systematic literature review francais

How to Perform a Systematic Literature Review

A Guide for Healthcare Researchers, Practitioners and Students

• © 2020
• Edward Purssell   ORCID: https://orcid.org/0000-0003-3748-0864 0 ,
• Niall McCrae   ORCID: https://orcid.org/0000-0001-9776-7694 1

School of Health Sciences, City, University of London, London, UK

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Florence Nightingale Faculty of Nursing Midwifery & Palliative Care, King’s College London, London, UK

• Presents a logical approach to systematic literature reviewing
• offers a corrective to flawed guidance in existing books
• An accessible but intellectually stimulating guide with illuminating examples and analogies

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Table of contents (11 chapters)

Front matter, introduction.

• Edward Purssell, Niall McCrae

A Brief History of the Systematic Review

The aim and scope of a systematic review: a logical approach, searching the literature, screening search results: a 1-2-3 approach, critical appraisal: assessing the quality of studies, reviewing quantitative studies: meta-analysis and narrative approaches, reviewing qualitative studies and metasynthesis, reviewing qualitative and quantitative studies and mixed-method reviews, meaning and implications: the discussion, making an impact: dissemination of results, back matter.

• Methodology
• Evidence-based practice

About this book

The systematic review is a rigorous method of collating and synthesizing evidence from multiple studies, producing a whole greater than the sum of parts. This textbook is an authoritative and accessible guide to an activity that is often found overwhelming. The authors steer readers on a logical, sequential path through the process, taking account of the different needs of researchers, students and practitioners. Practical guidance is provided on the fundamentals of systematic reviewing and also on advanced techniques such as meta-analysis. Examples are given in each chapter, with a succinct glossary to support the text.  

This up-to-date, accessible textbook will satisfy the needs of students, practitioners and educators in the sphere of healthcare, and contribute to improving the quality of evidence-based practice. The authors will advise some freely available or inexpensive open source/access resources (such as PubMed, R and Zotero) to help students how to perform a systemic review, in particular those with limited resources.

Authors and Affiliations

Edward Purssell

Florence Nightingale Faculty of Nursing Midwifery & Palliative Care, King’s College London, London, UK

Niall McCrae

About the authors

Dr. Niall McCrae teaches mental health nursing and research methods at the Florence Nightingale Faculty of Nursing, Midwifery & Palliative Care at King’s College London. His research interests are dementia, depression, the impact of social media on younger people, and the history of mental health care. Niall has written two previous books: The Moon and Madness (Imprint Academic, 2011) and The Story of Nursing in British Mental Hospitals: Echoes from the Corridors (Routledge, 2016). He is a regular writer for Salisbury Review magazine. 

In partnershipPurssell and McCrae have written several papers on research methodology and literature reviewing for healthcare journals. Both have extensive experience of teaching literature reviewing at all academic levels, and explaining complex concepts in a way that is accessible to all

Bibliographic Information

Book Title : How to Perform a Systematic Literature Review

Book Subtitle : A Guide for Healthcare Researchers, Practitioners and Students

Authors : Edward Purssell, Niall McCrae

DOI : https://doi.org/10.1007/978-3-030-49672-2

Publisher : Springer Cham

eBook Packages : Medicine , Medicine (R0)

Copyright Information : The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2020

Softcover ISBN : 978-3-030-49671-5 Published: 05 August 2020

eBook ISBN : 978-3-030-49672-2 Published: 04 August 2020

Edition Number : 1

Number of Pages : VII, 188

Number of Illustrations : 7 b/w illustrations, 12 illustrations in colour

Topics : Nursing Research , Nursing Education , Research Skills

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DADA2 diagnosed in adulthood versus childhood: A comparative study on 306 patients including a systematic literature review and 12 French cases

Affiliations.

• 1 Sorbonne Université, AP-HP, Tenon hospital, Department of Internal Medicine, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Paris, France.
• 2 Sorbonne Université, AP-HP, Tenon Hospital, Department of Dermatology, Paris, France.
• 3 AP-HP, Saint-Louis Hospital, Department of Clinical Immunology, Paris University, Paris, France.
• 4 Pasteur 2 Hospital, Department of Rheumatology, Cote d'Azur University, Nice University Hospital, Nice, France.
• 5 Hôpital Nord, Department of Internal Medicine, Jean Monnet University, Saint-Etienne University Hospital, Saint-Etienne, France.
• 6 AP-HP, Cochin Hospital, Department of Dermatology, Paris Universisty, Paris, France.
• 7 Service de Médecine Interne, Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile de France, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France, Université de Paris, Paris F-75006, France.
• 8 Saint-Eloi Hospital, Department of Dermatology, Montpellier University, Montpellier University Hospital, Montpellier, France.
• 9 Estaing Hospital, Department of Internal Medicine, Clermont-Auvergne University, Clermont Ferrand University Hospital, Clermont Ferrand, France.
• 10 AP-HP, Bicêtre Hospital, Department of Pediatric Rheumatology, Paris-Saclay University, Le-Kremlin-Bicêtre, France.
• 11 Hospices Civils de Lyon, Femme Mère Enfant Hospital, Centre de référence des rhumatismes inflammatoires et maladies autoimmunes de l'enfant (RAISE), Lyon University, Lyon, France.
• 12 Metz-Thionville Regional Hospital, Department of Dermatology, Metz, France.
• 13 Hôpital du Sacré-Cœur de Montréal, Department of Internal Medicine, Montreal, QC, Canada.
• 14 Arnaud de Villeneuve Hospital, Laboratory of rare and autoinflammatory genetic diseases, Centre de référence des maladies auto-Inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Montpellier University, Montpellier University Hospital, Montpellier, France.
• 15 Sorbonne Université, AP-HP, Tenon hospital, Department of Internal Medicine, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Paris, France. Electronic address: [email protected].
• PMID: 34571400
• DOI: 10.1016/j.semarthrit.2021.09.001

Background: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease usually presenting before the age of 10 years. Non-specific clinical features or late-onset presentation may delay its diagnosis until adulthood.

Objective: To determine whether DADA2 diagnosed in adulthood is associated with specific characteristics compared to DADA2 diagnosed in childhood.

Methods: We pooled a cohort of 12 adult DADA2 patients followed in France with cases identified through a systematic literature review. For each patient, we determined the type of clinical presentation and assessed six key organ involvements.

Results: A total of 306 cases were included. Among the 283 patients with available data regarding age at diagnosis, 140 were diagnosed during adulthood and 143 during childhood. The vascular presentation of DADA2 was more frequent in the adult diagnosis group (77.9% vs. 62.9%, p < 0.01), whereas the hematological presentation (bone marrow failure) prevailed in the pediatric diagnosis group (10.0% vs. 20.3% p = 0.02). In patients with vasculopathy, severe skin manifestations developed in 35% and 10% of the adult and pediatric diagnosis groups, respectively. Conversely, fewer strokes occurred in the adult group presenting with systemic vasculopathy (54% vs. 81%). Symptomatic humoral immune deficiency (HID) was rarely a clinical presentation in itself (5% and 2.8%) but accompanied other phenotypes of DADA2, especially the hematological phenotype in the adult group (33% vs. 4%).

Conclusion: DADA2 diagnosed in adulthood presents more often with a vascular phenotype and less often with bone marrow failure than DADA2 diagnosed in childhood. Adults diagnosed with DADA2 vasculopathy display more severe skin involvement but fewer strokes.

Keywords: Adenosine deaminase 2; Bone marrow failure disorders; DADA2; Polyarteritis nodosa; Pure red-cell aplasia; Vasculitis.

Copyright © 2021 Elsevier Inc. All rights reserved.

Publication types

• Systematic Review
• Adenosine Deaminase* / genetics
• Immunologic Deficiency Syndromes*
• Intercellular Signaling Peptides and Proteins / genetics
• Intercellular Signaling Peptides and Proteins
• Adenosine Deaminase

College & Research Libraries ( C&RL ) is the official, bi-monthly, online-only scholarly research journal of the Association of College & Research Libraries, a division of the American Library Association.

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Mê-Linh Lê is Acting Head, Health Sciences Division at the University of Manitoba, email: [email protected] .

Christine J. Neilson is a Health Sciences Librarian at the University of Manitoba, email: [email protected] .

Janice Winkler is a Social Sciences Librarian at the University of Manitoba, email: [email protected] .

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Benchmarking Librarian Support of Systematic Reviews in the Sciences, Humanities, and Social Sciences

Mê-Linh Lê, Christine J. Neilson, and Janice Winkler *

Systematic reviews, along with other types of knowledge synthesis, are a type of research methodology that attempt to find all available evidence on a topic to help answer specific questions. Librarian involvement in systematic reviews is well established in the health sciences, and in recent years there has been growing awareness of, and literature about, librarians outside of health supporting systematic reviews. This study benchmarks librarian support of systematic reviews in the sciences, humanities, and social sciences (SHSS) by looking at the growth of demand for support, the disciplines requesting this kind of librarian support, and the specific types of support needed. It also examines what SHSS librarians need to be successful in this type of work, including administrative support and workload adjustments.

Knowledge synthesis is a collection of secondary research methods that use the systematic collection, evaluation, and integration of previous research to answer a research question. Over 40 types of reviews which go by a variety of names (sometimes used interchangeably by researchers) fall under the knowledge synthesis category, including systematic reviews, scoping reviews, integrative reviews, and meta-analyses. 1 For simplicity, we use the term systematic review (SR) in this article to refer to all types of knowledge synthesis. Different areas of research adopted SR methods at different rates. We often hear anecdotally that SRs originated in the health sciences and have since spread to other disciplines, but this is not accurate. SRs took hold and spread widely in health along with the Evidence-Based Practice Movement in the mid-1990s, but the social science disciplines of education, psychology, and business and economics have continuously used the SR methodology since the mid to late 1970’s, albeit without the same fervor seen in the health disciplines. 2

Library literature has discussed library support for SRs since at least the mid 1990s. 3 Health librarians found roles on SR research teams, likely due to well-established methodological guidelines from the Cochrane Collaboration and the Institute of Medicine, that advise reviewers to consult with an experienced health sciences librarian to ensure a high-quality literature search for the project. 4 As secondary research, the literature search that identifies the existing knowledge base forms the foundation for a SR’s data collection. Research has demonstrated that health librarian participation on SR teams is associated with better quality search strategies, lower risk of bias, and better reporting of search methods. 5 Health sciences librarians increasingly contribute to SRs in roles that extend beyond searching, including protocol development, source selection, and teaching. 6 The number of SRs published by health researchers is high and continues to grow. Hoffman and colleagues used the PubMed database to estimate that 80 SRs alone—that is, not including other types of knowledge synthesis reviews like scoping reviews, rapid reviews, etc.,—were published per day in 2019. According to their analysis, this publication rate is 20 times greater than it was 20 years earlier, in 2000. 7 Unsurprisingly, the ever-increasing popularity of SRs, as well as the demand for health librarian involvement, have led to concerns over librarian workload and the capacity to provide SR support along with other library services. 8

While SRs and librarians’ role in that research have long occupied a large amount of the health librarianship discourse, SR research—and library support for it—within the humanities, social sciences, and sciences has only started to gain more attention in the library literature relatively recently. 9 Outside of health, the reported involvement of librarians in published SRs in the social sciences and sciences is low. Premji found that two percent of SRs on business topics published from 2014 to 2019 mentioned consulting a librarian, and only one percent credited the librarian with running the search itself. 10 Similarly, Slebodnik et al. found that 3.3 percent of the science and social science SRs they examined reported that a librarian was consulted for the review. 11 Given this evidence, one might assume that even though SRs are being conducted in these fields, librarians are typically not involved in the process. However, we know that librarians regularly work on SRs without receiving credit for their contribution in a resulting publication. 12 Indeed, Kogut and colleagues reported in 2020 that the number of librarian consults at their institution for SRs in education increased over a period of six years, from fewer than 20 consults per year to more than 100 per year. This increase in demand threatened to exceed the library’s capacity to provide support services and required training additional education librarians to provide SR support to maintain the service. 13

We know that a variety of disciplines use SRs, but existing library literature has not provided an overview of librarian involvement in SRs outside of health. This article starts to fill this gap by benchmarking Association of Research Libraries (ARL) and Canadian Association of Research Libraries (CARL) SHSS librarians’ involvement in SRs. We collected the data presented here as part of a larger survey regarding SHSS librarian involvement in SRs, their comfort and competence with SR processes, and their perception of library administrators’ level of support for SHSS librarian participation in SRs.

