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Section Objective

What is a literature review, clearly stated research question, search terms, searching worksheets, boolean and / or.

The content in the Literature Review section defines the literature review purpose and process, explains using the PICO format to ask a clear research question, and demonstrates how to evaluate and modify search results to improve the accuracy of the retrieval.

A literature review seeks to identify, analyze and summarize the published research literature about a specific topic.  Literature reviews are assigned as course projects; included as the introductory part of master's and PhD theses; and are conducted before undertaking any new scientific research project.

The purpose of a literature review is to establish what is currently known about a specific topic and to evaluate the strength of the evidence upon which that knowledge is based. A review of a clinical topic may identify implications for clinical practice. Literature reviews also identify areas of a topic that need further research.

A systematic review is a literature review that follows a rigorous process to find all of the research conducted on a topic and then critically appraises the research methods of the highest quality reports. These reviews track and report their search and appraisal methods in addition to providing a summary of the knowledge established by the appraised research.

The UNC Writing Center provides a nice summary of what to consider when writing a literature review for a class assignment. The online book, Doing a literature review in health and social care : a practical guide (2010), is a good resource for more information on this topic.

Obviously, the quality of the search process will determine the quality of all literature reviews. Anyone undertaking a literature review on a new topic would benefit from meeting with a librarian to discuss search strategies. A consultaiton with a librarian is strongly recommended for anyone undertaking a systematic review.

Use the email form on our Ask a Librarian page to arrange a meeting with a librarian.

The first step to a successful literature review search is to state your research question as clearly as possible.

It is important to:

• be as specific as possible
• include all aspects of your question

Clinical and social science questions often have these aspects (PICO):

• People/population/problem  (What are the characteristics of the population?  What is the condition or disease?)
• Intervention (What do you want to do with this patient?  i.e. treat, diagnose)
• Comparisons [not always included]  (What is the alternative to this intervention?  i.e. placebo, different drug, surgery)
• Outcomes  (What are the relevant outcomes?  i.e. morbidity, death, complications)

If the PICO model does not fit your question, try to use other ways to help be sure to articulate all parts of your question. Perhaps asking yourself Who, What, Why, How will help.  

Example Question:  Is acupuncture as effective of a therapy as triptans in the treament of adult migraine?

Note that this question fits the PICO model.

• Population: Adults with migraines
• Intervention: Acupuncture
• Comparison: Triptans/tryptamines
• Outcome: Fewer Headache days, Fewer migraines

A literature review search is an iterative process. Your goal is to find all of the articles that are pertinent to your subject. Successful searching requires you to think about the complexity of language. You need to match the words you use in your search to the words used by article authors and database indexers. A thorough PubMed search must identify the author words likely to be in the title and abstract or the indexer's selected MeSH (Medical Subject Heading) Terms.

Start by doing a preliminary search using the words from the key parts of your research question.

Step #1: Initial Search

Enter the key concepts from your research question combined with the Boolean operator AND. PubMed does automatically combine your terms with AND. However, it can be easier to modify your search if you start by including the Boolean operators.

migraine AND acupuncture AND tryptamines

The search retrieves a number of relevant article records, but probably not everything on the topic.

Step #2: Evaluate Results

Use the Display Settings drop down in the upper left hand corner of the results page to change to Abstract display.

Review the results and move articles that are directly related to your topic to the Clipboard .

Go to the Clipboard to examine the language in the articles that are directly related to your topic.

• look for words in the titles and abstracts of these pertinent articles that differ from the words you used
• look for relevant MeSH terms in the list linked at the bottom of each article

The following two articles were selected from the search results and placed on the Clipboard.

Here are word differences to consider:

• Initial search used acupuncture. MeSH Terms use Acupuncture therapy.
• Initial search used migraine.  Related word from MeSH Terms is Migraine without Aura and Migraine Disorders.
• Initial search used tryptamines. Article title uses sumatriptan. Related word from MeSH is Sumatriptan or Tryptamines.

With this knowledge you can reformulate your search to expand your retrieval, adding synonyms for all concepts except for manual and plaque.

#3 Revise Search

Use the Boolean OR operator to group synonyms together and use parentheses around the OR groups so they will be searched properly. See the image below to review the difference between Boolean OR / Boolean AND.

Here is what the new search looks like:

(migraine OR migraine disorders) AND (acupuncture OR acupuncture therapy) AND (tryptamines OR sumatriptan)

• Search Worksheet Example: Acupuncture vs. Triptans for Migraine
• Search Worksheet

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

Literature Searching

In this guide.

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

Students and researchers in the health sciences are often required to conduct literature searches for a number of reasons including identifying appropriate studies and methods to include in a literature review manuscript. Understanding the basics of database searching can allow you to effectively and efficiently find the information you need. This guide takes you through the process of developing an advanced, robust literature search in PubMed . 

While the guide is based on searching in the PubMed database, the strategies can be applied appropriately to other databases, such as Embase , CINAHL , PsycINFO , etc. (see search syntax for more information on search translation). For more information on searching in other databases, attend Lane's Literature Reviews Beyond PubMed: Crafting Effective Searches in Other Databases  course.

If you're interested in conducting a systematic review, please visit Introduction to Systematic Reviews . 

Research Services

• Literature Searches
• Data Service
• Research Metrics Service
• Authoring and Publishing Support

Literature or reviews of a systematic nature is a value-added service available for current members of the Stanford Medicine community. To qualify for the service, the project lead and point-of-contact to Lane must be a Stanford affiliate.

Lane Medical Library staff can help you with your search strategy creation, collaborate on systematic reviews and other knowledge syntheses, provide guidance on documentation, processes, and tools, among others. Reviews or projects the team can help you with include but are not limited to:

• Systematic Review
• Meta-Analysis
• Literature Review for Grant Application
• Thesis or Dissertation
• Course Assignment
• Scoping Review
• Book Chapter
• Thesis Report

If you are interested in collaborating with a Lane Medical Librarian on a review project, please submit a  literature search request .

Data management and sharing is a component of Open Science, which aims to make scientific research more transparent and accessible. Proper data management and sharing benefit you as an individual and the research community as a whole. Lane's data service provides: 

• Best practices related to data management and sharing
• Assistance in complying with requirements related to the management and sharing of research data (e.g. from a publisher or funder)
• Consultations related to research data management, data security, data publishing, data curation, and long-term preservation
• Workshops and classes related to best practices in data management and sharing

For more information, visit the Data Management and Sharing guide  or contact data librarian John Borghi ([email protected]). 

Research metrics measure the impact of a scholar, article, book, journal, or research institution. Metrics can be informed through different approaches, such as citation counts, that can add to a broader understanding of impact. Lane's research metrics service assists with:

• Understanding, measuring and using bibliometrics and other statistical analysis of publications 
• Using alternative metrics (also known as altmetrics) 
• Common tools for assessing research impact

For more information on research metrics, visit the Research Impact guide or contact Research Communications Librarian Lily Ren ([email protected]).

Lane Librarians can help you with the authoring and publishing of your manuscript such as:

• Learn about unique author identifiers and how to create an ORCID ID
• How to find journals relevant to areas of research/interest for possible submission
• How to find journal impact factors
• Help find instructions for authors
• Explore alternate publishing models including open access journals
• How to verify citations

We also provide discounted Open Access author processing fees. For more information, visit our Understanding Open Access guide.  

• Next: Steps for searching the literature in PubMed >>
• Last Updated: Jan 9, 2024 10:30 AM
• URL: https://laneguides.stanford.edu/LitSearch

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• CAREER FEATURE
• 04 December 2020
• Correction 09 December 2020

How to write a superb literature review

Andy Tay is a freelance writer based in Singapore.

You can also search for this author in PubMed   Google Scholar

Literature reviews are important resources for scientists. They provide historical context for a field while offering opinions on its future trajectory. Creating them can provide inspiration for one’s own research, as well as some practice in writing. But few scientists are trained in how to write a review — or in what constitutes an excellent one. Even picking the appropriate software to use can be an involved decision (see ‘Tools and techniques’). So Nature asked editors and working scientists with well-cited reviews for their tips.

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doi: https://doi.org/10.1038/d41586-020-03422-x

Interviews have been edited for length and clarity.

Updates & Corrections

Correction 09 December 2020 : An earlier version of the tables in this article included some incorrect details about the programs Zotero, Endnote and Manubot. These have now been corrected.

Hsing, I.-M., Xu, Y. & Zhao, W. Electroanalysis 19 , 755–768 (2007).

Article   Google Scholar  

Ledesma, H. A. et al. Nature Nanotechnol. 14 , 645–657 (2019).

Article   PubMed   Google Scholar  

Brahlek, M., Koirala, N., Bansal, N. & Oh, S. Solid State Commun. 215–216 , 54–62 (2015).

Choi, Y. & Lee, S. Y. Nature Rev. Chem . https://doi.org/10.1038/s41570-020-00221-w (2020).

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• Volume 19, Issue 1
• Reviewing the literature
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• Joanna Smith 1 ,
• Helen Noble 2
• 1 School of Healthcare, University of Leeds , Leeds , UK
• 2 School of Nursing and Midwifery, Queens's University Belfast , Belfast , UK
• Correspondence to Dr Joanna Smith , School of Healthcare, University of Leeds, Leeds LS2 9JT, UK; j.e.smith1{at}leeds.ac.uk

https://doi.org/10.1136/eb-2015-102252

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Implementing evidence into practice requires nurses to identify, critically appraise and synthesise research. This may require a comprehensive literature review: this article aims to outline the approaches and stages required and provides a working example of a published review.

Are there different approaches to undertaking a literature review?

What stages are required to undertake a literature review.

The rationale for the review should be established; consider why the review is important and relevant to patient care/safety or service delivery. For example, Noble et al 's 4 review sought to understand and make recommendations for practice and research in relation to dialysis refusal and withdrawal in patients with end-stage renal disease, an area of care previously poorly described. If appropriate, highlight relevant policies and theoretical perspectives that might guide the review. Once the key issues related to the topic, including the challenges encountered in clinical practice, have been identified formulate a clear question, and/or develop an aim and specific objectives. The type of review undertaken is influenced by the purpose of the review and resources available. However, the stages or methods used to undertake a review are similar across approaches and include:

Formulating clear inclusion and exclusion criteria, for example, patient groups, ages, conditions/treatments, sources of evidence/research designs;

Justifying data bases and years searched, and whether strategies including hand searching of journals, conference proceedings and research not indexed in data bases (grey literature) will be undertaken;

Developing search terms, the PICU (P: patient, problem or population; I: intervention; C: comparison; O: outcome) framework is a useful guide when developing search terms;

Developing search skills (eg, understanding Boolean Operators, in particular the use of AND/OR) and knowledge of how data bases index topics (eg, MeSH headings). Working with a librarian experienced in undertaking health searches is invaluable when developing a search.

Once studies are selected, the quality of the research/evidence requires evaluation. Using a quality appraisal tool, such as the Critical Appraisal Skills Programme (CASP) tools, 5 results in a structured approach to assessing the rigour of studies being reviewed. 3 Approaches to data synthesis for quantitative studies may include a meta-analysis (statistical analysis of data from multiple studies of similar designs that have addressed the same question), or findings can be reported descriptively. 6 Methods applicable for synthesising qualitative studies include meta-ethnography (themes and concepts from different studies are explored and brought together using approaches similar to qualitative data analysis methods), narrative summary, thematic analysis and content analysis. 7 Table 1 outlines the stages undertaken for a published review that summarised research about parents’ experiences of living with a child with a long-term condition. 8

• View inline

An example of rapid evidence assessment review

In summary, the type of literature review depends on the review purpose. For the novice reviewer undertaking a review can be a daunting and complex process; by following the stages outlined and being systematic a robust review is achievable. The importance of literature reviews should not be underestimated—they help summarise and make sense of an increasingly vast body of research promoting best evidence-based practice.

