https://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20000824_cellule-staminali_en.html ; Ohara, N. (2003). Ethical Consideration of Experimentation Using Living Human Embryos: The Catholic Church’s Position on Human Embryonic Stem Cell Research and Human Cloning. Department of Obstetrics and Gynecology . Retrieved from https://article.imrpress.com/journal/CEOG/30/2-3/pii/2003018/77-81.pdf.

[63] Smith, G. A. (2022, May 23). Like Americans overall, Catholics vary in their abortion views, with regular mass attenders most opposed . Pew Research Center. https://www.pewresearch.org/short-reads/2022/05/23/like-americans-overall-catholics-vary-in-their-abortion-views-with-regular-mass-attenders-most-opposed/

[64] Rosner, F., & Reichman, E. (2002). Embryonic stem cell research in Jewish law. Journal of halacha and contemporary society , (43), 49–68.; Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[65] Schenker J. G. (2008). The beginning of human life: status of embryo. Perspectives in Halakha (Jewish Religious Law).  Journal of assisted reproduction and genetics ,  25 (6), 271–276. https://doi.org/10.1007/s10815-008-9221-6

[66] Ruttenberg, D. (2020, May 5). The Torah of Abortion Justice (annotated source sheet) . Sefaria. https://www.sefaria.org/sheets/234926.7?lang=bi&with=all&lang2=en

[67] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[68] Gert, B. (2007). Common morality: Deciding what to do . Oxford Univ. Press.

[69] World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA , 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053 Declaration of Helsinki – WMA – The World Medical Association .; see also: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979).  The Belmont report: Ethical principles and guidelines for the protection of human subjects of research . U.S. Department of Health and Human Services.  https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

[70] Zakarin Safier, L., Gumer, A., Kline, M., Egli, D., & Sauer, M. V. (2018). Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes.  Journal of assisted reproduction and genetics ,  35 (7), 1219–1225. https://doi.org/10.1007/s10815-018-1171-z https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063839/ see also: Riordan, N. H., & Paz Rodríguez, J. (2021). Addressing concerns regarding associated costs, transparency, and integrity of research in recent stem cell trial. Stem Cells Translational Medicine , 10 (12), 1715–1716. https://doi.org/10.1002/sctm.21-0234

[71] Klitzman, R., & Sauer, M. V. (2009). Payment of egg donors in stem cell research in the USA.  Reproductive biomedicine online ,  18 (5), 603–608. https://doi.org/10.1016/s1472-6483(10)60002-8

[72] Krosin, M. T., Klitzman, R., Levin, B., Cheng, J., & Ranney, M. L. (2006). Problems in comprehension of informed consent in rural and peri-urban Mali, West Africa.  Clinical trials (London, England) ,  3 (3), 306–313. https://doi.org/10.1191/1740774506cn150oa

[73] Veatch, Robert M.  Hippocratic, Religious, and Secular Medical Ethics: The Points of Conflict . Georgetown University Press, 2012.

[74] Msoroka, M. S., & Amundsen, D. (2018). One size fits not quite all: Universal research ethics with diversity.  Research Ethics ,  14 (3), 1-17.  https://doi.org/10.1177/1747016117739939

[75] Pirzada, N. (2022). The Expansion of Turkey’s Medical Tourism Industry.  Voices in Bioethics ,  8 . https://doi.org/10.52214/vib.v8i.9894

[76] Stem Cell Tourism: False Hope for Real Money . Harvard Stem Cell Institute (HSCI). (2023). https://hsci.harvard.edu/stem-cell-tourism , See also: Bissassar, M. (2017). Transnational Stem Cell Tourism: An ethical analysis.  Voices in Bioethics ,  3 . https://doi.org/10.7916/vib.v3i.6027

[77] Song, P. (2011) The proliferation of stem cell therapies in post-Mao China: problematizing ethical regulation,  New Genetics and Society , 30:2, 141-153, DOI:  10.1080/14636778.2011.574375

[78] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[79] International Society for Stem Cell Research. (2024). Standards in stem cell research . International Society for Stem Cell Research. https://www.isscr.org/guidelines/5-standards-in-stem-cell-research

[80] Benjamin, R. (2013). People’s science bodies and rights on the Stem Cell Frontier . Stanford University Press.

Mifrah Hayath

SM Candidate Harvard Medical School, MS Biotechnology Johns Hopkins University

Olivia Bowers

MS Bioethics Columbia University (Disclosure: affiliated with Voices in Bioethics)

Article Details

This work is licensed under a Creative Commons Attribution 4.0 International License .

• Introduction
• Conclusions
• Article Information

Composite scores of 10 or greater indicate greater aggregate severity and complexity of social determinants of health needs.

eFigure 1. GAM Partial Effects Smooth Plots Illustrating Nonlinear Associations Between SVI and Assessment Responses (Faceted by Assessment Response Domain)

eFigure 2. GAM Partial Effects Smooth Plots Illustrating Nonlinear Associations Between SVI and Assessment Responses (Faceted by SVI)

eTable 1 . Scoring Rubric for Composite Social Determinants of Health Risk

eTable 2. GAM-Model Estimated Adjusted Odds Ratios for SDoH Needs Calculated Across the Range of Each SVI Quintile

eTable 3. Results of GAM Models Estimating Risk for Positive Assessment by Domain as a Function of Overall SVI

eTable 4. Results of GAM Models Estimating Risk for Positive Assessment by Domain as a Function of Socioeconomic SVI

eTable 5. Results of GAM Models Estimating Risk for Positive Assessment by Domain as a Function of Household Characteristics SVI

eTable 6. Results of GAM Models Estimating Risk for Positive Assessment by Domain as a Function of Minority Status SVI

eTable 7. Results of GAM Models Estimating Risk for Positive Assessment by SDoH Domain as a Function of Housing and Transportation SVI

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Brignone E , LeJeune K , Mihalko AE , Shannon AL , Sinoway LI. Self-Reported Social Determinants of Health and Area-Level Social Vulnerability. JAMA Netw Open. 2024;7(5):e2412109. doi:10.1001/jamanetworkopen.2024.12109

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Self-Reported Social Determinants of Health and Area-Level Social Vulnerability

• 1 Highmark Health Research Institute, Pittsburgh, Pennsylvania
• 2 Allegheny Health Network Research Institute, Pittsburgh, Pennsylvania
• 3 Social Determinants of Health Department, Highmark Health, Pittsburgh, Pennsylvania
• 4 Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania

Question   Are self-reported social determinants of health (SDoH) needs associated with area-level social vulnerability as measured by the Social Vulnerability Index (SVI)?

Findings   This cross-sectional study of 841 874 assessments in 401 697 individuals found that self-reported SDoH needs were positively associated with SVI, with socioeconomic and racial and ethnic minority status themes most strongly associated with self-reported needs across all domains. Targeting individual SDoH needs based on SVI is likely to yield many false-positive results.

Meaning   While self-reported SDoH needs are generally more prevalent in socially vulnerable areas, individual-level data can enhance service provision planning and research.

Importance   Many health care systems are investing resources in identifying social determinants of health (SDoH) needs and facilitating interventions among the populations they serve. Because self-reported SDoH information is lacking, area-level measures are often used to estimate needs and direct resources.

Objective   To describe the large-scale deployment of SDoH assessments by a health system and determine the extent to which self-reported SDoH needs identified therein are associated with census tract–level social vulnerability measured using the Social Vulnerability Index (SVI).

Design, Setting, and Participants   This cross-sectional study assessed SDoH needs between January 1, 2020, and April 30, 2023, in both payer and clinical care settings. Modalities included telephonic outreach, face-to-face clinical interactions, self-entry into a tablet or kiosk, and web-based survey tools. Participants included individuals who responded to the assessment and had sufficient information for census tract identification. Respondents included both Highmark Health Plan members and nonmembers. Health plan members responded to the assessment through health plan programs or platforms, and both members and nonmembers responded to assessments during inpatient or outpatient encounters with the affiliated health system.

Main Outcomes and Measures   Overall and domain-specific SDoH needs self-reported through assessments, and severity and complexity of needs identified. Residential social vulnerability measures included overall SVI and the 4 conceptual themes comprising overall SVI.

Results   In total, 841 874 assessments were recorded for 401 697 individuals (55.1% women; median [IQR] age, 55 [41-70] years). Social determinants of health needs were identified in 120 769 assessments (14.3%). Across all SDoH domains, increasing SVI was associated with a higher positivity rate (eg, 11.2% of those residing in the lowest-risk SVI quintile reported a need compared with 22.7% among those residing in the highest-risk quintile). Associations varied by SDoH domain and SVI theme. After adjusting for demographic and screening characteristics, odds of positive screening among those residing in the highest-risk SVI quintile were 1.74 (95% CI, 1.62-1.86) to 3.73 (95% CI, 3.48-4.00) times the odds among those residing in lowest risk quintile.

Conclusions and Relevance   In this cross-sectional study, the overall level of SDoH needs generally corresponded to area-level vulnerability. Some SDoH domains appeared far more sensitive to community characteristics than others. Notably, even among individuals from the highest-risk areas, the positive screening rate was roughly 1 in 4. These findings underscore the importance of individual-level SDoH data for service provision planning and health services research.

According to the World Health Organization, social determinants of health (SDoH) “are the nonmedical factors that influence health outcomes. They are the conditions in which people are born, grow, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life.” 1 These factors include socioeconomic status, health behaviors, health care access and quality, and the physical environment. They contribute up to 80% to a patient’s quality of life and life expectancy 2 and exist at multiple interacting levels (eg, individual, family, community) to influence health outcomes. 3 The social ecological model of health provides a useful framework for understanding how these factors interact to create health risks or protective factors, which can identify individuals and communities at risk.

In 1989, the Centers for Disease Control and Prevention created the Social Vulnerability Index (SVI) to identify populations at risk of harm in response to natural disasters. 4 The SVI uses 15 census measures to estimate vulnerability using 4 themes: socioeconomic status, household characteristics, racial and ethnic minority status, and housing type and transportation. 5 The SVI has been used to explain and project infectious disease spread 6 , 7 and demonstrate the importance of social vulnerability in risk for cardiometabolic conditions, 8 cancer, 9 and chronic lung disease mortality. 10

Recognizing the importance of community-level SDoH factors in health outcomes is essential for understanding and solving social needs. However, in the health care setting, community-level measures can be challenging to integrate into clinical care and service provision. Inferring individual circumstances using community averages could lead to ecological fallacy and misallocation of resources. For example, well-resourced patients without SDoH needs may be targeted for outreach based on their address. Conversely, vulnerable patients residing in low-risk communities may be missed. Nonetheless, because individual-level data have not been available until recently, SVI is often used in its absence to estimate individual needs. While assessing individuals for SDoH needs is becoming more common, large-scale screening programs require significant investments in infrastructure, training, and time. Thus, coverage is still often poor, with self-reported data unavailable for most individuals. 11

In 2019, Highmark Health, a national health and wellness organization, established a team to develop an SDoH assessment tool. The team included clinical case managers, project managers, information technology representatives, and executive and physician leadership from an affiliated health system, Allegheny Health Network. Clinically validated screening questions were used to create a 13-question assessment covering SDoH needs across several domains. The assessment was implemented in phases across multiple payer and clinical settings, with most assessments initiated by a staff member during face-to-face or telephonic interactions.

In this study, we compared self-reported SDoH needs and SVI associated with the individual’s residence. Drawing on the social ecological model, we hypothesized that composite SVI would be positively associated with self-reported needs, and SVI component themes would be most closely associated with SDoH needs in corresponding domains. We also hypothesized that associations would vary by theme and SDoH domain, with stronger associations among economic measures. We expect findings to underscore the importance of individualized assessments and guide their implementation, while informing the application and interpretation of community-level data in their absence.

The full retrospective dataset included 841 874 SDoH assessments administered in the payer and clinical care settings between January 1, 2020, and April 30, 2023. Observations represent unique assessments. Observations were excluded when the census tract could not be identified (n = 11 642) or when age or sex information was missing (n = 1446), with 11 776 (1.4%) excluded overall due to overlap. Respondents included Highmark Health Plan members who answered 1 or more payer-initiated assessment questions through a health plan program or platform, and both health plan members and nonmembers who answered 1 or more clinician-initiated assessment questions during an inpatient or outpatient encounter with the affiliated health system.

Most assessments were recorded in the clinical setting (676 815 [80.4%]). Individuals assessed multiple times during this period contributed multiple observations. Because the planned regression analyses assume independence of observations (ie, observations that are not related to one another), we created a secondary dataset of independent observations by randomly selecting exactly 1 assessment instance per unique respondent (n = 401 697). The study was approved by the institutional review board of the Allegheny Health Network Research Institute (acting for Highmark Health). Informed consent was waived because person-level records in the study were drawn from administrative data that were originally collected for other purposes, with no feasible method of retroactively obtaining consent and no risk of identifiability in published results. We followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline.

Assessments of SDoH were captured using multiple modalities, including telephonic outreach, face-to-face clinical interactions, self-entry into tablets or kiosks during clinical encounters, and online survey tools. Clinic-based assessments were documented in electronic medical records, while payer-based assessments were recorded in corporate databases. A member-to-patient identifier crosswalk file was used to uniquely identify respondents across sources. All data sources were aggregated into a single working dataset.

The assessment included 13 questions covering 7 domains (social connections, health literacy, financial resource strain, transportation, food insecurity, safety, and housing stability). Table 1 lists questions with their sources and response options, including which responses indicate need. All questions included a decline option. Decline responses were counted as assessed with no need identified. Questions without responses were marked as missing. For the 806 862 assessments recorded in face-to-face or telephonic encounters (95.8% overall), a missing response indicated that the question was not asked. For the remaining digital self-entry assessments, missing responses indicate that the respondent skipped the question. Question-level completion rates and the share of declined are provided in Table 1 . Calculations for domain-specific SDoH needs were based on the subset of assessments that included at least 1 response pertaining to the given domain. In addition to needs by domain, indicators for overall and combined SDoH needs were calculated, including a composite score ranging from 0 to 58 that used a scoring rubric to summarize aggregate severity and complexity of SDoH needs across all domains (eTable 1 in Supplement 1 ).