Survey Design

We created an open survey using SurveyMonkey software. The survey included 29 potential questions in total, over 14 “screens” or pages; 23 questions were closed-ended and six open-ended. The survey used conditional logic so that respondents were only asked applicable questions. Responses to all questions were optional. Participants could return to previous questions using the back button on their browser to revisit their responses, if desired. The survey began with background questions about participants’ subject responsibilities and years of experience. Next, it asked respondents details about involvement or requests for involvement with SRs. The next set of questions asked about supports available to respondents in their provision of SR support. The final set of questions related to training involvement and preferences, which we will explore in a forthcoming C&RL article. We piloted the survey with five colleagues, using their feedback to refine questions for clarity. The University of Manitoba Research Ethics Board approved the final questions and study design (JFREB J2020:062). We translated the recruitment materials and survey instrument into French to obtain responses from librarians who speak both official Canadian languages.

Study Population and Recruitment

Academic librarians working at ARL and CARL institutions were invited to participate in the survey in a convenience sample using 22 listservs maintained by Canadian and American library associations. Due to restrictions from our research ethics board, we could not contact libraries or librarians directly and were only permitted to use listservs. We obtained consent through a form at the beginning of the survey. We offered no incentives in exchange for completing the survey.

To be included in the study, respondents had to be librarians at an ARL or CARL institution, who currently, or within the last 5 years, provided direct library services and support to faculty, staff, or students within the SHSS disciplines. The survey did not provide definitions for which subject areas fell under these categories because programs can be interdisciplinary and their points of focus can vary, leaving this open to interpretation. Instead, it provided a definition of health sciences to allow respondents to determine whether their subjects fell under the category of health sciences and allowed them to use their judgment as to the categorization of their liaison areas. The provided definition was as follows:

For the purposes of this study, the Health Sciences is deemed to include programs or disciplines where health or health care is the primary focus and includes: Allied Health, Dentistry, Dental Hygiene, Nursing, Medicine (including Public Health), Pharmacy, and Rehabilitation Sciences (Physical Therapy, Occupational Therapy, Rehabilitation Therapy). We urge those librarians working with other disciplines that may include strong health components (e.g., kinesiology, psychology) to fill out this survey .

We excluded responses from librarians serving the health sciences, except in cases where respondents supported SHSS disciplines as well as the health sciences.

Librarians who identified themselves as not meeting these inclusion criteria were rejected prior to beginning the survey. The survey was open for seven weeks, with an initial recruitment email sent out in November 2020 and a reminder email sent three weeks later in December 2020. Supplementary materials, including the survey instrument, a list of listservs the survey was sent to, and anonymized data, are available via Open Science Framework (OSF) at https://osf.io/mqxf2 .

Data Analysis

We downloaded all responses from SurveyMonkey to a private group in Microsoft Teams, which our institution approved as a secure location for research data. We discarded responses that did not meet the inclusion criteria.

Original data files are stored in password-protected files, accessible only to the authors. We anonymized responses prior to data sharing via OSF in the following manner. We categorized reported liaison areas into four broad disciplinary areas for analysis: Humanities, Sciences, Social Sciences, and Health Sciences (see the OSF page ( https://osf.io/mqxf2 ) for the categorization scheme). As there is no definitive list of liaison areas assigned to a specific discipline, our standard for those liaison areas (e.g., kinesiology) that could be part of different disciplines depending on the institution was to categorize based on where they sat within our home institution. We separated references to specific employers from the data set that we analyzed, and we completely removed them from the shared dataset to maintain participant anonymity. Open-ended responses also presented the possibility of including identifiable information, so we removed them from the shared dataset. The statistical consultant who conducted data analysis signed the required oath of confidentiality, as per research ethics board requirements.

We conducted descriptive analysis for each close-ended question included in the survey. Because of the conditional logic used in the survey and the optional nature of the questions, percentages reported below are based on the number of responses received for individual questions, rather than the total number of individual respondents. We coded responses provided in the free-text questions into broad themes that indicated common issues brought up by multiple respondents.

Because we were interested in relationships between specific variables, we created a list of these variables and hired a statistical consultant to complete more sophisticated statistical analysis. Depending on the type of data gathered and quantity of responses, the consultant determined whether and how to best complete the analyses. In most cases, this involved cross-tabulations (shown in Table 1). Spearman’s correlation coefficient could be calculated to measure the correlation between variables in two cases: the correlation between librarians’ years of experience and their confidence in all aspects of SR support; and their years of experience and the number of SRs they had supported in the last 5 years.

The survey received 379 responses. After filtering for the inclusion criteria, the total number of usable responses was 161. Not all respondents answered every question, so the true number of responses is indicated for each individual question below. Anonymized study data is freely available online at OSF.

Due to our recruitment strategy of library listservs, calculating a response rate was not possible, however, respondents were asked to provide the name of their CARL/ARL institution. There were 98 total responses for this question, but multiple respondents came from the same institution. In total, 42 out of 108 US-based ARL institutions (38.8 percent) and 20 out of 31 CARL institutions (64.5 percent) are represented. Of the 42 ARL institutions represented, 38 (90.4 percent) are R1 institutions, three (seven percent) are R2 institutions, and one (two percent) is an M1 institution. Of the CARL institutions, 13 (87 percent) are U15 institutions. 14

Liaison Area

As outlined above, we categorized liaison areas into four broad disciplinary categories: Humanities, Sciences, Social Sciences, and Health Sciences. Individual respondents may support more than one discipline, faculty, or department. As a result, a total of 521 liaison support areas were indicated; 17 percent were classified as the Humanities; 41 percent were classified as the Social Sciences; 32 percent belonged to the Sciences; and ten percent of liaison areas were classified as the Health Sciences (see Figure 1). As noted in the inclusion criteria above, all included respondents who had liaison responsibilities in the Health Sciences also had liaison responsibilities in non-health disciplines. Of the 151 respondents, 84 (52 percent) had liaison responsibilities within a single category; 58 (36 percent) had liaison responsibilities across two categories; and nine (5.5 percent) had liaison responsibilities across three categories.

Total Years as a Librarian

To analyze based on years of experience and other factors, respondents were asked how many years they had worked as a librarian. Of the 157 responses, eight (five percent) answered zero to one years; 25 (15.9 percent) answered two to five years; 35 (22.3 percent) answered six to ten years; 20 (12.7 percent) answered 11 to 14 years; and 69 (43.9 percent) answered 15+ years. Spearman’s correlation coefficient analyses were done to look for potential relationships between years of experience as a librarian, and either confidence in SR support or the number of SRs completed in the last five years, but no correlations were found.

Systematic Review Requests from The Past 5 Years

Respondents were asked whether they had been asked by a faculty member, researcher, or student to participate in a systematic review in the past 5 years. Of the 149 responses received for this question, 104 (70 percent) indicated yes; 38 (26 percent) said no, and seven (five percent) were unsure. When asked how many systematic reviews they had supported during the last five years, out of 139 respondents, 34 (25 percent) had not supported any SRs; 37 (27 percent) had supported one to four; 32 (23 percent) supported five to nine; and 26 (25.9 percent) had supported ten or more (see figure 2 below). Statistical analysis between the number of SRs performed in the last five years and years of experience as a librarian, using Spearman’s rank correlation, found no significant correlation between the two variables. Our analysis also did not find a difference in the number of reviews completed based on whether respondents were given time away from regular duties to complete reviews. For example, 29.7 percent of those who were not given time away from regular duties to work on SRs completed five to seven SRs in the last five years, compared to 34.5 percent of those who were given time away from their regular duties. When asked if the frequency of SR support requests has changed over the past five years, just over half of respondents (56.6 percent, n=81) indicated that they had experienced a change, 31.5 percent of respondents reported no change, and 11.9 percent were unsure if there had been a change in the frequency of requests. Of the 81 respondents who reported a change, one reported a decrease in the number of requests, while the remaining 80 reported an increase in the number of requests received. This translates to 55.9 percent of respondents indicating an increase in the frequency of requests overall.

Most respondents (93, or 67.9 percent) received requests for SR support from only one of the broad disciplinary areas. Close to one third of respondents (44, or 32.1 percent) indicated that they received requests from a combination of two or three disciplinary areas. Over the past five years, Social Science and Health Science disciplines were the main source of requests for SR support, making up 39.3 percent and 37.7 percent of total requests respectively (see figure 3). Respondents received 65 requests (18 percent) from Science disciplines, and six requests (1.7 percent) from Humanities disciplines.

Types of Systematic Review Support

Respondents were asked to indicate the type of SR support they had provided, with the ability to select as many support types as applicable. As Table 2 shows, the areas with greater number of responses were those that are typically seen as an area of expertise for librarians, such as search development, search execution, and search translation. Consultation, which was not explicitly defined, had the highest number of responses.

Acknowledgement

Respondents were asked to indicate the types of acknowledgement they had received for their support of SRs; respondents could select as many answers as were applicable. A thank you via email/in-person/phone had the most responses (70; 50.7 percent); followed by: co-authorship of a paper or presentation (55; 39.3 percent); no acknowledgement (42; 30 percent); mention of working with a librarian in a paper or presentation (29; 30 percent); mention of working with a librarian by name in a paper or presentation (29; 20.7 percent); mention of working with a librarian by name in the formal acknowledgement of a paper or presentation (26; 18.6 percent); co-investigator/collaborator/investigator status on a grant application (seven; five percent).

Administration Communication, Administration Attitude, and Librarian Workload

Most respondents discussed participation in SR projects with their library administrators or otherwise received communication from administration on the topic (100; 68 percent). Of those who had discussed SR participation with their administration, 80 (54.4 percent) said administration was supportive of participation; 34 (23.1 percent) believed their administration to be neutral on participation; 5 (3.4 percent) perceived their administration as discouraging of participation; 21 (14.3 percent) were unsure of administration attitude; and seven (four percent) marked not applicable.

Statistical analysis shows that administrative attitudes toward SRs (discouraging, neutral, or supportive) did not appear to correlate with the actual numbers of reviews the respondents completed over the last five years. Of those who had had discussions with administration, 27.1 percent of respondents had supported five to nine SRs; 11.5 percent supported ten to 14 SRs; and 13.5 percent supported 20 or more SRs. The majority of respondents (52.6 percent) with no discussion with their administration did not support any systematic reviews.

The survey included two questions related to workload adjustments. It asked respondents whether they were or would be given time away from regular duties, and/or granted a reduction in their existing workload to accommodate the work involved in participating in SRs. A small number indicated that they were, or would be, granted protected time (29 or 19.9 percent) and/or a reduction in workload (nine or 6.1 percent). The majority indicated that they would not receive time away from regular duties (77 or 52.7 percent) and/or reduction in workload (98 or 66.7 percent) to participate in SRs. The remaining respondents were unsure if these accommodations were possible (24 or 16.4 percent for time away from regular duties; 22 or 15 percent for reduction in workload) or responded with “not applicable.”

Interest in Supporting Systematic Reviews

When asked to rank their interest in participating in SRs on a 100 point scale, the largest number of respondents indicated a high level of interest (see figure 4 below). Forty-three (28 percent) respondents indicated an interest level ranging from 91 to 100; 24 (16 percent) participants entered a ranking in the 81 to 90 range; and 25 (16 percent) entered a ranking in the 71 to 80 range. Thirty-six participants (23 percent) indicated interest in the middle range (41 to 70), and 26 participants (17 percent) registered their interest in the low range (zero to 40).

Statistical analysis indicated that respondents’ interest in working on SRs was not related to administration attitude towards support of SRs, whether that attitude is perceived as discouraging, neutral, supportive, or if the respondent was unsure of administration attitude. However, the data suggests that interest in supporting SRs is highest among those who are now, or would be, given time away from regular duties (average of 88 on a 100 point scale) or have their workload adjusted to accommodate SR support (average of 91). Those who are not, or would not be, given time away from regular duties showed an average interest of 68, and those who do not have other aspects of their workload decreased showed an average interest of 70. Respondents who indicated they were unsure if they are or would be eligible for time away from regular duties indicated an average interest score of 56, and those who were unsure if they are eligible to receive a reduction in other aspects of their workload indicated an average interest score of 66.

