layout for a research paper

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13.1 Formatting a Research Paper

Learning objectives.

• Identify the major components of a research paper written using American Psychological Association (APA) style.
• Apply general APA style and formatting conventions in a research paper.

In this chapter, you will learn how to use APA style , the documentation and formatting style followed by the American Psychological Association, as well as MLA style , from the Modern Language Association. There are a few major formatting styles used in academic texts, including AMA, Chicago, and Turabian:

• AMA (American Medical Association) for medicine, health, and biological sciences
• APA (American Psychological Association) for education, psychology, and the social sciences
• Chicago—a common style used in everyday publications like magazines, newspapers, and books
• MLA (Modern Language Association) for English, literature, arts, and humanities
• Turabian—another common style designed for its universal application across all subjects and disciplines

While all the formatting and citation styles have their own use and applications, in this chapter we focus our attention on the two styles you are most likely to use in your academic studies: APA and MLA.

If you find that the rules of proper source documentation are difficult to keep straight, you are not alone. Writing a good research paper is, in and of itself, a major intellectual challenge. Having to follow detailed citation and formatting guidelines as well may seem like just one more task to add to an already-too-long list of requirements.

Following these guidelines, however, serves several important purposes. First, it signals to your readers that your paper should be taken seriously as a student’s contribution to a given academic or professional field; it is the literary equivalent of wearing a tailored suit to a job interview. Second, it shows that you respect other people’s work enough to give them proper credit for it. Finally, it helps your reader find additional materials if he or she wishes to learn more about your topic.

Furthermore, producing a letter-perfect APA-style paper need not be burdensome. Yes, it requires careful attention to detail. However, you can simplify the process if you keep these broad guidelines in mind:

• Work ahead whenever you can. Chapter 11 “Writing from Research: What Will I Learn?” includes tips for keeping track of your sources early in the research process, which will save time later on.
• Get it right the first time. Apply APA guidelines as you write, so you will not have much to correct during the editing stage. Again, putting in a little extra time early on can save time later.
• Use the resources available to you. In addition to the guidelines provided in this chapter, you may wish to consult the APA website at http://www.apa.org or the Purdue University Online Writing lab at http://owl.english.purdue.edu , which regularly updates its online style guidelines.

General Formatting Guidelines

This chapter provides detailed guidelines for using the citation and formatting conventions developed by the American Psychological Association, or APA. Writers in disciplines as diverse as astrophysics, biology, psychology, and education follow APA style. The major components of a paper written in APA style are listed in the following box.

These are the major components of an APA-style paper:

Body, which includes the following:

• Headings and, if necessary, subheadings to organize the content
• In-text citations of research sources
• References page

All these components must be saved in one document, not as separate documents.

The title page of your paper includes the following information:

• Title of the paper
• Author’s name
• Name of the institution with which the author is affiliated
• Header at the top of the page with the paper title (in capital letters) and the page number (If the title is lengthy, you may use a shortened form of it in the header.)

List the first three elements in the order given in the previous list, centered about one third of the way down from the top of the page. Use the headers and footers tool of your word-processing program to add the header, with the title text at the left and the page number in the upper-right corner. Your title page should look like the following example.

The next page of your paper provides an abstract , or brief summary of your findings. An abstract does not need to be provided in every paper, but an abstract should be used in papers that include a hypothesis. A good abstract is concise—about one hundred fifty to two hundred fifty words—and is written in an objective, impersonal style. Your writing voice will not be as apparent here as in the body of your paper. When writing the abstract, take a just-the-facts approach, and summarize your research question and your findings in a few sentences.

In Chapter 12 “Writing a Research Paper” , you read a paper written by a student named Jorge, who researched the effectiveness of low-carbohydrate diets. Read Jorge’s abstract. Note how it sums up the major ideas in his paper without going into excessive detail.

Write an abstract summarizing your paper. Briefly introduce the topic, state your findings, and sum up what conclusions you can draw from your research. Use the word count feature of your word-processing program to make sure your abstract does not exceed one hundred fifty words.

Depending on your field of study, you may sometimes write research papers that present extensive primary research, such as your own experiment or survey. In your abstract, summarize your research question and your findings, and briefly indicate how your study relates to prior research in the field.

Margins, Pagination, and Headings

APA style requirements also address specific formatting concerns, such as margins, pagination, and heading styles, within the body of the paper. Review the following APA guidelines.

Use these general guidelines to format the paper:

• Set the top, bottom, and side margins of your paper at 1 inch.
• Use double-spaced text throughout your paper.
• Use a standard font, such as Times New Roman or Arial, in a legible size (10- to 12-point).
• Use continuous pagination throughout the paper, including the title page and the references section. Page numbers appear flush right within your header.
• Section headings and subsection headings within the body of your paper use different types of formatting depending on the level of information you are presenting. Additional details from Jorge’s paper are provided.

Begin formatting the final draft of your paper according to APA guidelines. You may work with an existing document or set up a new document if you choose. Include the following:

• Your title page
• The abstract you created in Note 13.8 “Exercise 1”
• Correct headers and page numbers for your title page and abstract

APA style uses section headings to organize information, making it easy for the reader to follow the writer’s train of thought and to know immediately what major topics are covered. Depending on the length and complexity of the paper, its major sections may also be divided into subsections, sub-subsections, and so on. These smaller sections, in turn, use different heading styles to indicate different levels of information. In essence, you are using headings to create a hierarchy of information.

The following heading styles used in APA formatting are listed in order of greatest to least importance:

• Section headings use centered, boldface type. Headings use title case, with important words in the heading capitalized.
• Subsection headings use left-aligned, boldface type. Headings use title case.
• The third level uses left-aligned, indented, boldface type. Headings use a capital letter only for the first word, and they end in a period.
• The fourth level follows the same style used for the previous level, but the headings are boldfaced and italicized.
• The fifth level follows the same style used for the previous level, but the headings are italicized and not boldfaced.

Visually, the hierarchy of information is organized as indicated in Table 13.1 “Section Headings” .

Table 13.1 Section Headings

A college research paper may not use all the heading levels shown in Table 13.1 “Section Headings” , but you are likely to encounter them in academic journal articles that use APA style. For a brief paper, you may find that level 1 headings suffice. Longer or more complex papers may need level 2 headings or other lower-level headings to organize information clearly. Use your outline to craft your major section headings and determine whether any subtopics are substantial enough to require additional levels of headings.

Working with the document you developed in Note 13.11 “Exercise 2” , begin setting up the heading structure of the final draft of your research paper according to APA guidelines. Include your title and at least two to three major section headings, and follow the formatting guidelines provided above. If your major sections should be broken into subsections, add those headings as well. Use your outline to help you.

Because Jorge used only level 1 headings, his Exercise 3 would look like the following:

Citation Guidelines

In-text citations.

Throughout the body of your paper, include a citation whenever you quote or paraphrase material from your research sources. As you learned in Chapter 11 “Writing from Research: What Will I Learn?” , the purpose of citations is twofold: to give credit to others for their ideas and to allow your reader to follow up and learn more about the topic if desired. Your in-text citations provide basic information about your source; each source you cite will have a longer entry in the references section that provides more detailed information.

In-text citations must provide the name of the author or authors and the year the source was published. (When a given source does not list an individual author, you may provide the source title or the name of the organization that published the material instead.) When directly quoting a source, it is also required that you include the page number where the quote appears in your citation.

This information may be included within the sentence or in a parenthetical reference at the end of the sentence, as in these examples.

Epstein (2010) points out that “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive” (p. 137).

Here, the writer names the source author when introducing the quote and provides the publication date in parentheses after the author’s name. The page number appears in parentheses after the closing quotation marks and before the period that ends the sentence.

Addiction researchers caution that “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive” (Epstein, 2010, p. 137).

Here, the writer provides a parenthetical citation at the end of the sentence that includes the author’s name, the year of publication, and the page number separated by commas. Again, the parenthetical citation is placed after the closing quotation marks and before the period at the end of the sentence.

As noted in the book Junk Food, Junk Science (Epstein, 2010, p. 137), “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive.”

Here, the writer chose to mention the source title in the sentence (an optional piece of information to include) and followed the title with a parenthetical citation. Note that the parenthetical citation is placed before the comma that signals the end of the introductory phrase.

David Epstein’s book Junk Food, Junk Science (2010) pointed out that “junk food cannot be considered addictive in the same way that we think of psychoactive drugs as addictive” (p. 137).

Another variation is to introduce the author and the source title in your sentence and include the publication date and page number in parentheses within the sentence or at the end of the sentence. As long as you have included the essential information, you can choose the option that works best for that particular sentence and source.

Citing a book with a single author is usually a straightforward task. Of course, your research may require that you cite many other types of sources, such as books or articles with more than one author or sources with no individual author listed. You may also need to cite sources available in both print and online and nonprint sources, such as websites and personal interviews. Chapter 13 “APA and MLA Documentation and Formatting” , Section 13.2 “Citing and Referencing Techniques” and Section 13.3 “Creating a References Section” provide extensive guidelines for citing a variety of source types.

Writing at Work

APA is just one of several different styles with its own guidelines for documentation, formatting, and language usage. Depending on your field of interest, you may be exposed to additional styles, such as the following:

• MLA style. Determined by the Modern Languages Association and used for papers in literature, languages, and other disciplines in the humanities.
• Chicago style. Outlined in the Chicago Manual of Style and sometimes used for papers in the humanities and the sciences; many professional organizations use this style for publications as well.
• Associated Press (AP) style. Used by professional journalists.

References List

The brief citations included in the body of your paper correspond to the more detailed citations provided at the end of the paper in the references section. In-text citations provide basic information—the author’s name, the publication date, and the page number if necessary—while the references section provides more extensive bibliographical information. Again, this information allows your reader to follow up on the sources you cited and do additional reading about the topic if desired.

The specific format of entries in the list of references varies slightly for different source types, but the entries generally include the following information:

• The name(s) of the author(s) or institution that wrote the source
• The year of publication and, where applicable, the exact date of publication
• The full title of the source
• For books, the city of publication
• For articles or essays, the name of the periodical or book in which the article or essay appears
• For magazine and journal articles, the volume number, issue number, and pages where the article appears
• For sources on the web, the URL where the source is located

The references page is double spaced and lists entries in alphabetical order by the author’s last name. If an entry continues for more than one line, the second line and each subsequent line are indented five spaces. Review the following example. ( Chapter 13 “APA and MLA Documentation and Formatting” , Section 13.3 “Creating a References Section” provides extensive guidelines for formatting reference entries for different types of sources.)

In APA style, book and article titles are formatted in sentence case, not title case. Sentence case means that only the first word is capitalized, along with any proper nouns.

Key Takeaways

• Following proper citation and formatting guidelines helps writers ensure that their work will be taken seriously, give proper credit to other authors for their work, and provide valuable information to readers.
• Working ahead and taking care to cite sources correctly the first time are ways writers can save time during the editing stage of writing a research paper.
• APA papers usually include an abstract that concisely summarizes the paper.
• APA papers use a specific headings structure to provide a clear hierarchy of information.
• In APA papers, in-text citations usually include the name(s) of the author(s) and the year of publication.
• In-text citations correspond to entries in the references section, which provide detailed bibliographical information about a source.

Writing for Success Copyright © 2015 by University of Minnesota is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

How to format a research paper

Last updated

7 February 2023

Reviewed by

Miroslav Damyanov

Writing a research paper can be daunting if you’re not experienced with the process. Getting the proper format is one of the most challenging aspects of the task. Reviewers will immediately dismiss a paper that doesn't comply with standard formatting, regardless of the valuable content it contains. 

In this article, we'll delve into the essential characteristics of a research paper, including the proper formatting.

Make research less tedious

Dovetail streamlines research to help you uncover and share actionable insights

• What is a research paper?

A research paper is a document that provides a thorough analysis of a topic , usually for an academic institution or professional organization. A research paper may be of any length, but they are typically 2,000–10,000 words. 

Unlike less formal papers, such as articles or essays, empirical evidence and data are key to research papers. In addition to students handing in papers, scientists, attorneys, medical researchers, and independent scholars may need to produce research papers.

People typically write research papers to prove a particular point or make an argument. This could support or disprove a theoretical point, legal case, scientific theory, or an existing piece of research on any topic. 

One of the distinguishing characteristics of research papers is that they contain citations to prior research. Citing sources using the correct format is essential for creating a legitimate research paper. 

• Top considerations for writing a research paper

To write a research paper, you must consider several factors. Fields such as the sciences, humanities, and technical professions have certain criteria for writing research papers. 

You’ll write a research paper using one of several types of formatting. These include APA, MLA, and CMOS styles, which we’ll cover in detail to guide you on citations and other formatting rules. 

Specific requirements of the assignment

If the paper is for a college, university, or any specific organization, they’ll give you certain requirements, such as the range of topics, length, and formatting requirements.

You should study the specifics of the assignment carefully, as these will override more general guidelines you may find elsewhere. If you're writing for a particular professor, they may ask for single or double spacing or a certain citation style. 

• Components of a research paper

Here are the basic steps to writing a quality research paper, assuming you've chosen your topic and considered the requirements of the paper. Depending on the specific conditions of the paper you're writing, you may need the following elements:

Thesis statement

The thesis statement provides a blueprint for the paper. It conveys the theme and purpose of the paper. It also informs you and readers what your paper will argue and the type of research it will contain. As you write the paper, you can refer to the thesis statement to help you decide whether or not to include certain items.

Most research papers require an abstract as well as a thesis. While the thesis is a short (usually a single sentence) summary of the work, an abstract contains more detail. Many papers use the IMRaD structure for the abstract, especially in scientific fields. This consists of four elements:

Introduction : Summarize the purpose of the paper

Methods : Describe the research methods (e.g., collecting data , interviews , field research)

Results: Summarize your conclusions.  

Discussion: Discuss the implications of your research. Mention any significant limitations to your approach and suggest areas for further research.

The thesis and abstract come at the beginning of a paper, but you should write them after completing the paper. This approach ensures a clear idea of your main topic and argument, which can evolve as you write the paper.

Table of contents

Like most nonfiction books, a research paper usually includes a table of contents. 

Tables, charts, and illustrations

If your paper contains multiple tables, charts, illustrations, or other graphics, you can create a list of these. 

Works cited or reference page

This page lists all the works you cited in your paper. For MLA and APA styles, you will use in-text citations in the body of the paper. For Chicago (CMOS) style, you'll use footnotes. 

Bibliography

While you use a reference page to note all cited papers, a bibliography lists all the works you consulted in your research, even if you don't specifically cite them. 

While references are essential, a bibliography is optional but usually advisable to demonstrate the breadth of your research.

Dedication and acknowledgments

You may include a dedication or acknowledgments at the beginning of the paper directly after the title page and before the abstract.

• Steps for writing a research paper

These are the most critical steps for researching, writing, and formatting a research paper:

Create an outline

The outline is not part of the published paper; it’s for your use. An outline makes it easier to structure the paper, ensuring you include all necessary points and research. 

Here you can list all topics and subtopics that will support your argument. When doing your research, you can refer to the outline to ensure you include everything. 

Gather research

Solid research is the hallmark of a research paper. In addition to accumulating research, you need to present it clearly. However, gathering research is one of the first tasks. If you compile each piece of research correctly, it will be easier to format the paper correctly. You want to avoid having to go back and look up information constantly.

Start by skimming potentially useful sources and putting them aside for later use. Reading each source thoroughly at this stage will be time-consuming and slow your progress. You can thoroughly review the sources to decide what to include and discard later. At this stage, note essential information such as names, dates, page numbers, and website links. Citing sources will be easier when you’ve written all the information down.

Be aware of the quality of your sources. A research paper should reference scholarly, academic, or scientific journals. It’s vital to understand the difference between primary and secondary sources. 

A primary source is an original, firsthand account of a topic. A secondary source is someone else covering the topic, as in a popular article or interview. While you may include secondary sources, your paper should also include primary research . Online research can be convenient, but you need to be extra careful when assessing the quality of your sources.

Write the first draft

Create a first draft where you put together all your research and address the topic described in your thesis and abstract. 

Edit and format the paper

Proofread, edit, and make any necessary adjustments and improvements to the first draft. List your citations as described below. Ensure your thesis and abstract describe your research accurately. 

• Formatting a research paper: MLA, APA, and CMOS styles

There are several popular formats for research papers: MLA (Modern Language Association) and APA (American Psychological Association). Certain academic papers use CMOS (Chicago Manual of Style). Other formats may apply to particular fields. 

For example, medical research may use AMA (American Medical Association) formatting and IEEE (Institute of Electrical and Electronics Engineers) for particular technical papers. The following are the guidelines and examples of the most popular formats:

The humanities typically use MLA format, including literature, history, and culture. Look over examples of papers created in MLA format . Here are the main rules to keep in mind:

Double-spaced lines.

Indent new paragraphs 1/2 inch.

Title case for headings, where all major words are capitalized, as in "How to Write a Research Paper." 

Use a popular font such as Times New Roman. This applies to all formatting styles.

Use one-inch margins on all sides. 

Number sections of the paper using Arabic numerals (1, 2, 3, etc.). 

Use a running head for each page on the upper right-hand corner, which consists of your last name and the page number.

Use an in-text citation within the text, using the author's last name followed by the page number: "Anything worth dying for is certainly worth living for" (Heller 155).  

On the citations page, list the full name, book or periodical, and other information. For MLA, you will not need footnotes, only in-text citations.