Person-level characteristics were drawn from claims and clinical data, including age, sex, race (categorized as American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific Islander, White, other, or unknown), ethnicity (categorized as Hispanic or Latino, non-Hispanic or non-Latino, or unknown), and address at time of assessment. Race and ethnicity data were collected because of their interrelated nature with social vulnerability, health care utilization, and health outcomes. Addresses were geocoded to identify census tracts, which served as the joining key for SVI data. In addition to raw scores and percentile ranks in the SVI, overall and theme vulnerability scores were divided into 5 quintiles using the national distribution of tract-level scores. Five quintiles were found to capture meaningful variability across the distribution of scores while providing ease of interpretation.

Descriptive statistics were computed for study variables and stratified by overall screening result (any vs no SDoH need) for the full dataset and for the independent observations subset. Because our large sample produced statistically significant results even at small effect sizes, P values were omitted from descriptive summaries.

Rates of positive assessments were computed for each SDoH domain and stratified by quintile for composite SVI and each component theme. Using the independent observations data subset (ie, 1 assessment per respondent), we computed a series of regression models estimating risk for a positive assessment in each domain as a function of SVI and several covariates. Covariates were selected based on hypothesized confounding and included age, sex, and assessment source. Race and ethnicity were summarized for context but not used in models, as roughly 30% of observations were missing not at random.

Univariate logistic regression was first used to estimate risk for a positive assessment overall and by domain as a function of SVI. Next, multivariate logistic regression models were used to additionally adjust for age, sex, and assessment source. Model estimates were computed in 2 ways to illustrate associations between independent variables and responses: first, as odds ratios (ORs) representing the estimated increase in positive assessment risk corresponding to a 1-U increase in SVI quintile; and second, as ORs representing the estimated increase in risk for a positive assessment, comparing the highest risk group (quintile 5) with the lowest risk group.

Because logistic regression models assumed that the association between SVI and the outcome was consistent across all levels, additional robustness tests were conducted using generalized additive models (GAM). These determined whether more complex models accounting for nonlinear associations between SVI and the log odds of a positive assessment produced meaningfully different results. The GAM inputs were identical to logistic regression model inputs, except SVI was measured in percentile ranks rather than quintiles to allow for the capture of full measure variability. Smoothing functions were included for SVI and age. To interpret and compare results from GAMs to logistic regression results, marginal contrasts transformed to the response scale were computed to produce ORs for intervals approximating the quintiles used in logistic regression models. Specifically, ORs were estimated across each 20% increment of the SVI distribution to mirror the estimated effect of a 1-U increase in quintile. Because this involves a large number of statistical comparisons, the Holm method of P value correction was implemented, with 2-sided P < .05 indicating statistical significance. All statistical analyses were completed in R, version 4.0.0 (R Project for Statistical Computing).

Overall, 841 874 assessments were recorded for 401 697 unique individuals ( Table 2 ). The respondent population included 180 545 men (44.9%) and 221 152 women (55.1%) with a median (IQR) age of 55 (41-70) years. In terms of race, 342 respondents (0.1%) were American Indian or Alaska Native, 2915 (0.7%) were Asian, 20 034 (5.0%) were Black, 153 (0.03%) were Native Hawaiian or Other Pacific Islander, 281 090 (70.0%) were White, 3760 (0.9%) were of other race, and 93 403 (23.3%) were of unknown race. In terms of ethnicity, 3365 respondents (0.8%) were Hispanic or Latino, 295 299 (73.5%) were non-Hispanic or non-Latino, and 103 033 (25.6%) were of unknown ethnicity. The mean overall SVI for the cohort was in the 35th percentile, indicating that on average, the study population resided in communities somewhat less vulnerable than the national average. Individuals reporting SDoH needs were more likely to live in neighborhoods with above-average SVI than those reporting no needs (35.1% vs 24.9%). Needs were identified in 120 769 assessments (14.3%), with little variation in overall positivity rates during the collection period. The most commonly reported needs were financial resource strain (44 187 [6.6%]), housing instability (29 579 [4.0%]), health literacy (29 662 [4.3%]), and social connections (22 803 [3.5%]). Among positive assessments, 35 172 (29.1%) indicated needs in multiple domains.

Across all domains, increasing social vulnerability was associated with higher positivity rates in the SDoH assessment; in total, 11.2% of those residing in the lowest-risk quintile for overall SVI reported a need compared with 22.7% among those residing in the highest-risk quintile ( Figure 1 ). 12 - 18 However, the strength of the associations varied by domain. Financial resource strain, food insecurity, transportation access, and safety had the strongest association with SVI. Health literacy and social connections had the weakest associations with SVI. While absolute percentage point differences in positivity between low and high SVI were especially large for more prevalent needs like financial resource strain, smaller percentage point differences for less prevalent needs like transportation and safety translated to large relative increases in positivity. Associations also varied considerably across the 4 individual SVI themes. Overall, socioeconomic and racial and ethnic minority status themes were more strongly associated with positive assessments for all SDoH needs than household characteristics or housing type and transportation themes. Results from logistic regression models ( Table 3 ) largely mirrored bivariate findings. Even after adjusting for covariates, odds of a positive assessment were significantly higher with increasing SVI for all combinations of outcome and SVI theme. There were clear differences in the strength of the various SVI scores. The socioeconomic theme had the strongest association with 6 SDoH domains (range of adjusted ORs [AORs], 1.70 [95% CI, 1.58-1.84] to 4.03 [95% CI, 3.75-4.34]) and had a stronger association with every domain than did the composite SVI. The racial and ethnic minority status theme was most strongly associated with housing instability (AOR, 2.37 [95% CI, 2.20-2.56]) and more strongly assocated with all 7 outcomes than with household characteristics and housing type and transportation themes.

Even among the consistently stronger SVI estimates, associations varied greatly by SDoH domain. By a large margin, food insecurity was most closely associated with SVI. On average, risk for food insecurity increased by 39% with each quintile increase in socioeconomic SVI, and odds were 300% higher among those in the highest vs the lowest risk quintile (AOR, 4.03 [95% CI, 3.75-4.34]; AOR range, 1.74 [95% CI, 1.62-1.86] to 3.73 [95% CI, 3.48-4.00] for the other SVI measures). Financial resource strain, housing instability, transportation, and safety all had positive associations with overall, socioeconomic, and racial and ethnic minority status SVI, with AORs ranging from 2.23 (95% CI, 2.09-2.38) to 3.05 (95% CI, 2.71-3.42).

Results of generalized additive models suggest that some degree of nonlinearity in the association between SVI and positive SDoH screening was typical and easily detected in our very large sample. eFigures 1 to 2 and eTables 2 to 7 in Supplement 1 provide full model information, including parametric coefficients and smoothed terms, partial effects smooth plots, and ORs calculated across the SVI distribution. These models highlight notable themes regarding the specific shape of the positive relationship between SVI and positive responses. For overall and socioeconomic SVI, the largest increases in risk were seen at the low and high end of the SVI range, particularly from the 80th to 100th risk percentile. The racial and ethnic minority status theme was generally associated with larger increases in risk over each increasing quintile. The household characteristics theme had the most nonlinearity of all SVI measures, in part due to a consistently steep increase in risk over the top 20% of the SVI distribution.

The severity and complexity of assessed needs was also positively associated with overall SVI ( Figure 2 ). A total of 4382 assessments from individuals living in the lowest quintile SVI areas (1.7%) had a composite score at or above 10, while 3567 assessments from individuals living in the highest quintile SVI areas (6.7%) met or exceeded a composite risk score of 10.

We found that social needs identified through the broad deployment of an SDoH assessment tool correlated with a geographically based community vulnerability index. 4 This was true for domain-specific SDoH needs and for composite scores representing overall severity and complexity of SDoH needs. As hypothesized, the strength of the associations varied across the 4 SVI themes. Individual SDoH needs were not necessarily most closely associated with the corresponding SVI theme.

There are important practical implications for these findings. Appropriate provision of limited resources for addressing social needs is often complicated by the lack of individual-level data. As a result, area-level measures like SVI are commonly used to guide targeting, despite little evidence linking these measures to self-reported needs. While these findings confirmed a general positive association between SDoH and SVI, the socioeconomic and racial and ethnic minority status SVI themes were more closely associated with the full range of SDoH needs than other themes. These themes likely reflect broader societal and historical factors, including longstanding laws and policy decisions such as redlining and unfair lending practices that contribute to ongoing systemic and structural racism. Notably, among study participants with race and ethnicity data available, only approximately 7.5% identified as Black or Hispanic. Thus, racial and ethnic minority status SVI may reflect not only the direct consequences of structural racism on members of marginalized racial and ethnic minority groups, but also effects of the resulting inequitable distribution of resources on communities more broadly. Self-reported SDoH needs related to health literacy and social connections had a much weaker association with SVI measures than needs in other domains, suggesting that alternative approaches to risk stratification may be required for these domains. Finally, although the odds of positive screening for 1 or more SDoH needs were up to 3 times higher among those in the highest quintile of SVI risk compared with the lowest, more than 3 in 4 individuals in the highest risk group reported no SDoH need. Despite the COVID-19 pandemic, SDoH identification rates remained relatively constant over 40 months of follow-up, never deviating more than 1.2% in any year.

This study has several strengths. First, we are unaware of any prior reports in which a cohort of this size was used to compare an SDoH assessment tool with the often-cited census-based SVI. Second, several features of the study strengthen generalizability: the cohort was diverse and included individuals with all insurance statuses and types, and individuals were assessed in a variety of settings and modalities. Third, self-reported SDoH needs were captured using a standard instrument consisting of validated questions.

This study also has several limitations. While self-reporting is the gold standard for capturing SDoH needs, the true extent of needs may be underreported due to distrust of the health care system, stigma, or fear of negative consequences, which may vary by SVI. Additionally, assessments capture a snapshot of needs. This may lead to underreporting of needs, as they are often episodic in nature. While in aggregate this population had a below average SVI risk, there were still several thousand individuals in every SVI quintile, allowing for high-powered comparisons across all levels. Because most respondents engaged with the assessment during a clinical encounter or through a payer program related to clinical factors, the assessed population tended to be biased toward those who use medical services. Notably, for identifying or intervening in issues closely related to limited access to medical services, measures like SVI that do not contain this bias may be more suitable. We did not assess comorbidities, so it is unknown whether differences in health status by SVI may contribute to the higher rate of SDoH needs among those in highly vulnerable neighborhoods. However, the association between SVI and SDoH needs in regression models was robust to age, sex, and assessment source, which likely captures some variability related to health status. The study was also limited by unavailable or incomplete data for race and ethnicity, language, income, and educational level.

In this cross-sectional study of self-reported SDoH needs and their association with community-level social vulnerability measures, individuals who lived in high SVI areas were more likely to have 1 or more SDoH issues and were far more likely to have significant needs across multiple domains. These findings cross-validate both assessment tools and underscore the interrelated nature and relevance of both personal and community context in social needs. 19 - 23 A more complete understanding of risk and protective factors at both levels, including their interactions, can inform targeted and cross-sector interventions to significantly affect health care outcomes. We believe that using person-level SDoH data in conjunction with area-level data will allow clinicians, health systems, scientists, and payers to advance clinical outcomes and health equity through more cost-effective outreach efforts.

Future studies should analyze differences by individual factors like sociodemographic characteristics and health status, as well as other community-level factors like rurality and treatment access, to help identify meaningful heterogeneity in patterns of SDoH needs. Such investigations may inform the development of more tailored interventions and improve targeted outreach and services. Additionally, future research leveraging longitudinal assessment data may elucidate need patterns over time and the factors that contribute to or hinder SDoH gap closure and maintenance. Finally, predictive models trained on existing assessment results and other associated data points may be leveraged to identify individuals at high risk for SDoH needs who have not yet been assessed.

Accepted for Publication: March 18, 2024.

Published: May 20, 2024. doi:10.1001/jamanetworkopen.2024.12109

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2024 Brignone E et al. JAMA Network Open .

Corresponding Author: Emily Brignone, PhD, SDOH and Research Enablement Analytics, Highmark Health Research Institute, 120 Fifth Ave Pl, Pittsburgh, PA 15222 ( [email protected] ).

Author Contributions: Dr Brignone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Brignone, Sinoway.

Drafting of the manuscript: Brignone, Lejeune, Sinoway.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Brignone.

Administrative, technical, or material support: Lejeune, Mihalko, Shannon.

Supervision: Sinoway.

Conflict of Interest Disclosures: None reported.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We thank the Richard King Mellon Foundation for programming to identify and address the social needs of communities in Pennsylvania, including funding for programs administered by our institution that are interrelated with the screening and referral practices described in the study. Sarah Carey, MS, Jade Chang, MA, and Jacalyn Newman, PhD, of Allegheny Health Network’s Health System Publication Support Office (HSPSO) assisted in editing and formatting the manuscript, for which they received no additional compensation.

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• Published: 17 May 2024

Metabolic landscape and pathogenic insights: a comprehensive analysis of high ovarian response in infertile women undergoing in vitro fertilization

• Ling-Ling Ruan 1 , 2 ,
• Xing-Yu Lv 6 ,
• Yu-Lin Hu 6 ,
• Ming-Xing Chen 2 ,
• Jing-Tang 9 ,
• Zhao-Hui Zhong 2 ,
• Mei-Hua Bao 7 ,
• Li-Juan Fu 2 , 7 ,
• Xin Luo 8 ,
• Shao-Min Yu 3 ,
• Qi Wan 4 , 5 , 6 &
• Yu-Bin Ding 1 , 2  

Journal of Ovarian Research volume  17 , Article number:  105 ( 2024 ) Cite this article

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In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients’ unique serum metabolic profiles and provide insights into the disease’s pathogenesis.

We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL.

The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR.

Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.