• ↵ Centre for Reviews and Dissemination . Guidance for undertaking reviews in health care . 3rd edn . York : CRD, York University , 2009 .
• ↵ Canadian Best Practices Portal. http://cbpp-pcpe.phac-aspc.gc.ca/interventions/selected-systematic-review-sites / ( accessed 7.8.2015 ).
• Bridges J , et al
• ↵ Critical Appraisal Skills Programme (CASP). http://www.casp-uk.net / ( accessed 7.8.2015 ).
• Dixon-Woods M ,
• Shaw R , et al
• Agarwal S ,
• Jones D , et al
• Cheater F ,

Twitter Follow Joanna Smith at @josmith175

Competing interests None declared.

Read the full text or download the PDF:

Implemented Interventions in Preventing Surgical Site Infection in Pediatric Appendicitis Patients: A Scoping Review

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Objective: Surgical site infections (SSIs), especially deep/organ-space SSIs, are common and serious complications following appendectomy. This review aimed to explore the interventions that have been implemented to reduce the risk of SSIs in pediatric appendicitis patients. Methods: A literature search was performed using PubMed, Cochrane, and Embase databases of studies in English published between January 01, 1973, and April 30, 2023. Studies on pediatric patients (≤ 18 years) with appendicitis that described any interventions aimed at reducing SSIs and reported SSIs as an outcome were included. Results: A total of 56 studies were included in the final scoping review. The interventions included antibiotic stewardship, clinical practice guidelines/pathways, different surgical approaches, timing of appendectomy, irrigation or lavage, use of peritoneal drains, timing of wound closure and management, parenteral nutrition, pain management, and outpatient management. Conclusion: A wide variety of interventions have been studied in pediatric appendicitis patients to reduce the SSI rates. Very few publications have studied low-cost, widely available intraoperative interventions to reduce deep/organ-space SSIs.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study did not receive any funding

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Data Availability

No data was produced in this scoping review manuscript. All the research studies that were included in this manuscript are available on PubMed, Cochrane, and Embase databases

View the discussion thread.

Thank you for your interest in spreading the word about medRxiv.

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• Published: 16 May 2024

DNA methylation and type 2 diabetes: a systematic review

• Nikhil Nadiger 1 , 2 ,
• Jyothisha Kana Veed 2 ,
• Priyanka Chinya Nataraj 2   nAff3 &
• Arpita Mukhopadhyay 2  

Clinical Epigenetics volume  16 , Article number:  67 ( 2024 ) Cite this article

69 Accesses

Metrics details

DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics.

A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436.

PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively.

Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets ( TXNIP , ABCG1 , PPARGC1A , PTPRN2 ) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2 , MSI2 , FTO , TXNIP , SREBF1 , PHOSPHO1 , SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle).

This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.

Introduction

Type 2 diabetes mellitus (T2DM) is a disorder of genetic and environmental factors. It is projected to affect 693 million people worldwide by 2045 [ 1 ]. DNA methylation had been proposed as one of the epigenetic phenomena for explaining the missing heritability of T2DM, as multiple, large genome-wide association studies have been able to account for only < 20% of the estimated T2DM heritability [ 2 ]. DNA methylation is an epigenetic phenomenon in which the C5 carbon of the cytosine residue is attached to a methyl group, predominantly in cytosine-phosphate-guanine (CpG) sites [ 3 , 4 , 5 ]. This epigenetic alteration influences gene expression, and thereby, gene function [ 6 , 7 ].

DNA methylation has been studied extensively in relation to T2DM, and 3 systematic reviews have summarized the findings a few years back [ 8 , 9 , 10 ]. From systematic literature done till August 2015, Muka et al. [ 10 ] could not find any consistent association between global DNA methylation with T2DM, glucose, insulin and insulin resistance and reported epigenetic regulation of few candidate genes in blood cells, muscle, adipose tissue and placenta without any overlap between them. Walaszczyk et al . [ 9 ] could replicate association of methylation with T2DM in blood samples from the Lifelines study at 5 CpGs (in ABCG1 , LOXL2 , TXNIP , SLC1A5 and SREBF1 ) out of the 52 CpGs they identified as reported to be differentially methylated in T2DM through a systematic review of the literature done till April 2017. Willmer et al . [ 8 ] also focused on differential methylation signatures in blood samples and reported TCF7L2 , KCNQ1 , ABCG1 , TXNIP , PHOSPHO1 , SREBF1 , SLC30A8 and FTO genes to be reproducibly associated with T2DM across multiple population groups in the literature reviewed between January 2002 and July 2018.

DNA methylation has been touted as a strong candidate biological process for identification of diagnostic and therapeutics for T2DM [ 11 ]. While the available systematic reviews have looked at DNA methylation associated with T2DM [ 8 , 9 , 10 ], they have not evaluated T2DM-associated DNA methylation comprehensively in all available human tissue and cell types. We set out to fill this research gap with the no time period cutoff until October 19, 2023, and including all available human tissue and cell types. We also report associated gene expression data, role of sex and ethnicity, in relation to DNA methylation in our review.

PubMed and Science Direct databases were independently searched by authors (NN, PN and JKV) using the key terms “type 2 diabetes mellitus” and “DNA methylation,” and their associated terms for all studies published up to October 19, 2023. All articles from the time of publication listing were considered, and as such no start date was set. No filters were applied during the search using the keywords, so as to not exclude any mislabeled/mis-annotated article type. The detailed search strategy is given in Additional file 1 : Table S1.

Study inclusion and exclusion criteria

The inclusion criteria were full-text English language articles on DNA methylation associated with T2DM in human subjects. Case–control and prospective studies investigating genome-wide methylation were included. Reviews, animal model studies, in vitro studies, irrelevant articles and articles published in other languages were excluded.

All participants, regardless of gender and ethnicity, classified as adults aged 18 years and above were included. All individuals who did not satisfy these criteria—children and adolescents under 18 years of age; as well as subjects with type 1 diabetes (T1DM) or gestational diabetes were excluded. As the association of DNA methylation with T2DM was the focus of this systematic review, intervention studies and clinical trials were excluded. Studies reporting association of DNA methylation with diabetes-related traits (hyperglycemia and insulin resistance) were retained.

All the articles were assessed for their eligibility based on their abstract or full text.

Disagreements between the authors, such as categorization and selection of articles, and data extraction, were resolved through discussion with AM. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was followed to represent the method used [ 12 ]. A total of 32 full-text articles are included in this systematic review.

The assessment of quality of the studies was done by adapting the New Castle Ottawa scale (NOS) [ 13 ]. The parameters used for the assessment are adequacy of case definition, representativeness of cases, selection of controls, definition of controls, comparability of cases and controls, ascertainment of exposure and method used for ascertainment of cases and controls. Scores were given to each of the included studies, and the total score was calculated according to the score sheet (NOS).

This review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database ( https://www.crd.york.ac.uk/prospero/ ) [ 14 ] (accessed April 18, 2023) (registration ID: CRD42020140436).

Pathologically connected pathways with differentially methylated genes in T2DM were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Jensen Disease database via Enrichr-KG [ 15 ].

We identified a total of 5819 articles during the initial search. Duplicates, irrelevant articles based on the study design, publication language, article type, and other articles not within our scope of review were removed. Thirty-two full-text articles were finally selected (Fig.  1 ).

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [ 12 ] flowchart for the literature search process, performed up to October 19, 2023

NOS was used to access the quality of the articles. Of the 32 studies, 16 were assigned a score of more than 5, indicating high quality (Additional file 2 : Table S2). As all the studies have used the same method of ascertainment for cases and controls, and the authors are not blinded to case–control status, these redundant scores are not presented. As the nonresponse rate was not available for any of the studies, this also has been omitted from the quality assessment table.

Case–control studies that reported differential DNA methylation between T2DM (case) and normoglycemic (control) subjects or reported associations between DNA methylation and clinical parameters related to glycemic control of the subjects (HbA1c, fasting blood glucose) and prospective nested case–control studies that reported differential DNA methylation measured at baseline/recruitment between subjects who developed T2DM (incident cases) and those that remained normoglycemic (control) during the follow-up period were finally included.

Participant details such as number of cases and controls and location of the study are also included. Details of the study participants who do not explicitly belong to either case or control group are also presented. The tissue source of the gene/loci identified in; method used for determining methylation status; and the validation method used for confirming the methylation status are tabulated in Table  1 .

The loci/genes reported to be differentially methylated are tabulated in Table  2 , where their methylation status is represented as downward arrow (hypomethylation) or upward arrow (hypermethylation). Wherever reported, the statistical significance of methylation ( P value) is also mentioned. For studies reporting more than 10 differentially methylated genes, the top 5 hypo- and hypermethylated genes are listed.

Methods of DNA methylation analysis

Majority of the evaluated studies had employed array-based techniques to assess DNA methylation levels. Eighteen of 32 studies used Illumina 450 k array. Other array-based studies used Illumina 27 k array (2 studies), Illumina EPIC BeadChip array (4 studies; of which 2 studies specifically mentioned using the 850 k array—EPIC v1 array targeting 850 k probes), Affymetrix SNP6 microarray (1 study), Affymetrix GeneChip promoter 1.0R array (1 study) or Affymetrix axiom genome-wide Taiwan BioBank (TWB) array (1 studies). Rest of the studies used techniques such as methylated DNA immunoprecipitation (MEDIP) (2 studies), MEDIP-chromatin immune precipitation (1 study), reduced representation bisulfite sequencing (1 study) or next-generation sequencing (1 study) to measure DNA methylation levels.

Tissues used in DNA methylation analyses

Of the 32 articles retrieved, 17 (53%) studies used blood samples, 4 (13%) studies used pancreatic islet samples, 5 (16%) studies used adipose tissue samples, 2 (6%) studies used liver samples, 1 (3%) study used spermatozoa samples and 3 (9%) used skeletal muscle samples for their DNA methylation analyses. None of the 32 studies reviewed here utilized more than one tissue from the same subjects for DNA methylation analyses.

Genome-wide methylation analysis for T2DM

Of the 32 genome-wide methylation studies reviewed here, we identified a total of 130 loci that were differentially methylated between T2DM cases and controls across. In an instance where a study reports < 10 differentially methylated genes/loci, they are presented individually. However, in the case of a study which reports > 10 genes/loci, only the top 5 hypo- and 5 hypermethylated genes are highlighted for brevity and reported in Table  2 . The direction of methylation (hyper- or hypomethylated in T2DM, compared to controls) and the reported P values (both unadjusted, and after multiple testing correction) have been included.

We identified genes such as ABCG1, PPARGC1A , PTPRN2 and TXNIP with well-known T2DM genetic risk variants, which were consistently reported to be differentially methylated in more than one study (Fig.  2 ). Tissues used in identification of these gene were blood cells, liver, pancreatic islets and adipose tissue. TXNIP (cg19693031) was the most common gene identified consistently as hypomethylated in diabetic blood (9 studies). TXNIP also harbors established T2DM genetic risk variants [ 16 , 17 ].

A pie chart depicting the genes that were consistently reported to be differentially methylated in ≥ 2 studies in various tissues from T2DM subjects. ↑: Hypomethylation, ↓: Hypermethylation in T2DM individuals compared to normoglycemics. PPARGC1A (chr4: 24,024,251–500) hypomethylated, (chr4: 24,111,501–750) hypermethylated in spermatozoa [ 57 ]

Although blood is not an insulin-responsive tissue, it is the prime minimally invasive tissue available for investigating T2DM-associated epigenetic markers. With the bulk (50%) of the studies coming from Europe, ABCG1 [ 18 , 19 ] and TXNIP [ 16 , 17 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] were some of the blood-based epigenetic markers which were reported to be associated with T2DM in more than one study. We were unable to find any study where differential methylation was investigated simultaneously in blood and other tissues from the same subjects.