List citations in alphabetical order on a separate page at the end of the paper entitled “Works Cited.” 

Continuing with the above example from Heller, the listing would be: Heller, Joseph. Catch-22, Simon & Schuster, 1961.

For a periodical, the format is "Thompson, Hunter S. "The Kentucky Derby is Decadent and Depraved" Scanlon's, June 1970."

Use title case for source titles, as in "On the Origin of Species."

The sciences typically use APA format, including physical sciences such as physics and social sciences such as psychology. Simply Psychology provides examples of APA formatting . The following are the most important rules of the APA format.

Begin the paper with a title page, which is not required for MLA.

Use double-line spacing.

Use a running head for each page in the upper right-hand corner, which consists of the paper's title in capital letters followed by the page number.

The citations page at the end should be titled "References."

In-text citations should include the publication date: (Smith, 1999, p. 50). Note also that there's a "p" for "page," whereas in MLA, you write the page number without a "p."

As with MLA, use title case for headings, as in "Most Popular Treatments for Cognitive Disorders."

Use sentence case for titles of sources, as in "History of the decline and fall of the Roman empire." Note "Roman" starts with a capital because it's a proper noun.  

When citing in-text references, use the author's last name and the first and middle initials. 

Always use the Oxford comma. This comma goes before the words "or" and "and" in a list. For example, "At the store, I bought oranges, paper towels, and pasta."

CMOS formatting

Book publishers and many academic papers use CMOS formatting based on the Chicago Manual of Style. CMOS is also called Turabian, named after Kate L. Turabian, who wrote the first manual for this style. Here are examples of CMOS style formatting and citations.

Include an unnumbered title page.

Place page numbers on the upper right-hand corner of the page. Do not list your name or the paper's title as you would for MLA or APA styles.

Use title case for both headings and sources (same as MLA).

Unlike MLA and APA, the Chicago style uses footnotes for citations. Use a superscript for footnotes: "Smith argues against Jones' theory¹.” Footnotes may appear at the bottom of the page or the end of the document.  

CMOS supports both short notes and full notes. In most cases, you'll use the full note: "Michael Pollan, The Omnivore's Dilemma: A Natural History of Four Meals (New York: Penguin, 2006), 76." For further references to the same source, use a short note: " Pollan, Omnivore's Dilemma, 45." The requirements of some papers may specify using only short notes for all footnotes.

• General guidelines for writing and formatting research papers

Keep these guidelines in mind for all types of research papers:

Initial formatting

As you create your first draft, don't worry about formatting. If you try to format it perfectly as you write the paper, it will be difficult to progress and develop a flow of thought. With the first draft, you don't have to be concerned about ordering the sections. You can rearrange headings and sections later. 

Citation tools

Use automation tools for citations . Some useful tools make citations easier by automatically generating a citation list and bibliography. Many work with APA, MLA, and CMOS styles.

Check for plagiarism

Use a plagiarism detector to make sure your paper isn't unintentionally plagiarizing. There are many free and paid plagiarism checkers online, such as Grammarly. 

Proofread your work

Do several rounds of editing and proofreading. Editing is necessary for any type of writing, but you’ll need to revisit several distinct areas with a research paper:

Check for spelling and grammatical errors.

Read the paper to make sure it's well-argued and that you’ve organized it properly. 

Check that you’ve correctly formatted citations. It's easy to make errors, such as incorrect numbering of footnotes (e.g., Chicago style) or forgetting to include a source on your citations page.

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What’s Included: Research Paper Template

If you’re preparing to write an academic research paper, our free research paper template is the perfect starting point. In the template, we cover every section step by step, with clear, straightforward explanations and examples .

The template’s structure is based on the tried and trusted best-practice format for formal academic research papers. The template structure reflects the overall research process, ensuring your paper will have a smooth, logical flow from chapter to chapter.

The research paper template covers the following core sections:

• The title page/cover page
• Abstract (sometimes also called the executive summary)
• Section 1: Introduction 
• Section 2: Literature review 
• Section 3: Methodology
• Section 4: Findings /results
• Section 5: Discussion
• Section 6: Conclusion
• Reference list

Each section is explained in plain, straightforward language , followed by an overview of the key elements that you need to cover within each section. We’ve also included links to free resources to help you understand how to write each section.

The cleanly formatted Google Doc can be downloaded as a fully editable MS Word Document (DOCX format), so you can use it as-is or convert it to LaTeX.

FAQs: Research Paper Template

What format is the template (doc, pdf, ppt, etc.).

The research paper template is provided as a Google Doc. You can download it in MS Word format or make a copy to your Google Drive. You’re also welcome to convert it to whatever format works best for you, such as LaTeX or PDF.

What types of research papers can this template be used for?

The template follows the standard best-practice structure for formal academic research papers, so it is suitable for the vast majority of degrees, particularly those within the sciences.

Some universities may have some additional requirements, but these are typically minor, with the core structure remaining the same. Therefore, it’s always a good idea to double-check your university’s requirements before you finalise your structure.

Is this template for an undergrad, Masters or PhD-level research paper?

This template can be used for a research paper at any level of study. It may be slight overkill for an undergraduate-level study, but it certainly won’t be missing anything.

How long should my research paper be?

This depends entirely on your university’s specific requirements, so it’s best to check with them. We include generic word count ranges for each section within the template, but these are purely indicative. 

What about the research proposal?

If you’re still working on your research proposal, we’ve got a template for that here .

We’ve also got loads of proposal-related guides and videos over on the Grad Coach blog .

How do I write a literature review?

We have a wealth of free resources on the Grad Coach Blog that unpack how to write a literature review from scratch. You can check out the literature review section of the blog here.

How do I create a research methodology?

We have a wealth of free resources on the Grad Coach Blog that unpack research methodology, both qualitative and quantitative. You can check out the methodology section of the blog here.

Can I share this research paper template with my friends/colleagues?

Yes, you’re welcome to share this template. If you want to post about it on your blog or social media, all we ask is that you reference this page as your source.

Can Grad Coach help me with my research paper?

Within the template, you’ll find plain-language explanations of each section, which should give you a fair amount of guidance. However, you’re also welcome to consider our private coaching services .

How to Write and Publish a Research Paper for a Peer-Reviewed Journal

• Open access
• Published: 30 April 2020
• Volume 36 , pages 909–913, ( 2021 )

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• Clara Busse   ORCID: orcid.org/0000-0002-0178-1000 1 &
• Ella August   ORCID: orcid.org/0000-0001-5151-1036 1 , 2  

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Communicating research findings is an essential step in the research process. Often, peer-reviewed journals are the forum for such communication, yet many researchers are never taught how to write a publishable scientific paper. In this article, we explain the basic structure of a scientific paper and describe the information that should be included in each section. We also identify common pitfalls for each section and recommend strategies to avoid them. Further, we give advice about target journal selection and authorship. In the online resource 1 , we provide an example of a high-quality scientific paper, with annotations identifying the elements we describe in this article.

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Introduction

Writing a scientific paper is an important component of the research process, yet researchers often receive little formal training in scientific writing. This is especially true in low-resource settings. In this article, we explain why choosing a target journal is important, give advice about authorship, provide a basic structure for writing each section of a scientific paper, and describe common pitfalls and recommendations for each section. In the online resource 1 , we also include an annotated journal article that identifies the key elements and writing approaches that we detail here. Before you begin your research, make sure you have ethical clearance from all relevant ethical review boards.

Select a Target Journal Early in the Writing Process

We recommend that you select a “target journal” early in the writing process; a “target journal” is the journal to which you plan to submit your paper. Each journal has a set of core readers and you should tailor your writing to this readership. For example, if you plan to submit a manuscript about vaping during pregnancy to a pregnancy-focused journal, you will need to explain what vaping is because readers of this journal may not have a background in this topic. However, if you were to submit that same article to a tobacco journal, you would not need to provide as much background information about vaping.

Information about a journal’s core readership can be found on its website, usually in a section called “About this journal” or something similar. For example, the Journal of Cancer Education presents such information on the “Aims and Scope” page of its website, which can be found here: https://www.springer.com/journal/13187/aims-and-scope .

Peer reviewer guidelines from your target journal are an additional resource that can help you tailor your writing to the journal and provide additional advice about crafting an effective article [ 1 ]. These are not always available, but it is worth a quick web search to find out.

Identify Author Roles Early in the Process

Early in the writing process, identify authors, determine the order of authors, and discuss the responsibilities of each author. Standard author responsibilities have been identified by The International Committee of Medical Journal Editors (ICMJE) [ 2 ]. To set clear expectations about each team member’s responsibilities and prevent errors in communication, we also suggest outlining more detailed roles, such as who will draft each section of the manuscript, write the abstract, submit the paper electronically, serve as corresponding author, and write the cover letter. It is best to formalize this agreement in writing after discussing it, circulating the document to the author team for approval. We suggest creating a title page on which all authors are listed in the agreed-upon order. It may be necessary to adjust authorship roles and order during the development of the paper. If a new author order is agreed upon, be sure to update the title page in the manuscript draft.

In the case where multiple papers will result from a single study, authors should discuss who will author each paper. Additionally, authors should agree on a deadline for each paper and the lead author should take responsibility for producing an initial draft by this deadline.

Structure of the Introduction Section

The introduction section should be approximately three to five paragraphs in length. Look at examples from your target journal to decide the appropriate length. This section should include the elements shown in Fig.  1 . Begin with a general context, narrowing to the specific focus of the paper. Include five main elements: why your research is important, what is already known about the topic, the “gap” or what is not yet known about the topic, why it is important to learn the new information that your research adds, and the specific research aim(s) that your paper addresses. Your research aim should address the gap you identified. Be sure to add enough background information to enable readers to understand your study. Table 1 provides common introduction section pitfalls and recommendations for addressing them.

The main elements of the introduction section of an original research article. Often, the elements overlap

Methods Section

The purpose of the methods section is twofold: to explain how the study was done in enough detail to enable its replication and to provide enough contextual detail to enable readers to understand and interpret the results. In general, the essential elements of a methods section are the following: a description of the setting and participants, the study design and timing, the recruitment and sampling, the data collection process, the dataset, the dependent and independent variables, the covariates, the analytic approach for each research objective, and the ethical approval. The hallmark of an exemplary methods section is the justification of why each method was used. Table 2 provides common methods section pitfalls and recommendations for addressing them.

Results Section

The focus of the results section should be associations, or lack thereof, rather than statistical tests. Two considerations should guide your writing here. First, the results should present answers to each part of the research aim. Second, return to the methods section to ensure that the analysis and variables for each result have been explained.

Begin the results section by describing the number of participants in the final sample and details such as the number who were approached to participate, the proportion who were eligible and who enrolled, and the number of participants who dropped out. The next part of the results should describe the participant characteristics. After that, you may organize your results by the aim or by putting the most exciting results first. Do not forget to report your non-significant associations. These are still findings.

Tables and figures capture the reader’s attention and efficiently communicate your main findings [ 3 ]. Each table and figure should have a clear message and should complement, rather than repeat, the text. Tables and figures should communicate all salient details necessary for a reader to understand the findings without consulting the text. Include information on comparisons and tests, as well as information about the sample and timing of the study in the title, legend, or in a footnote. Note that figures are often more visually interesting than tables, so if it is feasible to make a figure, make a figure. To avoid confusing the reader, either avoid abbreviations in tables and figures, or define them in a footnote. Note that there should not be citations in the results section and you should not interpret results here. Table 3 provides common results section pitfalls and recommendations for addressing them.

Discussion Section

Opposite the introduction section, the discussion should take the form of a right-side-up triangle beginning with interpretation of your results and moving to general implications (Fig.  2 ). This section typically begins with a restatement of the main findings, which can usually be accomplished with a few carefully-crafted sentences.

Major elements of the discussion section of an original research article. Often, the elements overlap

Next, interpret the meaning or explain the significance of your results, lifting the reader’s gaze from the study’s specific findings to more general applications. Then, compare these study findings with other research. Are these findings in agreement or disagreement with those from other studies? Does this study impart additional nuance to well-accepted theories? Situate your findings within the broader context of scientific literature, then explain the pathways or mechanisms that might give rise to, or explain, the results.

Journals vary in their approach to strengths and limitations sections: some are embedded paragraphs within the discussion section, while some mandate separate section headings. Keep in mind that every study has strengths and limitations. Candidly reporting yours helps readers to correctly interpret your research findings.

The next element of the discussion is a summary of the potential impacts and applications of the research. Should these results be used to optimally design an intervention? Does the work have implications for clinical protocols or public policy? These considerations will help the reader to further grasp the possible impacts of the presented work.

Finally, the discussion should conclude with specific suggestions for future work. Here, you have an opportunity to illuminate specific gaps in the literature that compel further study. Avoid the phrase “future research is necessary” because the recommendation is too general to be helpful to readers. Instead, provide substantive and specific recommendations for future studies. Table 4 provides common discussion section pitfalls and recommendations for addressing them.

Follow the Journal’s Author Guidelines

After you select a target journal, identify the journal’s author guidelines to guide the formatting of your manuscript and references. Author guidelines will often (but not always) include instructions for titles, cover letters, and other components of a manuscript submission. Read the guidelines carefully. If you do not follow the guidelines, your article will be sent back to you.

Finally, do not submit your paper to more than one journal at a time. Even if this is not explicitly stated in the author guidelines of your target journal, it is considered inappropriate and unprofessional.

Your title should invite readers to continue reading beyond the first page [ 4 , 5 ]. It should be informative and interesting. Consider describing the independent and dependent variables, the population and setting, the study design, the timing, and even the main result in your title. Because the focus of the paper can change as you write and revise, we recommend you wait until you have finished writing your paper before composing the title.

Be sure that the title is useful for potential readers searching for your topic. The keywords you select should complement those in your title to maximize the likelihood that a researcher will find your paper through a database search. Avoid using abbreviations in your title unless they are very well known, such as SNP, because it is more likely that someone will use a complete word rather than an abbreviation as a search term to help readers find your paper.

After you have written a complete draft, use the checklist (Fig. 3 ) below to guide your revisions and editing. Additional resources are available on writing the abstract and citing references [ 5 ]. When you feel that your work is ready, ask a trusted colleague or two to read the work and provide informal feedback. The box below provides a checklist that summarizes the key points offered in this article.

Checklist for manuscript quality

Data Availability

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Acknowledgments

Ella August is grateful to the Sustainable Sciences Institute for mentoring her in training researchers on writing and publishing their research.

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Busse, C., August, E. How to Write and Publish a Research Paper for a Peer-Reviewed Journal. J Canc Educ 36 , 909–913 (2021). https://doi.org/10.1007/s13187-020-01751-z

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Published : 30 April 2020

Issue Date : October 2021

DOI : https://doi.org/10.1007/s13187-020-01751-z

MLA General Format 

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MLA Style specifies guidelines for formatting manuscripts and citing research in writing. MLA Style also provides writers with a system for referencing their sources through parenthetical citation in their essays and Works Cited pages. 

Writers who properly use MLA also build their credibility by demonstrating accountability to their source material. Most importantly, the use of MLA style can protect writers from accusations of plagiarism, which is the purposeful or accidental uncredited use of source material produced by other writers. 

If you are asked to use MLA format, be sure to consult the  MLA Handbook  (9th edition). Publishing scholars and graduate students should also consult the  MLA Style Manual and Guide to Scholarly Publishing  (3rd edition). The  MLA Handbook  is available in most writing centers and reference libraries. It is also widely available in bookstores, libraries, and at the MLA web site. See the Additional Resources section of this page for a list of helpful books and sites about using MLA Style.

Paper Format

The preparation of papers and manuscripts in MLA Style is covered in part four of the  MLA Style Manual . Below are some basic guidelines for formatting a paper in  MLA Style :

General Guidelines

• Type your paper on a computer and print it out on standard, white 8.5 x 11-inch paper.
• Double-space the text of your paper and use a legible font (e.g. Times New Roman). Whatever font you choose, MLA recommends that the regular and italics type styles contrast enough that they are each distinct from one another. The font size should be 12 pt.
• Leave only one space after periods or other punctuation marks (unless otherwise prompted by your instructor).
• Set the margins of your document to 1 inch on all sides.
• Indent the first line of each paragraph one half-inch from the left margin. MLA recommends that you use the “Tab” key as opposed to pushing the space bar five times.
• Create a header that numbers all pages consecutively in the upper right-hand corner, one-half inch from the top and flush with the right margin. (Note: Your instructor may ask that you omit the number on your first page. Always follow your instructor's guidelines.)
• Use italics throughout your essay to indicate the titles of longer works and, only when absolutely necessary, provide emphasis.
• If you have any endnotes, include them on a separate page before your Works Cited page. Entitle the section Notes (centered, unformatted).

Formatting the First Page of Your Paper

• Do not make a title page for your paper unless specifically requested or the paper is assigned as a group project. In the case of a group project, list all names of the contributors, giving each name its own line in the header, followed by the remaining MLA header requirements as described below. Format the remainder of the page as requested by the instructor.
• In the upper left-hand corner of the first page, list your name, your instructor's name, the course, and the date. Again, be sure to use double-spaced text.
• Double space again and center the title. Do not underline, italicize, or place your title in quotation marks. Write the title in Title Case (standard capitalization), not in all capital letters.
• Use quotation marks and/or italics when referring to other works in your title, just as you would in your text. For example:  Fear and Loathing in Las Vegas  as Morality Play; Human Weariness in "After Apple Picking"
• Double space between the title and the first line of the text.
• Create a header in the upper right-hand corner that includes your last name, followed by a space with a page number. Number all pages consecutively with Arabic numerals (1, 2, 3, 4, etc.), one-half inch from the top and flush with the right margin. (Note: Your instructor or other readers may ask that you omit the last name/page number header on your first page. Always follow instructor guidelines.)