Introduction

The latest report from the World Health Organization (WHO) highlights a statistic: approximately 17.5% of adults globally, equivalent to one in six patients, grapple with infertility [ 1 ]. Assisted reproductive technology (ART) emerges as a potent solution to help this demographic achieve pregnancy [ 2 ]. At the core of ART lies controlled ovarian stimulation (COS), which employs ovulation-stimulating drugs to simultaneously foster the simultaneous development of multiple ovarian follicles, facilitating the retrieval of numerous mature oocytes [ 2 ]. However, the pursuit of a high ovarian response presents a formidable challenge: mitigating the risk of ovarian hyperstimulation syndrome (OHSS). This iatrogenic complication manifests as ovarian cystic enlargement, heightened vascular permeability, and fluid extravasation into the third space, potentially leading to severe consequences such as acute respiratory distress, anuria/acute renal failure, thromboembolism, etc [ 3 ]. Current estimates indicate the incidence of moderate to severe OHSS in patients undergoing in vitro fertilization (IVF) at 1-5% [ 4 ]. Although various strategies have been employed to reduce OHSS incidence, consensus remains elusive due to divergent efficacy and safety outcomes [ 4 , 5 ].

Concurrently, when COS technology is employed to augment oocyte numbers, some patients may experience high ovarian response, with 29.7% of these patients being at high risk of developing OHSS (Supplementary Fig.  1 ). For this high-risk group of OHSS, clinicians will generally cancel embryo transfer to minimize the occurrence of late-onset OHSS in them [ 6 , 7 ]. This decision not only prolongs the path to successful conception but also poses a mental and physical challenge for the patient. However, there has been insufficient research attention directed towards this specific group, as the majority of studies have predominantly focused on individuals already diagnosed with OHSS. Therefore, urgent investigation is warranted to delineate differences between these patients and those with normal ovarian response, elucidate the underlying physiological and pathological mechanisms, and provide clues for targeted care in the future.

Metabolomics has proven valuable in exploring disease etiology and understanding normal physiological conditions [ 8 , 9 , 10 ]. Recent studies have unveiled notable differences in maternal serum levels of niacin and niacinamide metabolic-pathway-related substances between women with poor ovarian response and control groups [ 11 ]. Simultaneously, changes in maternal serum glutamic acid, aspartate, and 1-methylnicotinamide levels were significantly associated with improved symptoms in women with PCOS [ 12 ]. In cases of OHSS symptoms, researchers identified elevated follicular fluid levels of mannitol and pyruvate alongside decreased levels of L-carnitine and creatinine [ 13 ]. Additionally, investigations into women undergoing IVF revealed correlations between the majority of amino acids in serum and the number of mature oocytes [ 14 ]. Despite these advancements, the metabolic profiles of patients who exhibit high ovarian response and are at risk for OHSS remain unknown.

Given the prevalence of OHSS risk among a significant number of patients with PCOS and the close association between PCOS and reproductive issues [ 15 ], it is imperative to investigate the pathogenic mechanisms within the PCOS population. This exploration is essential for enhancing OHSS incidence management and improving pregnancy success rates despite the apparent effectiveness of infertility treatments/strategies, including IVF as the final step [ 16 ]. Furthermore, while some studies have identified abnormal expression of unsaturated fatty acid metabolites in follicular fluid as a risk factor for OHSS in PCOS patients using metabolomics [ 17 ], it remains unclear whether the presence of abnormally expressed metabolites in maternal serum is also associated with high ovarian response in PCOS patients.

Considering the intricate connection among high ovarian response, PCOS, and OHSS, this study aims to investigate the serum metabolic profiles of patients who exhibit high ovarian response and are at risk for OHSS within the tubal infertility and PCOS framework. The objective is to elucidate the metabolic profiles of this frequently overlooked population, thereby offering a valuable reference point for further research on the pathological mechanisms.

Materials and methods

Participants.

This study obtained ethical approval from both Sichuan Jinxin Xinan Women & Children’s Hospital (No. 2021014) and the Ethics Committee of Chongqing Medical University (No. 2021060). Informed consent was acquired from all participants, adhering to the principles outlined in the Declaration of Helsinki. The proportion of different ovarian responses following COS in ART was conducted utilizing data from 19,240 participants who underwent ART for the first time between January 2021 and December 2022. This data was sourced from the electronic database of Sichuan Jinxin Xinan Women & Children’s Hospital. The metabolomics investigation focused on participants from the “CYART Cohort,” a study group established at Sichuan Jinxin Xinan Women and Children ’ s Hospital in southwest China [ 18 ]. From December 2021 to December 2022, serum samples from 145 participants were selected for metabolic analysis based on specific inclusion and exclusion criteria, which are outlined as follows:

Inclusion criteria: (1) Ovulation-Stimulating Regimen: GnRH antagonist regimen. (2) Embryo Transfer Cycle Specification: the first embryo transfer cycle. (3) Age between 20 and 35 years, (4) Body Mass Index (BMI) ≤ 28 kg/m². (5) Infertility factors in the CON group: Tubal factors. (6) The diagnosis of PCOS is based on the “Chinese Polycystic Ovary Syndrome Diagnosis and Treatment Guide,” established by the Endocrinology Group of the Gynecology and Obstetrics Branch of the Chinese Medical Association in 2018 [ 19 ]. These diagnostic criteria are derived from the Rotterdam criteria [ 20 ].

Exclusion criteria: (1) History of ovarian surgery, including procedures such as cyst dissection and oophorectomy. (2) Hormone therapy within three months before treatment. (3) Contraindications to ovulation induction therapy. (4) Other systemic abnormalities, including genetic, endocrine, infectious and autoimmune diseases.

Subsequently, these 145 participants were categorized into two main groups based on clinical diagnosis: The control group (CON, n  = 80) comprised patients clinically diagnosed with tubal factor infertility during IVF. The PCOS group ( n  = 65) consisted of patients clinically diagnosed with PCOS infertility during IVF. Within the CON group, we further subdivided them into two categories: The normal response group (CON-NOR, n  = 40) comprised patients diagnosed with tubal infertility who exhibited a normal ovarian response during IVF (10–15 oocytes after COS). The high response group (CON-HOR, n  = 40) comprised patients diagnosed with tubal infertility who exhibited a high ovarian response and were at risk for OHSS during IVF (> 15 oocytes after COS). Similarly, within the PCOS group, we subdivided them into two categories: The normal response group (PCOS-NOR, n  = 26) comprised patients diagnosed with PCOS infertility who exhibited a normal ovarian response during IVF (10–15 oocytes after COS). The high response group (PCOS-HOR, n  = 39) comprised patients diagnosed with PCOS infertility who exhibited a high ovarian response and were at risk for OHSS during IVF (> 15oocytes after COS). The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL.

GnRH antagonist regimen

Between the second and fourth days of the menstrual period, gonadotropin (Gn) medications (such as Urofollitropin, Menotropins, Gonal F, Puregon, Fostimon, Menopur, Kim Sai Heng) were administered at a dosage ranging from 100 to 300 IU/day, with close monitoring of follicle development. Dosage adjustments to the Gn were made as necessary. Upon reaching a dominant follicle diameter of ≥ 12–14 mm or on gonadotropin days 5–6, daily subcutaneous injections of 0.25 mg of gonadotropin-releasing hormone (GnRH) antagonists (ganirelix acetate) were initiated and continued until the day of ovulation trigger.

The reference standards for triggering ovulation can be determined based on the size and quantity of target follicles and the levels of E2, LH, and progesterone. Ovulation triggering is initiated when there are three dominant follicles with a diameter of ≥ 17 mm each or two dominant follicles with a diameter of ≥ 18 mm each, while also considering the progesterone and estradiol levels. Two options are available for the triggering process: recombinant hCG at 250 µg or triptorelin acetate at 0.2 mg can be utilized.

Serum collection

All serum samples were obtained on the day of the ovulation trigger. Fasting venous blood was carefully collected into tubes, followed by centrifugation at 3500 rpm for 10 min at 4 ℃. The isolated serum was then subpackaged into new EP tubes, rapidly frozen in liquid nitrogen, and stored in a -80 °C refrigerator for long-term preservation until further analysis.

Serum sample preparation and derivatization for GC-MS analysis

Thawing was conducted in an ice bath to ensure the quality of serum samples. A 150 µl aliquot of serum was then mixed with 50 µl 4 M NaOH, 4 µl internal standard (10 mM 2,3,3,3-D4-alanine, Sigma, USA), and 200 µl methanol. After a 15-minute incubation at room temperature, the mixture underwent centrifugation at 12,000 rpm for 15 min. Following centrifugation, 300 µl of the supernatant was carefully transferred to a new glass test tube, where 34 µl pyridine (Sigma, USA) was added and thoroughly mixed. Next, 20 µl methyl chloroformate (Sigma, USA) was added twice, with a vortex mix for 30 s after each addition. Subsequently, 400 µl of chloroform and 400 µl of NaHCO 3 solution were sequentially added, with a vortex mix for 10 s after each addition. To facilitate phase separation, the blended liquid was centrifuged at 2000 rpm for 10 min, and the upper water and intermediate protein layers were carefully discarded. Following this step, sodium sulfate, similar to mung beans, was added to the lowest chloroform layer for water absorption. Finally, 200 µl of the resulting liquid phase, containing derivatized metabolites, was transferred into the GS automatic sampler sample bottle for subsequent analysis.

2.5 Instrumentation and parameters for metabolomic profiling

This study utilized an Agilent Intuvo 9000 gas chromatograph coupled to an Agilent MSD5977B mass spectrometer detector employing electron-impact ionization(70 eV) to analyze derivatized metabolites. Metabolite separation was achieved using a BD-1701 gas phase capillary column (30 m × 0.25 mm × 0.25 μm film thickness, Agilent Technologies).

The GC inlet was configured in splitless mode, with the injector temperature set at 290 °C. Helium was the carrier gas at a flow rate of 1.0 ml/min. The GC oven temperature followed a gradient protocol, starting at 45 °C and increasing to 180 °C at a rate of 9.0 °C/min, then to 220 °C at 40.0 °C/min, followed by an increase to 240 °C at 40.0 °C/min, and finally reaching 280 °C at 80.0 °C/min. The temperature settings for the auxiliary, MS quadrupole, MS source, and guard chip were 250 °C, 230 °C, 150 °C, and 280 °C, respectively. Mass detection occurred within the range of 50 μm to 550 μm, with a scan speed of 1.562 µs after a solvent delay of 5.5 min.

Metabolite deconvolution was facilitated by the Automatic Mass Spectrometry Deconvolution & Identification system software. Metabolite identification relied on comparing MS fragmentation patterns, specifically the mass-to-charge ratio and relative strength of the mass spectrum, alongside respective GC retention times, referencing an in-house MS library constructed with chemical standards. Any remaining putative compounds were identified using a commercial NIST mass spectral library. Relative concentrations of metabolites were extracted using a MassOmics R-based script through the peak height of the most abundant fragment ion mass.

Absolute quantification of metabolite concentration

Each metabolite analyzed was paired with a corresponding chemical standard for quantification. Chemical compound standards, including typical amino acids, fatty acids, and glucose metabolites, were utilized for this purpose. A standard curve for these metabolites was established based on the peak height corresponding to their concentrations. Subsequently, the concentration of metabolites detected in serum samples was normalized by the internal standard and quantified according to the standard curve established previously.

Quality control

Quality Control (QC) samples were incorporated into this study to ensure data quality and mitigate batch-to-batch variations. Preparing QC samples involved mixing samples of the same volume to be tested and subjecting them to the same pre-treatment method as the samples under investigation. Subsequently, the processed QC samples were introduced into the GC-MS system alongside the test samples for detection and analysis. The operation followed the protocol of inserting a processed 20 µl QC sample after every 15 test samples. Each metabolite’s relative standard deviation (RSD) was computed during the data processing stage. Metabolites with an RSD > 30% were excluded from further data analysis.

Data processing and statistical analysis

The Human Metabolome Database (HMDB) and PubChem were referenced to retrieve and further identify the detected metabolites in this study. Subsequently, all metabolite concentration values underwent normalization through Metaboanalyst 5.0 ( www.metaboanalyst.ca ). The differential metabolites were identified through a combined approach utilizing the False Discovery Rate (FDR) from the t-test and the Variable Importance in Projection (VIP) value based on the Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) model. The threshold criteria were VIP > 1.0, P  value < 0.05, and FDR < 0.2. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to elucidate the potential pathways involved. Binary logistic regression models, adjusted for age, BMI, and AMH as covariates, were utilized to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationship between differential metabolites and the risk of HOR. Metabolites with significant associations ( P  value < 0.05) were identified as related to HOR risk within the defined groups. Spearman correlation analysis examined the associations between metabolites and clinical characteristics. Correlations with coefficients (R2) ≥ 0.2 or R2 ≤ -0.2 and P  value < 0.05 were deemed statistically significant. All statistical analyses and visualizations were executed using the R software.

Clinical characteristics of participants

In this study, 145 infertile patients were categorized into two main groups: 80 in the CON group and 65 in the PCOS group. Within the CON group, there were two subgroups: CON-NOR ( n  = 40) and CON-HOR( n  = 40). Similarly, within the PCOS group, there were two subgroups: PCOS-NOR ( n  = 26) and PCOS-HOR ( n  = 39).

The clinical characteristics are depicted in Fig.  1 A and Supplementary Table 1 . Notably, within the CON group, the CON-HOR subgroup displayed lower basal serum FSH levels than the CON-NOR subgroup. However, no such difference was observed between the two PCOS subgroups. Furthermore, no significant differences were found between NOR and HOR patients in both CON and PCOS groups regarding other characteristics such as age, BMI, basal serum E2 levels and basal P levels. Additionally, HOR patients in both groups demonstrated significantly higher levels of various characteristics, including E2 level on hCG day, the number of follicles ≥ 14 mm and ≥ 17 mm in diameter on hCG day, as well as the number of follicles, oocytes retrieved, mature oocytes, and MII oocytes compared to the NOR patients.