Additional Comments

Respondents received the option to provide additional comments following the closed-ended questions. A common theme from the respondents’ comments was the need to create new positions for SR support, such as a SR librarian, or evidence synthesis librarian, to meet increasing demand for SR support coming from areas outside of the health sciences. Unfortunately, this increase in demand is not always matched with the commensurate support needed. One comment stated:“The requests are repeated and overwhelming […] We’ve talked about how to support this need but honestly, without a reduction in workload, it’s just unsupportable.” One reason noted for an increase in SR requests was the disruption of in-person research caused by the COVID-19 pandemic. A different respondent noted that, even though researchers are increasingly turning to SRs, faculty do not necessarily understand what SR research involves, writing: “They don’t really know what it [systematic reviews] means but it sounds good and could get their work published so they want it – whatever it is.” Lack of support for librarians participating in SRs, whether through training or workload reduction in other areas, was also emphasized in the comments. While the ability to support SRs was seen as an important way to demonstrate value to faculty and the academic community, the need for educating library administrators on this type of research and its importance was also noted.

While most additional comments on SRs were positive, notwithstanding noted areas requiring improvements, some respondents did not see a need for this kind of support in their liaison areas, stating that their faculty do this type of work themselves. For example, one respondent stated: “The other, more newfangled aspects of systematic reviews that you mention here I’d not heard of and do not seem to apply yet to doing comprehensive literature reviews in my collection areas.” For some librarians, there was simply a lack of interest in this type of work, stating that “If poorly implemented, [SRs] represents one of the lesser inspiring and also quite robotic activities in which librarians might engage.”

Librarian support of SRs in the SHSS disciplines can be viewed positively in many ways, including acknowledgement of librarian expertise, demonstrating value in library services, and relationship building between research teams and librarians. Our data indicate that SHSS librarians are facing an increasing number of requests for SR support, and many are rising to the challenge regardless of the number of years of experience as a librarian they may have. This supports what the growth in literature over the last ten years, 15 development of robust training programs, 16 and anecdotal evidence have indicated. Broadly, disciplines within the social sciences are more likely to request librarian support than the sciences or humanities. This aligns with a strong history of SR in psychology, business, and education. 17

Consultation was the most frequently reported form of SR support requested. Consultation, whether provided over email, video, or in-person, is a chance for a librarian to provide guidance and answer any questions that a research team may have. Consultation as the most common form of SR support aligns with a thank you via email/in-person/phone as the most common form of acknowledgement (50.7 percent). The percentage of librarians who receive co-authorship of a paper or presentation (39.3 percent) is high and similar to numbers reported by health science librarians, 18 although it does not reach the numbers reported by health science library administrators. 19 As noted by Ross-White 20 authorship on SRs is an important indicator that researchers value librarians’ work and contributions to the team. Consults alone do not typically lead to authorship, but can be formally acknowledged in a paper; they are often the first step to a librarian taking on a more substantive role on a SR team, such as search strategy development, translation, and execution, which were the next most frequently requested support that respondents reported. These types of requests are unsurprising, as they draw upon fundamental areas of librarian expertise.

One of the most striking themes to emerge from our data is the high level of interest in supporting SRs among SHSS librarians. Library administrators should recognize that there is both demand for SR support in SHSS and an appetite by librarians to take on this work. Administrators who wish to encourage SR services should note that librarians who reported knowing that they had organizational supports in place reported higher levels of interest in participating in SR work, while those who were unsure of the organizational supports available to them expressed a similar level of interest to those who said they had no organizational supports. Providing resources for SHSS librarians involved in SR research is important to prevent burnout 21 and to ensure the long-term viability of offering this type of service to SHSS researchers and faculty. As such, consideration of SR services and organizational support for SHSS librarians should be a part of library planning.

Librarians and administrators must exercise caution regarding scalability and capacity to provide SR services. Providing high levels of SR support requires extensive training and education by the librarian and a significant time investment. One study found that the average time a librarian spent on a single SR is 26.9 hours (median 18.5 hours). 22 Adding support for multiple SRs to an already full workload can lead to burnout; one study found that SR-related burnout is a problem for health sciences librarians, but those who are assigned to spend more than 80 percent of their time on SRs had lower personal burnout scores. 23 This suggests that employing dedicated SR librarians or providing time away from regular duties for SR work can help reduce burnout. SHSS librarians who are already involved in SRs or are interested in it for the future, must pay attention to how they manage their workload. SHSS administrators or department heads planning on offering or expanding SR services in the SHSS disciplines should carefully examine existing workflow and capacity to ensure there is adequate staffing, tools, and resources to ensure the long-term feasibility of that type of service. Researchers in SHSS disciplines where SR are a new research methodology will likely need even higher levels of librarian support and training to successfully complete the process.

Limitations and Future Research

The findings of this research are limited by the small sample size and use of convenience sampling. Due to restrictions from our research ethics board, we were unable to directly contact ARL or CARL libraries or librarians to increase the sample size and instead had to rely on the use of listservs to recruit respondents. Based on the actual number of ARL or CARL academic libraries that support institutions or researchers in the SHSS disciplines, we believe there is a larger number of librarians doing this work than is indicated in this study. The original design of this study only included librarians working at ARL or CARL institutions to narrow a suspected large potential number of respondents; future research should include librarians working at any academic institution who support SRs in the SHSS disciplines. Another possible limitation is that SHSS librarians who have not been asked to support SRs in their liaison areas, or who serve disciplines where this methodology is rarely used, may not have considered this survey on SRs relevant, which may have biased the sample. However, the fact that 26 percent of respondents had not yet been asked to participate in a SR demonstrates that at least some librarians who had not completed a SR filled out the survey, providing a small amount of information about the views of this group.

Another limitation of this study relates to data analysis. Most of this analysis is descriptive, as more sophisticated analysis was not possible with the data available. While this prevents us from drawing firm conclusions about the data that can be generalized more broadly, it does provide a snapshot of SR support in an area that has been under-examined to date.

A final limitation is the process used to categorize a librarian’s liaison area(s) into one or more broad categories (e.g., a librarian who listed psychology as their liaison area was categorized into “Social Sciences” ). This is an imperfect process and is open to interpretation, particularly in multidisciplinary areas (e.g., biomedical computing) or those that may be classified differently at different institutions (e.g., kinesiology). However, broad categorization was necessary to maintain participant anonymity and facilitate data analysis. Fortunately, liaison areas that could potentially have been assigned to multiple disciplines were in the minority (see OSF for the categorization scheme). Future surveys could, instead of asking respondents to list their liaison areas in free-text format, provide standardized liaison areas or disciplines and ask respondents to select those they feel most closely aligns with their liaison areas.

This study is among the earliest investigations into SHSS librarians’ involvement in SRs. There are many potential avenues of research and inquiry into library support of SRs in the SHSS disciplines. Examples could include subsequent benchmarking studies that document growth in demand for library support and librarian participation, development of discipline-specific SR standards, and documentation of time spent supporting SHSS SRs.

This study provides evidence that demand for SR support from librarians serving the sciences, humanities, and social sciences at ARL and CARL institutions has increased, and that many SHSS librarians are rising to the challenge of providing that support. However, SR support is a labor-intensive endeavor that is not sustainable as an “off the side of the desk” activity. Library administrators should consider both the benefits and challenges of providing such service and should take steps to adequately provide for the development of library SR expertise and ensure the scalability of library services.

Supplemental Material

All supplemental material, including survey instrument, listservs contacted, and anonymized data are available on the Open Science Framework at https://osf.io/mqxf2 .

Acknowledgements

This study was funded by the Canadian Association of Research Libraries’ (CARL) Research in Librarianship grant, and we are extremely grateful for their support. We are also indebted to our colleagues at the University of Manitoba for testing early forms of the survey. We acknowledge the help of Loring Chuchmach from the George & Fay Yee Centre for Healthcare Innovation (CHI) for statistical consulting services.

Contributorship

M.L., C.J.N, & J.W. contributed to the design and implementation of the research, the analysis of the results, and the writing of the manuscript.

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* Mê-Linh Lê is Acting Head, Health Sciences Division at the University of Manitoba, email: [email protected] ; Christine J. Neilson is a Health Sciences Librarian at the University of Manitoba, email: [email protected] ; and Janice Winkler is a Social Sciences Librarian at the University of Manitoba, email: [email protected] . ©2024 Mê-Linh Lê, Christine J. Neilson, and Janice Winkler, Attribution-NonCommercial ( https://creativecommons.org/licenses/by-nc/4.0/ ) CC BY-NC.

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Mastering the Art of Systematic Literature Review and Meta-Analysis: Techniques, Tools, and Best Practices-Joint workshop by SIG-III and SIG-InfoLearn

This is a comprehensive workshop designed to equip participants with the essential skills and knowledge to conduct rigorous systematic literature reviews (SLRs) and meta-analyses effectively. Participants will delve into the methodology behind conducting SLRs, understanding the nuances of literature search strategies, data extraction techniques, quality assessment, and data analysis for SLRs. Moreover, the workshop will explore the intricacies of meta-analysis, including the process of data extraction for meta-analysis, quantitative synthesis, effect size calculation, heterogeneity assessment, model selection, and publication bias detection. Participants will also gain insights into selecting appropriate statistical tools and software for conducting meta-analyses effectively.

• Open access
• Published: 02 May 2024

Risk factors and long-term outcomes of oropharyngeal dysphagia in persons with multiple sclerosis: a systematic review protocol

• Zahra Sadeghi 1 ,
• Mohamadreza Afshar 2 ,
• Asefeh Memarian 3 &
• Heather L. Flowers   ORCID: orcid.org/0000-0001-6742-9459 3  

Systematic Reviews volume  13 , Article number:  121 ( 2024 ) Cite this article

Metrics details

Oropharyngeal dysphagia (OPD) can be functionally debilitating in persons with multiple sclerosis (pwMS). OPD induces alterations in safety and efficiency of food and/or liquid ingestion and may incur negative sequalae such as aspiration pneumonia or malnutrition/dehydration. Early detection and timely management of OPD in pwMS could prevent such complications and reduce mortality rates. Identifying risk factors of OPD relative to its onset or repeat manifestation will enable the development of care pathways that target early assessment and sustained management. The aims of this systematic review are to compile, evaluate, and summarize the existing literature reporting potential risk factors and associated long-term outcomes (e.g., aspiration pneumonia, malnutrition, dehydration, and/or death) of OPD in pwMS.

We will undertake a systematic review to identify studies that describe patterns and complications of OPD in pwMS. Variables of interest include predictors of OPD along with long-term outcomes. We will search MEDLINE, Embase, CINAHL, AMED, the Cochrane Library, Web of Science, and Scopus. We will consider studies for inclusion if they involve at least 30 adult participants with MS and report risk factors for OPD and/or its long-term outcomes. Studies will be excluded if they refer to esophageal or oropharyngeal dysphagia induced by causes other than multiple sclerosis. Study selection and data extraction will be performed by two independent assessors for abstract and full article review. We will present study characteristics in tables and document research findings for dysphagia-related risk factors or its complications via a narrative format or meta-analysis if warranted (e.g., mean difference and/or risk ratio measurements). All included studies will undergo risk-of-bias assessment conducted independently by two authors with consensus on quality ratings.

There is a lacune for systematic reviews involving risk factors and long-term outcomes of dysphagia in pwMS to date. Our systematic review will provide the means to develop accurate and efficient management protocols for careful monitoring and evaluation of dysphagia in pwMS. The results of this systematic review will be published in a peer-reviewed journal.

Systematic review registration

PROSPERO CRD42022340625.

Peer Review reports

Oropharyngeal dysphagia (OPD) is common in multiple sclerosis (MS) [ 1 ] due to injury to the corticobulbar tracts, potentially involving the brainstem, the cerebellum [ 2 , 3 ], and the cortex [ 4 ]. There may be a differing clinical course across types of MS, classified based on disease onset and progression over time [ 5 ]. The most frequent includes relapsing–remitting MS (RRMS), usually beginning with acute exacerbation and detrimental impacts that recover fully or partially over time. The other forms of MS are all defined as progressive, including secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS). Patients with RRMS develop SPMS within 10 years of the onset of RRMS. PPMS is the least frequent type of MS and is characterized by deteriorating neurological function from disease onset coupled with a lack of remittance. Nevertheless, superimposed relapses are also evidenced in this type. Overall, the course of MS is unpredictable, and depending on the severity, the diversity of anatomic impacts, and the onset of associated lesions, its clinical manifestations are also heterogeneous.

Symptoms of OPD in MS may include coughing and/or choking on saliva or other liquid and food boluses, feelings of bolus sticking in the throat, the need to swallow multiple times per bolus, difficulty initiating a swallow (accompanied by drooling), and alterations to usual eating patterns (such as viscosity or texture changes) [ 3 , 4 , 6 ]. Oropharyngeal dysphagia may incur severe and multifaceted poor outcomes, such as aspiration pneumonia, malnutrition/dehydration [ 3 , 4 , 6 ], increased psychosocial comorbidities [ 7 , 8 ], and even death during periods of medical instability [ 9 ]. Identifying risk factors for OPD in pwMS will provide the means to develop accurate and efficient management protocols for careful monitoring and evaluation by dysphagia experts. By extension, sustained management will permit timely and comprehensive care to mitigate potential serious complications.