Here is a sample of the first page of a paper in MLA style:

The First Page of an MLA Paper

Section Headings

Writers sometimes use section headings to improve a document’s readability. These sections may include individual chapters or other named parts of a book or essay.

MLA recommends that when dividing an essay into sections you number those sections with an Arabic number and a period followed by a space and the section name.

MLA does not have a prescribed system of headings for books (for more information on headings, please see page 146 in the MLA Style Manual and Guide to Scholarly Publishing , 3rd edition). If you are only using one level of headings, meaning that all of the sections are distinct and parallel and have no additional sections that fit within them, MLA recommends that these sections resemble one another grammatically. For instance, if your headings are typically short phrases, make all of the headings short phrases (and not, for example, full sentences). Otherwise, the formatting is up to you. It should, however, be consistent throughout the document.

If you employ multiple levels of headings (some of your sections have sections within sections), you may want to provide a key of your chosen level headings and their formatting to your instructor or editor.

Sample Section Headings

The following sample headings are meant to be used only as a reference. You may employ whatever system of formatting that works best for you so long as it remains consistent throughout the document.

Formatted, unnumbered:

Level 1 Heading: bold, flush left

Level 2 Heading: italics, flush left

Level 3 Heading: centered, bold

Level 4 Heading: centered, italics

Level 5 Heading: underlined, flush left

Research Library

A step-by-step guide to writing a research paper outline

A research outline guides the flow of the research paper , it is meant to ensure that the ideas, concepts and points are coherent and that the study and research has a well-defined point of focus. The outline sets guidelines for each section of the research paper, what it will address, explore and highlight. Working on a research paper outline is considered an important preliminary activity that improves the structure of the research paper, this is critical for categorising collected data. Think of it as a brainstorm session for your research paper that also implements effective time management.

Understanding research paper outline

A research paper ideally consists of 5 sections; abstract, introduction, body, conclusion and references. Each of these sections contributes to collating key information on the research design , in this section of the blog we dive into the purpose or each section.

Step-by-step guide to conducting research outline

• Choose a topic that aligns with your research requirements.
• Gather background information on your topic by reading through key scholarly articles, books, and credible online sources.
• Take notes on key ideas, findings, and arguments from reviewing the literature.
• Formulate a focused research question or thesis statement that defines the purpose of your study.
• Write an informative title that accurately reflects the main topic and focus of your research paper.
• Summarize the objectives, methods, results, and conclusions of your research in a brief abstract.
• Include background information to contextualize the research.
• Present the research question or thesis statement.
• Outline the scope and objectives of the study.
• Take the reader through the structure of the paper by mapping it out.
• Organise and structure the main points and subpoints of your research.
• Ensure the content flows cohesively.
• Include supporting evidence, examples, data, or arguments.
• Summarise the key findings and insights.
• Highlight the thesis statement or research question.
• Discuss the implications of your findings and suggest methods for future research.
• End the conclusion by highlighting the significance of the study.
• Create a list of references following the appropriate citation style (e.g., Harvard, APA, MLA, Chicago).
• Ensure that all sources are accurately cited and formatted.
• Review your research outline for coherence and clarity.
• Edit the outline as needed to improve organization, flow, and accuracy of information.
• Ensure the reference list follows the requirements of the correct format

Research outline formats

• Traditional outline - Where thesis statement is provided at the end of the introduction, body paragraphs support thesis with research and a conclusion is included to emphasise key concepts of research paper.
• Alphanumeric outline - Outline format uses letters and numbers in this order: A, I, II, III
• Decimal outline - This format requires each main point to be labeled with a whole number, and each sub-point 

Conduct your research on Zendy Today

As a thriving AI-powered academic research library, Zendy hosts a wide variety of academic research across various disciplines and branches of study. Draft your next or brush up your current research paper outline by skimming through the millions of credible resources Zendy offers!

Webinar Recap: Supporting the publishing and discovery journey of young and emerging scholars in the Global South

On the 25th of April, Zendy partnered with Bristol University Press to host an insightful joint webinar titled, supporting the publishing and discovery journey of young and emerging scholars in the Global South. The discussion panel was moderated by the Editorial Director of Bristol University Press, Victoria Pittman and featured the President of African Gong, Elizabeth Rasekoala, the Deputy Editorial Director at Bristol University Press, Stephen Wenham and the Partnerships Relations Manager at Zendy, Sara Crowley Vigneau. In this blog, we summarise the contributions of each speaker to the joint webinar. Elizabeth Rasekoala - President of African Gong Addressed key systematic issues within publishing in the Global South Academic research is predominantly published in English, which is not the first language of many in the Global South, hence publishers should be open to accepting research in different languages. Discussed the concept of “helicopter research syndrome” wherein more established researchers allocate data collection tasks to locals in the Global South and monitor their work but don’t credit them in the final academic papers Highlighted the book published by Bristol University Press titled, Race and cultural inclusion: Innovation, decolonization, and transformation. The book had a total of 30 contributing writers. 10 young scholars, 10 seasoned scholars and 10 senior scholars to facilitate emerging scholars get published. Stephen Wenham - Deputy Editorial Director at Bristol University Press Highlighted BUP’s international reach and efforts to work with young authors Bristol University Press has publications that are available globally. In the global south, BUP tries to match the books to the local market. Local distributors receive a discount and local publishers assist in localising the publications and releasing local editions of books Works with sales agents to ensure publications by local authors are highlighted in relevant regions Sara Crowley Vigneau - Partnerships Relations Manager at Zendy Highlighted the relationship between publishers and libraries in advancing access in developing regions Zendy supports scholars in the Global South through offering an affordable global subscription, while also working with publishers to include research generated by researchers in the Global South. Most of Zendy’s global users are aged between 18-34 and 20% of Zendy’s userbase is situated in African countries and territories. Zendy is actively working on “countries in crisis’ initiative where in Zendy works with publishers to make research content free in developing regions Conduct your research on Zendy As a growing AI-powered research library, Zendy is committed to hosting webinars that address important challenges and highlight key initiatives in the world of academia. Head to Zendy’s YouTube channel now to watch all our webinar recordings. Furthermore, take your research to the next level and head to Zendy now to try out our suite of AI tools including ZAIA! ul { margin-top: 5px !important; margin-bottom: 5px !important; } p, ul, li, h1, h2, h4 { word-break: normal !important; }

What is a DOI? Strengths, Limitations & Components

DOI is short for Digital Object Identifier. It is a unique alphanumeric sequence assigned to digital objects, it is used to identify intellectual property on the internet. DOI’s are usually assigned to scholarly articles, datasets, books, videos and even pieces of software. Understanding DOI's The digital object identifier is a unique number made up of a prefix and suffix, segregated by a forward slash. For example: 10.1000/182 The sequence always begins with a 10. The prefix is a unique 4 or more digit number assigned to establishments and the suffix is assigned by publisher as it is designed to be flexible with publisher identification standards. Where can I find a DOI? In most scholarly articles, the DOI should be on the cover page. If the DOI isn't included in the article, you may search for it on CrossRef.org by using the "Search Metadata" function. How can I use the digital object identifier to find the article it refers to? If the DOI starts with http:// or https://, pasting it on your web browder will help you locate the article. You can turn any DOI starting with 10 into a URL by adding http://doi.org/ before the DOI. For example, 10.3352/jeehp.2013.10.3 becomes https://doi.org/10.3352/jeehp.2013.10.3 If you're off campus when you do this, you'll need to use this URL prefix in front of the DOI to gain access to UIC's full text journal subscriptions: https://proxy.cc.uic.edu/login?url=https://doi.org/ . For example: https://proxy.cc.uic.edu/login?url=http://doi.org/10.3352/jeehp.2013.10.3 Strengths of Digital Object Identifier Permanent identification: Digital object identifier provides a permanent link to digital content, making sure it remains accessible even if URL or metadata is updated. Citations: It uniquely identifies research papers, which facilitates accurate referencing and citing. Interoperability: DOIs are widely recognized as they can be utilised across different platforms, databases and systems. Tracking and metrics: DOIs provide key information like publication date, authors, keywords and more. This can be used to track usage metrics, measuring impact and improving discoverability Integration with services: DOIs are integrated with various tools like reference managers, academic search engines, and digital libraries. These mediums enhance the visibility and accessibility of research material with DOIs. Limitations of Digital Object Identifier Cost: Digital object identifiers are costly for smaller organisations or individual researchers. While some services offer free digital object identifier registration for certain content, there may be fees associated with others, particularly for maintenance and updates. Accessibility: There may still be barriers to access for individual researchers or organisations in regions with limited resources. Ensuring equitable access to digital object identifier services and content remains a challenge. Content Preservation: While the sequence provide persistent links to digital content, they do not guarantee the preservation or long-term accessibility of that content. Ensuring the preservation of digital objects linked to DOIs require additional efforts and infrastructure beyond the system itself. Granularity: Sequences are assigned to individual digital objects, such as articles, datasets, or books. However, there may be cases where more granular identification is required, such as specific sections within a larger work or versions of a dataset. Addressing these granularity issues within the digital object identifier system can be complex. Conduct your research on Zendy today Now that you’ve gained a better understanding of how DOI works and impacts the world of research, you may begin your search and find your next academic discovery on Zendy! Our advanced search allows you to input DOI, ISSN, ISBN, publication, author, date, keyword and title. Give it a go on Zendy now. ul { margin-top: 5px !important; margin-bottom: 5px !important; } p, ul, li, h1, h2, h4 { word-break: normal !important; }

Learn to use ZAIA - Zendy's AI Research Assistant

What is ZAIA? ZAIA - AI Assistant is a domain-specific LLM (Large Language Model) that has been fine tuned with research available on Zendy. ZAIA was designed to make the discoverability and accessibility of academic research simpler on Zendy, while also enhancing the efficiency and effectiveness of literature review. In our latest version release, ZAIA has seen significant improvements, these include:  Ask ZAIA: Users and readers can now ask ZAIA specific paper-level questions, introducing a new way to conduct literature analysis. PDF Analysis: ZAIA now has the capability to analyse any PDF. Upload or link a research paper with sections and ZAIA will extract, analyse and summarise each section. Reference validation and verification: using techniques such as chain of verification, all references go through a validation and verification process to increase accuracy. Conversation and analysis history: once you log in, you can now see a complete history of all conversations with ZAIA and a history of PDFs analysed. An enhanced fine-tuned model for increased accuracy. ZAIA is also now accessible without registration. In this blog, we run you through the various features on ZAIA to teach you to use it to its full potential! Ask ZAIA Step 1: Access ZAIA - AI Assistant through the Zendy home page Step 2: Once your prompt is solved by ZAIA, you may double check the references ZAIA provides through the “Reference Details” section on the right. PDF Analysis Step 1: To access the PDF analysis feature on ZAIA, switch from “Conversation” to “PDF Analysis” Step 2: Enter a research paper of your choice and then click “Analyse document” Step 3: ZAIA then provides a summary of each section within the research paper, including references so you can quickly grasp the key concepts. Conversation History Step 1: You may access your conversation and analysis history on both pages from the left side bar, simply click on the session you’d like to revisit and ZAIA will load the entire conversation and analysis. In this blog, we’ve covered how to conduct PDF analysis on ZAIA, access your history and how to cross-check references. As we further build and improve ZAIA, we look forward to adding helpful functionalities that further accelerate the efficiency and effectiveness of literature review. Visit zendy.io and utilise ZAIA - AI Research Assistant to help you with your next research project.

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Original research article, a community health worker led approach to cardiovascular disease prevention in the uk—spices-sussex (scaling-up packages of interventions for cardiovascular disease prevention in selected sites in europe and sub-saharan africa): an implementation research project.

• 1 Department of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, United Kingdom
• 2 Department of Disease Control and Environmental Health, Makerere University, Kampala, Central Region, Uganda
• 3 Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

Background: This paper describes a UK-based study, SPICES-Sussex, which aimed to co-produce and implement a community-based cardiovascular disease (CVD) risk assessment and reduction intervention to support under-served populations at moderate risk of CVD. The objectives were to enhance stakeholder engagement; to implement the intervention in four research sites and to evaluate the use of Voluntary and Community and Social Enterprises (VCSE) and Community Health Worker (CHW) partnerships in health interventions.

Methods: A type three hybrid implementation study design was used with mixed methods data. This paper represents the process evaluation of the implementation of the SPICES-Sussex Project. The evaluation was conducted using the RE-AIM framework.

Results: Reach: 381 individuals took part in the risk profiling questionnaire and forty-one women, and five men participated in the coaching intervention. Effectiveness: quantitative results from intervention participants showed significant improvements in CVD behavioural risk factors across several measures. Qualitative data indicated high acceptability, with the holistic, personalised, and person-centred approach being valued by participants. Adoption: 50% of VCSEs approached took part in the SPICES programme, The CHWs felt empowered to deliver high-quality and mutually beneficial coaching within a strong project infrastructure that made use of VCSE partnerships. Implementation: Co-design meetings resulted in local adaptations being made to the intervention. 29 (63%) of participants completed the intervention. Practical issues concerned how to embed CHWs in a health service context, how to keep engaging participants, and tensions between research integrity and the needs and expectations of those in the voluntary sector. Maintenance: Several VCSEs expressed an interest in continuing the intervention after the end of the SPICES programme.

Conclusion: Community-engagement approaches have the potential to have positively impact the health and wellbeing of certain groups. Furthermore, VCSEs and CHWs represent a significant untapped resource in the UK. However, more work needs to be done to understand how links between the sectors can be bridged to deliver evidence-based effective alternative preventative healthcare. Reaching vulnerable populations remains a challenge despite partnerships with VCSEs which are embedded in the community. By showing what went well and what did not, this project can guide future work in community engagement for health.

1 Introduction

Cardiovascular disease (CVD) is among the most prevalent, costly to treat, and deadly medical issues in the world ( 1 ). As part of the continual effort to combat CVD, greater emphasis is being placed on prevention. This often takes the form of behavioural or lifestyle change, focusing on the reduction of risk factors (e.g., hypertension, poor diet, obesity). Reducing these risk factors using evidence-based interventions not only works to lower rates of CVD, but also impacts rates of a variety of other medical issues, including susceptibility to severe COVID-19 infection ( 2 ), many common Noncommunicable Diseases (NCDs) including Type 2 diabetes and a wide range of cancers ( 3 ). Furthermore these preventative interventions are less expensive than reactionary care and can lower the treatment burden on strained medical systems ( 4 ).

Community-Based Participatory Research (CBPR) and Community Engagement (CE) have grown increasingly popular as potential methods to engender sustainable, long-term change in communities—particularly those communities under-served by existing medical systems and/or those at heightened risk of CVD ( 5 ). One's behaviour is influenced by their environment and the community they live in, meaning that tapping into a community's resources can be effective in changing lifestyle behaviour as well as having impacts on the wider community ( 6 , 7 ). The use of community-based practices fits within the growing South-North collaboration that this project joins as part of an international collaboration known as “Scaling-up Packages of Interventions for Cardiovascular disease prevention in selected sites in Europe and Sub-Saharan Africa: An implementation research project” (SPICES). In the Low- and Middle-Income countries (LMIC) there is evidence for the successful implementation of evidence-based community-based interventions in increasing knowledge of, and changing behaviour related to, CVD ( 8 ) however their use in the Global North is less well tested or understood ( 9 ).

In the UK, the flagship intervention to address preventative health issues is the National Health Service's (NHS) Health Check initiative, which is free to individuals ages 40–76 and which assesses risk for long term health conditions including CVD ( 10 ). Following initial assessment by a health professional, patients are advised on a course of action which often includes some degree of preventative prescribing to address behavioural risk factors ( 11 ). Just under half of eligible individuals accepts a first health-checks appointment (44.2%)—it is associated with increased detection of CVD risk, but uptake is skewed by several demographic factors (principally, age, gender, and socio-demographics), and it has struggled to create change in underserved groups ( 12 , 13 ). Marginalised coastal communities in Sussex face overall below-average healthy-life expectancy ( 14 ). This, alongside heightening inequality and the impact of COVID-19, has left some communities in Sussex significantly deprived in terms of access and engagement with health services ( 15 ). People in these communities experience transgenerational poverty, precarity, and lifestyle behaviours ingrained into the communities that lead many to be at higher risk for CVD. CBPR and CE models have the potential to lead to improved health and health behaviours among disadvantaged populations if designed properly and implemented through effective community consultation and participation ( 16 ).

CBPR and CE offer the chance to bring lessons from effective programmes in the Global South and apply them to programmes in the Global North. Community-based strategies to promote evidence-based preventative health interventions using Community Health Workers (CHWs) are often more established in the Global South where more tightly knit communities and established community health programmes fulfil a range of public health needs ( 17 , 18 ). CHWs interventions are a form of “task-sharing” intervention in which responsibility and power is shared between professional health workers and communities which have been proposed to effectively manage non-communicable disease risk ( 19 ). Lay Community Health Workers are individuals who are trained to perform of health-related functions but lack a formal professional health education. They can provide links between local communities and health care institutions thereby building and on and developing the social capital that already exists in communities ( 20 ). Although there is plenty of evidence communicating the importance and usefulness of these methods (the “what”), there remains a lack of attention given to how to do it . This article joins the work and voices attempting to begin filling that lacuna.