Comparative Analysis of Clinical Characteristics

Comparative analysis of clinical characteristics among different subgroups was conducted using the Wilcoxon rank-sum test. The legend indicates key abbreviations: CON (Tubal infertility), PCOS (Polycystic Ovarian Syndrome), NOR (Normal Ovarian Response), HOR (High Ovarian Response and at risk for OHSS), BMI (Body Mass Index), FSH (Follicle-Stimulating Hormone), E2 (Estradiol), Gn (Gonadotropin), and hCG (Human Chorionic Gonadotropin). Statistical significance was set at P  < 0.05 (* P  < 0.05; ** P  < 0.01; *** P  < 0.001)

Metabolic landscape within subgroups

A total of 125 different metabolites were identified in this study. Principal Component Analysis (PCA) initially indicated no significant difference in metabolic profiles between NOR and HOR patients in CON and PCOS groups (data not presented). To further verify the differences between NOR and HOR patients, we proceeded with OPLS-DA analysis to maximize the differences between subgroups in the model. The results demonstrated a significant divergence between NOR and HOR patients within the CON and PCOS groups (Supplementary Fig.  2 ).

In the CON group, four metabolites exhibited significant differences between the CON-NOR and CON-HOR subgroups ( P  < 0.05, FDR < 0.2, VIP > 1): 10-pentadecenoic acid, glycine oxidized, glutathione, and N-acetyl-L-leucine (Fig.  2 A and Supplementary Table 2 ). Similarly, in the PCOS group, 14 metabolites serum metabolites displayed significant variances between the PCOS-NOR and PCOS-HOR subgroups ( P  < 0.05, FDR < 0.2, VIP > 1). Among these metabolites, eight were amino acid metabolites, including glycine, N-acetyl-L-leucine, sarcosine, tyrosine, beta-alanine, ornithine, alanine, and valine, with lower levels observed in the PCOS-HOR subgroup (Fig.  2 and Supplementary Table 3 ). Furthermore, oxidized glutathione, another amino acid metabolite, was elevated in the PCOS-HOR subgroup. Additionally, tricarboxylic acid cycle (TCA) metabolites, such as succinic acid and fumaric acid, showed significantly lower levels in the PCOS-HOR subgroup compared to the PCOS-NOR subgroup. Similarly, fatty acid metabolites such as (10E,12Z)-octadecadienoic acid (C18_2n-10) and tryptamine metabolites like 5-methoxytryptamine were notably elevated in the PCOS- HOR subgroup compared to the PCOS-NOR subgroup.

Differential metabolic profiles in serum of HOR patients

( A ) Heatmap illustrating the detected differential metabolites across each group, indicating the ratio of metabolite levels in subgroup comparisons. The color gradient reflects concentration disparities, with red indicating higher concentrations in the HOR group compared to the NOR group and blue representing lower concentrations. ( B ) The box and scatter plots display the concentrations of differential metabolites across various subgroups. Statistical significance was set at P  < 0.05 (* P  < 0.05; ** P  < 0.01; *** P  < 0.001), while ‘ns’ denotes non-significance

Interestingly, glycine and oxidized glutathione emerged as differentiated metabolites between NOR and HOR patients in both the CON and PCOS groups. Specifically, glycine levels consistently trended lower in HOR patients compared to NOR patients across both groups, while oxidized glutathione levels consistently trended higher in HOR patients (Fig.  2 ).

KEGG enrichment analysis of key metabolic signatures in all participants

We conducted a KEGG enrichment analysis on the identified differential metabolites. In the CON group, where only four metabolites displayed significant differences between the CON-NOR and CON-HOR subgroups, the decision was made to discontinue the KEGG analysis for this group. However, for the PCOS-NOR and PCOS-HOR subgroups, encompassing 14 differential metabolites, KEGG analysis revealed significant enrichment across several pivotal pathways, namely aminoacyl-tRNA biosynthesis, glutathione metabolism, and pantothenate and CoA biosynthesis (Fig.  3 ). These pathways are crucial for maintaining essential cellular processes and physiological functions. Specifically, aminoacyl-tRNA biosynthesis is vital for protein synthesis [ 21 ], glutathione metabolism plays a key role in cellular defense against oxidative stress [ 22 ], and pantothenate and CoA biosynthesis is critical for energy metabolism and the TCA cycle [ 23 ].

KEGG pathway enrichment analysis of differential metabolites in PCOS subgroup

KEGG pathway enrichment analysis of differential metabolites identified in the comparison between the PCOS-NOR and PCOS-HOR subgroups. The vertical axis represents distinct metabolic pathways, while the horizontal axis indicates the Holm-adjusted P  value. The circle size reflects the number of Hits, and the color indicates Hits.Ratio

Identification of HOR Risk-Associated metabolites

After thorough adjustments for age, BMI, and AMH using binary logistic regression, a specific differential metabolite emerged as significantly associated with CON-HOR risk in the CON group. Specifically, 10-pentadecenoic acid demonstrated an increased risk of CON-HOR by 1.16-fold (95% CI 1.02–1.31; P =0.020) with each standard deviation (SD) increment (Fig.  4 and Supplemental Table 4 ).

Associations between differential metabolites for HOR: adjusted OR (95% CIs) from binary logistic regression analysis

aOR: adjusted odds ratio; CI: confidence interval

In the PCOS group, we observed 14 differential metabolites between the PCOS-NOR and PCOS-HOR subgroups. Due to the limitations in sample size, we prioritized metabolites for further analysis based on the VIP scores. Specifically, we focused on the top four metabolites ( P  < 0.001, FDR < 0.1) for subsequent binary logistic regression analysis. Notably, after adjustments for age, BMI, and AMH, our findings revealed that the risk of PCOS-HOR escalated by 1.02 (95% CI 1.01–1.05;  P =0.019) with each SD increase in cysteine levels and 4.17 (95% CI 1.58–11.16; P =0.004) with each SD increase in 5-methoxytryptamine levels (Fig.  4 and Supplemental Table 5 ).

Correlations of Differential Metabolite with Clinical Characteristics in NOR and HOR Subgroups of CON and PCOS

Four differential metabolites differed between the CON-NOR and CON-HOR subgroups in the CON group. These four metabolites showed significant correlations with the number of oocytes retrieved and MII oocytes. However, none correlated with the total dose of Gn (Fig.  5 and Supplemental Tables 6 – 7 ).

Spearman correlation analysis between differential metabolites and clinical characteristics

Positive correlations are denoted in blue, while negative correlations are depicted in red. The size of each sector corresponds to the correlation coefficient. The green-filled sectors represent correlations lacking statistical significance

Within the PCOS group, 14 metabolites differed significantly between the PCOS-NOR and PCOS-HOR subgroups. Among these, excluding (10E,12Z)-octadecadienoic acid (C18_2n-10) and valine, the remaining 12 metabolites demonstrated notable correlations with the number of oocytes retrieved and MII oocytes. Noteworthy is that only alanine and proline displayed significant correlations with the total dosage of Gn, while the others showed no such correlation (Fig.  5 and Supplemental Tables 8 – 9 ).

Interestingly, glycine and oxidized glutathione emerged as differential metabolites between NOR and HOR patients in both the CON and PCOS groups. In both groups, glycin displayed significant negative correlations with basal AMH levels, E2 levels on hCG day, the number of follicles ≥ 14 mm and ≥ 17 mm in diameter on hCG Day, as well as the number of oocytes retrieved, mature oocytes, and MII oocytes. Conversely, oxidized glutathione demonstrated significant positive correlations with these clinical characteristics (Fig.  5 and Supplemental Tables 6 – 9 ).

3.6. Unveiling Shared metabolic signatures: insights into PCOS and HOR Pathogenesis

To investigate potential similarities in metabolic profiles between PCOS and HOR, we analyzed metabolite changes within the PCOS group. Our findings revealed 29 metabolites identified as differential between the PCOS and CON-NOR groups ( P  < 0.05, FDR < 0.2, VIP > 1, Supplementary Table 10 ). Notably, three of these metabolites—10-pentadecenoic acid, glycine, and oxidized glutathione—were also identified as differentially expressed between the CON-NOR and CON-HOR groups (Supplemental Fig.  3A ). Further analysis demonstrated that these three metabolites exhibited significant upregulation in both the PCOS and CON-HOR groups relative to the CON-NOR group (Fig.  6 ). This consistent alteration suggests a parallel in metabolic profiles between PCOS and HOR, hinting at a potential shared etiological similarity between the two conditions.

Comparative metabolite profiling in PCOS and CON subgroups

The box plot and scatter plot illustrate the concentrations of differential metabolite between PCOS and CON subgroups. Panels ( A , C , E ) display the metabolite concentrations between the CON-NOR and PCOS groups, while panels ( B , D , F ) show the metabolite concentrations between the CON-NOR and CON-HOR subgroups

Furthermore, KEGG pathway analysis of these metabolites revealed significant enrichment in aminoacyl-tRNA biosynthesis and glutathione metabolism pathways (Supplementary Fig.  3B ). These findings support earlier KEGG pathway analysis of differential metabolites in PCOS subgroups, indicating a close link between these pathways and the development of PCOS and PCOS-HOR.

In this study, we utilized GC-MS to investigate the serum metabolic profiles of patients with normal ovarian response and those exhibiting high ovarian response and at risk for OHSS in tubal and PCOS infertility. Our analysis revealed the identification of 4 and 14 differential metabolites between these two ovarian response patient subsets in each infertility background, respectively. Additionally, we observed a certain degree of similarity in the metabolic profiles between PCOS patients and those exhibiting high ovarian response and at risk for OHSS.

Previous studies have highlighted significant differences in amino acid and lipid metabolites within the follicular fluid of OHSS patients compared to control groups [ 13 , 17 , 24 ]. Similarly, multiple lipid components in the serum or follicular fluid of PCOS patients exhibit alterations [ 25 , 26 ], particularly noticeable in obese individuals with PCOS, where lipid abnormalities are most pronounced [ 27 ]. In line with these findings, our study also revealed abnormal elevations in several lipid metabolites, including myristic acid (C14_0), 10-pentadecenoic acid, lignoceric acid (C24_0), nervonic acid (C24_1n-9c), and hexanoic acid (C6_0), within the serum of PCOS group when compared to CON-NOR group.

Furthermore, some researchers explored the metabolic profiles of populations exhibiting different ovarian responses. Mu et al. [ 28 ] discovered that elevated glycine levels are associated with a heightened response to COS. Interestingly, our study contradicts this finding, as we observed lower glycine levels in the HOR patients across both infertility backgrounds. Additionally, glycine also showed negative correlations with several clinical characteristics, including levels of AMH, the number of oocytes retrieved, mature oocytes, and MII oocytes. The propensity for ovarian hyperstimulation significantly escalates in PCOS patients following COS stimulation [ 15 , 29 ]. Several metabolomic studies on PCOS patients have consistently documented significantly reduced glycine levels compared to controls [ 30 , 31 , 32 ], which aligns with our results of lower glycine levels in the PCOS group compared to the CON-NOR group. Furthermore, research has indicated heightened glycine expression in women with diminished ovarian reserve (DOR) [ 33 ], which is correlated with a poor response to ovarian stimulation [ 34 ]. However, it is noteworthy that a research has found a positive correlation between glycine and one marker of ovarian reserve, the antral follicle count (AFC) [ 35 ]. Considering these diverse research findings, the role of glycine in ovarian response remains unclear. Future studies should incorporate larger sample sizes from various regions and employ more rigorous experimental designs to elucidate the relationship between glycine and ovarian response.

Hood et al. [ 14 ] discovered that most fatty acids and amino acids in the serum metabolome correlate with the number of mature oocytes. Our study echoes these findings, as most differential metabolites between NOR and HOR patients are within the amino acid class. Moreover, these differential metabolites, including alanine, cysteine, glycine, ornithine, glutathione oxide, sarcosine, and tyrosine, demonstrate significant associations with the number of mature oocytes. This alignment underscores the importance of amino acid metabolism in modulating ovarian response and highlights its potential as a target for interventions to optimize oocyte yield.

Furthermore, our study revealed a significant enrichment of differential metabolites in the aminoacyl-tRNA biosynthesis pathway, both between PCOS-NOR and PCOS-HOR groups, and between PCOS and CON-NOR groups. This finding aligns with the investigation by Li et al., who focused on metabolic profiles in patients with DOR [ 36 ]. In their study, researchers noted a similar trend, wherein the metabolites distinguishing the DOR patients from patients with normal ovarian reserve were prominently associated with the aminoacyl-tRNA biosynthesis pathway [ 36 ]. The aminoacyl-tRNA biosynthesis pathway plays a pivotal role in cellular processes by coupling amino acids with their corresponding tRNA molecules, forming aminoacyl-tRNA complexes crucial for protein synthesis [ 21 , 37 ]. This fundamental process ensures the precise integration of amino acids into nascent polypeptide chains, thereby dictating proteins’ ultimate structure and function. These findings imply a potential link between the aminoacyl-tRNA biosynthesis pathway and reproductive disorders like PCOS and DOR. Nevertheless, further investigation is required to ascertain whether this pathway influences the onset of these conditions through its impact on protein synthesis.

In summary, this study identified the serum metabolic profiles of patients exhibiting high ovarian response and at risk for OHSS. However, several limitations should be acknowledged. Firstly, the relatively small overall sample size and the sole reliance on samples from a single medical institution limit the generalizability of our findings. Furthermore, this constraint impedes randomization and stratification of the sample, necessitating caution in interpreting our results. Secondly, to mitigate potential confounding effects, we applied stringent inclusion criteria for participant recruitment, restricting the age range to 20–35 years and setting a BMI threshold of ≤ 28 kg/m² for both groups. Hence, our study did not include older individuals or those with a higher BMI, and therefore, our findings may not fully represent the metabolic profile of the entire PCOS patients. Thirdly, our results offer an overview of metabolic aspects in PCOS patients but lack the detailed information required to identify different phenotypes within the patients. As a result, we are unable to characterize the unique metabolic profiles associated with these phenotypes.

Conclusions

Utilizing GC-MS technology, we described the metabolic profiles of specific patients who exhibit high ovarian response and are at risk for OHSS within both the tubal infertility group and the PCOS infertility group. The discovery of risk metabolites in these unique patients provides clues to studying their pathological mechanisms. Further, similarities in metabolic profiles between patients with PCOS and high ovarian response suggest a potential common underlying cause, urging more research into their connection.