Pancreatic islets

Insufficient secretion of insulin from pancreatic beta cells and increased secretion of glucagon from pancreatic alpha cells leads to development of T2DM and is known to be regulated by DNA methylation [ 26 ]. Three of the 32 studies, from Italy, South Korea and Sweden, included in this review have interrogated DNA methylation in pancreatic islets from T2DM individuals, donated after their death. Regions in SFRS2IP [ 3 ], MSI2 [ 27 ], which are known to be associated with critical roles in nucleic acid binding, and B3GNT7 [ 28 ] that is involved in synthesis of glycoprotein, were reported to be hypomethylated in pancreatic islets from T2DM individuals. Considering that DNA methylation can change based on the time of collection of tissue after death [ 29 , 30 ], findings from these studies need to be interpreted in cognizance of the lack of details available in these studies about the cause of death or collection and storage of pancreatic islet tissue after death.

Adipose tissue

Adipose tissue is known to play a critical role in regulating body metabolism and energy homeostasis [ 31 ]. Dysregulation in adipose biology imposes serious health complications such as obesity and development of T2DM [ 31 ]. DNA methylation is an important regulator factor in development [ 32 , 33 ] and dysfunction [ 34 , 35 ] of adipose tissue. Five studies—4 of these representing the European population—included in this review have dissected whether T2DM, and related risk factors are associated with epigenetic modifications in human adipose tissue [ 36 , 37 , 38 , 39 , 40 ]. It is possible that DNA methylation alterations in these reported genes including C1orf52 [ 36 ], HOOK2 [ 37 ], MFSD1 [ 38 ], HNF4A [ 39 ] and L1TD1 [ 40 ] contribute to or are caused by T2DM.

C1orf52 is involved in RNA binding in adipose tissue [ 41 ], and HOOK2 is responsible for cytoskeleton maintenance via regulation of microtubules [ 42 ], while MSFD1 regulates lysosome transport [ 43 ]. Epigenetic alterations in such genes involved in cell structure and function can cause dysfunction in adipose tissue, thereby leading to insulin resistance. While HNF4A mainly regulates transcription in hepatocytes and is associated with Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young [ 44 ] and maturity-onset diabetes of the young, type 1 [ 45 ], it is also known to play a role in lipid and glucose metabolism [ 46 , 47 ]. L1TD1 is predicted to be involved in single-stranded RNA-binding activity [ 48 ].

Liver is known to be involved in regulating glucose level by storing and releasing glycogen in response to insulin and glucagon [ 49 ]. Impaired hepatic gluconeogenesis, glycogenolysis and insulin sensitivity are known to play an important role in T2DM development and other risk factors. Altered hepatic metabolism could be the cause or consequence of DNA methylation modification. Genes involved in intracellular tyrosine kinase activity— PDGFA [ 50 ], transferring phosphorus-containing groups and protein tyrosine kinase activity— RIPK4 [ 51 ], heme binding and oxidoreductase activity— CYB561D1 [ 51 ], were found to be hypomethylated in the diabetic groups. However, the gene involved in inflammation— IL23Ap19 [ 51 ] was identified to be hypermethylated in the diabetic group. Of the two studies reported here, one was from France and the other from Finland.

Gene expression studies

Out of the 32 studies reviewed, 8 had also examined differences in gene expression between T2DM and normoglycemic individuals. To examine if increase in methylation of a gene causes decrease in expression of that gene, we analyzed the studies that report both differentially methylated genes and gene expression, in the same population and study setting, using tissues from the same study participants (Table  3 ). For most of the loci with both DNA methylation and gene expression data available, we found that increase in methylation was associated with decrease in expression, concurrent to the current understanding [ 6 ]. Hypermethylation of PPARGC1A in skeletal muscles [ 52 ], ABCG1 in blood [ 18 ] and PER2 in pancreatic islets [ 3 ] was associated with lower expression of the corresponding genes.

Twin studies

Five of the 32 studies reviewed here have investigated DNA methylation in monozygotic twin cohorts [ 17 , 21 , 28 , 36 , 53 ] (Table  4 ). MALTI [ 53 ] which is known to be involved in energy and insulin signaling pathways [ 54 ], PTBP1 [ 36 ] that is involved in nucleic acid binding, and ANO8 [ 28 ] that is involved in calcium transport, were hypermethylated in diabetic twins in peripheral blood, adipose tissue and pancreatic islets, respectively. TXNIP [ 17 , 21 ], COL21A1 [ 36 ] and B3GNT7 [ 28 ] were hypomethylated in blood cells, adipose tissue and pancreatic islets, respectively, from the diabetic twins. Dayeh et al . reported differential methylation of ABCG1 (hypermethylated in blood and adipose tissue) and PHOSPHO1 (hypomethylated in skeletal muscle) in monozygotic twins discordant for T2DM [ 55 ].

Association between diabetes related traits and DNA methylation

Only 4 of the 32 studies reported association between diabetes-related traits (hyperglycemia and insulin resistance) and DNA methylation [ 17 , 18 , 19 , 22 ]. Kriebel et al . reported significant association between measures of glucose metabolism phenotypic traits and methylation levels of 31 CpG sites in PBMCs [ 18 ]. Five CpGs were found to be associated with fasting glucose, 1 CpG with 2-h glucose, 8 with fasting insulin and 26 with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in model 1 (Table  2 ) [ 18 ]. There was no significant association between HbA1c and DNA methylation levels in model 1; in model 2, after adjustment for body mass index (BMI), the effect strength was reduced by 30% for DNA methylation associations with fasting glucose suggesting that the associations between DNA methylation and diabetes-related traits are partially mediated by BMI [ 18 ].

Kulkarni et al . investigated association between 446,356 autosomal CpG sites and phenotypic traits in PBMCs, of which a total of 51 CpG sites were significantly associated with T2DM, 19 with FBG and 24 with HOMA-IR (Table  2 ) [ 19 ].

Wang et al . report association between 63 differential methylated loci and fasting blood glucose and association between 6 differentially methylated loci with HbA1c in blood samples from twins discordant for diabetes [ 17 ]. Among these, hypomethylation of TXNIP [ 17 , 19 ] and hypermethylation of ABCG1 [ 18 , 19 ] were positively associated with fasting blood glucose (FBG), and hypermethylation of SAMD12 was negatively associated with FBG [ 19 ]. TXNIP hypomethylation in blood cells was found to be associated with hyperglycemia in individuals from Taiwan [ 23 ], France [ 24 ], the USA [ 21 ] and China [ 17 ].

Dawes et al . performed genome-wide DNA methylation on blood samples from normoglycemic (n = 142), pre-diabetic (n = 274) and diabetic (n = 90) individuals [ 22 ]. They identified HbA1c-associated DNA methylation loci by regressing the probes against HbA1c values, while controlling for age, sex and BMI [ 22 ]. They report cg19693031 ( TXNIP ) as the locus most highly associated with HbA1c [ 22 ].

Enrichment analysis of genes differentially methylated in T2DM

Enrichment analysis of signaling pathways relevant to the pathophysiology of T2DM using Enrichr-KG [ 15 ] was done in two steps. Initially, all 130 genes differentially methylated in T2DM in all 32 studies reviewed were included (Fig.  3 ). To take into account reproducibility of these findings, enrichment analysis was separately done specifically for the genes ( ABCG1 , TXNIP , PTPRN2 , PPARGC1A ) that were reported to be differentially methylated in T2DM in more than one study (Fig.  4 ). TXNIP hypomethylation in blood was linked to hyperglycemia. PPARGC1A hypermethylation in skeletal muscles, and two CpG sites that were hyper- and hypomethylated, respectively, in spermatozoa, was linked to hyperglycemia and adipocytokine signaling pathway. PTPRN2 that was reported to be hypermethylated in blood and hypomethylated in adipose tissue was associated with T2DM and T1DM.

Gene enrichment analysis of 17 of the 130 genes reported to be differentially methylated in T2DM subjects in the 32 studies included for review using Enrichr-KG. These genes were mapped to diabetes and related disorders. Insulin resistance, glucagon signaling pathway, glaucoma, AMPK signaling pathway, cholinergic synapse, ovarian cancer, amphetamine addiction and Huntington’s disease were found to be associated with KCNQ1 , FTO , PPARGC1A , PTPRN2 , ELOVL5 , HNF1B , HNF4A , VPS13A , MAEA , CREB1 , CPT1A , PRKCZ , PRKCB , CREB3L2 , CDKN2A and TGFBR3

Gene enrichment analysis of 4 genes reported to be differentially methylated in T2DM subjects in > 1 study from among the 32 studies included for review using Enrichr-KG. Hyperglycemia, type 1 diabetes, adipocytokine signaling pathway, glucagon signaling pathway, longevity regulating pathway and ABC transporters were found to be associated with PPARGC1A , TXNIP , PTPRN2 and ABCG1

Subgroup analysis based on ethnicity

Out of the 32 studies, 16 (50%) were from Europe, 4 (13%) were from North America, 8 (25%) were from Asia and 1 (3%) from Africa. Three studies (9%) did not report their subjects’ ethnicity/demography.

TXNIP was the most commonly reported hypomethylated gene in blood cells of T2DM individuals from all the geographic locations [ 16 , 17 , 19 , 20 , 21 , 22 , 23 , 24 ]. ABCG1 was found be to hypermethylated in blood cells of type 2 diabetics in studies from Europe [ 18 ] and the USA [ 19 ]. PTPRN2 was reported to be hypermethylated in peripheral blood in studies from China [ 56 ] and France [ 24 ]. Conversely, PTPRN2 was reported to be hypomethylated in adipose tissue from a Spanish study [ 37 ].

Subgroup analysis based on sex

PPARGC1A was assessed for differential methylation in two studies which had only male participants [ 52 , 57 ]. PPARGC1A was hypermethylated in skeletal muscle of T2DM men [ 52 ]. Of the two differentially methylated regions in PPARGC1A identified in sperm, chr4: 24,111,501–750 was reported to be hypermethylated, and chr4: 24,024,251–500 was reported to be hypomethylated [ 57 ]. We did not find other epigenome-wide studies that report differential methylation of PPARGC1A in female-only or mixed-sex populations.

PDGFA was found to be hypomethylated in hepatocytes from liver biopsies of female T2DM participants of the discovery group and was later confirmed in both men and women by Abderrahmani et al . [ 50 ]. Similarly, hypomethylation of MSI2 in blood cells was first observed in a discovery group comprised of only men, and then in a replication group of both men and women by Jeon et al . [ 27 ].

In the cg 11,738,485-region (5 CpG nucleotides) of HOOK2 , female T2DM visceral adipose tissue samples were hypermethylated, while male T2DM samples were hypomethylated, compared to non-diabetic sex-matched control samples [ 37 ]. None of the other loci/genes were reported to be differentially methylated in a sex-specific manner.

Internal and/or external validation

Only 22% of the studies reviewed (7 out of 32) validated their findings in an independent set of subjects using the same DNA methylation measurement method that they had used for the discovery set of samples [ 17 , 25 , 27 , 36 , 37 , 50 , 53 ]. Others used either bisulfite pyrosequencing/sequencing (10 studies) [ 3 , 19 , 27 , 28 , 37 , 39 , 52 , 58 , 59 , 60 ], qPCR (1 study) [ 51 ], EpiTYPER (1 study) [ 16 ], Illumina 450 k (3 studies) [ 36 , 50 , 53 ] or MEDIP (1 study) [ 61 ] for their internal validation. Sixteen studies (50%) did not perform any validation for their findings.