Within the literature on CBPR and CE, a handful of common themes emerge. The first is a push for human-centred research design ( 21 , 22 ). Yardley et al. ( 23 ) focused on this idea in their “person-based” approach to digital health interventions, where they recommended a “focus on understanding and accommodating the perspectives of the people who will use the intervention” ( 24 ). Hopkins and Rippon's ( 25 ) “asset-based” approach to CE interventions recommends recognising and adapting to the need, wants, and strengths already present in the community. Particularly the strengths, or “assets” already present in the community provide an opportunity for projects to use those assets. Such an implementation approach requires flexibility and adaptability, as well as deep involvement with the community. The second theme builds on the first, with the idea that not only should project design be person-centred, but those participants and other stakeholders in the community should be involved at every level of project planning through co-design. Yardley et al. ( 23 ) included this as a key element of their paper, writing that people from the target population should be involved in project development as well as at every stage of the intervention. Similarly, Berrera et al. ( 26 ) emphasise the need to adapt all projects to the cultural context of the community. This insight speaks to the third theme, continuous evaluation ( 27 ). As the needs of the community will be ever-shifting, so must the project adapt to those needs continually. Instead of designated periods of evaluation, a shift to continual processes of qualitative evaluation is called for to identify and adjust to the needs of the community. These processes require elevated levels of trust and participation from the community, which has its own challenges. Trust especially takes significant time and resources to develop and is an under-studied area of community engagement ( 28 ).

The SPICES-Sussex project was carried out from January 2019 and aimed to answer the following overarching research question: How can Community Health Workers (CHW) CVD prevention interventions, that have been used in the Global South, be developed, and implemented in a Global North setting and what barriers and enablers exist to their implementation? The project began with a situational analysis which included an exploration of the views and experiences of the local community with regards to CVD health and Community Health Workers and early stakeholder mapping of the research sites which was carried out between 2019 and 2020 ( 29 , 30 ).

The primary aim of the current paper is to provide a comprehensive examination of the project's implementation including complementary mixed methods analyses according to the Reach Effectiveness-Adoption Implementation and Maintenance (RE-AIM) framework ( 31 ). The secondary aims of the project are to inform future CE projects what worked (and did not work) for our project and to tie insights from our project to broader discussions in the discipline. The project is based on a protocol published in 2020 prior to the onset of COVID and was conducted through the period of the COVID-19 pandemic ( 29 ). Subsequently, several aspects of the original protocol were adapted to make implementation feasible within the constraints of this period (see Supplementary Appendix 2 ).

2.1 Study design

The project uses a type 3 hybrid implementation design ( 29 ) meaning that the primary aim of the research was to determine utility of an implementation intervention/strategy whilst the secondary aim was to assess clinical outcomes associated with the implementation trial. This means that we focused on understanding what barriers and enablers existed for the project's implementation and the context within which it operated. Effectiveness of the intervention remained important, however we were primarily interested in how and why it did (or did not) work. The project was carried out at four geographic research sites within Sussex (see Section 2.3 ) and implementation was conducted on an iterative basis from research site to research site broadly following the Medical Research Council's (MRC) framework for the development and implementation of complex interventions ( 32 ). The research team developed and then began delivering the intervention at each site before moving onto the next. At each site the following stages were carried out: (1) Development: this included stakeholder mapping, formation of implementation partners, and codesign/local adaptation of the intervention [covered in the study's pre-implementation paper ( 30 )]; (2) Implementation: this included the delivery of the CHW intervention at the research sites and collection of mixed method data pertaining to effectiveness and stakeholder experiences, and (3) Evaluation: this included the analysis of the mixed method data in line with the MRC guidance on analysis complex interventions.

2.2 Research site and voluntary and community sector enterprise partner selection

Four study sites were selected across East Sussex by identifying Middle Layer Super Output Area (MSOA) postcodes with high levels of deprivation according to the Indices of Multiple Deprivation (IMD) ( 33 ). Selection of the research sites was based on the pre-implementation community mapping phase of the project ( 30 ). Following on from CBPR practices, VCSEs and Volunteer Coordinators (VCs) were recruited to co-design and deliver the implementation strategy at each of the research sites.

VCSEs organisations were recruited as partners at each research site. The intervention was primarily run through these organisations and a paid staff member was recruited at each organisation. Their responsibilities included, CHW management, and participant recruitment. They also had a role in local adaptation activities. VCSE organisations were eligible to take part in the organisations if they were based in the research site, if they had interests and existing activities that aligned with the project's goals (CVD risk reduction and community development), and if they had existing experience of volunteer recruitment and management.

2.3 Community health worker recruitment and training

The aim was for each site to recruit a pool of five to eight CHWs. As part of this each site was asked for input into local CHW recruitment flyers, which were shared on VCSE websites and social media pages and shared on social media via existing CHWs at the VCSEs. CHWs were recruited through intermediary organisation recruitment via the VCSE partner organisation. The project was also advertised at a Virtual Volunteer Fair. Local contacts and existing volunteer pools at the VCSEs meant that the target number of CHWs was rapidly recruited at each site. CHWs were eligible to take part in the intervention if they were over 18 years of age, if they lived within the research site (determined by postcode), and if they had some kind of pre-existing relationship with the VCSE partner organisation (i.e., as a volunteer).

Potential CHWs who expressed an interest in the project were invited to attend an induction to the project, and then the local adaptation co-design meeting. Those who decided they would like to become a CHW then went on to receive five online, group training sessions (each of which lasted for 2 h, 10 h in total): an introductory session, a session covering project policies, heart health and the structure of the intervention, and three sessions on behaviour change techniques. These training sessions were developed and delivered by an external organisation (National Centre for Behaviour Change) specifically for the project after a consultation and planning process with the research team. Before the onset of the intervention at each site CHWs made various recommendations in the local adaptation meetings on the design of the training programme. These included providing information on listening techniques, engaging, and managing resistance, providing simple health information, using accessible language, using different starting points depending on the CHW's background knowledge and experience, training on conducting coaching virtually, and providing a training handbook. A Volunteer coordinator (VC) was recruited at each site. This VC was a trained and experience health coach (KFS) and provided training support and guidance through monthly group training support sessions in addition to the initial 10 h training block the received prior to the intervention onset. These monthly training and support sessions were organised into specific themes and agendas that were set with the CHW participants.

2.4 Local adaptation

Elements of the evidence-based intervention were tailored to the individuals and their community in the stakeholder-mapping phase using qualitative interviews, workshops, and focus groups with a range of stakeholders across the study site ( 30 ). Further rounds of local adaptation were carried out with VCs and CHWs at each of the research sites to tailor to individuals and their community context through iterative co-design workshops ( 34 ). CHWs and VCSE also agreed on a “volunteer charter” during the co-design session. This was a list of principles, behaviours, and practices upon which guided interactions between research staff, CHWs, VCSE and participants. The charter was designed to ensure that the practices of the project aligned with the principles of the CHW and partner organisation.

2.5 Participant recruitment and screening questionnaire

Participants (who received coaching) were eligible to take part in the eligibility screening if they lived in, or adjacent to, the study site's postcode and if they were aged eighteen or older. Participant recruitment was also based on intermediary organisation recruitment, community outreach, paid social media advertisement (through Meta™), gatekeeper and snowball sampling. Gatekeeper recruitment was conducted when interacting with a relevant statutory or non-statutory service provider (i.e., a fitness/weight loss group leader) and involved asking them to recommend the intervention to their members or to recommend participants who may be interested in taking part. Snowball sampling involved asking participants who participated in the study to sending email invitations to their social group. A social media recruitment strategy was undertaken to recruit people from the local area to the risk profiling survey to supplement the community-based recruitment through the VCSE partners. Social media was conducted on Facebook via paid advertisement in four waves of recruitment which took place over 1–2 weeks at each site. The advert targeted people who were 35+ and over and to people with 5 km of each research site. Messages were changed regularly from a list of recruitment messages drafted with CHWs during co-design sessions. Additionally, CHWs and VCSE participants were asked to send recruitment emails to any social or professional networks they thought would be interested in taking part. We did not record where participants were recruited.

Screening and risk profiling for the CVD coaching was carried out using the validated non-laboratory based INTERHEART questionnaire, presented online, for all participants that expressed an interest in the study ( 35 ). This questionnaire assessed modifiable and non-modifiable CVD risk factors and categorised participants as either “Low,” “Moderate.” Or “High” risk. See the protocol paper for further information on the INTERHEART risk profiling; for more information on the screening questionnaire, see the study protocol paper ( 29 , 35 ). Questionnaire data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at the University of Antwerp ( 36 ). Participants were considered to be eligible for the intervention if they were aged eighteen or over, if they lived within the research site (determined by postcode), and if they were categorised as “Moderate” risk of CVD according to the INTERHEART questionnaire. High risk participants were not included as their needs were considered to be too high for a pilot study involving CHWs. Eligible participants were then emailed by the research team with an invitation to take part in the CVD coaching intervention. After recruitment for the intervention was closed for each site, an online questionnaire survey was sent to eligible participants to gather information the reasons for not accepting the invitation to the intervention. Open response questions were used which the research team later categorised into codes.

2.6 The CVD prevention coaching intervention

The coaching intervention was based on motivational interviewing techniques which are promoted by the European commission on cardiovascular disease prevention in clinical practice ( 37 ) and which include techniques such as Open questions, Affirmation, Reflective listening and Summary reflections (OARS) ( 38 , 39 ). The use of these Behaviour Change Techniques (BCTs) used during the intervention were based on five target behaviours highlighted by the World Health Organisation including: reduce/cease smoking, increase moderate physical activity, reduce the fat, salt, and sugar content of the diet, increase fibre, oily fish (or alternatives), fruit, and vegetable content of the diet, reduce sedentary hours. The intervention involved six, one-hour long coaching sessions between participants and CHWs which were delivered every two weeks. Participants were also considered to have completed the intervention if they only completed three sessions and then notified the team of their withdrawal from the intervention.

The study team included two participant co-ordinators (PCs) who managed the participant journey through the intervention, sending welcome emails, questionnaires, and invitations to post-intervention interviews, and co-ordination between participants and CHWs to book coaching sessions. Reminders of appointments were also sent to CHWs and participants one week and two days before the session. Participants and CHWs were matched, based on gender preference and availability, and supported throughout the coaching intervention the PCs. CHWs were provided with guidance, resources, and signposting information throughout the intervention but were also given the flexibility to deliver the coaching in a way that suited them and their participant(s). Initially, counselling and goalsetting were based on their individual item INTERHEART assessment scores. Participants and CHWs were then encouraged to create an action plan with appropriate goal setting for the behaviours they wanted to change (e.g., diet, exercise habits). The goals were set in relation to when, where, and how they would undertake the behaviour, e.g., when the physical activity will be performed, where it will be performed, how often it will be performed (i.e., in a group or using specific equipment). CHWs helped participants to analyse any factors which might influence their ability to achieve the goals and to generate strategies which could help them overcome these barriers using problem solving. Full details of the participant journey through the intervention are given in Supplementary Appendix 2 in the Supplementary Material . All coaching was conducted virtually using Zoom™ to host and monitor coaching sessions and Microsoft OneDrive to store, recruit, and communicate written and visual resources with CHWs and participants. Monitoring in Zoom calls was called out by the PCs who checked whether both the participant began and ended the coaching session. If either the participants or CHW did not join, the PC could join the call to help the attendee. Feedback was obtained from the participant about the coaching session through emails after the session and by inviting participants to a follow-up interview after the intervention (see qualitative evaluation).

2.7 Evaluation

The evaluation was underpinned by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework ( 31 ) which allows for an understanding of the multifaceted and interactive effects of personal, social, and environmental factors that determine behaviour; and for identifying behavioural and organisational leverage points and intermediaries for health promotion within organisations and communities. RE-AIM has been used to evaluate programs and setting in public health and community settings and is thought to be particularly useful when evaluate interventions in “real-world” settings ( 40 , 41 ). It has also been used to evaluate public health interventions which make use of community health workers in community-based setting ( 42 – 44 ). Results are made up of quantitative measures from the participant questionnaires, qualitative interviews with the participants, the CHWs, VCSE partners, and the research team. Primary quantitative outcome measures included implementation measures such as uptake and engagement and the pre/post changes to the self-report CVD behavioural questions which included the following three questionnaires: (1) the INTERHEART CVD risk questionnaire collected during the screening process was used as the baseline and collected again after completion of the intervention. (2) Physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ) ( 45 ). The IPAQ is an internationally validated instrument to capture information about weekly physical activity habits, behaviours, and routines. (3) Diet was assessed using a 20-item questionnaire based on a modified version of the UK Diet and Diabetes Questionnaire ( 46 ), a brief food frequency questionnaire designed to assess conformity to healthy eating guidelines, and to assist in the setting of dietary goals. It was used to estimate the number of portions eaten daily or weekly of fruit and vegetables, oily fish (or alternative), and foods high in fat, salt, and sugar, what proportion of the time wholegrain cereal products were chosen, weekly units of alcohol consumed and the frequency of binge drinking. Due to the small sample sizes and non-parametric data used in this study, Wilcoxon Sign test was used to evaluate for differences in continuous variables whilst McNemar's test was used for binary categorical data. The pre-intervention assessment of the primary outcome measures was sent to participants before they participated in the intervention (no participant could begin the intervention without completing the baseline measures). Post intervention primary outcome measures were collected after their participant in the intervention was completed.

Focus groups and one-to-one interviews were conducted with four groups of stakeholders: (1) VCSE partners; (2) CHWs; (3) members of the research team, (4) participants in the intervention. Individual interviews were conducted with VCs, members of the research team, and participants, while data from the CHWs was collected in focus groups. Discussion guides for VCs, CHWs and members of the research team all included questions on the respondents' role within the project, the process of community engagement, barriers, and facilitators the implementation process, recommendations for the future and sustainability. Discussion guides for participant interviews included questions on how and why participants became involved in the project, their experience of the health coaching, and their views on the impact and usefulness of the project. Interviews and focus groups were conducted online using Zoom or MS Teams. The analysis was conducted by TGJ, IR, and RD and using qualitative framework analysis based on the components of the RE-AIM framework. Following data collection interviews and focus groups were transcribed by a professional transcription service and TGJ, IR, and RD familiarised themselves with the full set of data. They then undertook line-by-line coding of the data in NVivo using descriptive primary codes which were then interlinked with secondary codes. These secondary codes were then organised under the five elements of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance). The analysis was interpreted, findings were synthesised with reference to the stakeholder group and theme descriptions were produced with supplementary illustrative quotes.

The Reach of the intervention was assessed through recruitment rates for the VCSE partners, CHWs and Intervention participants and qualitative data collected from the VCSE partners, and the research team was used to understand barriers and facilitators to recruitment. Effectiveness was assessed during the primary outcome measures and barriers and facilitators to effectiveness were assessed through qualitative interviews with the participants and CHWs. Adoption was at the setting level was determined through assessment of the retention of VCSE partners and qualitatively through interviews with VCSE partners and the research team. At the individual level, Adoption was assessed through CHW retention rates and qualitatively assessed through interviews with the research team and the CHWs. Implementation was assessed qualitatively through interviews with the intervention participants focusing on intervention fidelity. Maintenance was assessed at the setting level qualitatively through interviews with VCSE partners and the research team and through a report of the status of the intervention after 6 months. No individual level maintenance data is reported. A description of the data sources which contributed to each component of the RE-AIM framework is listed in Table 1 .

Table 1 . Description of data source used to evaluate the SPICES-Sussex intervention for each of the RE-AIM components.

Ethical approval for this research was obtained from Brighton and Sussex Medical School's Research Governance and Ethics Committee (R-GEC) (application reference: ER/DG241/17BSMS9E3G/1). This ethics review covered the methods described herein, key research materials, and recruitment and consent protocols for both intervention participants and staff/CHW interviews. Due to the changes imposed on the project by COVID-19 (see Supplementary Appendix 2 ) and because of minor adaptations from research site to research sites; several minor amendments were made (final application reference: ER/BSMS9E3G/6).

Informed consent was obtained in three ways from study participants depending on the nature of their participation. (1) Online screening questionnaire: these participants were presented with an approved information sheet on the first page of the online screening questionnaire, they were then provided with an Informed Consent Form (ICF) which they had to sign with a digital signature. (2) Intervention participants: just prior to participation and data collection participants met with a research staff member to review the information sheet and to sign the ICF if they agreed to participate, consent was sought again for those intervention participants who took part in a post-intervention interview. (3) CHW and research staff members: participants were sent the information sheet and consent form several days before their interview and were asked to sign and return the ICF prior to their interview appointment.

3.1 Participant characteristics

Risk profiling data was collected from 381 participants (Females: 310, Males: 71; mean (SD) age = 58 (12.39) years. Forty-Six participants began the intervention (39 Females, 7 Males; age = 58 (11.94) years. Sixteen participants took part in one-to-one interviews at the end of the intervention (thirteen females and two males, aged 32–67 years). Seven members of the research team (6 females, 1 male), and four VCSE partners (3 females and 1 male) took part in the research team interviews. Four focus groups with a total of thirteen participants (10 females and 3 males) were conducted with CHWs from each of the research sites. Thirteen participants (no gender data collected) took part in the post-intervention questionnaire for non-participants.