In two recent systematic reviews, the authors provided an estimate of the pooled frequency of dysphagia in pwMS based on a range of evaluation methods, whether screening, clinical, or instrumental examination [ 1 , 10 ]. Guan et al. [ 1 ] reported a pooled frequency estimate of 36% based on subjective screenings or cursory evaluations (such as the Dysphagia in Multiple Sclerosis Questionnaire, the water swallowing test, and various dysphagia checklists from individual clinical swallowing centers) and 81% based on objective measurements (such as videofluoroscopy or fiber-optic nasoendoscopy). More specifically, the frequency of dysphagia was 46% in pwMS when Expanded Disability Status Scale (EDSS) scores were stratified as 4.5 or higher and 40% for those below 3.0. Similarly, patients with longer disease duration (over 10 years) were more likely to have dysphagia symptoms compared with shorter disease duration.

Various individual studies have also shown a higher frequency of dysphagia with greater disability [ 11 , 12 , 13 , 14 , 15 ] and/or disease duration [ 15 , 16 ]. Nevertheless, a few studies have reported that pwMS with low EDSS scores still had dysphagia [ 15 , 17 , 18 ]. To illustrate, Abraham et al. [ 18 ] reported that 43% of pwMS in their sample had dysphagia including 17% with low levels of disability (EDSS score lower than 2.5). Aghaz et al. [ 10 ] estimated the pooled frequency of dysphagia as 37% based on subjective evaluations or cursory checklists versus 47% for objective instrumental evaluations respectively. In contrast to the findings of Abraham et al. [ 18 ], they failed to demonstrate associations for the presence of dysphagia according to EDSS-based disease severity, duration of disease, or MS stage.

Taken together, reported frequencies of dysphagia hover around one-third of pwMS at a given point in time [ 1 , 10 ], whereby varied frequencies relate primarily to evaluation methods, whether screening, clinical assessment, or instrumental evaluation. The most common patient-report tool used to identify dysphagia in pwMS is the Dysphagia in Multiple Sclerosis Questionnaire (DYMUS) [ 1 , 10 , 19 ], involving 10 items with very good reliability and internal consistency. However, frequencies of reported dysphagia based on questionnaires are lower than those based on standardized tools or instrumental evaluations [ 1 ]. In general, instrumental assessment remains the gold standard for dysphagia and aspiration detection, whether by videofluoroscopy or fiber-optic nasoendoscopy rather than various types of screening tools, bedside evaluations, or patient-reported questionnaires. Some pwMS may underestimate their dysphagia severity due to altered sensory appreciation of symptoms, despite instrumental evidence to the contrary.

In addition to our poor understanding of the frequency of dysphagia in pwMS, gaps exist regarding patterns of associations between disease severity, duration, or stage. Notwithstanding, certain predictive factors may well routinely accompany the expression of dysphagia in pwMS. Elucidating such information would require a comprehensive profile of patient groups with known disease severity, duration, and stage alongside MS type, neuroanatomical impacts, and concomitant deficits or disorders. For example, dysphagia may be precipitated by coexisting psychological or cognitive impairments [ 11 , 18 , 20 ]. Therefore, continual monitoring for risk of dysphagia in pwMS who also experience negative mental health symptoms or cognitive disorders [ 4 , 20 ] is warranted. Furthermore, speech impairments (e.g., dysarthria) may provide good and readily identifiable clinical indicators for the presence of dysphagia in persons with neuromuscular diseases [ 21 ]. A systematic appraisal of the literature is required to identify the best available evidence for risk factors of dysphagia along with ensuing long-term sequelae in pwMS.

A systematic review constitutes the highest level of research evidence, especially if there is a quality evaluation and meta-analysis. Therefore, a comprehensive systematic review, aimed at establishing the predictors of dysphagia in pwMS, ideally identified with gold standard evaluation methods (such as instrumental assessment), could facilitate the development of new tools for screening or assessing dysphagia and inform practice guidelines. In addition, a close consideration of associated outcomes over the long term (e.g., pneumonia, poor social participation, death) could contribute to our understanding of prognostic indicators for particular patient groups. Consequently, our purpose is to search the existing literature to systematically identify the risk factors and associated outcomes of oropharyngeal dysphagia over the long term in persons with pwMS.

The protocol of this systematic review has been registered in PROSPERO (registration number: CRD42022340625). We have applied PRISMA-P guidelines to develop this review protocol further. It served to direct our search strategy of databases and the gray literature as well as our data extraction and compilation methods. We will document our article selection results using the PRISMA flow diagram to delineate reasons for abstract and article exclusion until the final set of articles is identified. Our investigation of risk factors is in keeping with recommendations from the Cochrane Prognostic Methods Group ( https://methods.cochrane.org/prognosis/ ) [ 22 ]. We are submitting the protocol prior to undertaking the full search or any subsequent processes such as abstract screening and full article evaluation.

Operational definitions

Oropharyngeal dysphagia is defined as body and structure impairment [ 23 ] in swallowing physiology evidenced by expert clinical or instrumental assessment of function from the anterior aspect of the lips to inferior aspect of the upper esophageal sphincter. Diagnosis of multiple sclerosis is based on accepted criteria for both definite and probable MS, according to a classification scheme that involves expert clinical and objective evaluations (such as neuroimaging) [ 24 ].

Data sources

We will conduct an electronic search in the following databases for abstracts in languages that the co-authors can read (English, French, German, Persian, Portuguese, Spanish, and Turkish). No publication date or study design restrictions will be imposed. Relevant databases will include MEDLINE, Embase, CINAHL, AMED, the Cochrane Library (CENTRAL), Web of Science, and Scopus. The MeSH and search terms used in the search strategy were developed a priori (Table  1 ). A research librarian will consult to enable valid adaptations of the MEDLINE terms into the other databases. Our MEDLNE search was conducted in OVID, revealing 189 citations (April 2023). We will also search international gray literature sources (e.g., OpenGrey and Dissertation Abstracts) and review the bibliographies and citations for all included articles in a reiterative manner until no further possible references are identified.

Eligibility criteria

Studies will be considered for inclusion if they have observational intent and involve retrospective or prospective consecutive or randomly selected sampling (either from a particular cohort or population). Study designs may include case series, cross-sectional, longitudinal, case–control, and/or other observational investigations as well as the control arm (i.e., participants who are not receiving trial-related interventions for MS or dysphagia) of randomized controlled trials. We will consider studies with at least 30 adults (18 years or older) with MS. Studies must include an aim to identify risk factors (e.g., MS subtype, disease duration, EDSS score, age, gender, smoking or alcohol use, psychological symptoms, cognitive impairments, and/or dysarthria) that may precipitate oropharyngeal dysphagia (OPD). We have chosen not to prespecify all possible risk factors as we seek to identify new potential risk factors. The body of evidence is small, and risk factors are likely underrepresented at present. Any potential new risk factors will provide a path for future researchers to investigate them in a comprehensive way and thus extend the literature and knowledge base in this respect.

Corresponding studies that include follow-up time points will contribute to our interest in long-term outcomes (e.g., detrimental medical, activity/participation, or quality-of-life outcomes). Ideally, such studies would have comparable follow-up periods (e.g., yearly) that span the course of the disease and document the outcomes relative to the absence/presence and/or severity classifications of OPD. However, we will not exclude any studies based on their follow-up points or overall time horizon.

During our review of abstracts and full articles, we will apply pre-defined exclusion criteria. That is, we will exclude studies involving convenience samples, those without extractable data (e.g., studies involving aggregate results for multiple etiologies rather than pwMS alone) for our outcomes of interest, and those reporting duplicate data. Any abstracts without corresponding full study publications will be excluded. We will also exclude articles without a clear sample of at least 30 pwMS and corresponding OPD (for at least a declared portion of the sample), identified by clinical or instrumental swallowing assessments. Finally, articles will be excluded if they do not conform to our operational definitions of OPD and MS or if they refer to oropharyngeal dysphagia induced by causes other than multiple sclerosis. We will contact authors when we cannot find full articles or when we wish to elucidate study characteristics such as method of dysphagia assessment. Our full systematic review reporting will conform to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist [ 27 ].

Data collection

Study selection from primary articles will be performed in two stages:

Initial screening and coding of titles and abstracts whereby relevant abstracts (stage 1) will undergo full article review (stage 2) (Table  2 )

Evaluation and coding of full articles for inclusion in the final sample (Table  2 )

The review process will be conducted by two independent reviewers (blind to each other’s coding) across the two stages. Any discrepancies will be resolved by consensus discussion between the two reviewers, and, when agreement is not possible, a third reviewer (also a member of the research team) will read the abstract or article independently and contribute to a decision. All references for the excluded articles will be retained for documentation purposes.

One data extractor will identify pertinent information from the final set of included articles and compile it into a table or spreadsheet. Extracted data will be verified by a second independent reviewer to ensure the accuracy of information from the following categories:

Study characteristics: First author’s name, year of publication, country in which the study was conducted, study design, and size of the sample

Study population and participant characteristics: Age, gender, MS type, disease duration, and EDSS score

Diagnostic assessments for MS and dysphagia

Risk factors for dysphagia whether related to MS (e.g., MS type, disease duration, and EDSS score), to patient characteristics (e.g., age, gender, and smoking or alcohol abuse), and/or to comorbidities (e.g., psychological symptoms, cognitive impairments, or dysarthria)

Follow-up assessments of dysphagia in terms of type and timing

Frequency and impact (e.g., severity) of detrimental medical (e.g., aspiration pneumonia, dehydration, malnutrition, institutionalization, and mortality), activity/participation (e.g., fewer social engagements around meals), or quality-of-life outcomes.

Risk of bias in individual studies

We will apply appropriate risk-of-bias evaluations [ 22 , 28 ] such as the Newcastle–Ottawa scale (NOS) [ 29 ] as a quality evaluation of included obserervational studies. To illustrate, the NOS contains grading for categories of selection (e.g., sample representativeness), comparability (e.g., evaluation of confounders), and outcome (adequacy of follow-up period). Further, if warranted, the Cochrane Collaboration’s risk-of-bias tool will be used for randomized controlled trials, based on the domains: sequence generation, blinding of participants, blinding of outcome measurement, allocation sequence concealment, missing data, selective outcome reporting, and other biases such as sources of funding and conflicts of interest [ 30 ]. Additionally, the Quality in Prognosis Studies (QUIPS) tool will facilitate assessment for the risk factor studies [ 22 ]. For any type of quality appraisal (observational study quality scale, Cochrane’s risk-of-bias tool, or QUIPS), two authors will independently review the included studies and resolve discrepancies by discussion and consensus agreement within the review team.

Data analysis

We will provide a descriptive synthesis of the findings from the included studies, structured around target population characteristics, type of assessments, and outcomes of interest. We will consider meta-analyses if there is an adequate number of studies and homogeneity of study populations and assessment methods. Otherwise, we will present a narrative synthesis of the results. We anticipate that there will be restricted scope for meta-analysis due to differing study populations and/or assessment methods along with a paucity of existing literature. Where studies have similar sample characteristics (including potential comparison groups), assessment methods, and corresponding outcomes, we will pool the results and apply various types of meta-analyses such as mean difference, standard mean difference, or Cox regression for continuous outcomes and risk ratio measurement or logistic regression for categorical outcomes depicted in forest plots along with their 95% confidence intervals (CIs). Finally, we will evaluate the overall strength of the evidence based on discussion among authors through application of a tool such as GRADE.

Assessment of heterogeneity

If there is reason to consider meta-analysis, analyses will be performed using Cochrane’s Review Manager tool (Review Manager: RevMan [computer program]. The Cochrane Collaboration, 2024). We plan to assess study features such as participant age and sex, MS subtype, time course for follow-up, and primary outcome measures as the basis for determining if data pooling for meta-analysis is warranted. Subsequently, if meta-analysis is undertaken, we will apply and interpret the I 2 statistic [ 30 ] as an indictor of heterogeneity relative to the number of studies and direction of effect using the following guide: mild (between 0 and < 25%), moderate (between 25 and < 50%), severe (between 50 and < 75%), and highly severe (between 75 and 100%). If there is moderate heterogeneity, we will present a supplementary qualitative synthesis of the findings.