Replication for case–control studies

We later looked for candidate-gene DNA methylation studies to see if the differentially methylated genes found in genome-wide studies have been confirmed in them. The following genes were reported to be differentially methylated in T2DM compared to normoglycemic controls in independent candidate-gene DNA methylation studies in the same tissue as the initial discovery group— ABCG1 [ 62 , 63 ], FTO [ 64 , 65 , 66 ], TXNIP [ 67 ] and KCNQ1 [ 64 , 68 ] in PBMCs, and PPARGC1A in pancreatic islets [ 69 ].

Prospective studies

As prospective studies observe the disease condition over a long period, they help in better understanding the role of a gene/set of genes toward pathogenesis. In our review, we came across three such studies that looked at incidence of T2DM and epigenetic modifications in genes associated with this incidence (Table  5 ).

In a 1:1 matched nested case–control study of 290 incident diabetics, who developed T2DM and 290 controls, who remained normoglycemic during the 4-year follow-up, baseline methylation at 7 CpG sites of IGFBP2 in blood cells (4 hypermethylated and 3 hypomethylated in cases) was associated with increased risk of incident T2DM [ 70 ].

Jeon et al . reported that differential methylation of three CpG sites in blood cells at baseline was associated with T2DM/hyperglycemia after a 10-year follow-up [ 27 ]. These CpG sites were cg23586172 (annotated to MSI2 , hypomethylated), cg22604213 (annotated to CXXC4, hypomethylated) and cg25290098 (hypomethylated) in T2DM [ 27 ]. They further reported MSI2 hypomethylation in a replication group of 220 normoglycemic and 220 T2DM individuals [ 27 ]. Furthermore, whole-genome bisulfite sequencing of pancreatic islets of 2 T2DM and 16 normoglycemic individuals revealed that chr17:55,484,635 in MSI2 was hypomethylated in T2DM [ 27 ]. While MSI2 hypomethylation was seen in both pancreatic islets and PBMCs, pancreatic islets showed increased difference of 16% methylation versus 3% in PBMCs of MSI2 in T2DM when compared to normoglycemics [ 27 ]. MSI2 differential methylation was not found to be replicated in locus-specific case–control studies.

From the Jerusalem LRC longitudinal study, Toperoff et al . selected 58 individuals who developed impaired glucose metabolism over a 13-year follow-up and reported hypomethylation of a single CpG site in the first intron of FTO in peripheral blood samples collected at baseline [ 58 ]. Chen et al . similarly reported hypomethylation of FTO in their case–control study [ 57 ].

In a longitudinal study of Indian Asians living in London, UK (1074 incident T2DM and 1590 normoglycemic controls), over 8 years of follow-up, Chambers et al . reported that DNA methylation levels of TXNIP , PROC , C7orf29 , SREBF1 , PHOSPHO1 , SOCS3 and ABCG1 in blood cells were positively associated with future T2DM incidence [ 71 ]. Of these, higher baseline methylation levels in TXNIP , SREBF1 , PHOSPHO1 , SOCS3 and ABCG1 were also associated with incident T2DM in an European cohort of 377 incident T2DM and 764 normoglycemic individuals [ 71 ].

Differential methylation in animal models

To check if animal model studies exist that have investigated or reported differential methylation in the genes identified as differentially methylated in the human case–control studies as playing causal or mechanistic role in the development of T2DM, a simple literature search was done using PubMed and bibliography search. A study in rat pancreatic islets reported Kcnq1 was hypomethylated in older rats (15 months of age) when compared to younger rats (3 months of age), but this difference was not statistically significant, while there was no comparison done with a rat T2DM model [ 72 ]. Though Toperoff et al . reported hypomethylation of KCNQ1 in blood cells [ 58 ], there are no human pancreatic islet studies reporting hypomethylation of KCNQ1 . Identification of multiple variants in genome-wide association studies [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ] points toward the likely importance of KCNQ1 in T2DM pathophysiology.

High-fat diet was shown to induce hypermethylation of Tcf7l2, and subsequently, gene expression was decreased in mouse islets [ 82 ]. This is in contrast to the findings where TCF7L2 is hypomethylated in T2DM human blood cells [ 58 ] and pancreatic islets [ 59 ]. It is to be noted that the mice used were non-diabetic adult males aged 8 weeks (equivalent to middle-aged humans [ 83 ]) [ 82 ], while the human study group were a mix of men and women aged about 58–65 years, and for the human pancreatic islet study, the samples had been collected post-mortem [ 58 , 59 ]. Although there is an inverse differential methylation status among mice and humans, it is important to note that a high-fat diet caused suppression of Tcf7l2 gene expression and thus decreases pancreatic beta-cell survival (mediated via the transcription of Wnt/Beta-catenin signaling pathway [ 84 ]) [ 82 ].

From the 32 studies finally included for this systematic review, we identified 130 genes with T2DM-associated differential methylation across all tissues analyzed. These comprise of the top 5 hypo- and hypermethylated genes for studies reporting more than 10 differentially methylated genes/loci. Of these 130 genes, 4 (3%; ABCG1, PPARGC1A , PTPRN2 and TXNIP ) were reported in > 1 studies. The genes and associated pathways with altered DNA methylation in T2DM are conceptually summarized in Fig.  3 (for 16 of the 130 genes, for which pathway analysis could be conducted) and Fig.  4 (for the 4 genes reported to be differentially methylated in > 1 studies).

Previous systematic reviews [ 8 , 9 ] have reported differentially methylated loci in genes in T2DM blood cells including ABCG1 , TXNIP , KCNQ1 . While another such review by Muka et al . reported several epigenetically regulated genes from blood cells, adipose tissue, muscle and placenta, there was no overlap between them, and no association was found between global DNA methylation and T2DM/hyperglycemic markers [ 10 ].

We did not limit our search to a particular method used to identify DNA methylation, and several studies included have used Illumina’s 450 k array. The common method of validation/replication in the studies reviewed here was bisulfite pyrosequencing. We also looked at candidate-gene DNA methylation studies which aimed to replicate/validate the epigenome-wide studies reviewed here and found that in blood cells, ABCG1 [ 62 ], FTO [ 64 ] and KCNQ1 [ 64 ] were hypermethylated, while TXNIP was hypomethylated [ 67 ]. TXNIP codes for thioredoxin-interacting protein, and this protein plays a major role in pathways generating reactive oxygen species [ 85 ], regulating redox-dependent signaling pathways, mediating oxidative stress, suppressing cell growth and inducing pancreatic beta-cell apoptosis [ 86 ]. ABCG1 codes for the protein responsible for intracellular sterol transport [ 87 ], and it regulates cholesterol efflux from macrophages to high-density lipoprotein in diabetics [ 88 ], indicated by altered lipid levels [ 89 ]. While genetic variants and epigenetic modification of KCNQ1 have been linked with T2DM via whole body insulin sensitivity [ 90 ], there is no clear evidence for the mechanistic link. Likewise, there has been no clear evidence of FTO link with T2DM.

As gene expression is known to be regulated by DNA methylation, it is important to validate this claim in the epigenome-wide association studies. We were able to report the relation between DNA methylation in the promoter region and expression of the corresponding gene, as none of the studies had mentioned methylation status of other regions of the genes. Of the studies reviewed here, we found that DNA methylation of genes was inversely related to gene expression. For example, hypomethylation of S100A4 in adipose tissue [ 36 ] and PDGFA in hepatocytes [ 50 ] was associated with increased expression of these genes, and hypermethylation of PPARGC1A in skeletal muscles [ 52 ], ABCG1 in blood [ 18 ] and PER2 in pancreatic islets [ 3 ] was associated with lower expression of the corresponding genes. Even though we observed DNA methylation being related inversely with expression of the corresponding gene in the studies reviewed, this is not a rule as has been reported repeatedly [ 91 ]. It is also important to note that there have been reports of methylation levels differing between different regions of the gene that influence gene expression; for instance, Anastasiadi et al . recently reported that gene expression is dependent on methylation of the first exon, more than methylation of the promoter region [ 92 ]. Moreover, in other studies such as one by Ball and colleagues, highly expressed genes have been reported to have low methylation levels in the promoter region and high methylation levels in rest of the gene body [ 93 ]. We could not, however, evaluate the relations between DNA methylation in various regions of a gene and its corresponding expression in this study since the studies reviewed by us have reported DNA methylation specifically in the promoter region.

Epigenetic studies on twins discordant for disease status are crucial in understanding the genetic basis of epigenetic differences observed in cross-sectional studies. Of the 5 studies included in our search, 3 did not have any common differentially methylated genes among them, while the other two studies that used blood cells as the source tissue had TXNIP as the common differentially methylated gene between them, with hypomethylation of TXNIP in diabetic blood samples observed in both these studies [ 17 , 21 ]. TXNIP is the only gene reported to be hypomethylated in diabetic blood in both case–control studies [ 55 ] and in twin studies [ 17 , 21 ] where the influence of underlying genetic factors is not masked. TXNIP has also been reported to be hypomethylated in diabetic pancreatic islets [ 55 ] and skeletal muscle [ 55 ], making it a potentially important causal gene in the pathophysiology of T2DM.

T2DM is known to be associated with other comorbidities such as obesity and cardiovascular complication. These comorbidities share some common risk factors like age, BMI and cholesterol content in blood. These risk factors are influenced by genes such as KCNQ1 , TCF7L2 and FTO [ 94 ]. Other systematic reviews have looked at epigenetic changes in obesity [ 95 ], aging [ 96 , 97 ] and cardiovascular complications [ 98 ]. Andrade et al . aimed to identify epigenetic changes in human adipose tissue from obese/overweight individuals with and without metabolic disorders like T2DM [ 95 ]. They also report differentially methylated genes that we have been reported in this review, such as KCNQ1 , FASN , MFSD1 , TXNIP , PPARG , IRS1 and TCF7L2 , from the same studies [ 95 ]. Krolevets et al . report that in addition to about 75,000 CpG sites and 19,000 genes, PTPRN2 was among the most frequently reported gene that was associated with cardiac disorders, although the direction of methylation is not specified [ 98 ]. Of the two studies that investigated DNA methylation in aging [ 96 , 97 ], no genes/CpG sites/studies were common with the ones mentioned in our review.

One of the most important factors in looking at T2DM as an epidemic is the geographic location of the site of reported data. With a large amount of data coming in from Europe alone, it is important to perform similar studies in other parts of the world and including various other ethnic groups to validate these reports and also help in mapping the genetic diversity to be able to tackle T2DM. India being the most populous country [ 99 ] with about 11% of Indians suffering from T2DM (in 2020) [ 100 ], it is imperative to study this population to uncover T2DM susceptible loci/genes. Of note, Chambers et al . have followed up London resident Indian Asians, for 8 years, and found that DNA methylation levels of TXNIP , PROC , C7orf29 , SREBF1 , PHOSPHO1 , SOCS3 and ABCG1 were positively associated with future T2DM incidence [ 71 ], but similar studies are lacking in Indians living in India, where exposure to pollution and availability and consumption of healthy diet are vastly different.

As for sex-specific methylation signatures of T2DM, differences were not seen between men and women except in genes HOOK2 [ 37 ] and MSI2 [ 27 ], which were hypermethylated in adipose tissue, and hypomethylated in blood, respectively . Finally, we searched if the genes which we found to be highly reported to be differentially methylated in human were also reported to be differentially methylated in animal models. KCNQ1 was reported to be hypomethylated in both T2DM human [ 58 ], and older mice model compared with younger mice [ 72 ] suggesting age-related methylation changes across species. In both humans [ 58 ], and mice fed with a high-fat diet, TCF7L2 was hypomethylated, and this DNA methylation change in mice was induced because of their diet [ 82 ], suggesting that nutrient consumption plays a role in epigenetic modification of genes involved in beta-cell function, and a healthy diet can have a protective role in maintaining homeostasis.