Data Availability

To access the data supporting the findings of this study, kindly contact the corresponding author. They will be pleased to provide the necessary information upon request.

Abbreviations

Ovarian hyperstimulation syndrome

Tubal factor infertility

• Polycystic ovary syndrome

Normal ovarian response

High ovarian response and at risk for OHSS

Gas chromatography-mass spectrometry

In vitro fertilization

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Acknowledgements

We sincerely thank Dr Ting-Li Han and Miss Yang Yang from the Department of Obstetrics at the First Affiliated Hospital of Chongqing Medical University for their invaluable guidance and assistance in establishing the metabolomics methods and analyzing data. Their expertise and support were instrumental in making this work possible. Additionally, we would like to thank all the participants of this study and the medical staff for their valuable contributions.

This work received partial support from the National Key Research and Development Program of China (no. 2023YFC2705900), the National Natural Science Foundation of China (nos. 82171664, 81971391, 82171668), and the Natural Science Foundation of Chongqing Municipality of China (nos. CSTB2022NSCQ-LZX0062, CSTB2023TIAD-KPX0052).

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Ling-Ling Ruan & Yu-Bin Ding

Joint International Research Laboratory of Reproduction and Development of the Ministry of Education of China, School of Public Health, Chongqing Medical University, Chongqing, 400016, China

Ling-Ling Ruan, Ming-Xing Chen, Zhao-Hui Zhong, Li-Juan Fu & Yu-Bin Ding

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Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China

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Y.-B. D., QW and S.-M. Y.: Conceptualization and Design. L.-L. R., X.-Y. L., Y.-L. H., and M.-X. C.: Data Acquisition, Analysis, and Interpretation. L.-L. R.: Manuscript Writing. JT, Z.-H. Z., M.-H. B., and L.-J. F.: m. L.-L. R., and XL: Statistical Analysis. Y.-B. D. and XL: Funding acquisition.

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Ruan, LL., Lv, XY., Hu, YL. et al. Metabolic landscape and pathogenic insights: a comprehensive analysis of high ovarian response in infertile women undergoing in vitro fertilization. J Ovarian Res 17 , 105 (2024). https://doi.org/10.1186/s13048-024-01411-6

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Clinical differences between periprosthetic and native distal femur fractures: a comparative observational study

• Shana Kong 1 ,
• Shannon Tse 1 ,
• Aziz Saade 1 ,
• Barry Bautista 1 ,
• Max Haffner 1 &
• Augustine M. Saiz Jr. 1  

Journal of Orthopaedic Surgery and Research volume  19 , Article number:  303 ( 2024 ) Cite this article

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Introduction

The incidence of periprosthetic distal femur fractures (PDFF) is increasing as the number of total knee replacements becomes more common. This study compared the demographics, fracture characteristics, treatment, and outcomes of periprosthetic versus native distal femur fractures (NDFF).

Materials and methods

This was a retrospective cohort study of patients ≥ 18 who underwent surgical fixation of NDFF or PDFF from 2012 to 2020 at a level-1 trauma center. The main variables collected included demographics, AO/OTA fracture classification, fixation construct, concomitant fractures, polytrauma rates, bone density, and reduction quality. Primary outcomes were unexpected return to the operating room (UROR), hospital length of stay, and quality of reduction. T-tests, Fisher’s exact tests, and multivariate analyses were used for statistical analysis.

209 patients were identified, including 70 PDFF and 139 NDFF. PDFF patients were elderly females (81%) with isolated (80%) and comminuted (85%) 33 A.3 (71%) fractures. NDFF patients included 53% females, were commonly middle-aged, and displayed comminuted (92%) 33 C.2 fractures. 48% of NDFF patients had concomitant fractures. Intramedullary nailing was the primary fixation for both groups, followed by nail-plate combination (37%) for PDFF and lateral locking plates (21%) for NDFF. NDFF patients experienced significantly longer hospital stays, higher UROR rates, and worse quality of reduction ( p  < 0.05). PDFF patients had a significantly greater prevalence of low bone density ( p  < 0.05).

PDFF occur as isolated injuries with significant metaphyseal comminution in elderly females with low bone quality. NDFF commonly occurs in younger patients with less metaphyseal comminution and concomitant fractures. Intramedullary nailing was the most common treatment for both groups, although preference for nail-plate combination fixation is increasing. NDFF type 33 C fractures are at greater risk of UROR.

In 2012, total knee arthroplasty (TKA) was the single most common surgical procedure performed in the United States, with 94% of those procedures occurring in patients 65–84 years old [ 1 , 2 ]. As the population ages and the prevalence of TKA rises, the frequency of periprosthetic distal femur fractures (PDFF) has simultaneously increased. Multiple studies report that periprosthetic distal femur fractures are not uncommon following TKA [ 3 , 4 , 5 ]. Court-Brown et al. reported an increase in PDFF prevalence from 15.4 to 27.8% of all distal femur fractures from 2007 to 2011 [ 6 ]. Treatment of PDFF presents a challenge for orthopedic surgeons, who must consider not only the complex and variable fracture morphology associated with the prosthesis but also the specific populations at risk.

Previous studies have focused on analyzing PDFF and native distal femur fractures (NDFF) separately. Roy et al. analyzed NDFF exclusively at a single level-1 trauma center and characterized the affected population as middle-aged, female (66%), and more often overweight than osteoporotic [ 7 ]. Additionally, they identified similar rates of high-and low-energy trauma in their NDFF cohort and found that high-energy injuries were associated with more severe fracture types (AO/OTA 33B/C), open fractures, and additional orthopedic injuries, while low-energy injuries were associated with closed fractures and less severe fracture types (AO/OTA 33 A) [ 7 ]. Elsoe et al. first reported on the demographics of PDFF, noting a population distribution of elderly females (mean age = 77) with low-energy injuries [ 8 ]. Regarding treatment, lateral plating and retrograde intramedullary nailing (rIMN) have been reported as the most common and successful fixation methods for both PDFF and NDFF, although intramedullary nail-plate combination (NPC) fixation is a more recent technique developed to allow quicker weight bearing and achieve better purchase in osteoporotic bone [ 7 , 9 , 10 , 11 , 12 ]. Studies have reported similar 30-day and 90-day outcomes [ 13 , 14 ]. A previous case series reported that osteoporosis, comminution, intra-articular involvement, and soft tissue injury in open fractures were associated with worse long-term (> 5 years) outcomes such as malunion, nonunion, and infection in NDFF [ 15 ]. Reduction quality has yet to be studied in either group.

In the existing body of literature, there is a notable lack of comprehensive comparisons between PDFF and NDFF within single institutions. Studies have focused exclusively on one fracture type without directly comparing it with the other. As a result, there is limited understanding of the relative differences between PDFF and NDFF in terms of demographics, fracture characteristics, treatment modalities, and outcomes, as patients from both groups can only be compared from different studies, which potentially raises concerns such as selection bias, confounding, heterogeneity, and timeframe variations with historical comparisons.

While there is some consistency in the literature regarding these fracture types, there remains a need to systematically examine and compare them within the same population to further denote the remaining discrepancies which may arise from limited generalizability. Therefore, the primary objective of this study was to conduct a detailed comparison of PDFF and NDFF using data from a single institution. This paper contributes to our understanding of the differences in patient populations, specific injury patterns, and treatment strategies between periprosthetic and native distal femur fractures. Such insights are valuable for patient counseling. Moreover, attempting to adapt fixation strategies from one to the other may prove ineffective, thus prompting avenues for further exploration.

A secondary aim was to explore aspects such as the quality of reduction and long-term outcomes, which have not been extensively studied in prior literature. NDFF often have more complex fracture morphology and are not only more difficult to reduce but are further complicated by the need to restore length, planar alignment, and joint line congruity. In contrast, PDFF tend to be simpler fractures, but it can be challenging to achieve anchorage and maintain adequate fixation in highly comminuted, osteoporotic bone [ 16 ]. Studying reduction quality and long-term outcomes in these groups would provide valuable insight on whether current treatment strategies are achieving optimal fixation for both groups, and could guide future, more personalized treatment strategies to improve patient outcomes.

We hypothesize that PDFF are more likely to be isolated, simple, low-energy, injuries experienced by elderly patients while NDFF will be experienced by a younger population and result in more complicated fracture patterns due to higher levels of trauma.

Furthermore, we hypothesize that there will be no difference in postoperative outcomes between PDFF and NDFF groups.

Cohort selection

This retrospective study was approved by the Institutional Review Board. All patients who were at least 18 years of age at the time of admission with distal femur fractures between January 2012 and December 2020 at a single level-1 trauma center were identified. These patients were later classified as either NDFF or PDFF. Patients with bilateral distal femur fractures were excluded.

Data collection

Electronic medical records were used to obtain clinical and demographic data for each patient. American Society of Anesthesiologists (ASA) score and bone density status were obtained from clinical records. Presence of bone loss, classified as either osteopenia or osteoporosis, was determined by either previous diagnosis documented in the patient chart with a prior DEXA scan or by comments noted by radiologists from existing radiographs following a fragility fracture. Fracture characteristics, including AO/OTA fracture classification, were obtained from preoperative radiographs (Figs.  1 and 2 ) and computed tomography (CT) scans. Polytrauma was noted if present and defined as having two or more injuries affecting two or more bodily areas. Type of surgical fixation was obtained from operative notes and postoperative radiographs (Figs.  1 and 2 ). Patients with NPC fixation were categorized separately and did not contribute to nail or plate counts. Primary outcomes were unexpected return to the operating room (UROR), hospital length of stay, and quality of reduction. Postoperative outcome data was obtained using follow-up notes and postoperative radiographs.

Preoperative (left) and post-IMN (right) NDFF radiographs

Preoperative (left) and post-NPC (right) PDFF radiographs

Quality of reduction was assessed by calculating the difference in alignment from the population average anatomic lateral distal femoral angle (aLDFA) on postoperative anteroposterior (AP) radiographs. These measurements were made by a single trained grader. To measure the aLDFA (Fig.  3 ), a line was first drawn parallel to both femoral condyles of the affected femur, representing the knee joint line. Next, a line was drawn from the center of the femoral head to the intercondylar notch of the affected femur, representing the mechanical axis of the femur. The lateral angle formed between the mechanical axis of the femur and the knee joint line was recorded in degrees as the aLDFA. The aLDFA for the contralateral, unaffected femur was also calculated for use as a reference for each patient if contralateral films had been acquired. The mean difference from the published population average aLDFA of 81 degrees was calculated in the affected and unaffected femurs for both PDFF and NDFF groups [ 16 , 17 , 18 , 19 ]. A smaller deviation from the population average aLDFA was accepted as a more desirable outcome.

Measurement of aLDFA on AP radiographs

Statistical analyses

Differences between PDFF and NDFF patients were compared using Fisher’s exact tests, unpaired t-tests, or multivariate analyses, as appropriate for each variable using Microsoft Excel. Multivariate analysis was completed in Excel using a linear regression with all variables included. Results were described using incidence rates, means, and one standard deviation. A p-value < 0.05 indicated statistical significance.

In total, 209 patients were included in this study. Table  1 summarizes the preoperative characteristics of both cohorts. The mean age of NDFF patients was 23 years younger than the PDFF patients ( p  < 0.001). There were significantly fewer females in the NDFF cohort (53% compared to 81%, p  < 0.001). The PDFF cohort had significantly higher rates of bone loss (55.7% compared to 19.4%, p  < 0.001). There was no significant difference between the ASA scores of the two cohorts ( p  = 0.061).

Table  2 summarizes the fracture characteristics of the two cohorts. 33 A.2 and 33 A.3 classifications represented the entirety of PDFF. In comparison, NDFF AO/OTA classifications were represented by 33 C.2 (28%), 33 C.3 (22%), and 33B.1 (12%), which were significantly more prevalent than in the PDFF cohort ( p  < 0.001 for 33 C.2 and 33 C.3, and p  < 0.05 for 33B.1).

Table  2 also shows significant differences in the rate of isolated injuries and polytraumas between both cohorts. PDFF were more often isolated injuries in patients (80% versus 51.8%, p  < 0.001). NDFF patients were more likely to be polytraumatized (41% compared to 18.6%, p  < 0.001). Additionally, NDFF patients had higher rates of open fractures (30.7% compared to 11.2%, p  = 0.002). Out of 43 open NDFF fractures, 77% were Gustilo-Anderson type III open fractures (31 type 3 A, 2 type 3 C), 14% type II fractures, and 9% type I fractures (Table  2 ).

Of these open fractures, 41 underwent definitive fixation at first operation while 2 initially underwent external fixation due to the presence of an unstable knee (multiligamentous injury, fracture-dislocation). Out of 8 open PDFF fractures, 50% were Gustilo-Anderson type II, 25% type III, and 25% type I (Table  2 ). Only one PDFF patient was initially temporized with an external fixator before definitive fixation. There was no significant difference between the comminution rates of fractures in both cohorts ( p  = 0.274).

Table  3 summarizes the surgical fixation constructs used for both cohorts. Retrograde intermedullary nail was the most common fixation utilized in both groups, and there was no significant difference in the prevalence of rIMN between the two groups (NDFF = 36.7%, PDFF = 44.3%, p  = 0.297). NDFF patients had significantly higher rates of medial plate fixation (5.8% compared to 0%, p  < 0.05) and PDFF patients had significantly higher rates of NPC fixation (37.1% compared to 17.2%, p  < 0.05). Further analysis of NPC fixation revealed usage beginning in 2015 for both groups, with prevalence of usage increasing from 3.3% and 0.7–13.3% and 4.3% in 2019 (PDFF) and 2020 (NDFF) respectively. Of 13 PDFF that received plate fixation, only 2 had fracture patterns amenable for nail fixation but preexisting implants (long-stemmed proximal component, Schneider rods for osteogenesis imperfecta) precluded intramedullary fixation. The 11 PDFF patients that received plate fixation had stable femoral components and fracture morphology that could not be effectively reduced with intramedullary fixation.