Analysis of subgroups or subsets

If sufficient data are available, subgroup analyses may be conducted for different OPD assessment methods (e.g., clinical bedside evaluation, fiber-optic nasoendoscopic evaluation, and/or videofluoroscopic evaluation) relative to MS type and risk factors. Similarly, long-term outcomes based on dysphagia status or severity levels will be analyzed according to follow-up periods or comparable overall time horizon.

Assessment of publication bias

Publication bias will be evaluated using a funnel plot (i.e., plots of study results against precision) and Begg’s [ 31 ] and Egger’s [ 32 ] tests if an adequate number of studies (≥ 10) are identified. Additionally, we will incorporate Deek’s asymmetry test [ 33 ] to mitigate overestimation of effects when predictive modeling with odds ratios is applied for the determination of OPD across studies that involve low event proportions. However, if meta-analysis is not possible, publication bias will be assessed descriptively and involve documentation of direction of results across risk factors (whether significant or not) as well as potential follow-up time lags across studies.

Our search strategy is extensive compared to other recent systematic reviews in the field of multiple sclerosis [ 1 , 34 ] given the inclusion of numerous sources and comprehensive search terms. We believe that it will yield a broad capture of abstracts internationally, but that many articles will derive from western or developed countries. This may be an important limitation because many underrepresented countries, such as Iran, have a high and increasing prevalence of pwMS in certain regions [ 35 , 36 ].

Other systematic reviews have undertaken different lines of inquiry such as investigating the prevalence of dysphagia in pwMS without considering risk factors [ 1 ] or long-term outcomes [ 1 , 10 ]. Thus, we will extend the knowledge base in a new content area (involving predictors and long-term outcomes of dysphagia in pwMS). Our identification of literature in the field of MS will provide new insights into the repercussions of dysphagia and offer direction for the development of screening protocols, assessment methods, and improved therapeutic management in pwMS. In the event that our findings elucidate multiple predictors (e.g., related to MS, patient characteristics, and/or comorbidities) and varied outcomes (e.g., medical, activity/participation, or quality of life), they may warrant publication in multiple peer-reviewed papers.

We anticipate that various limitations will result during our search of the literature. First, studies may not report the timeframe between dysphagia onset, assessments, and associated outcomes. Second, dysphagia identification in specific studies might be based on cursory screenings, patient self-report (and potentially non-standardized) questionnaires, and/or subjective clinical assessments rather than on instrumental reference tests such as videofluoroscopy and fiber-optic nasoendoscopy. Finally, it may be difficult to pool results from the existing literature for some of the risk factors or outcomes if investigations restrict enrolment to particular types of pwMS, involving subsamples of larger studies, or if they fail to incorporate shared definitions and research methods in the field of multiple sclerosis [ 36 ].

Although the frequency of dysphagia in pwMS has been a topic of inquiry within the past two decades [ 1 , 10 ], a poor understanding of associations to disease-related risk factors and negative outcomes remains. Our proposed systematic review will address such a gap in the literature, as we will attempt to elucidate risk factors of dysphagia and long-term outcomes from observational studies reporting frequencies of dysphagia over the long term. Where relevant, we will pool results across studies or extract individual-level data that may permit us to model risk factors of dysphagia and/or its associated long-term outcomes in pwMS. Our inquiry will offer the means to inform best practices in the early detection of dysphagia and provide information that can be incorporated into guidelines and clinical practice initiatives for the management of dysphagia in pwMS.

Availability of data and materials

Not applicable.

Abbreviations

• Oropharyngeal dysphagia

Persons with multiple sclerosis

• Multiple sclerosis

Expanded Disability Status Scale

Dysphagia in Multiple Sclerosis Questionnaire

Strengthening the Reporting of Observational Studies in Epidemiology

Newcastle-Ottawa scale

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Department of Speech Therapy, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

Zahra Sadeghi

Department of Speech Therapy, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran

Mohamadreza Afshar

School of Rehabilitation Sciences, Faculty of Health Sciences, University of Ottawa, 200 Lees Avenue, Ottawa, ON, K1S 5S9, Canada

Asefeh Memarian & Heather L. Flowers

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ZS conceptualized, designed, and wrote much manuscript. HF conceptualized, designed, wrote, and edited the manuscript. MA conceptualized, designed, and wrote parts of the manuscript. AM developed the search terms and wrote parts of the manuscript.

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Sadeghi, Z., Afshar, M., Memarian, A. et al. Risk factors and long-term outcomes of oropharyngeal dysphagia in persons with multiple sclerosis: a systematic review protocol. Syst Rev 13 , 121 (2024). https://doi.org/10.1186/s13643-024-02530-3

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Laser and Light-Based Therapies for Hirsutism Management in Women With Polycystic Ovarian Syndrome : A Systematic Review

• 1 Monash Health, Department of Dermatology, Melbourne, Australia
• 2 Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine Nursing and Health Sciences, Monash University, Australia
• 3 Department of Obstetrics and Gynecology, Research Unit of Clinical Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland
• 4 Eastern Health Clinical School, Monash University, Melbourne, 3128, Australia
• 5 Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy

Question   Are laser and light-based hair reduction therapies, either as stand-alone treatments or in combination with other systemic therapies, effective in addressing hirsutism in adults and adolescents with polycystic ovary syndrome (PCOS)?

Findings   In this systematic review of 6 studies reporting data on 423 patients, laser and light-based therapies were found to be effective in reducing hirsutism severity, improving psychological well-being, and enhancing quality of life in women with PCOS, with generally tolerable adverse effects. Simultaneous use of metformin or the combined oral contraceptive pill may offer additional benefits.

Meaning   These findings alongside broader efficacy data and patient preference informed the 2023 International Evidence-based PCOS Guideline, which has now introduced new recommendations on the use of laser and light-based hair reduction therapies for women with PCOS and hirsutism.

Importance   Hirsutism represents a significant concern for women with polycystic ovary syndrome (PCOS), with deleterious psychological effects warranting acknowledgment and a clear imperative to provide effective management. To our knowledge, this is the first review to exclusively examine the effectiveness of laser and light-based therapies in addressing hirsutism in women with PCOS.

Objective   To synthesize the existing literature regarding the effectiveness of laser and light hair reduction therapies, either as stand-alone treatments or in combination with systemic agents, in treating hirsutism for women with PCOS.

Evidence Review   A systematic literature review was performed using MEDLINE, Embase, EMCARE, and CINAHL according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses ( PRISMA ) reporting guidelines. Articles written in English, reporting on patients who met pre-established inclusion criteria were selected. Objective and subjectively measured outcomes relating to the effect of laser or light-based hair reduction therapies on hirsutism were abstracted. Heterogeneity among included studies precluded a meta-analysis, necessitating a narrative synthesis.

Findings   Six studies reporting data on 423 individual patients with PCOS who underwent laser or light-based hair reduction therapies were included: 4 randomized clinical trials and 2 cohort studies. Alexandrite laser demonstrated significant improvements in hirsutism severity and psychological outcomes, particularly at high-fluence application. Alexandrite laser was also found to be more effective than intense pulsed light (IPL). The combination of diode laser with either metformin or combined oral contraceptive pill was superior to the application of diode laser alone, just as the addition of metformin to IPL demonstrated superior results to IPL treatment alone. Overall, most interventions were well tolerated. The overall certainty of evidence across all outcomes and comparisons was limited in part due to the observational nature of some studies.

Conclusions and Relevance   This systematic review highlights the potential of laser and light hair reduction therapies, both as stand-alone treatments and in combination with other pharmacological agents in PCOS. However, this review was limited by low certainty of the evidence, few studies evaluating effectiveness and safety in those with skin of color, and heterogeneity in outcome assessment. Future studies are needed to provide more robust evidence among diverse individuals with PCOS and hirsutism.

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Tan K , Coster T , Mousa A, et al. Laser and Light-Based Therapies for Hirsutism Management in Women With Polycystic Ovarian Syndrome : A Systematic Review . JAMA Dermatol. Published online April 17, 2024. doi:10.1001/jamadermatol.2024.0623

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SYSTEMATIC REVIEW article

The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis.

• 1 School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
• 2 School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States

Background: Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes.

Methods: We systematically searched PubMed for original research articles published between April 2013–January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC.

Results: In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent.

Discussion: A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.

1 Introduction

Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States ( 1 ). The incidence of CRC has steadily declined since the 1980s, largely attributed to greater uptake of colonoscopy screening by adults aged 50 years and older ( 2 ). Concurrently, the incidence of sporadic early-onset CRC, generally defined as CRC diagnosis before age 50 without an underlying hereditary cause, has significantly increased since the mid-1990s ( 2 ). Data from the Surveillance, Epidemiology, and End Results (SEER) program reflect a 2-3% annual increase in the incidence of early-onset CRC ( 3 ). The elevated incidence of early-onset CRC may be explained by birth cohort effects where more recent birth cohorts have increased prevalence of obesity and type 2 diabetes, lower levels of physical activity, and more often consume western-style diets characterized by lower consumption of fruits and vegetables ( 4 ), as well as changes in the composition of the gut microbiome ( 2 ). While early-onset CRC may be caused by hereditary conditions defined by germline mutations in DNA mismatch-repair genes (i.e. Lynch syndrome) or in the tumor suppressor APC (i.e. familial adenomatous polyposis) ( 5 ), these inherited conditions account for a relatively small percentage of early-onset CRC and do not explain the increased prevalence observed in recent decades ( 2 ).

CRC is a heterogeneous disease and the clinicopathological and molecular characteristics of tumors may influence prognosis and response to treatment ( 6 ). Beyond tumor stage, multiple potential prognostic and predictive markers have been identified, including mutations in oncogenes such as KRAS , BRAF , PIK3CA , and TP53 , histological subtypes including mucinous and signet ring carcinomas, and the microsatellite instability (MSI) phenotype ( 7 ). Further, several novel prognostic markers have recently been identified, including immune markers in the tumor microenvironment ( 8 ) and the CRC consensus molecular subtypes ( 9 ). It is anticipated that the continued characterization of molecular phenotypes in CRC will augment traditional clinical markers for therapeutic decision making and support the development of targeted approaches to treatment ( 10 ).

Given the increasing rate of early-onset CRC, recent publications have highlighted potential differences in the clinicopathological and molecular characteristics of tumors based on age of onset ( 11 – 14 ). However, it is currently unclear whether early-onset CRC is distinct from late-onset disease in terms of molecular characteristics and tumor developmental pathways ( 15 ). Understanding the molecular characteristics of early-onset CRC is necessary to guide the development of therapeutic approaches for this condition and to address underlying causes. Therefore, we have completed a systematic review and meta-analysis to comprehensively summarize the evidence linking early-onset CRC to differences in prognostic and predictive tumor markers, including oncogene mutations, histological subtypes, MSI status, as well as anti-tumor immunity and the consensus molecular subtypes.

2.1 Literature review

Articles for this systematic review were identified utilizing a Pubmed search incorporating PRISMA guidelines ( 16 ). Given the wide breadth of the topic and the limited number of relevant articles published prior to 2013, the search was limited to peer-reviewed, original research articles published in English from the last 10 years (April 2013 – April 2023), with relevant keywords and medical subject headings included in the title and/or abstract. The literature review was repeated in January 2024 to identify recently published articles. Specific biomarker terms to include in the literature search were identified from prior reviews, and the search terms “biomark*”, “mark*”, and “character*” were included to capture potentially novel prognostic markers. All search terms included for the literature review are displayed in Supplementary Table S1 . Manuscripts were included that reported the prevalence of prognostic biomarkers in CRC tumors separately for early- vs. late-onset disease. Articles were excluded if the prevalence of tumor clinicopathological or molecular biomarkers were not provided for participants with CRC (see Figure 1 flowchart), or if there was no comparison between early- vs. late-onset CRC (or if the comparison was limited to tumor stage or location only). Articles were also excluded that described hereditary CRC only (e.g. Lynch syndrome), site-specific metastases, or included non-CRC cancers in the analysis samples. For the purposes of this analysis, early-onset disease was defined as CRC diagnosed prior to age 50. To avoid misclassification of early- and late-onset CRC, we excluded papers where late-onset CRC was defined as ≥ 40 years at diagnosis or younger, or where early-onset CRC was defined as ≤ 60 years at diagnosis or older. Lastly, to limit sample overlap where possible, we excluded studies if there was evidence of complete overlap in sample and markers reported with a previously published study, or if a study reported the same outcome in a subsample of a previous study.