Although we did not look at clinical trials and candidate-gene studies that report differential DNA methylation, our review is an up-to-date report of epigenome-wide studies that includes prospective studies. We also report gene expression data in comparison with DNA methylation. Furthermore, a systematic report of differentially methylated gene/loci in tissues including blood cells, adipose tissue, pancreatic islet, skeletal muscles, liver and spermatozoa is included. While sex and ethnicity play a major role in pathology, we have tried to highlight these effects.

As with previous reviews, we emphasize the need for more prospective studies and replication of genome-wide association studies in different tissue types and populations.

From the 32 studies that report differentially methylated genes/loci between T2DM and normoglycemic individuals, ABCG1 (hypermethylated in blood), FTO (hypermethylated in blood and spermatozoa), KCNQ1 (hypermethylated in blood and hypomethylated in spermatozoa), TXNIP (hypomethylated in blood), PPARGC1A loci at chr4: 24,111,501–750 (hypermethylated in skeletal muscle and spermatozoa) and loci at chr4: 24,024,251–500 (hypomethylated in spermatozoa), PTPRN2 (hypermethylated in blood, hypomethylated in adipose tissue) were reported in more than one study. We found reports of hypermethylation of these genes that were associated with decreased gene expression, and vice versa. We also report findings from studies done on monozygotic twins. Various traits that can affect T2DM such as sex, glucose levels, BMI and ethnicity were also taken into consideration.

As there were multiple methods that were used to measure DNA methylation, internal and external validation of these results is also reported. Finally, animal model studies that have reported differential DNA methylation of the genes that were found to be differentially methylated in human studies were looked at to get an understanding of the likely mechanisms linking epigenetic dysregulation of these genes in T2DM to its pathophysiology.

Although the majority of the top differentially methylated genes are well known, other more recent genes reported here should be investigated further to understand their role in pathogenesis of T2DM.

Data availability statement

All relevant data are presented as tables and/or figures.

Abbreviations

ATP-Binding Cassette Subfamily G Member 1

Anoctamin 8

Beta 1,3-N-Acetylglucosaminyltransferase 7

Chromosome 1 Open Reading Frame 52

Chromosome 7 Open Reading Frame 29

Collagen Type XXI Alpha 1

Cytochrome B561 Family Member D1

CXXC Finger Protein 4

Alpha-Ketoglutarate Dependent Dioxygenase

Glucagon Like Peptide 1 Receptor

Glutathione Peroxidase 6

Hepatocyte Nuclear Factor 4 Alpha

Hook Microtubule Tethering Protein 2

Insulin-Like Growth Factor-Binding Protein 2

Interleukin-23 Subunit Alpha

Potassium Voltage-Gated Channel Subfamily Q Member 1

LINE1 Type Transposase Domain Containing 1

Lysyl Oxidase Homolog 2

Mucosa-Associated Lymphoid Tissue Lymphoma Translocation Protein 1

Major Facilitator Superfamily Domain Containing 1

Musashi RNA-Binding Protein 2

Platelet Derived Growth Factor Subunit A

Pancreatic and Duodenal Homeobox 1

Period Circadian Regulator 2

Phosphoethanolamine/Phosphocholine Phosphatase 1

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha

Protein C, Inactivator Of Coagulation Factors Va And VIIIa

Polypyrimidine Tract-Binding Protein 1

Protein Tyrosine Phosphatase Receptor Type N2

Receptor Interacting Serine/Threonine Kinase 4

S100 Calcium-Binding Protein A4

Sterile Alpha Motif Domain Containing 12

Solute Carrier Family 1 Member 5

Solute Carrier Family 22 Member 1

Solute Carrier Family 22 Member 3

Solute Carrier Family 30 Member 8

Sterol Regulatory Element-Binding Transcription Factor 1

Suppressor Of Cytokine Signaling 3

Transcription Factor 7-Like 2

Thioredoxin-Interacting Protein

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Acknowledgements

AM is supported by the Wellcome Trust/DBT India Alliance Fellowship [Grant Number IA/CPHI/19/1/504593]. We thank Ms. Ramya for her insightful comments.

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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Priyanka Chinya Nataraj

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Nikhil Nadiger

Division of Nutrition, St. John’s Research Institute, St. John’s Medical College, St Johns National Academy of Health Sciences, Sarjapura Road, Koramangala, Bangalore, 560034, India

Nikhil Nadiger, Jyothisha Kana Veed, Priyanka Chinya Nataraj & Arpita Mukhopadhyay

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AM was involved in conceptualization, review and editing of the manuscript. NN, JKV and PCN were involved in data extraction, formal analysis, investigation and writing the manuscript. All authors have read and approved the final manuscript.

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Additional file 1 search strategy for the systematic review of dna methylation association with t2dm, 13148_2024_1670_moesm2_esm.docx.

Additional file 2 Qualitative assessment of research articles included in the review based on the New Castle Ottawa Scale (NOS)

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Nadiger, N., Veed, J.K., Chinya Nataraj, P. et al. DNA methylation and type 2 diabetes: a systematic review. Clin Epigenet 16 , 67 (2024). https://doi.org/10.1186/s13148-024-01670-6

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Clinical Epigenetics

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Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology

• Special Article
• Published: 17 May 2024

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• Yuho Najima 1 ,
• Tomoya Maeda 2 ,
• Yutaro Kamiyama 3 ,
• Shinji Nakao 4 ,
• Yukinori Ozaki 5 ,
• Hiroshi Nishio 6 ,
• Kenji Tsuchihashi 7 ,
• Eiki Ichihara 8 ,
• Yuji Miumra 9 ,
• Makoto Endo 10 ,
• Dai Maruyama 11 ,
• Tetsuhiro Yoshinami 12 ,
• Nobuyuki Susumu 13 ,
• Munetaka Takekuma 14 ,
• Takashi Motohashi 15 ,
• Mamoru Ito 7 ,
• Eishi Baba 16 ,
• Nobuaki Ochi 17 ,
• Toshio Kubo 18 ,
• Keita Uchino 19 ,
• Takahiro Kimura 20 ,
• Shinobu Tamura 21 ,
• Hitomi Nishimoto 22 ,
• Yasuhisa Kato 23 ,
• Atsushi Sato 24 ,
• Toshimi Takano 5 &
• Shingo Yano 3  

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The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy.

We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized.

Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82–1.01), p  = 0.08; I 2  = 4%, p  = 0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS.

Conclusions

G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

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Data availability.

Data associated with this systematic review may be accessed from the corresponding author upon reasonable request.

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Acknowledgements

The authors are grateful to Ms. Natsuki Narita for her contribution to the initial literature search. The authors thank Ms. Natsuki Fukuda for her valuable comments and suggestions. We would like to thank Editage ( www.editage.jp ) for English language editing.

This study was partially supported by the Japan Society for the Promotion of Science, KAKENHI (grant number: JP22K15615).

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All the authors contributed to the conception and design of this present study. Y.N. wrote the draft of the manuscript, and all authors reviewed and commented on the manuscript. All the authors have read and approved the manuscript.

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T. Maeda reports scholarship donation from Chugai Pharmaceutical. SN reports honoraria from Kyowa Kirin. YO reports honoraria from Daiichi Sankyo, Pfizer, Chugai Pharmaceutical, Eli Lilly and Company, and Kyowa Kirin. KT reports honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, and Novartis Pharma. EI reports honoraria from Eli Lilly and Company, research funding from MSD, Ono Pharmaceutical, Jannsen Pharma, and Takeda Pharmaceutical. YM reports honoraria from Ono Pharmaceutical, MSD, Takeda Pharmaceutical, Eisai, Bristol Myers Squibb, research funding from MSD, and Ono Pharmaceutical. DM reports honoraria from Ono Pharmaceutical, Janssen Pharma, Nippon Shinyaku, Eisai, Mundipharma, Kyowa Kirin, Chugai Pharmaceutical, Zenyaku, MSD, SymBio Pharmaceuticals, Sanofi, AbbVie, Takeda Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Genmab, research funding from Amgen Astellas Biopharma, Novartis Pharma, Kyowa Kirin, Ono Pharmaceutical, Chugai Pharmaceutical, Janssen Pharma, Takeda Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Astellas, Bristol Myers Squibb, AbbVie, Eisai, MSD, Taiho Pharmaceutical, AstraZeneca, Eli Lilly and Company, and Genmab. TY reports honoraria from Kyowa Kirin, Pfizer, Chugai Pharmaceutical, Eli Lilly and Company, MSD, AstraZeneca, and Eisai. T. Motohashi reports honoraria from AstraZeneca, Chugai Pharmaceutical, and Myriad Genetics. EB reports honoraria from Chugai Pharmaceutical, Daiichi Sankyo, research funding from Taiho Pharmaceutical, and Chugai Pharmaceutical. T. Kubo reports honoraria from Chugai Pharmaceutical. T. Kimura reports honoraria from Sanofi. AS reports honoraria and research funding from Chugai Pharmaceutical, and Taiho Pharmaceutical. TT reports honoraria from Daiichi Sankyo, Chugai Pharmaceutical, and Eli Lilly and Company. SY reports research funding from Otsuka Pharmaceutical. The other authors declare that there are no conflicts of interest associated with this manuscript.

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Najima, Y., Maeda, T., Kamiyama, Y. et al. Effectiveness and safety of granulocyte colony-stimulating factor priming regimen for acute myeloid leukemia: A systematic review and meta-analysis of the Clinical Practice Guideline for the use of G-CSF 2022 from the Japan Society of Clinical Oncology. Int J Clin Oncol (2024). https://doi.org/10.1007/s10147-023-02461-4

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DOI : https://doi.org/10.1007/s10147-023-02461-4

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• Published: 13 May 2024

Sexual and reproductive health implementation research in humanitarian contexts: a scoping review

• Alexandra Norton 1 &
• Hannah Tappis 2  

Reproductive Health volume  21 , Article number:  64 ( 2024 ) Cite this article

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Meeting the health needs of crisis-affected populations is a growing challenge, with 339 million people globally in need of humanitarian assistance in 2023. Given one in four people living in humanitarian contexts are women and girls of reproductive age, sexual and reproductive health care is considered as essential health service and minimum standard for humanitarian response. Despite growing calls for increased investment in implementation research in humanitarian settings, guidance on appropriate methods and analytical frameworks is limited.

A scoping review was conducted to examine the extent to which implementation research frameworks have been used to evaluate sexual and reproductive health interventions in humanitarian settings. Peer-reviewed papers published from 2013 to 2022 were identified through relevant systematic reviews and a literature search of Pubmed, Embase, PsycInfo, CINAHL and Global Health databases. Papers that presented primary quantitative or qualitative data pertaining to a sexual and reproductive health intervention in a humanitarian setting were included.

Seven thousand thirty-six unique records were screened for inclusion, and 69 papers met inclusion criteria. Of these, six papers explicitly described the use of an implementation research framework, three citing use of the Consolidated Framework for Implementation Research. Three additional papers referenced other types of frameworks used in their evaluation. Factors cited across all included studies as helping the intervention in their presence or hindering in their absence were synthesized into the following Consolidated Framework for Implementation Research domains: Characteristics of Systems, Outer Setting, Inner Setting, Characteristics of Individuals, Intervention Characteristics, and Process.