Postoperative outcomes are summarized in Table  4 . Patients in the NDFF cohort had an approximately five-day longer length of stay compared to those in the PDFF cohort ( p  < 0.05). This was most likely because NDFF patients had more polytrauma (41% vs. 18.6%, p  < 0.001) and open injuries (30.7% vs. 11.2%, p  = 0.002) There was no significant difference in length of follow-up between the two cohorts ( p  = 0.564). Postoperatively, PDFF were significantly more likely to be weight bearing as tolerated (WBAT) compared to partial weight bearing (PWB) or non-weight bearing (NWB). NDFF postoperative weight bearing status consisted of 60% NWB, 21% WBAT, and 19% PWB. There was some correlation between postoperative weight bearing status and fixation. All NDFF patients who were WBAT underwent IMN, NPC, or lag screw fixation. Of patients who were NWB, 50% received plate fixation. There was no significant difference in WBAT assignment for NDFF who received NPC vs. nail or plate fixation alone ( p  = 0.88).

For NDFF patients who were NWB or PWB, there was no correlation with fixation. However, there was a correlation between weight bearing status and polytrauma. Rates of polytrauma were 99% and 52% in patients who were NWB and PWB, respectively. Additionally, a majority of patients (60%) who received IMN fixation and were PWB had concomitant extremity fractures, preventing them from having increased weight bearing.

PDFF postoperative weight bearing status consisted of 60% WBAT, 30% PWB, and 10% NWB. Again, there was some correlation between postoperative weight bearing status and fixation. 100% of patients who were WBAT underwent IMN or NPC fixation, while 50% of patients who were TDWB underwent plate fixation. PDFF that received NPC fixation were significantly more likely to be assigned WBAT compared to those that underwent nail or plate fixation alone ( p  < 0.05). For patients who were PWB or NWB, there was no correlation between postoperative weight bearing status and fixation.

Compared to their PDFF counterparts, NDFF patients had higher rates of any unexpected return to the operating room (UROR) occurrences (13.6% compared to 8.5%, p  < 0.05). Among the 19 NDFF requiring reoperation, 10 (52%) were AO/OTA type 33 C fractures. Irrigation and debridement (I&D) of the femur fracture of interest due to infection was the leading cause of UROR for NDFF patients (5% compared to 0%). NDFF UROR patients that initially experienced open fractures had a significantly greater risk of returning for I&D compared to closed NDFF fractures, likely due to an increased risk for infection ( p  < 0.05, Table  5 ). The most common reason for revision operation within the NDFF cohort was due to the intra-articular prominence of an intramedullary nail, and the other revision within the PDFF cohort was due to implant failure with valgus angulation. PDFF patients had significantly improved quality of reduction with respect to the average population aLDFA of 81 degrees. The mean aLDFA in PDFF patients was approximately 6 degrees less than that of NDFF patients ( p  < 0.001). When using the uninjured contralateral aLDFA, PDFF were approximately 1.2 degrees less in deviation. However, significance could not be determined given the limited availability of contralateral imaging.

Of 26 PDFF treated with NPC fixation, only 1 (4%) experienced long-term post-operative complications of malunion. Of 44 PDFF treated with either nail or plate fixation, 2 (4.5%) experienced postoperative complications of nonunion. There was no significant difference in malunion/nonunion rates between these two groups ( p  = 0.88).

All 24 NDFF treated with NPC fixation achieved fracture union. Of 115 NDFF treated with either nail or plate fixation, 5 experienced malunion/nonunion. There was no significant difference in malunion/nonunion rates between NDFF treated with NPC fixation compared to either plate or nail fixation ( p  = 0.59).

This study is the first to directly compare native and periprosthetic distal femur fractures. PDFF were found to be commonly isolated injuries with complete metaphyseal comminution, affecting elderly women and those with low bone quality. NDFF, on the other hand, tended to occur in younger patients with less metaphyseal comminution and additional fractures. NDFF had increased revision reoperation rates compared to PDFF, specifically for I&D of the femur fracture of interest. In addition to having generally more open fractures in the NDFF group, patients with open fractures within the NDFF group were more likely to result in infection requiring I&D than those with closed fractures. Multivariate regression analysis revealed that NDFF were an independent risk factor for reoperation, specifically I&D of the fracture of interest, compared to PDFF.

The present study reports a PDFF gender distribution similar to Elsoe et al., who documented a sample of mostly females with a mean age of 77 years old [ 8 ]. Generally, our PDFF sample was characterized by a high prevalence of low bone density. Additionally, the PDFF cohort had a higher rate of low bone density compared to the NDFF cohort, which can be explained by the higher average age and the female majority in the PDFF group [ 20 ]. Low bone density has been highlighted as a risk factor for femur fractures in past studies, and low-energy distal femur fractures are now considered fragility fractures [ 6 , 21 ]. Although trauma mechanisms were not formally investigated in our study, we observed that PDFF were mostly isolated injuries, which is more suggestive of a low-energy trauma mechanism as proposed by prior studies [ 7 , 22 ].

The most common fracture pattern for PDFF was extraarticular with complete metaphyseal comminution (AO/OTA 33 A.3). The increased metaphyseal comminution is likely related to both the presence of low bone quality and the TKA implant affecting the stress concentration locations of the fracture. Low bone quality leads to an overall decreased tolerance for withstanding forces. Additionally, with the presence of a TKA, the fracture cannot propagate into the joint, and more energy may be imparted to the metaphysis.

While previous studies have shown that rIMN and lateral locked plating are the most common methods for treating PDFF, our study revealed that rIMN and NPC fixation are the most common methods utilized at our institution [ 10 , 23 , 24 ]. Further analysis of NPC fixation rates revealed an increase in prevalence from 3.3% in 2015 to 13.3% of all fixation constructs used for PDFF in 2019. There was no significant difference in malunion/nonunion rates for those treated with NPC fixation compared to those treated with rIMN or plate fixation alone for either NDFF or PDFF. Regarding postoperative weightbearing status, there was no significant difference in WBAT assignment for NDFF NPC fixation compared to nail or plate fixation ( p  = 0.88). This was likely confounded by the high prevalence of polytrauma and concomitant fractures in this group, which would have limited weightbearing. However, PDFF treated with NPC fixation were significantly more likely to be WBAT compared to those treated with nail or plate fixation alone ( p  < 0.05). NPC fixation is a recently being used as an ideal treatment for osteoporotic distal femur fractures (both PDFF and NDFF) due to the balanced energy distribution between bone and implant [ 25 ]. Currently, only small cohort studies exist which have found no significant difference in nonunion rates between NPC compared to nail or plate fixation, although a multicenter propensity analysis suggested there may be significantly lower nonunion rates in DFF treated with NPC fixation [ 25 , 26 , 27 ]. In addition to potentially reducing the risk of nonunion, many surgeons see a biomechanical advantage of combination fixation to facilitate early weightbearing in elderly patients [ 25 ]. It is of the authors’ opinion that the results reflect an increasing preference for this treatment by orthopedic surgeons at our institution to stabilize fractures in elderly patients with low bone density to facilitate earlier mobilization/weight bearing.

We have identified a large NDFF population of middle-aged patients (average age = 57 years old) with a balanced sex distribution. The most common fracture pattern consisted of metaphyseal comminution with intra-articular extension (AO/OTA 33 C.2), suggesting a predominantly high-energy trauma mechanism. This contrasts with the findings of Roy et al., who reported a small sample of NDFF at a level-1 trauma center ( n  = 87) consisting mostly of middle-aged female patients with comparable rates of high-energy (47%) and low-energy injuries (53%) [ 28 ]. These differences may be reflective of differences in the demographics of the catchment area that our institution serves.

In contrast to prior literature, which reports coronal plane (AO/OTA 33B.3) fractures representing 38% of all partial articular (AO/OTA 33B) native fractures, our study reports an overall rate of 14% for 33B fractures with a majority being fractures of the lateral condyle (AO/OTA 33B.1) [ 29 ]. The mechanism of coronal plane fractures consists of vertical shear forces experienced during high-energy trauma, which is consistent with our findings in the NDFF population. The difference in our reported prevalence of 33B.3 fractures is less likely to be explained by low detection as CT scans were obtained for all patients. These demographic and injury severity differences may be reflective of population differences in sampling; however, we report an NDFF cohort that is much larger than the previously mentioned study, with greater potential for generalizability.

Regarding the treatment of NDFF, rIMN was also the most common fixation method used, followed by lateral plating, which contrasts with previous studies which report plating as the most common fixation for NDFF [ 7 , 11 , 12 ]. Additionally, NPC was the third most common construct employed, which may reflect its increasing popularity as a treatment alternative for distal femur fractures as well as institutional preference for nailing.

Quality of reduction was improved in the PDFF cohort compared to the NDFF cohort, based on normative values of alignment. This may be due to the simplicity of the fractures as PDFF were all type A fractures whereas NDFF commonly had intra-articular components. Additionally, the TKA implants force a certain nail start point given the box component with less variation so perhaps the nail is more on axis. However, nailing of these fractures has been previously associated with malalignment [ 30 , 31 ]. Finally, the increase in NPC versus lateral plating alone may account for some of the differences as the tendency for malreduction with a single lateral locked plate is well documented [ 32 ]. We did not observe any difference in nonunion, similar to prior studies but with an overall lower rate [ 30 ].

Contrary to our hypothesis, there were notable differences in outcomes between NDFF and PDFF. NDFF had significantly longer length of stays and were more likely to return to the operating room for additional treatment of the femur fracture compared to PDFF. The most common fracture pattern seen in NDFF undergoing reoperation was complete articular (AO/OTA 33 C), and the most common etiology for UROR was for irrigation and debridement of an initially open fracture due to infection risk, which is reflective of the more severe soft tissue injury and propensity for open fractures. Upfill-Brown et al. previously conducted a large retrospective review which found no significant differences in 30-day reoperation rates between PDFF and NDFF [ 13 ]. However, their study did not account for mechanism or fracture complexity. The differences in length of stay and UROR rates between the PDFF and NDFF groups noted in our study can be explained by the high prevalence of polytrauma, additional fractures, and increased fracture complexity (AO/OTA 33 C) in the NDFF group. Additionally, Kaufman et al. studied outcomes in a matched cohort of PDFF and NDFF and found that when controlling for age, sex, and injury severity, there was no significant difference in length of stay or < 90-day readmission rates between the two injuries [ 14 ]. The results of Kaufman et al. and our study support the notion that the risk for readmission is more closely tied to population-specific risk factors such as demographics, mechanism, and additional injuries than to the presence of periprosthetic fractures.

There are several notable strengths to this study. This investigation encompasses recent patient data from a large population spanning 8 years followed longitudinally. Our study takes into consideration the quality of reduction when assessing outcomes for PDFF and NDFF. Limitations to the study include retrospective-single site sampling and an unmatched patient cohort. Reduction quality measurements were made by a single grader, potentially introducing information bias. Our results reflect the treatment of distal femur fractures at a level-1 trauma center, and it is unclear whether similar results would be observed at a community hospital or arthroplasty surgical center. Finally, the addition of patient-reported outcomes would be beneficial but were not collected during the time frame investigated.

In conclusion, there are differences in the patient demographics, fracture patterns, and fixation construct strategies of PDFF and NDFF patient populations. PDFF frequently occur as isolated, extra-articular, and comminuted injuries. Elderly women and those with poor bone quality are at high risk for PDFF. NDFF often occur in middle-aged individuals of both genders, often involving intra-articular extension and are frequently accompanied by additional orthopedic injuries. Patients with NDFF are at a significantly greater risk of reoperation, particularly due to soft tissue complications from open fractures. Finally, although rIMN was the common fixation strategy for both fracture categories, rates of NPC fixation for PDFF are increasing at our institution, likely to facilitate earlier weight bearing in elderly, nonpolytraumatized patients with qualifying fracture morphology. These differences can guide future research to enhance treatment algorithms and implant designs specific to each population, ultimately improving patient outcomes.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

We gratefully acknowledge the valuable contributions of Judas Kelley and Kelsey Hideshima in the oversight of this project, along with the insightful feedback provided by Megan Terle, Gillian Soles, Sean T. Campbell, Ellen Fitzpatrick, and Mark A. Lee during the review process of this manuscript.

No funding was used for this study. For the remaining authors there are no relevant conflicts of interest.

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A.M.S. devised the study and directed the project. S.K. and B.B. contributed to data collection, analysis, study interpretation, and manuscript drafting. M.H., S.T., A.S., A.M.S. were involved in project oversight, study interpretation, and manuscript drafting.

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Kong, S., Tse, S., Saade, A. et al. Clinical differences between periprosthetic and native distal femur fractures: a comparative observational study. J Orthop Surg Res 19 , 303 (2024). https://doi.org/10.1186/s13018-024-04796-8

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To evaluate Hugo RAS against the Da Vinci system for Robot-Assisted Radical Prostatectomy (RARP) in prostate cancer treatment.

We compared outcomes of 150 patients with prostate cancer undergoing RARP with either Hugo or Da Vinci systems. Our analysis included operative, postoperative, pathological, and functional outcomes.

Both groups had 75 patients. Baseline characteristics and tumor features were similar. Intraoperatively, Da Vinci had a shorter docking time (10.45 vs. 18.62 min, p = 0.02), but total operative times were comparable (145.34 vs 138.95, p = 0.85). Hugo outperformed in neck dissection and lymphadenectomy times (22 vs 13.67 min, p = 0.027 and 37.82 vs 45.77 min, p = 0.025). Postoperative metrics like stay duration, catheter time, and complications showed no significant difference. Functional results, using IPSS and IIEF5, were similar between systems. Six Da Vinci patients (8%) and nine Hugo patients (12%) experienced social incontinence (p = 0.072). Pathological outcomes like T stage, Gleason Score, and nodes removed were alike. However, Hugo had more positive surgical margins (20% vs. 10.67%, p = 0.034).

Conclusions

RARP outcomes using Hugo RAS were similar to the Da Vinci system in our study. More research and extended follow-up are required to ascertain long-term oncological and functional results.