3.2 Analytical framework

The remainder of these findings are organised into RE-AIM dimensions with various quantitative and qualitative methods used to evidence each dimension, see Table 1 for a description of each of the data sources. Table 2 summarises concordance and discordance with expectations of the intervention [as described in the study protocol ( 29 )] in line with the RE-AIM framework. Supplementary Appendix 3 summarises changes to the study design from the published study protocol . Throughout this section participant codes are used to attribute quotations and references to specific terminology to a respondent. The codes identify the respondent as either a member of the Research team (RT), VCSE partners (VCSE), Community Health Worker (CHW) or Participants (PP). For VCSEs, CHWs and PPs references to their sites are also made (EB, HA, NH, HG). All codes refer to gender and (F/M), and their number within each respondent category.

Table 2 . Description of concordance/discordance with our pre-implementation expectations of the SPICES intervention for each of the RE-AIM components ( 29 ).

4.1 Recruitment of voluntary and community sector enterprise partners

A community-mapping exercise was carried out during the pre-implementation phase of the project ( 30 ) in which three partner organisations were identified across three research sites in East Sussex (Hastings, East Brighton, and Newhaven). All these organisations were volunteer based community organisations with a focus on local community development and improving health, with the Hastings organisations being focused on health and wellbeing. During the intervention set up phase, the East Brighton organisations dropped out of the study due to the impact of Covid-19 whilst the Hastings, and Newhaven organisations were carried forward to deliver the intervention. The East Brighton organisations helped the research team to develop links with a health and wellbeing organisation that was associated with a local General Practice (GP) clinic in East Brighton. Finally, a fourth research site was identified in West Hove and a final VCSE partner was identified. This organisation was a local community development organisation for the area. In total four VCSE organisations were partnered with across four research sites. In each site a VC was recruited from the partner organisation to deliver the intervention with the research team.

4.2 Community health worker recruitment

The research team and VCSE partners recruited 38 individuals who attended the introductory CHW meetings (Gender: 27 females and 11 males, NH n  = 7, EB n  = 13, HG n  = 10, HA n  = 8). Twenty-seven of these individuals completed the full training for CHWs (20 females and 7 males; NH n  = 5, EB n  = 9, HG n  = 7, HA n  = 6).

4.3 Participant recruitment

Social media recruitment had a wider reach to potential participants compared with gatekeeper recruitment, however, several participants did not complete the REDCap screening questions, had a poor understanding of the study, or were not part of the study's target population. VCSE gatekeepers yielded poor recruitment results apart from when a newsletter with a particularly large reach was used. Social media was the primary strategy for recruiting participants to the study. In total the messages reached 13,086 individuals across four waves of recruitment and of these 472 (3.6%) engaged with post by clicking on the survey link. Of those who clicked on the link 80% were female and 20% were male.

The INTERHEART screening data is shown in Figure 1 and Supplementary Appendix 1 for all those who completed the screening questionnaire ( N  = 381), participants who started the intervention and then withdrew ( N  = 17), and participants who completed the intervention and on whom we have full data ( n  = 27). Of the CVD risk factors measured by the INTERHEART screening tool, the two most prevalent were stress (reported by 61% of those screened, 56% of those who started the intervention, and 78% of those who went on to complete), and physical inactivity (reported by 55%, 81% and 64% respectively).

Figure 1 . Primary outcome measures for the “Reach” and “Effectiveness” components of the SPICES-Sussex intervention. ( A ) The proportion of “Low”, “Medium”, and “High” risk participants identified during the Interheart risk profiling questionnaire; ( B ) the mean Interheart score pre and post intervention for those who completed the intervention, p value from paired t -tests; ( C ) shows the % change regularly of dietary behaviours from pre/post intervention UKDDQ score, within-group t -tests; ( D ) the change in the % of intervention participants classified as having either low or medium/high activity levels pre and post intervention, p value from McNemar's test.

Forty-six participants took part in the CVD coaching intervention across the four research sites, all of whom completed the pre-intervention quantitative questionnaires. Sixty-three percent completed the full coaching intervention, and one participant withdrew from the project after three months. We had full data for twenty-seven of twenty-nine participants who completed the full 6-month coaching intervention (note: these participants have been removed from Supplementary Appendix 1 , n  = 2), Participants' characteristics are summarised in Table 3 . Several participants withdrew (37%), reasons given for withdrawing were: ill health/poor mental health/ill health in the family (13%); the intervention was considered a poor fit for the participant/did not meet their expectations/they did not need the intervention (9%); other commitments got in the way/they were too busy with their normal lives (7%); repeated non-attendance at planned coaching sessions from the CHW (4%); did not get on well with CHW (2%), language issues (2%).

Table 3 . Facilitators and barriers to reach and recruitment.

Due to low initial recruitment rates, the recruitment areas were expanded and included more affluent adjacent areas. The proportion of those completing the screening questionnaire and of those who went on to start the intervention who were in the target population (i.e., had an address with a postcode and IMD in the most deprived three deciles) was 30% in both cases. Despite recruitment being gender neutral and without gender/sex related parameters on social media our risk profiling questionnaire recruited far more women than men (77% female, 23% male, see Supplementary Appendix 1 ). This issue was carried forward to the main intervention in which only five of the forty-six who initially took part in the study were male.

4.4 Reasons for non-participation

Reasons given for not participating included missing or not receiving an invitation to take part ( n  = 4), lack of time due to responsibilities and commitments ( n  = 4), not feeling like the intervention was a good fit for them and their circumstances ( n  = 2), not being happy with the CHW allocated to them ( n  = 2), being reluctant to take part in online activities due to a lack of privacy at home ( n  = 1). When asked what would have made them more likely to participate the most common response was more clarity/detail on what was involved ( n  = 3).

4.5 Facilitators and barriers to reach

Intervention participants referred to several intervention components that functioned as facilitators or barriers to the reach of the intervention. These barriers and facilitators were organised into themes which include: (1) Experience of CHW recruitment; (2) The value of community partnerships; (3) The experience of the risk profiling questionnaire; (4) Impacts of COVID-19. These barriers and facilitators are described in more detail in Table 3 and illustrative quotes are provided.

5 Effectiveness

5.1 primary outcomes measures.

For those participants who completed the intervention, the before and after measures of cardiovascular risk, diet, physical activity, and readiness to change were compared (see Figure 1 and Supplementary Appendix 1 ). Mean INTERHEART score fell significantly from 11.7 to 9.9, taking the mean to within the low-risk range. There were also significant improvements in the self-reported dietary measures including: an increase in the proportion of time wholegrain foods were chosen, and the daily portions of fruit and vegetables eaten, and decreases in the consumption of fatty, salty, and sugary food. No changes were observed in the consumption of oily fish. Self-reported levels of physical inactivity also dropped over the course of the intervention with the proportion of those classified in the “low” physical activity category falling from 40% to 7%. Additionally, the self-reported levels of participants' “readiness to change” during the intervention increased from 3.6 to 4.5, which indicates increased levels of motivation as a result of the intervention.

5.2 Participant reported facilitators and barriers to the effectiveness

Intervention participants referred to several intervention components that functioned as facilitators or barriers to the effectiveness of the intervention. These barriers and facilitators were organised into themes which include: (1) accountability—the ways CHWs kept participants accountable about their health behaviours; (2) connection and community—the importance of making human connections with the CHWs and feelings of community togetherness; (3) judgement-free—the importance of a judgement-free intervention experience; (4) motivation and support—the coaching role that the intervention took in the lives of participants; (5) personalisation—the feeling that the intervention was adapted to their own needs and experiences; (6) reflection—the value of reflecting on experiences during the coaching intervention; (7) self-efficacy—the ways in which CHWs made participants feel in control of their health behaviours; (8) gradual or modest impact—the feeling that the intervention largely lead to modest impacts (9) generic or inappropriate advice—the feeling that the information provided during the coaching was too generic, obvious, or inappropriate to their needs. These barriers and facilitators are described in more detail in Table 4 and illustrative quotes are provided.

Table 4 . Facilitators and barriers to intervention effectiveness.

6.1 Retention of voluntary and community sector enterprise partnerships (setting level)

Of the six VCSE organisation engaged with during the pre-implementation phase of the project, four went on to be VCSE partner organisations during the implementation phase. Disruption and staff pressures resulting from the COVID-19 pandemic were a significant barrier to recruiting partner VCSEs, with two organisations who had been involved in initial discussions deciding not to proceed for this reason. Furthermore, interruptions to communication caused by COVID-19 and research team changes led to a loss of trust and engagement in some cases. One organisation which had a group of people ready to volunteer at the beginning of the project later withdrew as this group had fragmented due to COVID-19-related delays and substantial staffing changes that took place just prior to the implementation phase between 2019 and 2020. Other factors impacting on VCSE recruitment included the availability of funding, and issues with recruiting staff to the VC role. After one of the VCSE partners dropped out of the study just prior to the implementation phase, the same organisation linked the research team with another organisation who eventually functioned as VCSE partners for the implementation phase. The need to develop trust, and having the time to achieve this, was stated by several members of the research team as being key to recruiting partner VCSEs. Quality of communication was also felt to be especially important.

6.2 Facilitators of voluntary and community sector enterprise partnerships (setting level)

VCSES and research team members referred to several intervention components that functioned as facilitators or barriers to setting level adoption. These barriers and facilitators were organised into themes which include: (1) Trust—the importance of developing trust with community- partners; (2) Local Knowledge—the value of local knowledge and to delivering appropriate community care; (3) Local Skills—the value of the skills and experiences in local communities to delivering the intervention. These barriers and facilitators are described in more detail in Table 5 and illustrative quotes are provided.

Table 5 . Facilitators and barriers to intervention setting level adoption.

6.3 Retention of community health workers (individual level)

Of the twenty-seven CHWs who were recruited and trained to be a part of the intervention, twenty-one went on to deliver one or more session as an active CHW (Gender: 15 females and 6 males NH n  = 5, EB n  = 6 HG n  = 5, HA n  = 5). Each of these CHWs completed the intervention with at least one participant and the maximum number of participants who completed the intervention with one CHW was three.

6.4 Community health worker training needs feedback (individual level)

After training sessions in our first site, a short questionnaire was conducted with CHWs who attended the training in the formof one-to-one discussions with the training coordinator and the research team. Questions were asked about the anticipated barriers that CHWs thought they would face during the coaching as well as key training needs. Anticipated barriers and challenges during the project included: a sense of mistrust amongst participants, issues of poverty and deprivation, triggers, and sensitivities to the experiences of participants (i.e., trauma or addition triggers). The key training needs identified included: the sharing of personal stories to empower participants, how to set achievable health goals, preparing CHWs with tools to challenge the participant in a supportive way, improving CHW confidence, and advice on how to communicate CVD risk to participants in a straightforward way.

6.5 Community health worker facilitators and barriers to adoption (individual level)

CHWs referred to several intervention components that functioned as facilitators or barriers to the adoption of the intervention at the individual CHW level. These barriers and facilitators were organised into themes which include: (1) Local adaptation and Codesign Sessions; (2) CHW motivation for participating; (3) CHW experiences of the training; (4) CHW experience of the support provided to them. These barriers and facilitators are described in more detail in Table 6 and illustrative quotes are provided.

Table 6 . Facilitators and barriers to intervention individual level adoption.

7 Implementation

7.1 participant retention and fidelity.

Overall, 48% ( n  = 51) of those eligible ( n  = 106) to take part in the intervention agreed to do so and provided consent, of those 90% ( n  = 46) attended their first CHW coaching session and completed the baseline questionnaire. Of those who completed their first session 63% ( n  = 29) completed three sessions and 45% completed six sessions. For the 46 participants that began the intervention there were 276 planned program contacts of which 183 (66%) were completed. Retention and attendance data are summarised in Supplementary Appendix 2 . No data was collected on the amount of time each participant spent in their coaching session.

7.2 Participant facilitators and barriers to implementation

Intervention participants referred to several intervention components that functioned as facilitators or barriers to the implementation of the intervention. These barriers and facilitators were organised into themes which include: (1) expectations of the coaching intervention, (2) the virtual coaching sessions; (3) holistic and flexible, (4) length of the coaching session, (5) administrative support, (6) past experiences, (6) mental health. These barriers and facilitators are described in more detail in Table 7 and illustrative quotes are provided.

Table 7 . Facilitators and barriers to intervention implementation .

8 Maintenance

8.1 status of the intervention after six months.

Six months after the intervention's funding period ended the program was being continued at two of the sites. One of the sites continued it as volunteer opportunity and peer support program which was covered by their existing funding for peer support programs. A second site was awarded funding from the National Health Service to continue the intervention. The latter's findings will be reported as a program evaluation in the future.

8.2 Facilitators and barriers to maintenance

Interviewees referred to several intervention components that functioned as facilitators or barriers to the maintenance of the intervention at the setting level. These barriers and facilitators were organised into themes which include: (1) continuity of the intervention; (2) funding; (3) infrastructure These barriers and facilitators are described in more detail in Table 8 and illustrative quotes are provided.

Table 8 . Facilitators and barriers to maintenance.

9 Discussion

SPICES Sussex developed strategies to implement effective community-based CVD risk reduction interventions based on behaviour change coaching with CHWs by partnering with and leveraging the experience and influence of VCSE in four underserved communities in East Sussex, UK. Despite issues with recruitment and challenges associated with COVID-19 as well as other logistic, management, and research design challenges, the project showed clear markers of success. Participants experienced the interventions positively and many made gradual, and sometimes substantial, lifestyle changes. The quantitative results showed significant reduction in participants' CVD risk after taking part in the interventions. We think these successes were due to implementing our interventions in a flexible, personalised, and holistic way, which empowered CHWs to use their skills and experiences to aid participants. These results demonstrate how CHWs-led and community-based preventative CVD interventions could be implemented, such as those seen widely across the Global South ( 17 , 18 ). They also support a “person-based” and “asset-based” approach to community-based implementation design ( 23 , 25 ) in which the strengths and assets of communities and their members are used to promote health and wellbeing.

9.1 Intervention design

The SPICES-Sussex project used community-engagement and community health worker approaches to improve CVD health that are based on practices developed and tested in Kampala, Uganda ( 47 ). As part of the SPICES consortium these practices were adapted to several global north (UK, France, Belgium) and global south settings (South Africa). In the global south social public health approaches have long advocated for the decentralisation of healthcare to community partners and for a greater focus on prevention ( 48 ). Community-based public health practices such as task-sharing are often utilised in low-resource health systems in low-and middle income countries by recruiting and training community health workers to deliver low-intensity health intervention such as health coaching and signposting ( 49 ). In global south SPICES settings, there was greater buy-in to community-based interventions from governments and much of the trust building, and infrastructure for community health workers already exists ( 50 ). These settings, including the SPICES sites that influenced the Sussex site, often rely on voluntary or unpaid volunteers to conduct public health work in order to lower cost and to make use of existing social networks.

In resource-rich global north settings, healthcare is far more institutionalised and focused on secondary care and the infrastructure for community-based and participatory interventions is far less well developed. In the UK, most health interventions must adhere to the institutional demands of the National Health Service which presents a range of resource intensive training, recruitment, safeguarding, and management practices. There is much less history of CHWs in the UK; the role of these workers is not well understood or well defined outside of the third/voluntary sector despite recent calls for their use during the COVID-19 pandemic ( 51 ). This squeezed landscape for community-based intervention and the lack of familiarity with the role makes the development and implementation of these interventions challenging. In the global north there are increasing challenges to the volunteer nature of CHWs with researchers calling for compensation, capacity building, or payment of members of the public involved in intervention delivery of research and health interventions on moral and efficacy grounds ( 52 , 53 ). In our study, the decision not to pay CHW was made as a result of us following the SPICES approach developed in the Global South ( 17 ) and because the VCSE organisations we partnered with all had existing unpaid community volunteer programs. In our post-intervention qualitative evaluation interviews, participants and CHWs both discussed the value of paying CHWs. Furthermore, the drop in CHWs and the small number of participants they were able to take on implies that the lack of payment impacted the degree to which CHWs were able to engage with the project and therefore impacted the intervention's effectiveness and sustainability. In the UK, the NIHR now recommends that members of the public who are involved in research are properly reimbursed for their involvement and provide frequently updated guidelines on how to do so ( 54 ). In the future we argue that public health intervention that make use of CHWs should reimburse and pay them in some way for their involvement.

Community volunteers with low levels of training (10 h core training plus ongoing support), such as those used during this study, are not well-suited to complex cases or acute needs that required specialised support. In our findings, participants complained of generic, inappropriate, or obvious advice from the CHWs. Participants did not seem to prioritize the knowledge or expertise of the CHWs and instead valued the personalised, holistic, and supportive relationships that were offered by the CHWs. Participants in the intervention reported having good knowledge of what they needed to do to improve their health but struggled to do it in practice. Therefore, this kind of intervention may be well-suited to providing emotional and social support to people at risk of CVD who know what they “should” do but need a support and judgement free support mechanism to make changes.