Figure 1 Literature review flowchart. a Inappropriate study design includes studies concerning colorectal cancer incidence, colonoscopy or other colorectal cancer screening, population level summary statistics for colorectal cancer, and studies of colorectal cancer in model organisms or in vitro studies. b Markers of interest include oncogene mutations in KRAS , NRAS , BRAF , PIK3CA , PTEN , TP53 , APC , and HER2 ; histological phenotypes including high-grade tumors and mucinous or signet ring histology; molecular carcinogenesis pathways including microsatellite instability and the CpG island methylator phenotype (CIMP); and novel tumor prognostic phenotypes including immune markers in the tumor microenvironment and the consensus molecular subtypes. c Studies where late-onset colorectal cancer was defined as ≥ 40 years at diagnosis (or younger), or early-onset CRC was defined as ≤ 60 years at diagnosis (or older).

The systematic review and meta-analysis was limited to the following markers that have been shown associations with CRC survival and/or therapeutic response in CRC: oncogene mutations in KRAS ( 17 – 20 ), NRAS ( 17 , 21 , 22 ), BRAF ( 17 , 19 , 23 , 24 ), PIK3CA ( 17 , 25 , 26 ), PTEN ( 27 , 28 ), TP53 ( 29 ), APC ( 30 , 31 ), and HER2 amplifications ( 32 – 34 ); histological phenotypes including high-grade tumors ( 35 , 36 ) and mucinous ( 37 , 38 ) or signet ring histology ( 38 , 39 ); molecular carcinogenesis pathways including MSI ( 40 ) and the CpG island methylator phenotype (CIMP) ( 41 ); and novel tumor prognostic phenotypes including immune markers ( 42 , 43 ) in the tumor microenvironment and the consensus molecular subtypes ( 9 , 44 ). Because it is well-established that early-onset CRC is associated with advanced tumor summary stage at diagnosis and rectal tumor location, these markers are not summarized in this review. The literature review was completed by two authors (T.L. and L.P) independently. Disagreements between reviewers were resolved by further review of the manuscript to determine whether the study included a comparison of tumor markers of interest between early- and late-onset CRC. The final decision to include a manuscript was made by the lead author. In total, 1,694 articles were identified from the literature search and 149 were eligible for review ( Figure 1 ). For each study, the potential for bias was evaluated by the lead author using the Newcastle-Ottawa Scale adapted for cross-sectional studies ( 45 ). Pre-registration of the systematic review protocol was not performed.

2.2 Meta-analysis

From each eligible study, the number of mutant and wild-type tumors for each marker in early- and late-onset CRC was extracted by the lead author. Data extraction was completed in duplicate, and the results from the two extractions were compared to identify any errors or inconsistencies in the sample sizes, which were subsequently revised after further review of the original article. If these data were not available from the manuscript, sample sizes were requested from the corresponding author. One study was excluded for which we were unable to obtain the necessary sample sizes from each group ( 46 ). When necessary, sample sizes for separate age groups were combined to create a single category for early-onset and late-onset CRC. For most studies, age 45 or 50 at diagnosis was utilized as the threshold to distinguish early- vs. late-onset CRC, although occasionally other classifications were employed (see Supplementary S2 ). For each study, sample characteristics including overall sample size, country, tumor stage, sex, or other distinguishing features were also extracted. For each marker, an odds ratio (OR) and 95% confidence interval (CI) were calculated using a standard equation ( 47 ). For mutations in oncogenes KRAS, NRAS, BRAF, PIK3CA, PTEN, TP53 , and APC , as well as MSI status and histological subtypes, meta-analyses were completed to compare the prevalence in tumors from early- vs. late-onset CRC. Due to the wide variety of immune markers that have been reported, a meta-analysis was not attempted for the comparison of immune phenotypes in the tumor microenvironment. For each marker that was meta-analyzed, a pooled OR with 95% CI was obtained from a random effects model via inverse variance weighting. The random effects model was selected a priori , as between-study heterogeneity is plausible given variability in the definition of early-onset CRC, as well as differences in tumor location, race, nationality and stage between studies. The random effects meta-analysis is capable of providing unbiased estimates in the presence of heterogeneity and will generally provide more conservative estimates than the fixed-effects model (which assumes no between-study heterogeneity) ( 48 ). Heterogeneity was determined via the Cochrane’s Q statistic and the I 2 statistic. Significant heterogeneity was defined as P <.05 for Cochrane’s Q or I 2 ≥ 50%. To determine whether the meta-analysis estimates were influenced by a single study, a ‘leave-one-out’ sensitivity analysis was conducted for each marker. Because Lynch syndrome may influence the prevalence of tumor markers for individuals with early-onset CRC, a second sensitivity analysis was completed to limit the analysis to studies that specifically excluded individuals with Lynch syndrome or family history of CRC, or that restricted the sample to microsatellite stable tumors. All statistical tests were two-sided, with statistical significance defined using a threshold of P <.05. All meta-analyses were completed using Review Manager 5.4.1 from Cochrane.

In total, 149 articles were reviewed that compared the prevalence of clinicopathological tumor markers in early- vs. late-onset CRC. All meta-analysis results are summarized in Table 1 . Sample characteristics and references for all included studies are presented in Supplementary Table S2 . Results of the bias assessment utilizing the Newcastle-Ottawa Scale are presented in Supplementary Table S4 .

Table 1 Summary of meta-analysis results showing associations between early-onset colorectal cancer and the prevalence of tumor markers, compared to late-onset colorectal cancer.

3.1 Oncogene mutations

The number of studies identified for the following markers is as follows: KRAS mutation ( 49 ); BRAF mutation ( 49 ); NRAS mutation ( 20 ); PIK3CA mutation ( 21 ); PTEN mutation ( 8 ); HER2 amplifications ( 5 ); APC mutation ( 19 ); TP53 mutation ( 20 ). For early-onset CRC, there is evidence for a significantly lower prevalence of mutations in KRAS ( Figure 2 , OR 0.91, 95% CI 0.85-0.98), BRAF ( Figure 3 , OR 0.63, 95% CI 0.51-0.78) and APC ( Figure 4 , OR 0.70, 95% CI 0.58-0.84) compared to late-onset CRC. Early-onset CRC was associated with non-significantly lower prevalence of mutations in NRAS ( Figure 5 , OR 0.88, 95% CI 0.78-1.00, p = .06). Conversely, early-onset CRC is associated with a higher prevalence of mutations in TP53 ( Figure 6 , OR 1.34, 95% CI 1.24-1.45) and PTEN ( Figure 7 , OR 1.68, 95% CI 1.04-2.73). There was no significant difference in the prevalence of PIK3CA mutations ( Supplementary Figure S1 , OR 0.95, 95% CI 0.86-1.05), or HER2 amplifications ( Supplementary Figure S2 , OR 1.64, 95% CI 0.86-3.14). Significant inter-study heterogeneity was observed for mutations in KRAS , BRAF , PTEN , and APC . Hazard ratios for oncogene mutations were stable in the leave-one-out sensitivity analysis ( Supplementary Table S3 ), although the association for NRAS and PTEN mutations did not always reach statistical significance.

Figure 2 Odds ratios for KRAS mutation in early-onset CRC. Data presented as odds ratios (95% confidence interval) for KRAS mutation in early-onset relative to late-onset colorectal cancer. The pooled odds ratio is obtained via a random effects model using inverse variance weighting. AACR, American Association for Cancer Research; MDACC, MD Anderson Cancer Center; MSI, microsatellite instability; MSS, microsatellite stable.

Figure 3 Odds ratios for BRAF mutation in early-onset CRC. Data presented as odds ratios (95% confidence interval) for BRAF mutation in early-onset relative to late-onset colorectal cancer. The pooled odds ratio is obtained via a random effects model using inverse variance weighting. AACR, American Association for Cancer Research; MDACC, MD Anderson Cancer Center; MSI, microsatellite instability; MSS, microsatellite stable.

Figure 4 Odds ratios for APC mutation in early-onset colorectal cancer. Data presented as odds ratios (95% confidence interval) for APC mutation in early-onset relative to late-onset colorectal cancer. The pooled odds ratio is obtained via a random effects model using inverse variance weighting. AACR, American Association for Cancer Research; COH, City of Hope National Medical Center; CI, confidence interval; EO-CRC, early-onset colorectal cancer; MDACC, MD Anderson Cancer Center; MSKCC, Memorial Sloan Kettering Cancer Center; UCD, University of California, Davis.

Figure 5 Odds ratios for NRAS mutation in early-onset colorectal cancer. Data presented as odds ratios (95% confidence interval) for NRAS mutation in early-onset relative to late-onset colorectal cancer. The pooled odds ratio is obtained via a random effects model using inverse variance weighting. AACR, American Association for Cancer Research; CI, confidence interval; EO-CRC, early-onset colorectal cancer; MDACC, MD Anderson Cancer Center.

Figure 6 Odds ratios for TP53 mutation in early-onset colorectal cancer. Data presented as odds ratios (95% confidence interval) for TP53 mutation in early-onset relative to late-onset colorectal cancer. The pooled odds ratio is obtained via a random effects model using inverse variance weighting. AACR, American Association for Cancer Research; CI, confidence interval; EO-CRC, early-onset colorectal cancer; MDACC, MD Anderson Cancer Center; MSI, microsatellite instability; MSS, microsatellite stability.

Figure 7 Odds ratios for PTEN mutation in early-onset colorectal cancer. Data presented as odds ratios (95% confidence interval) for PTEN mutation in early-onset relative to late-onset colorectal cancer. The pooled odds ratio is obtained via a random effects model using inverse variance weighting. AACR, American Association for Cancer Research; CI, confidence interval; EO-CRC, early-onset colorectal cancer; MDACC, MD Anderson Cancer Center.

Fifty studies were identified that specifically excluded individuals with Lynch syndrome or family history of CRC, or that restricted the analysis to individuals with microsatellite stable tumors ( Table 1 ; Supplementary Table S2 ). Compared to the full analysis, the association between early-onset CRC and BRAF (OR 0.77, 95% CI 0.64-0.92) and APC mutations (OR 0.81, 95% CI 0.67-0.97) were attenuated but remained statistically significant, while the associations with KRAS , NRAS , and TP53 mutations were similar. Further, an inverse association between early-onset CRC and PIK3CA mutation was also observed (OR 0.88, 95% CI 0.78-0.99).

3.2 Molecular carcinogenesis pathways

There were 10 studies that compared the prevalence of CIMP-high status in early- vs. late-onset CRC, and 64 studies that compared MSI status. Individuals with early-onset CRC had significantly lower odds for CIMP-high tumors compared to individuals with late-onset disease ( Supplementary Figure S3 , OR 0.24, 0.10-0.57), but significantly higher odds for the MSI phenotype ( Supplementary Figure S4 , OR 1.31, 1.11-1.56). Significant heterogeneity was observed for both markers. Associations were stable in the leave-one-out sensitivity analysis ( Supplementary Table S3 ), and after limiting the analysis to studies that excluded individuals with Lynch syndrome or family history of CRC ( Table 1 ).

3.3 Histological characteristics

There were 86 studies that compared the prevalence of high-grade tumors (i.e. poorly differentiated or undifferentiated tumors) in early- vs. late-onset CRC, 57 studies that compared the prevalence of mucinous histology (or mucinous characteristics), and 44 studies that reported on signet ring cell carcinomas. In early-onset CRC, there was evidence for a significantly higher prevalence of high-grade (i.e., poorly differentiated) tumors ( Supplementary Figure S5 , OR 1.20, 95% CI 1.15-1.25), as well as mucinous tumors ( Supplementary Figure S6 , OR 1.22, 95% CI 1.16-1.27), and signet ring cell carcinomas ( Supplementary Figure S7 , OR 2.32, 2.08-2.57). Significant inter-study heterogeneity was observed for all histological markers. All associations were stable in the leave-one-out sensitivity analysis ( Supplementary Table S3 ) and after limiting the analysis to studies that excluded individuals with Lynch syndrome or family history of CRC ( Table 1 ).