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Data availability.

The data that support the findings of this study are available on request from the corresponding author.

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Ricardo Brime Menendez, Esther García Rojo, Vital Hevia Palacios, Javier Amalio Feltes Ochoa, Juan Justo Quintas, Fernando Lista Mateos, Agustín Fraile & Javier Romero Otero

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Ricardo Brime Menendez 1 , Esther García Rojo 1 , Vital Hevia Palacios 1 , Javier Amalio Feltes Ochoa 1 , Juan Justo Quintas 1 , Fernando Lista Mateos 1 , Agustín Fraile 1 , Celeste Manfredi 2 , Simone Belli 3 , Giorgio Bozzini 4 , Javier Romero Otero 1 * Authors whose names appear on the submission have contributed sufficiently to the scientific work and, therefore, share collective responsibility and accountability for the results. R. Brime Protocol development, Data collection, Manuscript editing and writing. E. García. Protocol development, Data collection, Manuscript editing and writing. V. Hevia Protocol development, Data collection, Manuscript editing and writing. J.A. Feltes Protocol development, Data collection. J. Justo Protocol development, Data collection. F. Lista Protocol development, Data collection. A. Fraile Protocol development, Data collection. C. Mafredi Protocol development, Manuscript editing and writing. S. Bellli Manuscript editing and writing. G. Bozzini Protocol development, Data collection, Manuscript editing and writing. J Romero: protocol development, Data collection, Manuscript editing and writing.

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Brime Menendez, R., García Rojo, E., Hevia Palacios, V. et al. Da Vinci vs. Hugo RAS for robot-assisted radical prostatectomy: a prospective comparative single-center study. World J Urol 42 , 336 (2024). https://doi.org/10.1007/s00345-024-05045-7

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DOI : https://doi.org/10.1007/s00345-024-05045-7

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• Sex differences in risk of incident microvascular and macrovascular complications: a population-based data-linkage study among 25 713 people with diabetes
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• http://orcid.org/0000-0001-8750-9720 Alice A Gibson 1 , 2 ,
• Emma Cox 1 , 2 ,
• Francisco J Schneuer 1 , 2 , 3 ,
• Jacob Humphries 4 ,
• Crystal MY Lee 5 ,
• Joanne Gale 1 ,
• Steven Chadban 2 , 6 ,
• Mark Gillies 7 ,
• Clara K Chow 2 , 8 , 9 ,
• Stephen Colagiuri 2 , 4 ,
• Natasha Nassar 1 , 2 , 3
• 1 Menzies Centre for Health Policy and Economics, Sydney School of Public Health, Faculty of Medicine and Health , The University of Sydney , Sydney , New South Wales , Australia
• 2 Charles Perkins Centre , The University of Sydney , Sydney , New South Wales , Australia
• 3 Child Population and Translational Health Research, The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health , The University of Sydney , Sydney , New South Wales , Australia
• 4 Faculty of Medicine and Health , The University of Sydney , Sydney , New South Wales , Australia
• 5 School of Population Health , Curtin University , Perth , Western Australia , Australia
• 6 Department of Renal Medicine, Kidney Centre , Royal Prince Alfred Hospital , Camperdown , New South Wales , Australia
• 7 Discipline of Ophthalmology and Eye Health, Save Sight Institute, Faculty of Medicine and Health , The University of Sydney , Sydney , New South Wales , Australia
• 8 Westmead Applied Research Centre, Faculty of Medicine and Health , The University of Sydney , Sydney , New South Wales , Australia
• 9 Department of Cardiology , Westmead Hospital , Westmead , New South Wales , Australia
• Correspondence to Dr Alice A Gibson, Menzies Centre for Health Policy and Economics, Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; alice.gibson{at}sydney.edu.au

Background The global prevalence of diabetes is similar in men and women; however, there is conflicting evidence regarding sex differences in diabetes-related complications. The aim of this study was to investigate sex differences in incident microvascular and macrovascular complications among adults with diabetes.

Methods This prospective cohort study linked data from the 45 and Up Study, Australia, to administrative health records. The study sample included 25 713 individuals (57% men), aged ≥45 years, with diabetes at baseline. Incident cardiovascular disease (CVD), eye, lower limb, and kidney complications were determined using hospitalisation data and claims for medical services. Multivariable Cox proportional hazards models were used to assess the association between sex and incident complications.

Results Age-adjusted incidence rates per 1000 person years for CVD, eye, lower limb, and kidney complications were 37, 52, 21, and 32, respectively. Men had a greater risk of CVD (adjusted hazard ratio (aHR) 1.51, 95% CI 1.43 to 1.59), lower limb (aHR 1.47, 95% CI 1.38 to 1.57), and kidney complications (aHR 1.55, 95% CI 1.47 to 1.64) than women, and a greater risk of diabetic retinopathy (aHR 1.14, 95% CI 1.03 to 1.26). Over 10 years, 44%, 57%, 25%, and 35% of men experienced a CVD, eye, lower limb, or kidney complication, respectively, compared with 31%, 61%, 18%, and 25% of women. Diabetes duration (<10 years vs ≥10 years) had no substantial effect on sex differences in complications.

Conclusions Men with diabetes are at greater risk of complications, irrespective of diabetes duration. High rates of complications in both sexes highlight the importance of targeted complication screening and prevention strategies from diagnosis.

• EPIDEMIOLOGY
• DIABETES MELLITUS
• CARDIOVASCULAR DISEASES
• COHORT STUDIES
• RECORD LINKAGE

Data availability statement

Data may be obtained from a third party and are not publicly available. This research was completed using data collected from the Sax Institute’s 45 and Up Study. Requests for access to data should be addressed to the corresponding author or the Sax Institute ( http://www.saxinstitute.org.au/ ).

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/jech-2023-221759

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WHAT IS ALREADY KNOWN ON THIS TOPIC

The absolute risk of cardiovascular disease appears to be higher in men with diabetes compared with women with diabetes. However, the evidence for sex differences in microvascular complications is limited and conflicting.

Further, there is little understanding of the potential impact of diabetes duration on sex differences in micro- and macrovascular complications.

WHAT THIS STUDY ADDS

Compared with women, men were at greater risk of incident cardiovascular disease, lower limb and kidney complications, and diabetic retinopathy.

Sex differences in rate of complications were similar for those with diabetes duration <10 years and ≥10 years.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY

Given the high rates of complication in both sexes, this study highlights the importance of targeted complication screening and prevention strategies from the time of diagnosis.

Introduction

Diabetes leads to numerous microvascular and macrovascular complications such as loss of vision, amputation, kidney failure, myocardial infarction and stroke, placing an enormous burden on individuals and their families, healthcare systems and society in general. Globally, the prevalence of diabetes continues to escalate. An estimated 537 million people aged 20–79 years were living with diabetes in 2021, which is projected to rise to a staggering 783 million by 2045. 1 In Australia, the prevalence of diabetes has tripled over the past three decades, affecting an estimated 1.3 million (5.1%) Australians in 2018–2021. 2

Although the prevalence of diabetes is similar in men and women (worldwide prevalence of 8.9% and 8.4%, respectively), 3 the incidence and progression of diabetes-related complications appears to be more sex-specific. It is well established that the absolute risk of cardiovascular disease (CVD) is higher in men with diabetes than women with diabetes. 4 However, the evidence for sex differences in microvascular complications such as retinopathy, neuropathy and nephropathy is limited and conflicting. For instance, in the UK Prospective Diabetes Study, the incidence of retinopathy was similar in men and women; however, women had a lower relative risk of retinopathy progression (RR 0.54, 95% CI 0.37 to 0.80). 5 In the prospective DiaGene cohort study of diabetes complications, the incidence of microalbuminuria (a biomarker of nephropathy) was higher in men, and men were more likely to develop two or three microvascular complications compared with women (OR 2.42, 95% CI 1.69 to 3.45). 6

Ample duration of follow-up is required to assess long-term diabetes-related complications. Multiple studies have provided strong evidence that individuals with longer diabetes duration are at greater risk of complications 7 8 ; however, there is little understanding of the potential impact of diabetes duration on sex differences in diabetes-related complications. The aim of this study was to investigate sex differences in incident micro- and macrovascular complications among a large population-based sample of people with diabetes. We also investigated whether sex differences were modified by duration of diabetes.

Study population and data sources

We used data from The Sax Institute’s 45 and Up Study, a large prospective cohort of 267 357 men and women aged over 45 years residing in the state of New South Wales (NSW), Australia. This cohort represents approximately 11% of the NSW population aged over 45. The cohort profile and research protocol have been published in detail previously. 9 Briefly, participants of the 45 and Up Study were randomly sampled from Services Australia Medicare enrolment database, between 2005 and 2009. Participants were invited by mail and agreed to participate by completing a sex-specific self-administered questionnaire and providing written consent for linkage of their survey responses to administrative health data collections. The estimated response rate was 19%. The full baseline survey questionnaires are available at https://www.saxinstitute.org.au/our-work/45-up-study/questionnaires/ .

For this study we used data from participants’ baseline questionnaires that were linked to their corresponding medical services claims (Medicare Benefits Schedule, MBS), prescription medication (Pharmaceutical Benefits Scheme, PBS), hospital admission (Admitted Patient Data Collection, APDC) and death registry data collections (Registry of Births Deaths and Marriages). Detailed information about the datasets and linkage process is provided in the online supplemental file 1 . The 45 and Up Study was approved by the University of NSW Human Research Ethics Committee, and use of linked data for this study was approved by the NSW Population and Health Services Research Ethics Committee (Cancer Institute NSW reference: 2017/HRE0206).

Supplemental material

Study sample.

The present study includes all participants in the 45 and Up Study identified with diabetes at baseline. The online supplemental file 1 provides a detailed overview of diabetes case ascertainment. In brief, we used a combination of self-report and the multiple linked administrative data sources (MBS, PBS, APDC) to ascertain diabetes status.

Study exposures

The main exposures of interest were sex and diabetes duration at baseline. Diabetes duration at baseline was calculated using the age at first diabetes diagnosis identified from the baseline survey and categorised into <10 years or ≥10 years.

Study outcomes

Study outcomes were determined following literature review and consultation with clinical experts and defined as incident hospitalisation or treatment for the following four major groups and subgroups of diabetes-related micro- and macrovascular complications 10 :

Cardiovascular complications: ischaemic heart disease, transient ischaemic attack (TIA), stroke, heart failure, diabetic cardiomyopathy

Eye complications: diabetes with ‘any ophthalmic complication’, cataract, diabetic retinopathy

Lower limb complications: peripheral neuropathy, ulcers, cellulitis, Charcot foot, osteomyelitis, peripheral vascular disease, and minor or major amputation

Kidney complications: ‘diabetes with kidney complication’, acute kidney failure, chronic kidney disease, unspecified kidney failure, dialysis, and kidney transplant.

Diabetes-related complications were primarily ascertained from hospital admission records (APDC) using principal and additional International Statistical Classification of Diseases and Related Health Problems, Australian Modification (ICD-10-AM) diagnosis or Australian Classification of Healthcare Interventions (ACHI) procedure codes. As not all diabetes-related complications included in this analysis require hospital admission, we also included out-of-hospital treatment for complications such as home dialysis for chronic kidney disease, or retinal laser. This was identified using relevant MBS treatment items. A complete list of outcomes and associated diagnosis, procedure and treatment codes are presented in online supplemental table 1 .

Self-reported sociodemographic, lifestyle and health characteristics were identified from the baseline survey. All questions, response options and categories are provided in online supplemental table 2 . Sociodemographic characteristics included age group, socioeconomic background (Index of Relative Socioeconomic Disadvantage (IRSD) quintile), household income, highest level of education, language other than English spoken at home, country of birth, and private health insurance. The IRSD is derived from income, education, unemployment, and other census data. 11

Lifestyle and health factors included body mass index (BMI), smoking status, physical activity, fruit and vegetable consumption, family history of diabetes, and previous history of CVD (including heart disease and stroke), history of high blood pressure and blood pressure treatment, and treatment for high cholesterol. Of note, previous history of CVD was not included in the CVD complications analysis, as individuals with a prior history were excluded from this analysis.

Statistical analysis

Contingency tables were used to describe the baseline characteristics of participants, grouped by sex. For all major groups and subgroups of diabetes complications, we calculated age-adjusted incidence rates of complications per 1000 person-years, based on the subpopulation at risk (time to first event, death or end of follow-up time). We used Kaplan-Meier estimators to compare age-standardised cumulative complication rates for major outcome groups stratified by sex and duration of diabetes.

Cox proportional hazards models were used to estimate crude and adjusted hazard ratios (aHR) to assess associations between sex and incident CVD, lower limb, eye, and kidney complications. For analysing each group of complications (ie, CVD, lower limb, eye, and kidney), we excluded those with a prior history of that group of complications (ie, between January 2001 and their baseline survey date). The models for each outcome were conducted adjusting for other factors in a sequential process: (1) unadjusted, (2) adjusted for age and sex, (3) adjusted for age, sex, sociodemographics, and lifestyle, and (4) adjusted for all sociodemographic, lifestyle, and health-related factors. Person-years were calculated from the date of recruitment until incident treatment or hospitalisation, death, or end of follow-up (ie, December 2019). All models account for the competing risk of death before complication. Proportionality assumptions were verified based on the methods of Lin et al . 12

Multiple imputation was performed using full conditional specification and incorporating sociodemographic, lifestyle and health factors described above. Thirty imputations were conducted and estimates from the imputed datasets were combined by calculating the mean of the parameter of interest and standard errors adjusted for the uncertainty produced by the imputation process. The missing at random (MAR) assumption required for imputation was considered reasonable based on the missingness patterns in the data ( table 1 ) and the large number of variables included in the imputation process. 13 All analyses were performed using SAS software version 9.4 (SAS Institute Inc, Cary, NC, USA).

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Baseline sociodemographic, lifestyle and health characteristics of the cohort of participants with diabetes by sex (n=25 713).