Interviews with participants revealed a tension in the study linked to the use of an individualistic lifestyle change intervention situated within a community-based and participatory study. The study design did not address community-level, socio-economic, or environmental issues known to be vital when addressing CVD health ( 55 ). Tengland ( 56 ) argues that an individualistic lens of behavioural change can limit understandings of a person's CVD health. The result can be too narrow, as the “secondary” effects of their wider environmental conditions (i.e., powerlessness, lack of control, or lack of hope), are not considered. They further suggest that interventions should focus more on the attainment of instrumental goals, such as increased real opportunities in life. For community-based projects to grow further, they should seek to become multi-faceted by combining individualistic interventions with environment/community activities such as community education ( 57 ).

The frequency with which mental health issues were raised in discussions was notable. Those who took part in the screening reported high levels of stress and depression, and rates were even higher amongst participants taking part in the programme, furthermore, participants reported lower levels of stress and depression at the end. This may show that this type of intervention is particularly well suited to people with mental health concerns for whom talking to someone can make a real difference. This was also observed in the SPICES consortium partner sites including Brest (France) ( 58 ), and Antwerp (Belgium) ( 59 ). Most non-specialist or non-clinical people do not think of their health siloed into CVD, mental health, digestive health etc ( 60 ). Instead, one's health is perceived holistically, and mental health is often the most prominent barrier and facilitator to behaviour change.

9.2 Implementation strategy

We adopted a type 3 hybrid implementation study which focused primarily on implementation factors rather than evaluation, dropping the randomisation approach and embracing flexible more emergent iterative development and growth perspective, co-design, and contextual/place-based factors. A rigid evaluation linear approach as required for a type 1/2 design, which was initially planned, caused tensions with the community-based, participatory, and “emergent” aspects of the project and (2) the pressures imposed on our voluntary sector partners by the pandemic meant that adhering to a rigid randomisation approach was less realistic ( 7 ). The planned approach placed power in the hands of the research team which negatively affected our stakeholder relationships, and a rigid adherence to study protocols would have meant we could not effectively adapt strategies or interventions to context.

Instead we adopted a type 3 approach, which has been used to assess a wide range of preventative health and eHealth interventions which operate in communities based on participatory principles ( 61 ). In their systematic review of such strategies to implement interventions, Haldane et al. ( 62 ) highlight the importance of building mutually beneficial and trust-based relationships particularly with marginalised stakeholders, and stress the importance of developing strategies and interventions contextually whilst reporting and acting on lessons learnt throughout the project. Wildman et al. ( 63 ) argue that successful community-based projects require extensive community input, learning and adaptation captured from existing programmes to facilitate the replicability of programmes in other community contexts. With the more flexible type three approach we were able to make local adaptation to meet the need and priorities of the local community and local VCSE partner organisation thereby listening to the voices of those who are involved. This iterative approach to intervention design is similar to the “scaling-out” approach suggested by Aaron et al. ( 64 ) which advocates iterative roll-out and local adaptation in place of simply “copy and pasting” interventions across context. In reality, during SPICES-Sussex the local adaption became less flexible as the intervention became more well-developed as the internal factors became more institutionalised within the research team. However, the principle of meeting the needs and priorities of the local VCSE organisation were maintained from site to site and the team sought input from local organisations where possible.

We do not know whether the changes observed will be maintained due to the short follow up period, both at an individual level or a setting level ( 65 ), and the research lacks an economic appraisal. The short follow-up period was forced on the research team because of delays to the project caused by COVID-19 which meant our funding period was not long enough to conduct a follow up assessment. An economic appraisal was not considered appropriate because the development approach taken during the study meant that any economic appraisal was not likely to reflect real-world roll-out. In the future we would advocate for greater scaling-out to include a larger sample and an economic appraisal.

9.3 Recruitment and retention

The impacts of the restrictions placed on the people, organisations, and communities involved in this research due to COVID-19 were extensive and wide-ranging. The per-implementation phase of the research began in January of 2020 with the recruitment of an implementation team and participant recruitment was due to begin in April 2020. Following the outbreak of COVID-19 in the UK, recruitment was stopped from 16 March 2020 to 1 October 2020. By June 2020, a decision was made to fully move to remote delivery of the coaching intervention using video conferencing services.

Research recruitment and retention were near constant challenges, and all activities were significantly impacted by the Covid restrictions. We believe that the use of the INTERHEART tool, presented on the REDCap platform, acted as a barrier to recruitment as evidenced through the follow sources: (1) Over 650 participants attempted to begin the screening questionnaire and our records show those who did not complete it stopped towards the beginning or mid-way through the questions, particularly when they were asked to measure their waist/hip circumference, (2) of the 380 participants who completed the survey only approximately 100 were eligible for the intervention meaning we were selecting from a very limited pool of participants, (3) many of the participants in the per implementation interviews mentioned finding the screening tool to be “clunky” or “annoying” to use. Its overly “medical” focus, as a basis for lifestyle discussions may not have been engaging for the target audience.

Our initial recruitment strategy was to rely heavily on our VCSE partners to act as gatekeepers for recruitment, a practice commonly seen in participatory research methods ( 66 ). Whilst the VCSE partners were adept in the recruitment and management of CHWs and in the development of practices and policies, they did not seem to have the reach or access for the recruitment of large numbers of potential participants. Our experience aligns with that of Williams ( 67 ), who states that VCSE and end users' relationships are often smaller in number but deep, based on trust and protection, and covered by a range of risk related policies. Instead, we relied heavily on the use of paid for social media adverts for recruitment due to our ethics restrictions. Much like the experience of other researchers who used these tools, we found that they were low cost and reached large numbers of people but engagement with the screening and risk profiling and participant recruitment was low ( 68 ). In future studies, it may be more suitable to use social media as an adjunct to mixed recruitment strategies which make use of community outreach, primary care recruitment, and media outreach ( 69 , 70 ).

The study sample was heavily skewed towards middle-aged females and much of the sample was not considered to be from vulnerable or low socio-economic groups. Furthermore, males are under-represented in both the risk profiling and intervention samples which represents a divergence with our planned recruitment targets in which we aimed for a more representative sample. The difficulties in recruiting men and vulnerable and other “seldom heard” populations to life style interventions are well-recognised ( 71 , 72 ). Recommended strategies to improve male participation in community-based interventions include engaging with male-friendly spaces, workplace-based interventions, and incorporating activity-based programming, social-support, and group activities ( 73 , 74 ). Some of these elements were suggested during the planning phase of SPICES but were not feasible due to COVID restrictions ( 30 ).

9.4 Project infrastructure

We made the key decision to bring VCSE organisations into the research team with paid roles to foster stronger community/research partnerships as promoted by CBPR researchers ( 75 ) and the NHS's PPIE (Public and Patient Involvement and Engagement) initiatives ( 76 ). Our research shows that the VCSE sector is an untapped resource within primary and community care that has a great deal of expertise, compassion, and enthusiasm to offer health provision ( 77 ). To facilitate this community-based project, we focused on the concept of trust building throughout the intervention as described by Christopher et al. ( 78 ).

VCSE partnerships brought knowledge and expertise of their local communities, policies/practices of volunteer management and, critically, perspectives of the motivations and drivers for CHWs and communities. CHWs were empowered to bring their own skills and abilities to the intervention through an asset based and flexible project development which included them in the co-design of the project ( 79 ). The strategies we used to implement the interventions were not prescriptive and did not force CHWs to follow a set of strict guidelines. This led to a highly personalised, flexible, and reflective experience for CHWs. However, our experience highlights potential problems with relying on unpaid volunteers to deliver complex interventions, including issues with volunteer commitment, attendance and drop out.

Our research highlights the importance of infrastructure when managing CHWs and partnering with VCSE sector organisations. We developed a bespoke behaviour change training course for CHWs, a range of CHW risk appraisal and mitigation policies with our VCSE partners, and a dedicated team of participant and CHW support and management coordinators. Clear protocols were developed and followed for the recruitment, onboarding, matching, and hosting of participant coaching sessions whilst CHWs were provided with multiple channels of regular communication and continuous training and feedback opportunities. We support calls for project managers, VCSEs, primary care providers, and community members to be more explicitly involved in the design and development of interventions which affect and include communities ( 80 ).

In this study, the research team also experienced issues of positionality throughout the project whereby the lines between implementor, community worker, and evaluator were blurred. Coulter et al. ( 81 ) have pointed out that research that includes CHWs in the design and delivery of interventions commonly experience a tension between fidelity of the intervention protocol and community expectations, needs, and norms. We also experienced differing goals between academic and community partners (including CHWs), where academic partners prioritized data collection and community partners prioritized funding, sustainability, and policy. This can be likened to the experience of Furman et al. ( 82 ) who discussed how community partners were hesitant to endorse their research due to conflicts with on-the-ground realities of the community members they served.

9.5 Recommendations

During this project the research team, VCSE partners, and CHWs constantly learnt lessons and were quick to make adaptations to their approach based on feedback from a range of stakeholders and capturing all of these in this paper would be an impossible task. However, several key insights can be drawn from our collective experience and evaluation of the project. They include:

1. Environmental issues are larger and more complex than any coaching intervention based on individualistic changes can hope to remedy.

2. The voluntary and community sector has a range of strengths and assets based on local experience and knowledge developed over significant periods of time that can be used for CVD prevention. However, the sector is highly under-resourced and spread thinly across a wide range of priorities. Individual VCSE partner organisations do not always have enough reach to facilitate recruitment.

3. Community engagement works best if it is built into a project early on through co-design and resources and time should be allocated to this activity.

4. CHWs bring significant advantages during the delivery of community-based interventions. They are trusted peers, they bring their own skills and experience, and they can benefit from the intervention alongside the participants.

5. Strategies to encourage the participation of men should be specifically considered during the planning phase.

6. Virtual coaching interventions are acceptable to participants, and in many cases preferable to participants, due to their flexibility and ease of use.

7. The issue of mental health must be addressed even when working with unrelated health public conditions.

8. A strong project infrastructure, made up of well-trained support/administrative staff, is essential when delivering community-based interventions.

9. CHWs should be paid or reimbursed for their involvement in research and public health interventions. Falling to do so is looked down on my stakeholders and has impacts on sustainability and effectiveness.

10. The Global North can look to innovations in the Global South for examples of success for community-based interventions, however, proper contextual or situational analyses must be conducted to understand the needs and priorities of target communities.

9.6 Conclusion

This study demonstrates the feasibility of a CHW-led preventative health interventions could be implemented with overseen and unheard communities in the UK. It highlights the wealth of untapped resources that exist with VCSE and CHWs and suggests how a beneficial community-based service could be set up to run alongside and support NHS Health Checks, to reduce the incidence of CVD. The aim was to empower CHWs to discuss health with people in their communities based on behaviour change principles. We have set out what worked well and what did not, to facilitate development of future community-based interventions in the Global North. We believe that the community-based approach need not be restricted to CVD risk reduction, and that it could easily be applied to low level mental health conditions, diabetes, or other preventable NCDs. If CHWs are confident, well supported, and well-trained, they will have the skills and ability to contribute to improving the health and wellbeing of people in their communities. The benefits do not only extend to patients but also to CHWs and to the VCSE partners involved. We believe our project shows how these interventions can become a supplementary tool that links primary care services with the VCSE sector.

Data availability statement

The datasets presented in this study can be found in the University of Sussex's data repository through the following link: https://sussex.figshare.com/ ; (doi: 10.25377/sussex.25569084).

Ethics statement

The studies involving humans were approved by Brighton and Sussex Medical School Research Governance and Ethics Committee (RGEC). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

First Author (First Authorship): Thomas Grice-Jackson Second Authors (Equal Contribution): Imogen Rogers, Elizabeth Ford, Robert Dickson Third Authors (Equal Contribution): Kat-Frere Smith, Katie Goddard, Linda Silver, Catherine Topham Fourth Author (Equal Contribution): Papreen Nahar, Geofrey Musinguzi, Hilde Bastiens. Senior Author (Senior Authorship): Harm Van Marwijk. All authors contributed to the article and approved the submitted version.

This project was funded as part of an EU Commission Horizon. CORDIS (The Community Research and Development Information Service (CORDIS) Grant agreement number: 733356.

Acknowledgments

We thank the following voluntary and community sector organisations for their partnerships whilst designing and delivering this project: Active Hastings, Wellsbourne Healthcare Community Interest Company, Sussex Community Development Association, the Crew Club, and the Hangleton and Knoll project. We thank the National Centre for Behaviour Change for their contribution to the development and delivery of the Community Health Workers training. We thank all members of the SPICES consortium and European Commission who provide consultation and advice throughout the project. Finally, we thank all our Community Health Workers for giving up their time for this project. They were central to every part of this work and their contribution is greatly appreciated. We would also like to thank the editorial and reviewer team assigned to this manuscript. Their contributions improved the quality of our manuscript presentation, structure, and discussion.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/frhs.2024.1152410/full#supplementary-material

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Keywords: community based participatory research, implementation research, RE-AIM (reach, effectiveness, adoption, implementation and maintenance), cardiovascular disease, community health workers (CHW)

Citation: Grice-Jackson T, Rogers I, Ford E, Dickinson R, Frere-Smith K, Goddard K, Silver L, Topham C, Nahar P, Musinguzi G, Bastiaens H and Van Marwijk H (2024) A community health worker led approach to cardiovascular disease prevention in the UK—SPICES-Sussex (scaling-up packages of interventions for cardiovascular disease prevention in selected sites in Europe and Sub-saharan Africa): an implementation research project. Front. Health Serv. 4:1152410. doi: 10.3389/frhs.2024.1152410

Received: 27 January 2023; Accepted: 20 March 2024; Published: 7 May 2024.

Reviewed by:

© 2024 Grice-Jackson, Rogers, Ford, Dickinson, Frere-Smith, Goddard, Silver, Topham, Nahar, Musinguzi, Bastiaens and Van Marwijk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Thomas Grice-Jackson [email protected]

This article is part of the Research Topic

Hybrid Effectiveness-Implementation Trial Designs: Critical Assessments, Innovative Applications, and Proposed Advancements

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• Published: 26 April 2024

Computationally guided synthesis of a hierarchical [4[2+3]+6] porous organic ‘cage of cages’

• Qiang Zhu   ORCID: orcid.org/0000-0001-6462-9340 1 , 2 ,
• Hang Qu   ORCID: orcid.org/0000-0001-8726-3062 1 ,
• Gokay Avci 3 ,
• Roohollah Hafizi 4 ,
• Chengxi Zhao 1 , 5 ,
• Graeme M. Day   ORCID: orcid.org/0000-0001-8396-2771 4 ,
• Kim E. Jelfs   ORCID: orcid.org/0000-0001-7683-7630 3 ,
• Marc A. Little   ORCID: orcid.org/0000-0002-1994-0591 6 &
• Andrew I. Cooper   ORCID: orcid.org/0000-0003-0201-1021 1 , 2  

Nature Synthesis ( 2024 ) Cite this article

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• Computational chemistry
• Computational methods
• Materials chemistry
• Molecular capsules
• Self-assembly

Here we report a two-step, hierarchical synthesis that assembles a trigonal prismatic organic cage into a more symmetric, higher-order tetrahedral cage, or ‘cage of cages’. Both the preformed [2+3] trigonal prismatic cage building blocks and the resultant tetrahedral [4[2+3]+6]cage molecule are constructed using ether bridges. This strategy affords the [4[2+3]+6]cage molecule excellent hydrolytic stability that is not a feature of more common dynamic cage linkers, such as imines. Despite its relatively high molar mass (3,001 g mol −1 ), [4[2+3]+6]cage exhibits good solubility and crystallizes into a porous superstructure with a surface area of 1,056 m 2  g −1 . By contrast, the [2+3] building block is not porous. The [4[2+3]+6]cage molecule shows high CO 2 and SF 6 uptakes due to its polar skeleton. The preference for the [4[2+3]+6]cage molecule over other cage products can be predicted by computational modelling, as can its porous crystal packing, suggesting a broader design strategy for the hierarchical assembly of organic cages with synthetically engineered functions.

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A class of organic cages featuring twin cavities

Self-assembled conjoined-cages

Non-statistical assembly of multicomponent [Pd2ABCD] cages

The chemical synthesis of complex organic molecules is part of our toolkit to access materials with unique structures and functions 1 , 2 , 3 , 4 , 5 . Supramolecular self-assembly is a powerful strategy to synthesize molecules comprising a number of separate precursors 6 , 7 , 8 ; these assemblies can also be nanometres in size 9 , 10 or chemically interlocked 11 , 12 . However, obtaining the desired self-assembly outcomes for more complex molecules quickly becomes synthetically challenging, particularly when the bond-forming chemistry has low reversibility. This creates a dichotomy: the more successful supramolecular reactions often lead to labile, unstable products, and this can limit the scope for applications. This challenge can be tackled by careful tuning of precursor structure and functionality, such as molecular geometry, or by iterative optimization of the synthetic procedures, but the best reaction conditions are often not intuitively obvious.

Some of the earliest supramolecular systems were synthesized by condensing simple bidentate building blocks, such as ethylenediamine and triethylene glycol, to form cryptands and crown ethers, respectively 13 . These molecules inspired the synthesis of larger and more complex architectures. For example, Fujita and co-workers introduced the concept of emergent behaviour in the assembly of large self-assembled macrocyclic products using carefully designed precursors 14 . Such supramolecular design strategies have allowed us to synthesize more complex self-assembled structures and, hence, to unlock new applications 2 , 15 , 16 . However, high structural complexity is often accompanied by increased synthetic challenges and lower predictability because of sensitivity to parameters such as the precise bond angles in the precursors 9 , 14 , 17 .