This review found a wide range of methodologies and only six of 69 studies using an implementation research framework, highlighting an opportunity for standardization to better inform the evidence for and delivery of sexual and reproductive health interventions in humanitarian settings. Increased use of implementation research frameworks such as a modified Consolidated Framework for Implementation Research could work toward both expanding the evidence base and increasing standardization.

Plain English summary

Three hundred thirty-nine million people globally were in need of humanitarian assistance in 2023, and meeting the health needs of crisis-affected populations is a growing challenge. One in four people living in humanitarian contexts are women and girls of reproductive age, and provision of sexual and reproductive health care is considered to be essential within a humanitarian response. Implementation research can help to better understand how real-world contexts affect health improvement efforts. Despite growing calls for increased investment in implementation research in humanitarian settings, guidance on how best to do so is limited. This scoping review was conducted to examine the extent to which implementation research frameworks have been used to evaluate sexual and reproductive health interventions in humanitarian settings. Of 69 papers that met inclusion criteria for the review, six of them explicitly described the use of an implementation research framework. Three used the Consolidated Framework for Implementation Research, a theory-based framework that can guide implementation research. Three additional papers referenced other types of frameworks used in their evaluation. This review summarizes how factors relevant to different aspects of implementation within the included papers could have been organized using the Consolidated Framework for Implementation Research. The findings from this review highlight an opportunity for standardization to better inform the evidence for and delivery of sexual and reproductive health interventions in humanitarian settings. Increased use of implementation research frameworks such as a modified Consolidated Framework for Implementation Research could work toward both expanding the evidence base and increasing standardization.

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Over the past few decades, the field of public health implementation research (IR) has grown as a means by which the real-world conditions affecting health improvement efforts can be better understood. Peters et al. put forward the following broad definition of IR for health: “IR is the scientific inquiry into questions concerning implementation – the act of carrying an intention into effect, which in health research can be policies, programmes, or individual practices (collectively called interventions)” [ 1 ].

As IR emphasizes real-world circumstances, the context within which a health intervention is delivered is a core consideration. However, much IR implemented to date has focused on higher-resource settings, with many proposed frameworks developed with particular utility for a higher-income setting [ 2 ]. In recognition of IR’s potential to increase evidence across a range of settings, there have been numerous reviews of the use of IR in lower-resource settings as well as calls for broader use [ 3 , 4 ]. There have also been more focused efforts to modify various approaches and frameworks to strengthen the relevance of IR to low- and middle-income country settings (LMICs), such as the work by Means et al. to adapt a specific IR framework for increased utility in LMICs [ 2 ].

Within LMIC settings, the centrality of context to a health intervention’s impact is of particular relevance in humanitarian settings, which present a set of distinct implementation challenges [ 5 ]. Humanitarian responses to crisis situations operate with limited resources, under potential security concerns, and often under pressure to relieve acute suffering and need [ 6 ]. Given these factors, successful implementation of a particular health intervention may require different qualities than those that optimize intervention impact under more stable circumstances [ 7 ]. Despite increasing recognition of the need for expanded evidence of health interventions in humanitarian settings, the evidence base remains limited [ 8 ]. Furthermore, despite its potential utility, there is not standardized guidance on IR in humanitarian settings, nor are there widely endorsed recommendations for the frameworks best suited to analyze implementation in these settings.

Sexual and reproductive health (SRH) is a core aspect of the health sector response in humanitarian settings [ 9 ]. Yet, progress in addressing SRH needs has lagged far behind other services because of challenges related to culture and ideology, financing constraints, lack of data and competing priorities [ 10 ]. The Minimum Initial Service Package (MISP) for SRH in Crisis Situations is the international standard for the minimum set of SRH services that should be implemented in all crisis situations [ 11 ]. However, as in other areas of health, there is need for expanded evidence for planning and implementation of SRH interventions in humanitarian settings. Recent systematic reviews of SRH in humanitarian settings have focused on the effectiveness of interventions and service delivery strategies, as well as factors affecting utilization, but have not detailed whether IR frameworks were used [ 12 , 13 , 14 , 15 ]. There have also been recent reviews examining IR frameworks used in various settings and research areas, but none have explicitly focused on humanitarian settings [ 2 , 16 ].

Given the need for an expanded evidence base for SRH interventions in humanitarian settings and the potential for IR to be used to expand the available evidence, a scoping review was undertaken. This scoping review sought to identify IR approaches that have been used in the last ten years to evaluate SRH interventions in humanitarian settings.

This review also sought to shed light on whether there is a need for a common framework to guide research design, analysis, and reporting for SRH interventions in humanitarian settings and if so, if there are any established frameworks already in use that would be fit-for-purpose or could be tailored to meet this need.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews was utilized to guide the elements of this review [ 17 ]. The review protocol was retrospectively registered with the Open Science Framework ( https://osf.io/b5qtz ).

Search strategy

A two-fold search strategy was undertaken for this review, which covered the last 10 years (2013–2022). First, recent systematic reviews pertaining to research or evaluation of SRH interventions in humanitarian settings were identified through keyword searches on PubMed and Google Scholar. Four relevant systematic reviews were identified [ 12 , 13 , 14 , 15 ] Table 1 .

Second, a literature search mirroring these reviews was conducted to identify relevant papers published since the completion of searches for the most recent review (April 2017). Additional file 1 includes the search terms that were used in the literature search [see Additional file 1 ].

The literature search was conducted for papers published from April 2017 to December 2022 in the databases that were searched in one or more of the systematic reviews: PubMed, Embase, PsycInfo, CINAHL and Global Health. Searches were completed in January 2023 Table 2 .

Two reviewers screened each identified study for alignment with inclusion criteria. Studies in the four systematic reviews identified were considered potentially eligible if published during the last 10 years. These papers then underwent full-text review to confirm satisfaction of all inclusion criteria, as inclusion criteria were similar but not fully aligned across the four reviews.

Literature search results were exported into a citation manager (Covidence), duplicates were removed, and a step-wise screening process for inclusion was applied. First, all papers underwent title and abstract screening. The remaining papers after abstract screening then underwent full-text review to confirm satisfaction of all inclusion criteria. Title and abstract screening as well as full-text review was conducted independently by both authors; disagreements after full-text review were resolved by consensus.

Data extraction and synthesis

The following content areas were summarized in Microsoft Excel for each paper that met inclusion criteria: publication details including author, year, country, setting [rural, urban, camp, settlement], population [refugees, internally displaced persons, general crisis-affected], crisis type [armed conflict, natural disaster], crisis stage [acute, chronic], study design, research methods, SRH intervention, and intervention target population [specific beneficiaries of the intervention within the broader population]; the use of an IR framework; details regarding the IR framework, how it was used, and any rationale given for the framework used; factors cited as impacting SRH interventions, either positively or negatively; and other key findings deemed relevant to this review.

As the focus of this review was on the approach taken for SRH intervention research and evaluation, the quality of the studies themselves was not assessed.

Twenty papers underwent full-text review due to their inclusion in one or more of the four systematic reviews and meeting publication date inclusion criteria. The literature search identified 7,016 unique papers. After full-text screening, 69 met all inclusion criteria and were included in the review. Figure  1 illustrates the search strategy and screening process.

Flow chart of paper identification

Papers published in each of the 10 years of the review timeframe (2013–2022) were included. 29% of the papers originated from the first five years of the time frame considered for this review, with the remaining 71% papers coming from the second half. Characteristics of included publications, including geographic location, type of humanitarian crisis, and type of SRH intervention, are presented in Table  3 .

A wide range of study designs and methods were used across the papers, with both qualitative and quantitative studies well represented. Twenty-six papers were quantitative evaluations [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], 17 were qualitative [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], and 26 used mixed methods [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Within the quantitative evaluations, 15 were observational, while five were quasi-experimental, five were randomized controlled trials, and one was an economic evaluation. Study designs as classified by the authors of this review are summarized in Table  4 .

Six papers (9%) explicitly cited use of an IR framework. Three of these papers utilized the Consolidated Framework for Implementation Research (CFIR) [ 51 , 65 , 70 ]. The CFIR is a commonly used determinant framework that—in its originally proposed form in 2009—is comprised of five domains, each of which has constructs to further categorize factors that impact implementation. The CFIR domains were identified as core content areas influencing the effectiveness of implementation, and the constructs within each domain are intended to provide a range of options for researchers to select from to “guide diagnostic assessments of implementation context, evaluate implementation progress, and help explain findings.” [ 87 ] To allow for consistent terminology throughout this review, the original 2009 CFIR domains and constructs are used.

Guan et al. conducted a mixed methods study to assess the feasibility and effectiveness of a neonatal hepatitis B immunization program in a conflict-affected rural region of Myanmar. Guan et al. report mapping data onto the CFIR as a secondary analysis step. They describe that “CFIR was used as a comprehensive meta-theoretical framework to examine the implementation of the Hepatitis B Virus vaccination program,” and implementation themes from multiple study data sources (interviews, observations, examination of monitoring materials) were mapped onto CFIR constructs. They report their results in two phases – Pre-implementation training and community education, and Implementation – with both anchored in themes that they had mapped onto CFIR domains and constructs. All but six constructs were included in their analysis, with a majority summarized in a table and key themes explored further in the narrative text. They specify that most concerns were identified within the Outer Setting and Process domains, while elements identified within the Inner Setting domain provided strength to the intervention and helped mitigate against barriers [ 70 ].

Sarker et al. conducted a qualitative study to assess provision of maternal, newborn and child health services to Rohingya refugees residing in camps in Cox’s Bazar, Bangladesh. They cite using CFIR as a guide for thematic analysis, applying it after a process of inductive and deductive coding to index these codes into the CFIR domains. They utilized three of the five CFIR domains (Outer Setting, Inner Setting, and Process), stating that the remaining two domains (Intervention Characteristics and Characteristics of Individuals) were not relevant to their analysis. They then proposed two additional CFIR domains, Context and Security, for use in humanitarian contexts. In contrast to Guan et al., CFIR constructs are not used nor mentioned by Sarker et al., with content under each domain instead synthesized as challenges and potential solutions. Regarding the CFIR, Sarker et al. write, “The CFIR guided us for interpretative coding and creating the challenges and possible solutions into groups for further clarification of the issues related to program delivery in a humanitarian crisis setting.” [ 51 ]

Sami et al. conducted a mixed methods case study to assess the implementation of a package of neonatal interventions at health facilities within refugee and internally displaced persons camps in South Sudan. They reference use of the CFIR earlier in the study than Sarker et al., basing their guides for semi-structured focus group discussions on the CFIR framework. They similarly reference a general use of the CFIR framework as they conducted thematic analysis. Constructs are referenced once, but they do not specify whether their application of the CFIR framework included use of domains, constructs, or both. This may be in part because they then applied an additional framework, the World Health Organization (WHO) Health System Framework, to present their findings. They describe a nested approach to their use of these frameworks: “Exploring these [CFIR] constructs within the WHO Health Systems Framework can identify specific entry points to improve the implementation of newborn interventions at critical health system building blocks.” [ 65 ]

Three papers cite use of different IR frameworks. Bolan et al. utilized the Theoretical Domains Framework in their mixed methods feasibility study and pilot cluster randomized trial evaluating pilot use of the Safe Delivery App by maternal and newborn health workers providing basic emergency obstetric and newborn care in facilities in the conflict-affected Maniema province of the Democratic Republic of the Congo (DRC). They used the Theroetical Domains Framework in designing interview questions, and further used it as the coding framework for their analysis. Similar to the CFIR, the Theoretical Domains Framework is a determinant framework that consists of domains, each of which then includes constructs. Bolan et al. utilized the Theoretical Domains Framework at the construct level in interview question development and at the domain level in their analysis, mapping interview responses to eight of the 14 domains [ 83 ]. Berg et al. report using an “exploratory design guided by the principles of an evaluation framework” developed by the Medical Research Council to analyze the implementation process, mechanisms of impact, and outcomes of a three-pillar training intervention to improve maternal and neonatal healthcare in the conflict-affected South Kivu province of the DRC [ 67 , 88 ]. Select components of this evaluation framework were used to guide deductive analysis of focus group discussions and in-depth interviews [ 67 ]. In their study of health workers’ knowledge and attitudes toward newborn health interventions in South Sudan, before and after training and supply provision, Sami et al. report use of the Conceptual Framework of the Role of Attitudes in Evidence-Based Practice Implementation in their analysis process. The framework was used to group codes following initial inductive coding analysis of in-depth interviews [ 72 ].