3.4 Immune markers

There have been nine studies to investigate age differences in the immune cell populations of CRC tumors, with inconsistent results ( 49 – 57 ). Du et al. reported that Chinese patients with sporadic early-onset CRC showed significantly higher densities of multiple immune cell populations in the tumor microenvironment compared to patients with late-onset disease, including higher levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells ( 50 ). By contrast, Ugai et al. reported no significant differences in the populations of T cells, macrophages, and other myeloid cells in participants with early- vs. late-onset CRC from the Nurses’ Health Study and Health Professionals Follow-up Study ( 51 ). In a small study of 14 tumors utilizing single cell RNA sequencing, Li et al. reported that early-onset CRC was associated with lower levels of effector CD8+ T cells and antigen-presentation in the tumor microenvironment, but higher levels of naïve CD8+ T cells and immunosuppressive regulatory T cells compared to individuals with late-onset disease, suggesting an impaired anti-tumor immune response for early-onset CRC ( 54 ). Because MSI status may influence the anti-tumor immune response, recent studies have examined associations between early-onset CRC and tumor lymphocyte populations in samples limited to microsatellite stable tumors, or after careful exclusion of participants with Lynch syndrome ( 56 , 57 ). In a matched analysis of microsatellite stable tumors, Lu et al. (2023) reported that there was no significant differences between early- and late-onset CRC for the infiltration of 22 different lymphocyte populations in the tumor microenvironment ( 57 ). Likewise, Andric et al. found no significant difference for five lymphocyte populations (total T cells, conventional CD4+ and CD8+ T cells, regulatory T cells, and γδ T cells) in a matched sample limited to cases of sporadic CRC ( 56 ). Other studies have reported no significant differences between early and late-onset CRC for the density of total tumor infiltrating lymphocytes ( 53 , 55 ).

3.5 The consensus molecular subtypes

There have been six studies to determine the distribution of consensus molecular subtypes (CMS) for CRC by age at diagnosis ( 50 , 57 – 61 ). Utilizing tumor tissues samples from 626 individuals diagnosed with CRC from The Cancer Genome Atlas and MD Anderson Cancer Center, Willauer reported that the CMS1 subtype was more common among patients aged 30-39 years at diagnosis (46%) compared to older participants, while the CMS4 subtype was less common (13%) ( 58 ). Conversely, in a smaller study from the Nanjing Colorectal Cancer Cohort, Du et al. reported a higher prevalence of the CMS4 subtype in early- vs. late-onset CRC (36.7% vs. 12.2%, respectively), although the comparison between age groups did not reach statistical significance ( 50 ). Recent results, including from a small sample of South Korean participants ( 59 ) and additional analyses of The Cancer Genome Atlas ( 60 , 61 ) did not show any significant association between early-onset tumors and the distribution of consensus molecular subtypes.

4 Discussion

Sporadic early-onset CRC is a significant public health concern, increasing by 2-3% per year in the U.S. since 1990 ( 3 , 62 ). Early-onset CRC is more often diagnosed at advanced stages compared to late-onset disease ( 63 , 64 ). However, there is inconsistent evidence that survival varies between early- and late-onset CRC ( 65 , 66 ), complicated by reports that younger patients receive more aggressive systemic treatment ( 67 – 69 ). Thus, international guidelines do not endorse separate treatment recommendations for early-onset disease ( 70 ). Investigating the associations between early-onset tumors and molecular and histological characteristics, and novel tumor markers including immune cell populations, may help to guide the development of therapies that benefit early-onset CRC. Further, highlighting associations between early-onset CRC and tumor markers may aid in the design of clinical trials for targeted therapies. To the authors’ knowledge, this is the first comprehensive systematic review and meta-analysis of tumor prognostic and predictive markers in early-onset CRC. We found that early-onset CRC was associated with a lower prevalence of oncogene mutations in KRAS , BRAF , NRAS , and APC , but a higher prevalence of TP53 and PTEN mutations and adverse histologic subtypes, with inconsistent associations for immune cell populations and the consensus molecular subtypes.

KRAS , BRAF , and NRAS encode proteins that act downstream of the epidermal growth factor receptor (EGFR) and activate Mek/Erk signaling ( 21 , 71 ). Mutations in these oncogenes are negative predictive markers for EGFR inhibition in metastatic CRC ( 17 , 18 ) and are associated with inferior survival outcomes across tumor stage ( 19 , 20 , 23 , 72 ), including for early-onset CRC ( 73 – 75 ). Early-onset CRC is associated with a lower prevalence of mutations in these genes compared to late-onset disease, indicating that individuals with metastatic early-onset CRC may be more likely to benefit from EGFR inhibition. Notably, the association with NRAS mutations was not statistically significant, which may be due to the scarcity of this marker ( 76 ). Further, the association with BRAF mutation was attenuated but still statistically significant in studies that excluded individuals with Lynch syndrome, who are less likely to have BRAF mutations compared to sporadic disease ( 77 ). Further, this sensitivity analysis revealed an inverse association with PIK3CA mutation, which has also been linked to higher risk for mortality and resistance to EGFR inhibition ( 17 , 78 ). Conversely, early-onset CRC was associated with a higher proportion of mutations in tumor suppressor PTEN , which encodes a lipid-phosphatase that suppresses the activity of PI3k/Akt/mTOR signaling and interacts with the EGFR pathway ( 27 ). Loss of PTEN activity has been linked to resistance to EGFR inhibition in metastatic CRC ( 79 ) but is not currently used in clinical decision making. Pharmaceutical therapies to restore normal PTEN activity are under development but have not been evaluated in CRC. Early-onset CRC was associated with a significantly higher prevalence of TP53 mutations, which cause loss of p53 tumor suppressor activity and pro-tumorigenic gain of function effects that accelerate cell proliferation, angiogenesis, and metastasis ( 80 ). TP53 mutations are found in approximately 60% of tumors and may promote resistance to EGFR inhibitors and chemotherapies that rely on wild type p53 to induce cellular apoptosis (e.g. 5-fluorouracil and Oxaliplatin) ( 29 ). Consequently, targeted therapies to restore wild type p53 activity or degrade mutant p53, or to inhibit downstream effector pathways, are currently being investigated in clinical trials ( 81 ). Potentially, individuals with early-onset CRC may be more likely to benefit from treatments that inhibit pro-tumorigenic p53 activity and should be targeted for enrollment in these trials.

Early-onset CRC was associated with a lower prevalence of APC mutation, a key driver of the canonical adenoma-carcinoma pathway ( 82 ). APC mutations are present in approximately 80% of CRC tumors ( 11 , 12 , 14 ), and recent evidence indicates that APC -mutant tumors are associated with extended overall and progression-free survival compared to wild type ( 30 , 31 ) ( 5 ). Notably, the association with APC mutation was attenuated but still statistically significant when limiting the analysis to studies that excluded individuals with Lynch syndrome, or that included microsatellite stable tumors only. Individuals with early-onset CRC had a higher prevalence of MSI, defined by a high density of somatic mutations in short, non-coding sequences caused by defects in DNA mismatch repair ( 40 ). MSI is associated with lower risk for overall mortality and distant metastases compared to microsatellite stable tumors, including in early-onset CRC ( 75 ). Further, MSI tumors secrete truncated proteins that trigger an anti-tumor immune response ( 83 ), and consequently MSI is a positive predictor for response to immune checkpoint inhibitors ( 83 ). Our findings therefore highlight the importance of MSI testing for individuals younger than 50, in accordance with clinical guidelines ( 70 ). Unexpectedly, the association between early-onset CRC and MSI status was modestly strengthened in studies that excluded individuals with known Lynch syndrome, which causes tumors with MSI ( 84 ). Because a significant proportion of individuals with Lynch syndrome may be unaware of the condition ( 85 ), it is possible that the exclusion of Lynch syndrome was incomplete in some studies. Early-onset CRC was associated with a lower prevalence of the CpG island methylator phenotype (CIMP), characterized by methylation and inactivation of tumor-suppressor genes ( 86 ). Although CIMP has been linked to poor prognosis in multiple studies, it currently has limited value as a prognostic marker due to a lack of standardized assessment and competing effects of MSI and BRAF mutation, which are associated with CIMP ( 41 ).

We also found that early-onset CRC is associated with higher odds for tumors with more aggressive histological features, including poorly differentiated tumors, mucinous carcinomas, and signet ring cell carcinomas ( 38 , 87 ). The association with signet ring features was especially pronounced (OR [95% CI]: 2.32 [2.08-2.57]). Although signet ring carcinomas comprise only 1% of CRC tumors ( 39 ), this feature is present in 2-3% of early-onset tumors. A recent meta-analysis showed that signet ring carcinomas were associated with significantly higher risk for overall mortality and recurrence compared to conventional adenocarcinomas ( 88 ). Results were similar for mucinous tumors, which comprise approximately 10-15% of CRCs ( 89 ). The associations between histological subtypes and colorectal cancer mortality, especially poorly differentiated tumors and signet ring carcinomas, have been validated in early-onset CRC ( 90 – 93 ). Currently, there are no treatments that specifically target mucinous or signet ring cell carcinomas and treatment guidelines do not distinguish between histological subtypes ( 70 ).

The observed associations between early-onset CRC and certain histological and molecular tumor characteristics may be explained in part by differences in tumor location ( 94 ). Approximately 30% of early-onset tumors are located in the rectum, versus 20% of late-onset tumors ( 64 , 95 ). KRAS, BRAF, PIK3CA , and NRAS mutations are enriched in proximal tumors ( 96 , 97 ) while TP53 mutations are enriched in rectal tumors ( 98 ). Notably, studies that were limited to individuals with tumors in the distal colon or rectum have not shown a consistent association between early-onset CRC and the presence of oncogene mutations ( 46 , 55 , 56 , 99 – 102 ). For example, a study with more than 1,000 distal and rectal tumors showed no significant age difference in KRA S, BRAF, NRAS , PIK3CA , TP53 , or APC mutations ( 46 ). Conversely, in a large-scale analysis with detailed stratification by tumor location, Ugai et al. found that early-onset CRC had a lower prevalence of BRAF mutations for all tumor sites except the sigmoid colon and rectum ( 103 ). Notably, aggressive histological subtypes are overrepresented in the proximal colon ( 104 ), and consequently the association with early-onset CRC is not explained by differences in tumor location.

We found inconsistent evidence linking early-onset CRC to differences in ‘novel’ tumor prognostic and predictive markers including populations of immune cells in the tumor microenvironment ( 8 ). A recent meta-analysis demonstrated that a higher density of tumor infiltrating lymphocytes was associated with reduced overall mortality among 20,015 individuals with CRC (HR [95% CI]: 0.65 [0.54-0.77]) ( 42 ), while others have shown that an ‘immunoscore’ encompassing cytotoxic T cells and CD3+ cells was a superior prognostic marker compared to the tumor stage ( 105 , 106 ). Currently, the association between early-onset CRC and the anti-tumor immune response has been inconsistent ( 48 – 50 , 52 , 53 , 55 , 56 , 58 ). Notably, higher rates of MSI in early-onset CRC due to Lynch syndrome may obscure associations with immune markers in sporadic disease, as MSI tumors trigger a robust anti-tumor immune response ( 83 ). Studies limited to microsatellite stable tumors or that carefully excluded participants with hereditary syndromes have tended to show no significant differences in immune cell populations between early- and late-onset CRC ( 51 , 56 , 57 ). Likewise, there is currently no consistent evidence that the distribution of consensus molecular subtypes differs between early- and late-onset CRC, with most studies reporting null findings ( 50 , 57 , 59 – 61 ). The consensus molecular subtypes have shown to be a robust predictor of mortality outcomes independent of tumor stage ( 107 ), but to the authors’ knowledge have not been validated specifically in early-onset CRC. Further, the identification of novel molecular subtypes in early-onset CRC based on tumor gene expression is an area for future research.

Strengths of this study include the comprehensive nature of the search strategy, as we were able to summarize the evidence for age-related differences in the prevalence of established tumor prognostic markers as well as emerging markers including immune cell populations in the tumor microenvironment and the consensus molecular subtypes. Further, the large number of studies identified for most markers allowed for relatively precise estimates of the association with early-onset CRC. Lastly, to better understand the associations between early-onset CRC and tumor markers in sporadic disease, we completed a sensitivity analysis limited to studies that excluded individuals with known Lynch syndrome (or family history of CRC). This analysis is also attended by several limitations. Due to the breadth of the review, our literature search was limited to original research studies published within the last ten years in Pubmed. Consequently, it is possible that a relevant study was missed. However, this is unlikely to be a significant limitation given the paucity of large tumor genomic studies published prior to 2013 and the comprehensive nature of our search strategy. Further, there was evidence for significant heterogeneity in the estimates for most tumor markers, but we were unable to investigate underlying sources of inter-study heterogeneity because the prevalence of tumor prognostic markers was rarely presented in subgroups defined by tumor location, tumor stage, or MSI status. Between-study differences in the definitions of early- and late-onset CRC may also have contributed to heterogeneity, although we excluded studies where misclassification of early-onset CRC was apparent. Lastly, although we attempted to control for bias by performing a sensitivity analysis limited to studies that accounted for Lynch syndrome in the study design, it is possible that residual confounding by hereditary conditions or differences in tumor location may have biased the results.