Postsynthetic modifications have been used previously to enhance the porosity of organic cages 18 , 19 , such as by hooping parts of the cage together 20 . More recently, we and others have used hierarchical assembly strategies to form topologically complex hydrogen-bonded organic frameworks 21 , 22 and covalently bonded materials, such as covalent organic frameworks 23 , 24 , 25 , 26 , using three-dimensional organic cages as the building blocks 27 . These studies have shown that cage-based building blocks can assemble into higher-order structures and increase the complexity of the resulting materials, for instance, by controlling network topology and interpenetration, while still offering a degree of structural predictability. In turn, this has afforded cage-based hydrogen-bonded organic frameworks and three-dimensional cage-based covalent organic frameworks with properties such as guest-responsive structural flexibility 23 and self-healing behaviour 28 . However, this hierarchical structuring approach does not appear to have been extended to the preparation of porous organic cage molecules 18 , 29 : that is, to synthesize larger porous cages from smaller organic cage precursors.

The use of organic cages as precursors to synthesize higher-order porous structures is attractive because it embeds cage molecules, with their own chemical complexity, into larger, hierarchical cages with the potential to create new functions while retaining useful properties such as solution processability 19 , 27 , 30 . For example, this strategy might produce porous materials with more sophisticated hierarchical porosities. To tackle this goal, we considered three criteria: (1) geometry—the cage precursors need geometries that can be arranged into a higher-order structure in a useful yield; (2) chemical stability—the chemical bonding in the cages must not be too labile, both to impart stability for applications and also to avoid the dynamic scrambling that might occur, for example, in trying to construct an imine cage from another imine cage 31 ; (3) rigidity—the precursors need sufficient rigidity to direct chemical reactivity to the desired product and to ensure that the resultant hierarchical cage is shape persistent and retains its porous structure after removal of solvent from the voids.

To meet these three criteria, we chose a trigonal prismatic [2+3] ether-bridged cage molecule, Cage-3-Cl , as the polyhedral building block to construct a hierarchical ‘cage of cages’ (Fig. 1 ). The preconfigured rigid geometry and excellent chemical stability of Cage-3-Cl allowed this [2+3] cage to assemble with tetrafluorohydroquinone ( TFHQ ) into the hierarchically structured organic ‘cage of cages’ compound, [4[2 + 3] + 6]cage .

The [ 4[2 + 3] + 6]cage molecule was synthesized via the S N Ar reaction between Cage-3-Cl and TFHQ in the presence of DIPEA. The triangular prism and the yellow sticks in the lower figure scheme represent Cage-3-Cl and TFHQ , respectively.

Results and discussion

Nucleophilic aromatic substitution (S N Ar) reactions have been reported to undergo reversible covalent bond formation when using electron-poor aromatic compounds 32 , 33 , 34 , while still leading to stable molecular products. Reversible error-correction is important for the formation of complex molecules that must self-sort during the reaction from a variety of possible products. Although the S N Ar reaction has been used in the synthesis of ether-bridged cages, most tend to be [2+3] or [2+4] cage products with small intrinsic cavities 35 , 36 , 37 , with the exception of a larger [4+6] ether-linked cage reported by Santos and co-workers 32 . One possible reason for the lack of larger cages synthesized via S N Ar chemistry is the less predictable orientation of the ether bridges compared to the imines and boronate esters for which larger cages are more commonplace 10 , 38 , 39 , 40 , 41 , 42 .

Previous investigations by our group and others have demonstrated that Cage-3-Cl has a highly symmetric and rigid triangular prism geometry both in solution and in the solid state 21 , 36 . This geometry makes Cage-3-Cl an ideal building block for forming higher-order cage molecules, such as molecular barrels 20 . The three residual chlorine atoms exhibit high reactivity 43 , 44 , which is essential for forming ether bridges. We selected TFHQ as the linear bridge between Cage-3-Cl molecules because the fluorine atoms might afford extra barriers to restrict the rotation of the ether bridges, and might improve the solubility of the resulting cage–cage molecules 36 , 45 .

To explore the available bond angles and the relative flexibility of the ether bridges in possible hierarchical cage products, we performed molecular dynamics (MD) and density functional theory (DFT) calculations. Models were constructed with the supramolecular toolkit (stk) software 46 to predict the most likely reaction products. As shown in Fig. 2 , the [4[2+3]+6] stoichiometry is predicted to form a stable, shape-persistent cage structure that exhibits a much lower energy than alternative [2[2+3]+3] and [8[2+3]+12] topologies. The [2[2+3]+3] topology has by far the highest relative energy (660.8 kJ mol −1 ) due to its highly strained geometry. The [8[2+3]+12] topology has higher relative energy (24.04 kJ mol −1 ) than the [4[2+3]+6] cage, which suggests that the [4[2+3]+6] topology is the thermodynamically favoured product, although we stress that these calculations do not include any solvent effects. As such, the [8[2+3]+12] topology might also be accessible under other synthesis conditions, whereas we predict that the [2[2+3]+3] topology is not. The cis – trans configurations of the ether bridges in the hypothetical [8[2+3]+12]cage can result in various positional configurations; all of these structural conformers were predicted to have relative energies that were between 24.0 and 229.1 kJ mol −1 higher than the [4[2+3]+6]cage, indicating a strong preference for the [4[2+3]+6] product (Supplementary Information Section 1 and Supplementary Figs. 1 – 4 ).

x  = number of Cage-3-Cl cages, y  = number of TFHQ linkers. Atom colours: carbon, grey; nitrogen, blue; oxygen, red; fluorine, green. Hydrogen atoms are omitted for clarity. Note the break in the energy scale for the highly strained [2[2+3]+3]cage, which has by far the highest relative energy (660.8 kJ mol −1 ). The DFT energies indicate that the [4[2+3]+6] stoichiometry is predicted to form a stable, shape-persistent cage structure that has a lower relative energy (24.04 kJ mol −1 ) than the alternative [8[2+3]+12] topology.

These simulation results suggested that it might be possible to synthesize [4[2 + 3] + 6]cage via the S N Ar reaction between Cage-3-Cl and TFHQ (Fig. 1 ). We therefore attempted the reaction experimentally, and screened a range of conditions in which we varied the reagent concentration, solvent and base (Supplementary Table 1 ). From these experiments, we found that the reaction in acetone in the presence of the acid scavenger N , N -diisopropylethylamine (DIPEA) afforded a new product with the highest yield of 53% after purification. The 1 H NMR spectrum for the purified reaction product from the acetone reaction with DIPEA showed two singlets at 7.09 and 6.85 ppm, which we assigned to the two aromatic protons in the [2+3] cage (H a and H b ; Fig. 3a and Supplementary Fig. 5 ). The presence of two singlets indicates different environments, which we attribute to one of the protons being more shielded. However, apart from this splitting of the aromatic proton singlet in Cage-3-Cl , the NMR spectroscopy data indicated that the resulting product had high symmetry in solution. In the 13 C NMR spectrum, we observed three signals in the 174.5–173.1 ppm range (Fig. 3b and Supplementary Fig. 6 ), which we assigned to the triazine ring carbon atoms. We attribute the characteristic splitting, observed at 142.5 and 140.0 ppm with a coupling constant of 250 MHz, to the coupling between the carbon and fluorine atoms in the TFHQ linker (Fig. 3b and Supplementary Fig. 6 ). We also confirmed the presence of these fluorinated aromatic rings by 19 F NMR spectroscopy, observing a singlet at −155.62 ppm (Supplementary Fig. 7 ), indicating that the fluorine atoms were symmetrically equivalent in solution. We also used high-resolution matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to analyse the reaction product. We found an ion with a mass-to-charge ( m / z ) ratio of 3,002.0756 (Fig. 3c and Supplementary Figs. 8 and 9 ), which matched well with the theoretical value of [ [4[2 + 3] + 6]cage  + H] + (3002.0871), indicating the formation of [4[2 + 3] + 6]cage .

a , 1 H NMR (400 MHz, acetone- d 6 ) spectra of Cage-3-Cl (green, bottom) and [4[2 + 3] + 6]cage (blue, top). b , 13 C NMR (100 MHz, dioxane- d 8 ) spectra: TFHQ (yellow, bottom), Cage-3-Cl (green, middle) and [4[2 + 3] + 6]cage (blue, top). Insets: zoom-ins of the boxed regions. The NMR spectra highlight the splitting of peaks due to the formation of a hierarchical ‘cage of cages’ structure. c , High-resolution MALDI-TOF spectrum of [4[2 + 3] + 6]cage , showing an ion with an m / z ratio of 3,002.0756 assigned to [ [4[2 + 3] + 6]cage  + H] + . Two internal calibrants (Spherical) with m / z ratios of 2,979 and 3,423 that bracketed the ion of interest were used to limit the m / z error to ±5 ppm.

Source data

We next grew crystals for single-crystal X-ray diffraction analysis to confirm the structure of the [4[2 + 3] + 6]cage molecule. Slow evaporation of a mixture of acetone/ethanol afforded single crystals suitable for X-ray analysis using synchrotron radiation (Supplementary Fig. 10 and Supplementary Table 2 ). The synchrotron single-crystal structure, which we refined in the monoclinic P 2 1 space group, revealed that the [4[2 + 3] + 6]cage molecule adopts a tetrahedral topology, where four Cage-3-Cl cage molecules serve as the vertices and six TFHQ molecules are located as the edges (Fig. 4a ). The interior and the exterior aryl caps of the Cage-3-Cl cage molecules form a core–shell structure, defining an inner and outer truncated tetrahedron with edge lengths of 6.4 and 13.7 Å, respectively (Fig. 4b ). We also calculated the electrostatic potentials for the [4[2 + 3] + 6]cage molecule, which showed that the centre of the [4[2 + 3] + 6]cage molecule is surrounded by aromatic rings, affording π–π interactions for any guest molecules within the cage (Fig. 4c and Supplementary Information Section 1 ).

a , Structure of an individual [4[2 + 3] + 6]cage molecule. Atom colours: carbon, grey; hydrogen, white; nitrogen, blue; oxygen, red; fluorine, green. b , Representation of the [4[2 + 3] + 6]cage molecule using two truncated tetrahedra on the inner and outer aryl caps of the [2+3] Cage-3-Cl cage molecules. For clarity, all atoms here are coloured grey. c , Electrostatic potential maps of the [4[2 + 3] + 6]cage molecule. The red and blue surfaces represent negative and positive regions of potential, respectively. Colour bar, −31.4 to 94.1 kcal mol −1 . d , e , Pore channels in the extended [4[2 + 3] + 6]cage crystal structure as viewed along the a axis ( d ) and the b axis ( e ). For clarity, hydrogen atoms are omitted in b , e and f . The yellow surfaces in d and e represent the contact surface as measured using a 1.2 Å diameter probe. f , Scheme explaining the window splitting in the [4[2 + 3] + 6]cage crystal structure along the a axis; the window of the lower blue cage is partially occluded by the aryl face of the upper yellow cage.

The interior of the cage core exhibits an electron-poor character because of the V-shaped electron-deficient clefts formed by the triazine rings of Cage-3-Cl and the fluorine-decorated aromatic rings. This environment might be useful for selective guest molecule separation 47 , 48 , 49 . In the extended crystal structure of this cage of cages, the asymmetric cell contains one [4[2 + 3] + 6]cage molecule, which assembles into a porous supramolecular structure by interacting with 12 neighbouring [4[2 + 3] + 6]cage molecules through van der Waals forces (Supplementary Fig. 11 ). Two of the windows in the [4[2 + 3] + 6]cage molecule are narrowed into smaller channels by the Cage-3-Cl vertices from neighbouring cage molecules (Fig. 4d,f and Supplementary Fig. 12 ), yielding three-dimensional interconnected pore channels (Fig. 4d,e ). Using Zeo++ 50 , we calculated that the pore-limiting diameter of the [4[2 + 3] + 6]cage crystal structure was 6.4 Å and the largest cavity diameter was 8.9 Å (Supplementary Table 3 and Supplementary Figs. 13 – 15 ), suggesting that the structure is microporous. From these calculations, we also determined that voids in the [4[2 + 3] + 6]cage crystal structure that are accessible to a 1.65 Å CO 2 probe occupy 32.0% of the unit cell volume (Supplementary Table 3 ).

There was strong agreement between the predicted structure for the [4[2 + 3] + 6]cage molecule and the molecule observed in the crystal structure (Fig. 5 ). This validates the theoretical predictions, and the close match between the crystal structure prediction (CSP)-predicted structure and experimental crystal structure adds confidence in the crystal structure refinement (Supplementary Fig. 17 ). The root mean squared displacement (r.m.s.d.) was calculated as 0.5 Å with a maximum distance between atoms of 1.4 Å. However, the experimental displacement parameters are large due to disorder in the crystal structure (Supplementary Fig. 11a ). Further attempts to synthesize the larger [8[2+3]+12] product by varying the reaction conditions were unsuccessful, based on MALDI-TOF analysis of the resulting products (Supplementary Table 1 and Supplementary Fig. 8 ), in line with the molecular stability predictions (Fig. 2 ).

a – c , The predicted structure (red) overlaid with the single-crystal X-ray diffraction structure (blue) is shown as viewed along the a ( a ), b ( b ) and c ( c ) crystallographic axes. The r.m.s.d. was calculated as 0.5 Å with a maximum distance between atoms of 1.4 Å, highlighting the close structural similarity between the predicted and experimental structures.

In principle, catenation of this cage is possible, given its large intrinsic voids (>10 Å diameter), as observed for considerably smaller imine cages 11 . However, we saw no evidence for catenated cage side-products, either by NMR or by MALDI-TOF characterization.

We next used CSP to explore the solid-state packing of these hierarchical cages. The lattice energy landscape was explored using quasi-random sampling of the crystal packing space with the Global Lattice Energy Explorer (GLEE) 51 . Initial trial structures were generated from rigid molecules and subjected to lattice energy minimization using an empirically parameterized potential with atomic multipole electrostatics 52 (see Supplementary Information Section 4 , Supplementary Tables 4 and 5 , and Supplementary Figs. 16 – 25 for full details).

Surprisingly, the CSP landscape for [4[2 + 3] + 6]cage (Fig. 6 ) showed catenated structures, along with the non-catenated cage that was observed experimentally, even though the discrete [4[2 + 3] + 6]cage molecule was used for the CSP calculations. Three distinct catenations were identified in the predicted crystal structures: triply interlocked cage dimers (Fig. 6c ), singly interlocked cage dimers (Fig. 6d ) and singly interlocked one-dimensional (1D) cage chains 12 , 53 (Fig. 6e ). The details of the methods used for catenation detection are provided in Supplementary Information Section 4 and Supplementary Figs. 18 ‒ 20 . All sampled structures within a 197 kJ mol −1 energy window from the global energy minimum were found to be catenanes (Supplementary Figs. 21 and 22 ), indicating a strong thermodynamic preference over the non-catenated cages observed by experiment. To verify the relative energies calculated using the rigid-molecule, force-field approach, a selection of catenated and non-catenated predicted structures were re-evaluated using periodic DFT, which confirmed this greater thermodynamic stability (see Supplementary Information Section 4 for full details).

a , Computational crystal energy landscape of [4[2 + 3] + 6]cage with colour-coded categorization based on catenation type: discrete, non-catenated cages (uncoloured circles), triply interlocked cage dimers (green circles), singly interlocked cage dimers (blue) and singly interlocked 1D cage chains (orange). The yellow star and blue cross represent the predicted structures matching the experimentally observed [4[2 + 3] + 6]cage crystal structure and [4[2 + 3] + 6]cage·acetone solvated structure, respectively. b , Energy landscape after removal of the catenated structures, with colour coding based on the diameter of the largest sphere ( D f ) capable of freely moving within the crystal structure’s channel(s). Channels are found based on their ability to accommodate a CO 2 molecule. D f  = 0 corresponds to no channel being found. c – e , Atomic structures depicted for examples of a triply interlocked cage dimer ( c ), a singly interlocked cage dimer ( d ) and a singly interlocked 1D cage chain ( e ).

While the CSP study did not explicitly target catenated structures, the sampled catenated configurations suggest that triply interlocked catenanes (green points, Fig. 6a ), in particular, might be much more thermodynamically stable in the solid state. This echoes previous findings for [4+6] imine cages, in which discrete cages were found to transform into triply interlocked catenanes upon exposure to acid, suggesting that the individual cages were the kinetic rather than the thermodynamic product 11 . The absence of catenanes in our experiments might be explained by the much lower reversibility of the ether bonding in the [4[2 + 3] + 6]cage molecule, which is not accounted for in the CSP calculations. Prompted by these solid-state CSP results, we also explored the relative thermodynamic stability of catenanes at the molecular level. DFT calculations of catenane dimers showed that the energy difference between the molecular equivalent non-catenated [4[2 + 3] + 6]cage dimer and trimer fragments retrieved from the global lowest-energy CSP, and the corresponding triply interlocked catenane molecular fragment was 373.7 kJ mol −1 and 324.7 kJ mol −1 , respectively, reaffirming strong thermodynamic favour towards the catenane structures.