Sample characteristics

The full baseline 45 and Up sample included 267 357 participants. There were 266 471 active participants available for this analysis. We excluded participants if they did not have diabetes at baseline (n=232 535), their diabetes status was uncertain (n=8166), or there were inconsistencies in their age, death, or baseline data (n=57). Our final sample included 25 713 participants ( online supplemental figure 1 ).

Table 1 presents the baseline characteristics of the cohort by sex, with almost half of the cohort aged 60–74 years and a slightly higher proportion of females aged 45–59 years with diabetes. A higher proportion of men were overweight (38.7% in men vs 27.8% in women), had higher educational attainment, held private health insurance, and had a history of heart disease. In terms of smoking status, although a similar proportion of men and women were current smokers, a higher proportion of men were ex-smokers (51% compared with only 29% women). Of the 19 277 (75%) people with diabetes who had an age of diagnosis, 58% had a duration of diabetes <10 years and 42% had a duration of diabetes ≥10 years at baseline. There were no meaningful differences in baseline characteristics between those with and without an age of diagnosis ( online supplemental table 3 ).

Incident CVD complications

During 177 851 person-years of follow-up, the overall incidence rate of CVD complications was 37 per 1000 person-years, which was higher among men than women (43 vs 30 per 1000) ( figure 1A ). After adjustment of covariates, compared with women, the aHR for any incident CVD complication in men was 1.51 (95% CI 1.43 to 1.59) ( figure 1B ). Among the CVD complication subgroups, associations were similar to the overall result for heart failure and stroke and stronger for myocardial infarction and other coronary heart disease ( online supplemental figure 2 ). These associations are reflected in the cumulative hazard curves which show that at 10 years’ follow-up, 44.4% (95% CI 43.0% to 45.9%) of men and 30.9% (95% CI 29.7% to 32.2%) of women with diabetes experienced a CVD complication (p<0.001) ( figure 2A ). The sex difference in rate of CVD complications at 10 years was similar, although slightly greater, for those with diabetes <10 years compared with ≥10 years’ duration ( online supplemental figure 6 , online supplemental table 4 ).

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(A) Age-adjusted incidence rates per 1000 person-years of incident diabetes-related complications by sex and (B) adjusted hazards ratio (aHR) (95% CI) for association between sex and incident diabetes-related complications. Hazards ratios are calculated from Cox proportional hazard models based on multiple imputed data adjusted for age, sociodemographics (education, SEIFA, income, language, country of birth, private insurance), lifestyle (BMI, smoking, diet and physical activity) and health history (family history of diabetes, cardiovascular disease, blood pressure and treatment for high cholesterol). BMI, body mass index; SEIFA, Socio-Economic Indexes for Areas.

Cumulative incidence of macrovascular and microvascular complications by sex: (A) CVD complications; (B) eye complications; (C) lower limb complications; (D) kidney complications. Hazard function survival curves using Kaplan-Meier methods. P values in the figures represent the results for the log-rank test. CVD, cardiovascular disease.

Incident eye complications

The incidence rate of eye complications was 52 per 1000 person years and was similar for men and women (52 vs 53 per 1000) ( figure 1A ). Compared with women, men had a lower risk of any eye complication (aHR 0.94, 95% CI 0.89 to 0.98) ( figure 1B ), with results largely influenced by the lower risk of cataract surgery among men (aHR 0.90, 95% CI 0.86 to 0.95) ( online supplemental figure 3 ). In contrast, men had a slightly greater rate and risk of diabetic retinopathy (10 vs 9 per 1000 person years; aHR 1.14, 95% CI 1.03 to 1.26) ( online supplemental figure 3 ). At 10 years’ follow-up, the cumulative incidence of eye complications was 57.0% (95% CI 55.3% to 58.8%) in men and 60.9% (95% CI 58.9% to 62.9%) in women (p<0.001) ( figure 2B ); for diabetic retinopathy these rates were 9.8% (95% CI 9.2% to 10.4%) in men and 8.9% (95% CI 8.2% to 9.5%) in women. When stratified by duration of diabetes, there was no statistical sex difference in risk of diabetic retinopathy for those with diabetes <10 years (aHR 1.12, 95% CI 0.95 to 1.31) at baseline and ≥10 years’ duration (aHR 1.16, 95% CI 0.99 to 1.36) at baseline ( online supplemental figure 6 , online supplemental table 4 ).

Incident lower limb complications

The incidence rate of lower limb complications was 21 per 1000 person years and was higher among men than women (25 vs 18 per 1000) ( figure 1A ). The risk of any lower limb complication was 1.5 times higher in men than women (aHR 1.47, 95% CI 1.38 to 1.57) ( figure 1B ), and the risks of peripheral neuropathy, ulcer and cellulitis were similar. The difference was stronger for peripheral vascular disease, with the risk of complications over two times higher for men. While the incidence was low, the risk of osteomyelitis and amputation was over 2.5-fold higher in men than in women ( online supplemental figure 4 ). The cumulative incidence of lower limb complications at 10 years was higher among men at 24.6% (95% CI 23.7% to 25.5%) versus 17.8% (95% CI 16.9% to 18.7%) in women ( figure 2C ), and this pattern was relatively similar irrespective of diabetes duration ( online supplemental figure 6 , online supplemental table 4 ).

Incident kidney complications

The incidence rate of kidney complications was 32 per 1000 person years and was higher among men than women (36 vs 26 per 1000) ( figure 1A ). The risk of any kidney complication was 1.6 times higher in men than in women (aHR 1.55, 95% CI 1.47 to 1.64) ( figure 1B ), with similar risk estimates for specific subgroups, including kidney failure, chronic kidney disease and dialysis ( online supplemental figure 5 ). This pattern of a higher risk of kidney complications in men is reflected in the cumulative incidence at 10 years, which was higher among men at 35.2% (95% CI 34.0% to 36.3%) versus 25.3% (95% CI 24.3% to 26.3%) in women ( figure 2D ). The sex difference in rate of kidney complications at 10 years was similar, although slightly greater, for those with diabetes ≥10 years compared with <10 years’ duration ( online supplemental figure 6 , online supplemental table 4 ).

Our study demonstrates that men with diabetes have a higher rate and greater risk of most diabetes-related complications compared with women, and this difference remained consistent irrespective of the duration of diabetes. For every 1000 people with diabetes, our findings suggest that an average of 37, 52, 21, and 32 people will develop CVD, eye, lower limb, and kidney complications every year. Men had a 1.5-fold increased risk of CVD, lower limb, and kidney complications, and risk of diabetic retinopathy was 14% greater in men than in women. These findings are reflected in the ~1.4 times higher 10-year rates for CVD, lower limb, and kidney complications in men compared with women.

The greater risk of CVD complications observed for men in our study is consistent with other large population-based studies in France 14 and Denmark. 15 These studies reported a higher incidence of major adverse cardiovascular events including heart failure in men with diabetes compared with women with diabetes (incidence rate (IR) 96 vs 66/1000 person-years, 14 and IR 24.9 vs 19.9/1000 person-years 15 ). Men, irrespective of diabetes status, have been shown to have a greater CVD risk factor burden than women. 16–18 A recent study using nationally representative survey data from Australians aged 45–74 years showed men had a higher average BMI, waist circumference, systolic and diastolic blood pressure, total: high density lipoprotein (HDL) cholesterol ratio, triglycerides and glycated haemoglobin (HbA1c) compared with women, and a higher proportion of men were also current or ex-smokers. 17 Our study observed similar differences in baseline characteristics, with men more likely to be overweight, have a history of heart disease or stroke, and be previous smokers. Men may also be less likely to adopt primary prevention strategies, such as healthy lifestyle change and medication use, 16 19 and to engage in health seeking behaviours, such as preventative health checks. 20 21 Further, women are known to be at lower risk of CVD complications compared with men due to the protective effects of reproductive factors such as breastfeeding and the use of hormone replacement therapy within 10 years of menopause. 22 There are important age-specific sex differences in CVD complications. Women have an older age of CVD onset compared with men, 23 and experience lower rates of CVD up until the age of 80 years. 18 It is possible that the sex differences in CVD complications observed in our study may resolve if the cohort were to be followed for a longer time.

Evidence for sex differences in microvascular diabetes complications is less conclusive than for macrovascular complications. A meta-analysis of 10 studies (nine cohort) reported an elevated, but non-significant, increase in incident chronic kidney disease among women compared with men (adjusted women-to-men relative risk ratio (WMR) 1.14, 95% CI 0.97 to 1.34), with risk particularly higher for end stage renal disease (adjusted WMR 1.38, 95% CI 1.22 to 1.55). 24 In contrast, studies from the Netherlands and UK found a higher baseline prevalence and risk of incident microalbuminuria in men. 6 25 Although no studies have examined overall lower limb complications, the risk of amputation has been shown to be greater in men than in women. 26 27 Similarly, a meta-analysis of 20 studies found that men with diabetic foot have an approximate 50% increased amputation risk compared with women. 28 In contrast to the results for CVD, kidney and lower limb complications, our study found that women with diabetes were at greater risk of eye complications. This appeared to be largely driven by the inclusion of cataracts as a sub-group, which are more prevalent in women compared with men. 29 30 Considering diabetic retinopathy specifically, our results indicate a 14% greater risk of incident retinopathy in men which is consistent with a study from Italy which showed the incidence of diabetic retinopathy to be associated with the male sex (HR 1.31, 95% CI 1.05 to 1.63). 31 The mechanisms for sex differences in microvascular complications remains under-researched, 32 but possible factors include worse glycaemic and blood pressure control and treatment, 18 and an underutilisation of medical care for microvascular complications 28 in men compared with women. Large-scale studies examining sex differences in adherence to guideline-recommended processes of care, including medication adherence and healthy lifestyle behaviours, are needed to understand these findings better.

It is well understood that individuals with longer diabetes duration are at greater risk of complications. The UK Biobank study showed that with each 5 year increase in diabetes duration, there was a 20% increase in excess risk of CVD complications for both men and women. 7 Despite the greater complication-risk with longer disease duration, we observed a similar sex difference in risk of complications for those with diabetes duration <10 years compared with those with diabetes duration ≥10 years. Few studies have examined the effect of diabetes duration on sex differences in risk of complications; however, Duarte et al found that the magnitude of the association between duration of diabetes and glycaemic control was stronger for women compared with men. 33 Only individuals with age of diagnosis reported in the baseline survey could be included in our analysis stratified by disease duration (approximately two-thirds of the full sample), which may have influenced our findings.

The strengths of this study include the large population-based sample, the long follow-up time, and use of objective linked data to identify incident diabetes-related complications, avoiding issues of loss to follow-up and self-report. The data in our study did not include diabetes complications not requiring hospitalisation, with the exception of diabetic retinopathy and home dialysis. While our analyses took into account competing risk of CVD-related death before hospitalisation, these numbers were small (n=163), with no meaningful sex differences that might have had an impact on our results ( online supplemental table 5 ). Given that diabetic kidney disease is frequently asymptomatic, unknown to patients, 34 and requires laboratory testing for detection, it is likely that the incidence of early-stage chronic kidney disease was underestimated in our study. On the other hand, as we excluded those with a prior history of complications to capture incident complications, this may have not allowed enough time for the development of end stage complications, such as limb amputations or requirement for kidney replacement therapy with dialysis or transplantation. As such, the absolute rates of complications should be interpreted with caution. The 45 and Up Study provides detailed information on sociodemographic, health and lifestyle covariates which we were able to adjust for in the analysis. However, we did not take into account all potential confounding/effect-modifying factors including glycaemic, lipid and blood pressure control, medication use 35 and adherence which may have impacted the strength of the association between sex and risk of complications. We were also not able to differentiate between type 1 and type 2 diabetes in our study, precluding an analysis by type of diabetes. Although the 45 and Up cohort are broadly representative of the Australian population aged ≥45 years, the sample does overrepresent higher income earners, people aged 80 and over, and residents of rural and remote areas, 36 which may limit the generalisability of the results. Although men have a higher absolute risk of CVD complications, studies in patients with diabetes compared to those without diabetes have shown that the relative CVD risk conferred by diabetes is greater in women. 37–39 Sex differences in relative risk of diabetes complications was not assessed in our study.

In conclusion, although men with diabetes are at greater risk of developing complications, in particular CVD, kidney and lower-limb complications, the rates of complications are high in both sexes. The similar sex difference for those with shorter compared with longer diabetes duration highlights the need for targeted complication screening and prevention strategies from the time of diabetes diagnosis. Further investigation into the underlying mechanisms for the observed sex differences in diabetes complications are needed to inform targeted interventions.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study involves human participants. The 45 and Up Study was approved by the University of NSW Human Research Ethics Committee, and use of linked data for this study was approved by the NSW Population and Health Services Research Ethics Committee (Cancer Institute NSW reference: 2017/HRE0206). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

This research was completed using data collected through the 45 and Up Study (www.saxinstitute.org.au). The 45 and Up Study is managed by the Sax Institute in collaboration with major partner Cancer Council NSW and partners the Heart Foundation and the NSW Ministry of Health. We thank the many thousands of people participating in the 45 and Up Study. We also acknowledge the support of the NSW Centre for Health Record Linkage (CHeReL; http://www.cherel.org.au ).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Contributors AAG, NN and SC conceived the idea for the study. All authors contributed intellectual content to the study design and interpretation of the findings. FS, JH, and JG conducted the analysis. AAG, EC, NN and JG drafted the manuscript and all authors provided edits and comments. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors have approved the final article. AAG is the guarantor of this work.

Funding This work was supported by an Australian Diabetes Society Servier Research Grant, an Australian Diabetes Research Trust Grant and a NSW Health EMCR CVD Capacity Grant. AAG is supported by an Australian National Health and Medical Research Council Emerging Leader 1 Investigator Grant (APP1173784). AAG is also grateful to the NSW Cardiovascular Research Network for a Professional Development Award. NN is supported by Financial Markets Foundation for Children and by an Australian National Health and Medical Research Council Leadership 2 Investigator Grant (APP1197940). Mark Gillies is supported by an NHMRC Level 3 Investigator grant. Clara K Chow is supported by an NHMRC Leadership Investigator grant (APP1195326). Funding bodies were not involved in the study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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