Three other papers cite use of specific frameworks in their intervention evaluation [ 19 , 44 , 76 ]. As a characteristic of IR is the use of an explicit framework to guide the research, the use of the frameworks in these three papers meets the intention of IR and serves the purpose that an IR framework would have in strengthening the analytical rigor. Castle et al. cite use of their program’s theory of change as a framework for a mixed methods evaluation of the provision of family planning services and more specifically uptake of long-acting reversible contraception use in the DRC. They describe use of the theory of change to “enhance effectiveness of [long-acting reversible contraception] access and uptake.” [ 76 ] Thommesen et al. cite use of the AAAQ (Availability, Accessibility, Acceptability and Quality) framework in their qualitative study assessing midwifery services provided to pregnant women in Afghanistan. This framework is focused on the “underlying elements needed for attainment of optimum standard of health care,” but the authors used it in this paper to evaluate facilitators and barriers to women accessing midwifery services [ 44 ]. Jarrett et al. cite use of the Centers for Disease Control and Prevention’s (CDC) Guidelines for Evaluating Public Health Surveillance Systems to explore the characteristics of a population mobility, mortality and birth surveillance system in South Kivu, DRC. Use of these CDC guidelines is cited as one of four study objectives, and commentary is included in the Results section pertaining to each criteria within these guidelines, although more detail regarding use of these guidelines or the authors’ experience with their use in the study is not provided [ 19 ].

Overall, 22 of the 69 papers either explicitly or implicitly identified IR as relevant to their work. Nineteen papers include a focus on feasibility (seven of which did not otherwise identify the importance of exploring questions concerning implementation), touching on a common outcome of interest in implementation research [ 89 ].

While a majority of papers did not explicitly or implicitly use an IR framework to evaluate their SRH intervention of focus, most identified factors that facilitated implementation when they were present or served as a barrier when absent. Sixty cite factors that served as facilitators and 49 cite factors that served as barriers, with just three not citing either. Fifty-nine distinct factors were identified across the papers.

Three of the six studies that explicitly used an IR framework used the CFIR, and the CFIR is the only IR framework that was used by multiple studies. As previously mentioned, Means et al. put forth an adaptation of the CFIR to increase its relevance in LMIC settings, proposing a sixth domain (Characteristics of Systems) and 11 additional constructs [ 2 ]. Using the expanded domains and constructs as proposed by Means et al., the 59 factors cited by papers in this review were thematically grouped into the six domains: Characteristics of Systems, Outer Setting, Inner Setting, Characteristics of Individuals, Intervention Characteristics, and Process. Within each domain, alignment with CFIR constructs was assessed for, and alignment was found with 29 constructs: eight of Means et al.’s 11 constructs, and 21 of the 39 standard CFIR constructs. Three factors did not align with any construct (all fitting within the Outer Setting domain), and 14 aligned with a construct label but not the associated definition. Table 5 synthesizes the mapping of factors affecting SRH intervention implementation to CFIR domains and constructs, with the construct appearing in italics if it is considered to align with that factor by label but not by definition.

Table 6 lists the CFIR constructs that were not found to have alignment with any factor cited by the papers in this review.

This scoping review sought to assess how IR frameworks have been used to bolster the evidence base for SRH interventions in humanitarian settings, and it revealed that IR frameworks, or an explicit IR approach, are rarely used. All four of the systematic reviews identified with a focus on SRH in humanitarian settings articulate the need for more research examining the effectiveness of SRH interventions in humanitarian settings, with two specifically citing a need for implementation research/science [ 12 , 13 ]. The distribution of papers across the timeframe included in this review does suggest that more research on SRH interventions for crisis-affected populations is taking place, as a majority of relevant papers were published in the second half of the review period. The papers included a wide range of methodologies, which reflect the differing research questions and contexts being evaluated. However, it also invites the question of whether there should be more standardization of outcomes measured or frameworks used to guide analysis and to facilitate increased comparison, synthesis and application across settings.

Three of the six papers that used an IR framework utilized the CFIR. Guan et al. used the CFIR at both a domain and construct level, Sarker et al. used the CFIR at the domain level, and Sami et al. did not specify which CFIR elements were used in informing the focus group discussion guide [ 51 , 65 , 70 ]. It is challenging to draw strong conclusions about the applicability of CFIR in humanitarian settings based on the minimal use of CFIR and IR frameworks within the papers reviewed, although Guan et al. provides a helpful model for how analysis can be structured around CFIR domains and constructs. It is worth considering that the minimal use of IR frameworks, and more specifically CFIR constructs, could be in part because that level of prescriptive categorization does not allow for enough fluidity in humanitarian settings. It also raises questions about the appropriate degree of standardization to pursue for research done in these settings.

The mapping of factors affecting SRH intervention implementation provides an example of how a modified CFIR framework could be used for IR in humanitarian contexts. This mapping exercise found factors that mapped to all five of the original CFIR domains as well as the sixth domain proposed by Means et al. All factors fit well within the definition for the selected domain, indicating an appropriate degree of fit between these existing domains and the factors identified as impacting SRH interventions in humanitarian settings. On a construct level, however, the findings were more variable, with one-quarter of factors not fully aligning with any construct. Furthermore, over 40% of the CFIR constructs (including the additional constructs from Means et al.) were not found to align with any factors cited by the papers in this review, also demonstrating some disconnect between the parameters posed by the CFIR constructs and the factors cited as relevant in a humanitarian context.

It is worth noting that while the CFIR as proposed in 2009 was used in this assessment, as well as in the included papers which used the CFIR, an update was published in 2022. Following a review of CFIR use since its publication, the authors provide updates to construct names and definitions to “make the framework more applicable across a range of innovations and settings.” New constructs and subconstructs were also added, for a total of 48 constructs and 19 subconstructs across the five domains [ 90 ]. A CFIR Outcomes Addendum was also published in 2022, based on recommendations for the CFIR to add outcomes and intended to be used as a complement to the CFIR determinants framework [ 91 ]. These expansions to the CFIR framework may improve applicability of the CFIR in humanitarian settings. Several constructs added to the Outer Setting domain could be of particular utility – critical incidents, local attitudes, and local conditions, each of which could help account for unique challenges faced in contexts of crisis. Sub-constructs added within the Inner Setting domain that seek to clarify structural characteristics and available resources would also be of high utility based on mapping of the factors identified in this review to the original CFIR constructs. As outcomes were not formally included in the CFIR until the 2022 addendum, a separate assessment of implementation outcomes was not undertaken in this review. However, analysis of the factors cited by papers in this review as affecting implementation was derived from the full text of the papers and thus captures content relevant to implementation determinants that is contained within the outcomes.

Given the demonstrated need for additional flexibility within an IR framework for humanitarian contexts, while not a focus of this review, it is worth considering whether a different framework could provide a better fit than the CFIR. Other frameworks have differing points of emphasis that would create different opportunities for flexibility but that do not seem to resolve the challenges experienced in applying the CFIR to a humanitarian context. As one example, the EPIS (Exploration, Preparation, Implementation, Sustainment) Framework considers the impact of inner and outer context on each of four implementation phases; while the constructs within this framework are broader than the CFIR, an emphasis on the intervention characteristics is missing, a domain where stronger alignment within the CFIR is also needed [ 92 ]. Alternatively, the PRISM (Practical, Robust Implementation and Sustainability Model) framework is a determinant and evaluation framework that adds consideration of context factors to the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) outcomes framework. It has a stronger emphasis on intervention aspects, with sub-domains to account for both organization and patient perspectives within the intervention. While PRISM does include aspects of context, external environment considerations are less robust and intentionally less comprehensive in scope, which would not provide the degree of alignment possible between the Characteristics of Systems and Outer Setting CFIR domains for the considerations unique to humanitarian environments [ 93 ].

Reflecting on their experience with the CFIR, Sarker et al. indicate that it can be a “great asset” in both evaluating current work and developing future interventions. They also encourage future research of humanitarian health interventions to utilize the CFIR [ 51 ]. The other papers that used the CFIR do not specifically reflect on their experience utilizing it, referring more generally to having felt that it was a useful tool [ 65 , 70 ]. On their use of an evaluation framework, Berg et al. reflected that it lent useful structure and helped to identify aspects affecting implementation that otherwise would have gone un-noticed [ 67 ]. The remaining studies that utilized an IR framework did not specifically comment on their experience with its use [ 72 , 83 ]. While a formal IR framework was not engaged by other studies, a number cite a desire for IR to contribute further detail to their findings [ 21 , 37 ].

In their recommendations for strengthening the evidence base for humanitarian health interventions, Ager et al. speak to the need for “methodologic innovation” to develop methodologies with particular applicability in humanitarian settings [ 7 ]. As IR is not yet routinized for SRH interventions, this could be opportune timing for the use of a standardized IR framework to gauge its utility. Using an IR framework to assess factors influencing implementation of the MISP in initial stages of a humanitarian response, and interventions to support more comprehensive SRH service delivery in protracted crises, could lend further rigor and standardization to SRH evaluations, as well as inform strategies to improve MISP implementation over time. Based on categorizing factors identified by these papers as relevant for intervention evaluation, there does seem to be utility to a modified CFIR approach. Given the paucity of formal IR framework use within SRH literature, it would be worth conducting similar scoping exercises to assess for explicit use of IR frameworks within the evidence base for other health service delivery areas in humanitarian settings. In the interim, the recommended approach from this review for future IR on humanitarian health interventions would be a modified CFIR approach with domain-level standardization and flexibility for constructs that may standardize over time with more use. This would enable use of a common analytical framework and vocabulary at the domain level for stakeholders to describe interventions and the factors influencing the effectiveness of implementation, with constructs available to use and customize as most appropriate for specific contexts and interventions.

This review had a number of limitations. As this was a scoping review and a two-part search strategy was used, the papers summarized here may not be comprehensive of those written pertaining to SRH interventions over the past 10 years. Papers from 2013 to 2017 that would have met this scoping review’s inclusion criteria may have been omitted due to being excluded from the systematic reviews. The review was limited to papers available in English. Furthermore, this review did not assess the quality of the papers included or seek to assess the methodology used beyond examination of the use of an IR framework. It does, however, serve as a first step in assessing the extent to which calls for implementation research have been addressed, and identify entry points for strengthening the science and practice of SRH research in humanitarian settings.

With one in 23 people worldwide in need of humanitarian assistance, and financing required for response plans at an all-time high, the need for evidence to guide resource allocation and programming for SRH in humanitarian settings is as important as ever [ 94 ]. Recent research agenda setting initiatives and strategies to advance health in humanitarian settings call for increased investment in implementation research—with priorities ranging from research on effective strategies for expanding access to a full range of contraceptive options to integrating mental health and psychosocial support into SRH programming to capturing accurate and actionable data on maternal and perinatal mortality in a wide range of acute and protracted emergency contexts [ 95 , 96 ]. To truly advance guidance in these areas, implementation research will need to be conducted across diverse humanitarian settings, with clear and consistent documentation of both intervention characteristics and outcomes, as well as contextual and programmatic factors affecting implementation.