When we remove the catenated structures from the CSP plot (Fig. 6b and Supplementary Fig. 23 ), this reveals the observed experimental structure positioned at the bottom of a low-density ‘spike’ in the energy landscape, approximately 13.6 kJ mol −1 higher than the global energy minimum for non-catenated cages. The predicted crystal structure reproduces the geometry of the experimentally determined [4[2 + 3] + 6]cage crystal structure accurately (Supplementary Fig. 17 ), confirming that the crystal structure determined by X-ray diffraction corresponds to a low-energy local minimum in lattice energy. The colour coding in this ‘non-catenated’ crystal structure landscape represents the diameter of the largest sphere capable of unrestricted movement within the crystal structure channels. Channel dimensions are determined based on their capacity to accommodate a CO 2 molecule with a kinetic radius of 1.65 Å (Supplementary Figs. 24 and 25 ). In the landscape depicted in Fig. 6b , void analysis has been restricted to structures within 20 kJ mol −1 of the low-energy edge of the energy-density distribution of structures. Except for a very small number of predicted structures (purple points, Fig. 6b ), all investigated structures, including the synthesized structure, show potential for CO 2 uptake. That is, CSP suggests that [4[2 + 3] + 6]cage has an intrinsic propensity to be porous in the majority of its potential crystalline packing modes.

Molecular crystals exhibiting permanent porosity in the solid state are attractive for applications such as gas capture, separation and catalysis 18 , 54 . One successful approach that we and others have developed is to form porous organic crystals by synthesizing cages with prefabricated shape-persistent cavities that are retained after solvents are removed during activation 18 , 50 , 54 . Our calculations revealed that the ether bridges in the [4[2 + 3] + 6]cage skeleton appeared to be relatively rigid, suggesting shape persistence. We therefore investigated the porosity in the [4[2 + 3] + 6]cage crystals using gas sorption analysis. We activated the [4[2 + 3] + 6]cage crystals by first exchanging the ethanol and acetone crystallization solvents with diethyl ether or n -pentane, which we chose because of their low surface tensions. Then, we removed any residual solvent from the crystals under a dynamic vacuum at room temperature. Subsequent powder X-ray diffraction (PXRD) analysis revealed that the [4[2 + 3] + 6]cage crystals retained some crystallinity after being activated using these conditions (Supplementary Fig. 26 ). The [4[2 + 3] + 6]cage crystals activated via the diethyl ether solvent exchange route appeared more crystalline, and this sample was used for the subsequent gas sorption experiments described here.

Nitrogen sorption isotherms recorded at 77 K revealed that the crystalline [4[2 + 3] + 6]cage exhibits a type I N 2 sorption isotherm with a relatively high Brunauer–Emmett–Teller surface of 1,056 m 2  g −1 (Fig. 6a and Supplementary Figs. 27 ‒ 29 ), consistent with a microporous solid and the pore size distribution plot calculated using Zeo++ 51 (Supplementary Table 3 and Supplementary Fig. 13 ). We found that crystalline [4[2 + 3] + 6]cage has a CO 2 uptake capacity of 3.98 mmol g −1 at 1 bar and 273 K (Fig. 7b and Supplementary Fig. 30 ). This CO 2 uptake is high compared with other porous organic crystalline materials, such as covalent organic frameworks 55 , at comparable temperatures and pressures, and is one of the highest CO 2 uptakes reported to date for a porous organic cage (Supplementary Table 6 ) 56 , 57 . The calculated isosteric heat of adsorption of CO 2 on crystalline [4[2 + 3] + 6]cage ranges between 21.1 and 23.2 kJ mol −1 (Supplementary Fig. 31 ), which indicates a strong affinity between the adsorbed CO 2 gas and polar [4[2 + 3] + 6]cage crystal pores, rationalizing this high uptake capacity. In addition, we found that crystalline [4[2 + 3] + 6]cage has a high SF 6 uptake capacity of 3.21 mmol g −1 at 1 bar and 273 K (Supplementary Fig. 32 ). The calculated isosteric heat of adsorption of SF 6 on crystalline [4[2 + 3] + 6]cage ranges between 29.2 and 29.5 kJ mol −1 , which again indicates a strong affinity between adsorbed SF 6 gas molecules and the [4[2 + 3] + 6]cage crystal pores (Supplementary Fig. 33 ). Analysis of the [4[2 + 3] + 6]cage powder after the gas sorption isotherms by PXRD analysis indicated that the material remained crystalline during these measurements (Supplementary Fig. 34 ).

a , N 2 sorption isotherms recorded at 77 K showing hysteresis in the desorption isotherm. b , CO 2 gas sorption isotherms recorded at 273 K (cyan) and 298 K (orange) showing an uptake capacity of 3.98 mmol g −1 at 1 bar and 273 K. Closed and open symbols represent the adsorption and desorption isotherms, respectively.

We also uncovered a second crystal structure of the [4[2 + 3] + 6]cage molecule during this study, referred to as [4[2 + 3] + 6]cage·acetone , which crystallized from slow evaporation of an acetone- d 6 solution (Supplementary Fig. 35 ). [4[2 + 3] + 6]cage·acetone crystallized in the cubic space group \(I\bar{4}3m\) ( a  = 23.2901(15) Å, V  = 12633(2) Å 3 , Supplementary Table 7 ) with the ether-bridged cage adopting a perfect tetrahedral geometry in the structure (Supplementary Fig. 36 ). The [4[2 + 3] + 6]cage·acetone lost crystallinity rapidly after being removed from the acetone- d 6 solvent and cracked (Supplementary Fig. 35 ). We therefore performed single-crystal analysis by sealing a solvated crystal in a borosilicate capillary containing residual acetone- d 6 solvent. However, due to the poorer crystal stability of 4[2 + 3] + 6]cage·acetone , we did not investigate its solid-state properties further. The instability of this form was further investigated through computational geometry optimization of the crystal structure. Employing the same energy model as used in the CSP study, rigid-molecule geometry optimization of the structure after solvent removal resulted in considerable structural distortion from the original cubic lattice, adopting a monoclinic form, in keeping with the observed experimental instability. Details can be found in Supplementary Information Section 8 . The relaxed structure, denoted by a blue cross in the landscape of Fig. 6a , is situated 103 kJ mol −1 above the global energy minimum on the landscape of non-catenated structures. This energy difference underscores the crucial role of solvent stabilization in the synthesis of this solvated structure, and can also help to rationalize why this tetrahedral molecular structure was not predicted using gas-phase (that is, solvent-free) DFT calculations (Fig. 5 ).

For practical applications, gas sorption capacity is not the only criterion. For example, most CO 2 capture applications involve wet or humid gas streams, and hence water stability is important. Many porous organic cage materials, such as imine cages and (particularly) boronate ester cages, are unstable to water. We therefore explored the hydrolytic stability of the [4[2 + 3] + 6]cage molecule by immersing the synthesized crystals in water for 12 days. Subsequent analysis of the sample by 1 H NMR spectroscopy revealed that [4[2 + 3] + 6]cage remained chemically intact under these conditions (Supplementary Fig. 38 ). PXRD analysis of the same sample also revealed that the [4[2 + 3] + 6]cage crystals retained their crystallinity under these conditions (Supplementary Fig. 39 ). Hence, both the chemical and crystal structure of [4[2 + 3] + 6]cage molecule appear to have good hydrolytic stability.

We report the assembly of a more complex type of porous organic cage—a ‘cage of cages’—that was synthesized using a two-step hierarchical self-assembly strategy. In this study, we demonstrate the strategy by assembling four trigonal cages into a larger tetrahedral cage. The resulting [4[2 + 3] + 6]cage molecule exhibits excellent stability in water, and crystals of the [4[2 + 3] + 6]cage show permanent porosity and a high surface area of 1,056 m 2  g −1 . The abundance of polar atoms in the cage cavity endows it with high CO 2 and SF 6 uptake capacity. The good solubility of [4[2 + 3] + 6]cage in acetone indicates it has the potential to be used as a building block for even more complex structures, such as porous cage co-crystals. More broadly, this illustrates a strategy for hierarchical molecular assembly using computation as a guide to assess the most likely reaction products. For example, it might be possible in the future to design analogous systems where the [2+3] cages contribute discrete, prefabricated porosity into a higher-order, hierarchically porous crystal.

This study also showcases the use of computational design in supramolecular synthesis, both at the molecular level (Fig. 5 ) and in the solid state (Fig. 6 ). It is notable that triply interlocked cage catenane dimers emerged as the most stable predicted crystal packings (Fig. 6a ). Such catenanes were not observed in experiments, most likely because they are kinetically disfavoured, but they are nonetheless synthetically plausible because analogous structures have been formed using more reversible [4+6] imine cage-forming reactions 11 . Less obviously, infinite 1D catenated cage chains are also produced in these simulations (Fig. 6e ), and in some cases these structures are predicted to have similar lattice energies to the experimentally observed non-catenated cage (Fig. 6a ). This highlights how a priori structure predictions have the power to suggest non-intuitive new materials, although it is unclear how one might design a kinetic pathway to these chain structures, even though analogous structures have been observed for less complex macrocycles 53 .

Molecular simulations

Both Cage-3-Cl and cage-of-cages models were constructed in Tri2Di3, Tri4Di6 and Tri8Di12 topologies using the stk software 46 . All cages were annealed with an MD simulation at 700 K for 50 ns with a time step of 0.5 fs after a 100 ps equilibration time with the OPLS4 force field as implemented in the Macromodel Suite 58 . Five hundred random configurations from the total MD duration were sampled and energy minimized, with the lowest energy configuration selected for DFT calculations. DFT calculations were performed with CP2K v.2023.1 (ref. 59 ) software using the generalized gradient approximation theory with the Perdew–Burke–Ernzerhof functional 60 and def2-TZVP basis sets 61 . A planewave cut-off value of 400 Ry and a relative cut-off value of 100 Ry were parameterized to obtain converged energy levels and dispersion interactions were accounted for with Grimme’s DFT-D3 approach 62 .

The geometries of the [4[2 + 3] + 6]cage were then fully optimized by means of the hybrid M06-2X functional in Gaussian16 (ref. 63 ). The def2-SVP basis set 64 , 65 was applied for all atoms. No symmetry or geometry constraint was imposed during optimizations. The optimized geometries were verified as local minima on the potential energy surface by frequency computations at the same theoretical level 63 .

Synthesis of [4[2+3]+6]cage

To synthesize [4[2 + 3] + 6]cage , DIPEA (61 µl, 0.35 mmol) was dissolved in acetone (25 ml) and purged with N 2 for 10 min. To the acetone solution, a mixture of Cage-3-Cl (58.7 mg, 0.1 mmol) and TFHQ (27.3 mg, 0.15 mmol) in acetone (6 ml) was added dropwise over 3 h under a N 2 atmosphere. After the addition was complete, the reaction was stirred at room temperature for 36 h. The solvent was then removed by rotary evaporation, and the crude product was purified by column chromatography using acetone/CH 2 Cl 2 (10% vol/vol acetone) as eluent to afford [4[2 + 3] + 6]cage as a white solid in 53% isolated yield: 40 mg (0.013 mmol). 1 H NMR (400 MHz, acetone- d 6 ): δ (ppm) 7.09 (s, 12H, H b ), 6.85 (s, 12H, H a ); 19 F NMR (376 MHz, acetone- d 6 ): δ (ppm) −155.62; 13 C NMR (100 MHz, dioxane- d 8 ): δ (ppm) 174.5, 173.5, 173.1, 153.2, 152.8, 142.5, 140.1, 140.0, 128.3, 115.2, 114.8. MALDI-TOF [M + H] + , [C 120 H 24 F 24 N 36 O 36  + H] + : calculated, 3002.0871; found, 3002.0756.

CSP involves the following general steps: (1) molecular geometry optimization; (2) trial crystal structure generation; (3) local lattice energy minimization of trial structures; and (4) duplicate removal.

The geometry of the molecular cage was optimized at the B3LYP/6-311 G(d,p) level using Gaussian09 software 66 , and the resulting geometry was kept fixed throughout the subsequent steps. Trial crystal structures are generated using the Global Lattice Energy Explorer (GLEE) code 51 . Subsequently, these trial structures undergo lattice optimization while preserving the rigidity of the molecular cage. For this task, we employ an empirically parameterized intermolecular atom–atom exp-6 potential coupled with atomic multipole electrostatics. The force-field parameters are acquired from the FIT force field 67 , 68 . Atom-centred multipoles up to hexadecapole on each atom were derived from the electron density through DMA, and partial charges (used in early stages of optimization) were fitted to the molecular electrostatic potential generated by these multipoles 69 , 70 . The overall model is denoted as FIT + DMA.

The search for space groups involves sampling the ten most common space groups for organic crystals along with four trigonal space groups (143, 144, 145 and 146), each with one molecule in the asymmetric unit. A quasi-random method is used to search these selected space groups separately, and valid structures are lattice energy minimized using DMACRYS software 52 in a two-stage protocol. The first stage involves FIT + DMA with partial charges, followed by the second stage with multipole electrostatics. More details can be found in Supplementary Information .

Data availability

The authors declare that the data supporting the findings of this study are available within the paper, its Supplementary Information files, and the Cambridge Crystallographic Data Centre (deposition numbers 2303319 for [4[2 + 3] + 6]cage and 2326368 for [4[2 + 3] + 6]cage·acetone ). The crystal structures and structure factor data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif . The CSP data are available at the University of Southampton Institutional Research Repository at https://doi.org/10.5258/SOTON/D2929 (ref. 71 ).

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Acknowledgements

A.I.C. thanks the Royal Society for a Research Professorship (RSRP\S2\232003). C.Z. acknowledges the China Scholarship Council for financial support (202106745008). R.H. acknowledges the Iridis 5 High Performance Computing facility, and associated support services at the University of Southampton. Via our membership of the UK’s HEC Materials Chemistry Consortium, which is funded by the Engineering and Physical Sciences Research Council (EPSRC) (EP/R029431 and EP/X035859), this work used the Archer2 HPC facility. We acknowledge A. Hunter for performing the MALDI-TOF analysis at the National Mass Spectrometry Facility (NMSF) at Swansea University, and Diamond Light Source for access to beamlines I19 (CY30461). We received funding from the EPSRC (EP/V026887/1) and the Leverhulme Trust via the Leverhulme Research Centre for Functional Materials Design. This project has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation programme (grant CoMMaD number 758370).

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Authors and affiliations.

Materials Innovation Factory and Department of Chemistry, University of Liverpool, Liverpool, UK

Qiang Zhu, Hang Qu, Chengxi Zhao & Andrew I. Cooper

Leverhulme Research Centre for Functional Materials Design, University of Liverpool, Liverpool, UK

Qiang Zhu & Andrew I. Cooper

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, UK

Gokay Avci & Kim E. Jelfs

Computational Systems Chemistry, School of Chemistry, University of Southampton, Southampton, UK

Roohollah Hafizi & Graeme M. Day

Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering East China University of Science and Technology, Shanghai, China

Chengxi Zhao

Institute of Chemical Sciences, Heriot-Watt University, Edinburgh, UK

Marc A. Little

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Contributions

Q.Z. led the experimental work and the synthesis and characterization of the materials. A.I.C., K.E.J. and M.A.L. conceived the idea and modelling strategy with Q.Z. and supervised the project. H.Q. and M.A.L. conducted the single-crystal X-ray diffraction analysis and solved the structure. G.A., K.E.J. and C.Z. performed the molecular simulations. R.H. and G.M.D. performed the CSP, and G.M.D. supervised this part of the project. Q.Z., G.A., R.H., G.M.D., K.E.J., M.A.L. and A.I.C. analysed the data and prepared the paper. All authors discussed the results and contributed to the paper.

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Correspondence to Marc A. Little or Andrew I. Cooper .

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Nature Synthesis thanks Chenfeng Ke, Bernhard Schmidt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Stoddart, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary information.

Supplementary Figs. 1–9, Tables 1–8, Scheme 1, synthetic procedures and methods, molecular simulation, NMR, MALDI-TOF, powder X-ray diffraction, single-crystal X-ray diffraction, crystal structure prediction and gas sorption analysis.

Supplementary Data 1

Simulated structures of [2[2 + 3] + 3]cage.xyz, 4[2 + 3] + 6]cage.xyz, [8[2 + 3] + 12]cage.xyz, [8[2 + 3] + 12]cage_1.xyz, [8[2 + 3] + 12]cage_2.xyz, and [8[2 + 3] + 12]cage_3.xyz.

Supplementary Data 2

X-ray crystallographic data of [4[2 + 3] + 6]cage, CCDC 2303319.

Supplementary Data 3

Crystallographic data of [4[2 + 3] + 6]cage·acetone, CCDC 2326368.

Supplementary Video 1

Video showing the single crystal structure of [4[2 + 3] + 6]cage.

Supplementary Data 4

Tabulated source data used to prepare Supplementary Figs. 1–2, 8, 13, 14, 26–34 and 39.

Supplementary Data 5

Raw NMR spectroscopy data used to prepare Supplementary Figs. 5, 7 and 38.

Source Data Fig. 3

Raw NMR spectroscopy data and MALDI-TOF data.

Source Data Fig. 7

Source data for carbon dioxide gas sorption isotherms recorded at 273 and 298 K in Fig. 7.

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Zhu, Q., Qu, H., Avci, G. et al. Computationally guided synthesis of a hierarchical [4[2+3]+6] porous organic ‘cage of cages’. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00531-7

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Received : 25 October 2023

Accepted : 26 March 2024

Published : 26 April 2024

DOI : https://doi.org/10.1038/s44160-024-00531-7

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