Conclusions

Implementation research has potential to increase impact of health interventions particularly in crisis-affected settings where flexibility, adaptability and context-responsive approaches are highlighted as cornerstones of effective programming. There remains significant opportunity for standardization of research in the humanitarian space, with one such opportunity occurring through increased utilization of IR frameworks such as a modified CFIR approach. Investing in more robust sexual and reproductive health research in humanitarian contexts can enrich insights available to guide programming and increase transferability of learning across settings.

Availability of data and materials

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

Abbreviations

Availability, Accessibility, Acceptability and Quality

Centers for Disease Control and Prevention

Consolidated Framework for Implementation Research

Democratic Republic of the Congo

Exploration, Preparation, Implementation, Sustainment

• Implementation research

Low and middle income country

Minimum Initial Service Package

Practical, Robust Implementation and Sustainability Model

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Reach, Effectiveness, Adoption, Implementation, Maintenance

• Sexual and reproductive health

World Health Organization

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AN and HT designed the scoping review. AN conducted the literature search. AN and HT screened records for inclusion. AN extracted data from included studies. Both authors contributed to synthesis of results. AN drafted the manuscript and both authors contributed to editorial changes.

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Additional file 1.

. Literature search terms: Exact search terms used in literature search, with additional detail on the methodology to determine search terms and definitions used for each component of the search

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Norton, A., Tappis, H. Sexual and reproductive health implementation research in humanitarian contexts: a scoping review. Reprod Health 21 , 64 (2024). https://doi.org/10.1186/s12978-024-01793-2

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An Overview of How to Search and Write a Medical Literature Review

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• 1 American Association for Respiratory Care, and Georgia State University, Atlanta, Georgia. [email protected].
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• PMCID: PMC10589118 (available on 2024-11-01 )
• DOI: 10.4187/respcare.11198

Without a literature review, there can be no research project. Literature reviews are necessary to learn what is known (and not known) about a topic of interest. In the respiratory care profession, the body of research is enormous, so a method to search the medical literature efficiently is needed. Selecting the correct databases, use of Boolean logic operators, and consultations with librarians are used to optimize searches. For a narrow and precise search, use PubMed, MEDLINE, Ovid, EBSCO, the Cochrane Library, or Google Scholar. Reference management tools assist with organizing the evidence found from the search. Analyzing the search results and writing the review provides an understanding of why the research question is important and its meaning. Spending time in reviewing published literature reviews can serve as a guide or model for understanding the components and style of a well-written literature review.

Keywords: MEDLINE; PubMed; bibliographies; biomedical research; database; evidence; index medicus; journals; literature review; literature synthesis; medical literature review; research; search engine.

Copyright © 2023 by Daedalus Enterprises.

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The Literature Review: A Foundation for High-Quality Medical Education Research

a  These are subscription resources. Researchers should check with their librarian to determine their access rights.

Despite a surge in published scholarship in medical education 1 and rapid growth in journals that publish educational research, manuscript acceptance rates continue to fall. 2 Failure to conduct a thorough, accurate, and up-to-date literature review identifying an important problem and placing the study in context is consistently identified as one of the top reasons for rejection. 3 , 4 The purpose of this editorial is to provide a road map and practical recommendations for planning a literature review. By understanding the goals of a literature review and following a few basic processes, authors can enhance both the quality of their educational research and the likelihood of publication in the Journal of Graduate Medical Education ( JGME ) and in other journals.

The Literature Review Defined

In medical education, no organization has articulated a formal definition of a literature review for a research paper; thus, a literature review can take a number of forms. Depending on the type of article, target journal, and specific topic, these forms will vary in methodology, rigor, and depth. Several organizations have published guidelines for conducting an intensive literature search intended for formal systematic reviews, both broadly (eg, PRISMA) 5 and within medical education, 6 and there are excellent commentaries to guide authors of systematic reviews. 7 , 8

• A literature review forms the basis for high-quality medical education research and helps maximize relevance, originality, generalizability, and impact.
• A literature review provides context, informs methodology, maximizes innovation, avoids duplicative research, and ensures that professional standards are met.
• Literature reviews take time, are iterative, and should continue throughout the research process.
• Researchers should maximize the use of human resources (librarians, colleagues), search tools (databases/search engines), and existing literature (related articles).
• Keeping organized is critical.

Such work is outside the scope of this article, which focuses on literature reviews to inform reports of original medical education research. We define such a literature review as a synthetic review and summary of what is known and unknown regarding the topic of a scholarly body of work, including the current work's place within the existing knowledge . While this type of literature review may not require the intensive search processes mandated by systematic reviews, it merits a thoughtful and rigorous approach.

Purpose and Importance of the Literature Review

An understanding of the current literature is critical for all phases of a research study. Lingard 9 recently invoked the “journal-as-conversation” metaphor as a way of understanding how one's research fits into the larger medical education conversation. As she described it: “Imagine yourself joining a conversation at a social event. After you hang about eavesdropping to get the drift of what's being said (the conversational equivalent of the literature review), you join the conversation with a contribution that signals your shared interest in the topic, your knowledge of what's already been said, and your intention.” 9

The literature review helps any researcher “join the conversation” by providing context, informing methodology, identifying innovation, minimizing duplicative research, and ensuring that professional standards are met. Understanding the current literature also promotes scholarship, as proposed by Boyer, 10 by contributing to 5 of the 6 standards by which scholarly work should be evaluated. 11 Specifically, the review helps the researcher (1) articulate clear goals, (2) show evidence of adequate preparation, (3) select appropriate methods, (4) communicate relevant results, and (5) engage in reflective critique.

Failure to conduct a high-quality literature review is associated with several problems identified in the medical education literature, including studies that are repetitive, not grounded in theory, methodologically weak, and fail to expand knowledge beyond a single setting. 12 Indeed, medical education scholars complain that many studies repeat work already published and contribute little new knowledge—a likely cause of which is failure to conduct a proper literature review. 3 , 4

Likewise, studies that lack theoretical grounding or a conceptual framework make study design and interpretation difficult. 13 When theory is used in medical education studies, it is often invoked at a superficial level. As Norman 14 noted, when theory is used appropriately, it helps articulate variables that might be linked together and why, and it allows the researcher to make hypotheses and define a study's context and scope. Ultimately, a proper literature review is a first critical step toward identifying relevant conceptual frameworks.

Another problem is that many medical education studies are methodologically weak. 12 Good research requires trained investigators who can articulate relevant research questions, operationally define variables of interest, and choose the best method for specific research questions. Conducting a proper literature review helps both novice and experienced researchers select rigorous research methodologies.

Finally, many studies in medical education are “one-offs,” that is, single studies undertaken because the opportunity presented itself locally. Such studies frequently are not oriented toward progressive knowledge building and generalization to other settings. A firm grasp of the literature can encourage a programmatic approach to research.

Approaching the Literature Review

Considering these issues, journals have a responsibility to demand from authors a thoughtful synthesis of their study's position within the field, and it is the authors' responsibility to provide such a synthesis, based on a literature review. The aforementioned purposes of the literature review mandate that the review occurs throughout all phases of a study, from conception and design, to implementation and analysis, to manuscript preparation and submission.

Planning the literature review requires understanding of journal requirements, which vary greatly by journal ( table 1 ). Authors are advised to take note of common problems with reporting results of the literature review. Table 2 lists the most common problems that we have encountered as authors, reviewers, and editors.

Sample of Journals' Author Instructions for Literature Reviews Conducted as Part of Original Research Article a

Common Problem Areas for Reporting Literature Reviews in the Context of Scholarly Articles

Locating and Organizing the Literature

Three resources may facilitate identifying relevant literature: human resources, search tools, and related literature. As the process requires time, it is important to begin searching for literature early in the process (ie, the study design phase). Identifying and understanding relevant studies will increase the likelihood of designing a relevant, adaptable, generalizable, and novel study that is based on educational or learning theory and can maximize impact.

Human Resources

A medical librarian can help translate research interests into an effective search strategy, familiarize researchers with available information resources, provide information on organizing information, and introduce strategies for keeping current with emerging research. Often, librarians are also aware of research across their institutions and may be able to connect researchers with similar interests. Reaching out to colleagues for suggestions may help researchers quickly locate resources that would not otherwise be on their radar.

During this process, researchers will likely identify other researchers writing on aspects of their topic. Researchers should consider searching for the publications of these relevant researchers (see table 3 for search strategies). Additionally, institutional websites may include curriculum vitae of such relevant faculty with access to their entire publication record, including difficult to locate publications, such as book chapters, dissertations, and technical reports.

Strategies for Finding Related Researcher Publications in Databases and Search Engines

Search Tools and Related Literature

Researchers will locate the majority of needed information using databases and search engines. Excellent resources are available to guide researchers in the mechanics of literature searches. 15 , 16

Because medical education research draws on a variety of disciplines, researchers should include search tools with coverage beyond medicine (eg, psychology, nursing, education, and anthropology) and that cover several publication types, such as reports, standards, conference abstracts, and book chapters (see the box for several information resources). Many search tools include options for viewing citations of selected articles. Examining cited references provides additional articles for review and a sense of the influence of the selected article on its field.

Box Information Resources

• Web of Science a
• Education Resource Information Center (ERIC)
• Cumulative Index of Nursing & Allied Health (CINAHL) a
• Google Scholar

Once relevant articles are located, it is useful to mine those articles for additional citations. One strategy is to examine references of key articles, especially review articles, for relevant citations.

Getting Organized

As the aforementioned resources will likely provide a tremendous amount of information, organization is crucial. Researchers should determine which details are most important to their study (eg, participants, setting, methods, and outcomes) and generate a strategy for keeping those details organized and accessible. Increasingly, researchers utilize digital tools, such as Evernote, to capture such information, which enables accessibility across digital workspaces and search capabilities. Use of citation managers can also be helpful as they store citations and, in some cases, can generate bibliographies ( table 4 ).

Citation Managers

Knowing When to Say When

Researchers often ask how to know when they have located enough citations. Unfortunately, there is no magic or ideal number of citations to collect. One strategy for checking coverage of the literature is to inspect references of relevant articles. As researchers review references they will start noticing a repetition of the same articles with few new articles appearing. This can indicate that the researcher has covered the literature base on a particular topic.

Putting It All Together

In preparing to write a research paper, it is important to consider which citations to include and how they will inform the introduction and discussion sections. The “Instructions to Authors” for the targeted journal will often provide guidance on structuring the literature review (or introduction) and the number of total citations permitted for each article category. Reviewing articles of similar type published in the targeted journal can also provide guidance regarding structure and average lengths of the introduction and discussion sections.

When selecting references for the introduction consider those that illustrate core background theoretical and methodological concepts, as well as recent relevant studies. The introduction should be brief and present references not as a laundry list or narrative of available literature, but rather as a synthesized summary to provide context for the current study and to identify the gap in the literature that the study intends to fill. For the discussion, citations should be thoughtfully selected to compare and contrast the present study's findings with the current literature and to indicate how the present study moves the field forward.

To facilitate writing a literature review, journals are increasingly providing helpful features to guide authors. For example, the resources available through JGME include several articles on writing. 17 The journal Perspectives on Medical Education recently launched “The Writer's Craft,” which is intended to help medical educators improve their writing. Additionally, many institutions have writing centers that provide web-based materials on writing a literature review, and some even have writing coaches.

The literature review is a vital part of medical education research and should occur throughout the research process to help researchers design a strong study and effectively communicate study results and importance. To achieve these goals, researchers are advised to plan and execute the literature review carefully. The guidance in this editorial provides considerations and recommendations that may improve the quality of literature reviews.