5 Conclusions

In summary, early-onset CRC was associated with a lower prevalence of mutations in several oncogenes linked to mortality and poor therapeutic response, including KRAS , BRAF , and NRAS compared to individuals with late-onset disease. Conversely, early-onset disease was associated with a higher prevalence of potentially harmful mutations in TP53 and PTEN , as well as aggressive histological subtypes including mucinous and signet ring cell carcinomas. In part, these associations may reflect the higher prevalence of rectal tumors in early-onset CRC and the effect of hereditary syndromes on tumor markers. Given these findings and the alarming rise in the incidence of early-onset CRC, it is essential that clinical trials for targeted therapies enroll sufficient numbers of individuals with early-onset disease to evaluate their efficacy in this subgroup. Additional research is required to clarify the relationships with novel tumor characteristics including immune markers and to identify molecular subtypes specific to early-onset CRC that can inform treatment and prognosis.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Author contributions

TL: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation. LP: Writing – review & editing, Writing – original draft, Investigation, Data curation. SW: Writing – review & editing, Supervision, Resources, Project administration, Methodology, Funding acquisition, Conceptualization.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Cancer Institute of the National Institutes of Health [NIH/NCI] under grants R00 CA207848 and R01 CA255318.

Conflict of interest

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

Publisher’s note

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

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2024.1349572/full#supplementary-material

Abbreviations

AACR, American Association for Cancer Research; APC, adenomatous polyposis coli; CI, confidence interval; CIMP, CpG island methylator phenotype; CMS, consensus molecular subtypes; COH, City of Hope (National Medical Center); CRC, colorectal cancer; EGFR, epidermal growth factor receptor; MDACC, MD Anderson Cancer Center; MSI, microsatellite instability; MSKCC, Memorial Sloan Kettering Cancer Center; MSS, microsatellite stable; OR, odds ratio; SEER, Surveillance, Epidemiology, and End Results; TIL, tumor infiltrating lymphocytes.

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Keywords: colorectal cancer, colon cancer, rectal cancer, early-onset, oncogenes, prognosis, molecular characteristics

Citation: Lawler T, Parlato L and Warren Andersen S (2024) The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis. Front. Oncol. 14:1349572. doi: 10.3389/fonc.2024.1349572

Received: 04 December 2023; Accepted: 16 April 2024; Published: 26 April 2024.

Reviewed by:

Copyright © 2024 Lawler, Parlato and Warren Andersen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Shaneda Warren Andersen, [email protected]

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

• Open access
• Published: 24 April 2024

Current updates relating to treatment for interstitial cystitis/bladder pain syndrome: systematic review and network meta-analysis

• Jae Joon Park 1   na1 ,
• Kwang Taek Kim 2 ,
• Eun Ji Lee 3 ,
• Joey Chun 1 , 4 ,
• Serin Lee 1 , 5 ,
• Sung Ryul Shim 6 , 7 &
• Jae Heon Kim 1   na1  

BMC Urology volume  24 , Article number:  95 ( 2024 ) Cite this article

235 Accesses

Metrics details

Despite the publication of several meta-analyses regarding the efficacy of certain therapies in helping individuals with interstitial cystitis (IC) / bladder pain syndrome (BPS), these have not provided a comprehensive review of therapeutic strategies. The study aimed to determine the efficacy of various therapies for IC/BPS and identify potential moderating factors using randomized controlled trials (RCTs).

We queried the PubMed, Cochrane, and Embase databases to identify prospective RCTs using inclusion criteria: 1) patients diagnosed with IC, 2) interventions included relevant treatments, 3) comparisons were a specified control or placebo, 4) outcomes were mean differences for individual symptoms and structured questionnaires. The pairwise meta-analysis and network meta-analysis (NMA) were performed to compare the treatments used in IC/BPS. Hedges’ g standardized mean differences (SMDs) were used for improvement in all outcomes using random-effects models. Efficacy outcomes included individual symptoms such as pain, frequency, urgency, and nocturia, as well as structured questionnaires measuring IC/BPS symptoms.

A comprehensive literature search was conducted which identified 70 RCTs with 3,651 patients. The analysis revealed that certain treatments, such as instillation and intravesical injection, showed statistically significant improvements in pain and urgency compared to control or placebo groups in traditional pairwise meta-analysis. However, no specific treatment demonstrated significant improvement in all outcomes measured in the NMA. The results of moderator analyses to explore influential variables indicated that increasing age was associated with increased nocturia, while longer follow-up periods were associated with decreased frequency.

This systematic review and meta-analysis provide insights into the efficacy of various treatments for IC. Current research suggests that a combination of therapies may have a positive clinical outcome for patients with IC, despite the fact that treatment for this condition is not straightforward.

Trial registration

PROSPERO CRD42022384024

Peer Review reports

A constellation of incapacitating systems, which encompass discomfort in the suprapubic region, nocturia and micturition frequency and urgency, are characteristic of interstitial cystitis (IC), a condition also referred to as bladder pain syndrome (BPS). Typically, such symptoms occur when the bladder is full, and dissipate once urine has been passed [ 1 , 2 ]. In addition to these symptoms, a major complaint of patients suffering from IC is pelvic pain, which originates from the urethra, vagina or rectum, amongst other viscera [ 3 ]. There is at present no standard definition for this condition, nor consensus regarding its management, recommended therapy or the treatment period required [ 4 ].

A range of drugs directed towards the treatment of IC have been the topic of recent debate, although the largest percentage of patients cured of the condition remains in the region of 60% [ 5 ]. It has been demonstrated that numerous factors are involved in the pathogenesis of IC. These include autoimmune phenomena [ 6 ], injury to the urothelial glycosaminoglycan layer [ 7 ], neurological discomfort and inflammatory processes [ 8 ].

Despite the publication of several meta-analyses as well as a network meta-analysis (NMA) [ 9 , 10 ], these have not provided a comprehensive review of therapeutic strategies. The lack of clarity regarding the efficacy of certain therapies in helping individuals with IC, owing to the low or very low degrees of supportive evidence, was expressed in a recent Cochrane review [ 9 ]. Although the results of numerous studies can be accessed, the majority only included small populations and so the outcomes of therapy could not be accurately evaluated. The same issue applied to a further NMA, and so the results were not apposite for the current work. Thus, studies with higher sample numbers and which are specifically targeted towards this condition are required to enhance the present quality of evidence. Randomized controlled trials (RCTs) have been added by the current authors to the literature, and they have concurrently carried out a traditional pairwise meta-analysis and an NMA to offer more evidence-based conclusions.

There are numerous types of therapy available for IC, some of which are extremely complicated, and so as well as carrying out an NMA, a general meta-analysis by effect variables has also been performed. Additionally, meta-regression analysis was applied to ascertain the moderator effect. The study is underpinned by the hypothesis that a high level of therapeutic success can be achieved in patients with IC using a combination of approaches; this theory could subsequently be tested in RCTs.

The systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [ 11 , 12 ]. This study completed PROSPERO registration (CRD42022384024).

Data sources and literature searches

A systematic literature search was conducted in the PubMed, Embase, and Cochrane databases using Medical Subject Headings terms and text keywords through April 2023 (eTable 1 in the Supplement). The subject headings and text keywords included those related to the population of interest (i.e., “IC”, “BPS”), intervention (relevant treatments such as “medication”, “instillation”, “intravesical injection”, “physical therapy” and/or others), comparison (“placebo” or “control”), and outcomes of treatments: 1) individual symptoms (“pain, frequency”, “urgency” and “nocturia”), 2) structured questionnaires (“interstitial cystitis problem index” [ICPI], “interstitial cystitis symptom index” [ICSI], “pelvic pain — urgency” – “frequency symptom scale” [PUF] and “functional bladder volume” [FBV]). Search terms were categorized using Boolean operators (e.g., AND, OR, NOT). Only RCTs were included in this meta-analysis. This search was conducted regardless of language or study type. Two independent researchers (SR Shim and JH Kim) identified additional studies by manually searching trial databases and reference lists.

Study selection

Study inclusion criteria were as follows: patients diagnosed with IC/BPS, interventions included relevant treatments, comparisons were specified as control or placebo, outcomes were mean differences for individual symptoms (pain, frequency, urgency and nocturia) and structured questionnaires (ICPI, ICSI, PUF and FBV) using an RCT study design. The specific study selection was described in eTable 6 in the Supplement.

Meta-analysis assessment of outcome findings and statistical analysis

The specific data extraction and calculation methods [ 13 ] were listed in eTable 6 in the Supplement. For traditional pairwise meta-analysis, the standardized mean difference (SMD) along with their 95% confidence intervals (Cls) were calculated for continuous variables. The random-effects model calculated by restricted maximum-likelihood estimator (REML) was used to obtain the pooled overall SMD and 95% CIs for outcomes [ 14 ].

Each moderator was subjected to a meta-regression analysis for continuous variables (e.g., number of patients, age and follow-up period) and categorical variables (e.g., treatments, country, cystoscopy and Hunner lesion group). To analyse potential moderators, the study estimated the variance of the true effects using a REML estimator.

For Bayesian NMA, specific graphical analysis was completed using the “gemtc” package in R software v.4.2.1 (R Foundation for Statistical Computing) [ 15 ]. The Markov chain Monte Carlo (MCMC) simulation method and surface under the cumulative ranking curve (SUCRA) [ 15 , 16 ] generation used for Bayesian NMA, and the potential publication bias [ 17 ] and quality assessment [ 18 ] were described in eTable 6 in the Supplement. A two-sided P -value of ≤ .05, or not containing a null value (SMD = 0) within the 95% CI was considered to be significant.

The initial search identified a total of 411 articles from different electronic databases (PubMed, n = 105; Cochrane, n = 98; Embase, n = 208). Of these, 185 studies contained overlapping data or appeared in more than one database and were therefore excluded. After screening the titles and abstracts, 119 studies were eliminated as they were trial registrations and abstracts only. Among 107 full-text articles, 37 studies were further excluded for the following reasons: not an original article type, n = 30 and not an RCT design, n = 7. Finally, 70 studies met the selection criteria for qualitative analysis (eTable 2 & 3 in the Supplement) and 47 studies for quantitative synthesis (eTable 4 in the Supplement and Fig. 1 ).

PRISMA flowchart

A systematic review and meta-analysis of the 47 studies involving a total of 3,651 patients were conducted to assess the detailed differences and subject descriptions provided in eTable 4 in the Supplement. All studies were RCTs and conducted in Western, Eastern, and Middle Eastern countries. The mean age range was 30.1 to 65.5 years, and the follow-up period ranged from one to 24 months. The specific treatments and outcomes displayed in eTable 4 in the Supplement include: 1) medication or system injection (i.e., analgesics, antidepressants, new immune modulator, old immune modulator), 2) instillation (i.e., botulinum toxin [BTX], sodium chondroitin sulfate [CS], sodium hyaluronic acid [HA]), 3) intravesical injection (i.e., BTX, RTX, anesthetics), 4) physical therapy (i.e., radiofrequency, nerve stimulation), 5) others (i.e., dietary, hydrogen-rich water, video intervention).

Outcome findings from pairwise meta-analysis

The pooled SMDs for overall pain assessment between treatments versus the control group was -0.33 (95% CI: -0.52, -0.14). The heterogeneity test produced a Higgins’ I 2 was 65.5%. In the subgroup analysis by outcome measures, the SMDs were -0.22 (95% CI; -0.39, -0.06) for instillation, and -0.53 (95% CI; -0.80, -0.27) for intravesical injection. The pooled SMDs for overall urgency assessment between treatments versus the control group was -0.40 (95% CI: -0.75, -0.05). The heterogeneity test produced a Higgins’ I 2 was 79.8%. In the subgroup analysis by outcome measures, the SMD of the others group was statistically significant -0.64 (95% CI; -0.97, -0.32). The pooled SMDs for overall nocturia assessment between treatments versus the control group was -0.37 (95% CI: -0.62, - 0.11). The heterogeneity test produced a Higgins’ I 2 was 44.5%. In the subgroup analysis by outcome measures, there were no statistically significant groups (Fig. 2 ). The pooled SMDs for overall ICPI was -0.22 (95% CI: -0.37, -0.07). The heterogeneity test produced a Higgins’ I 2 was 54.0%. In the subgroup analysis by outcome measures, the SMDs were -0.21 (95% CI; -0.38, -0.04) for instillation, and -0.63 (95% CI; -1.02, -0.28) for intravesical injection. The pooled SMDs for overall ICSI was -0.20 (95% CI: -0.32, -0.08). The heterogeneity test produced a Higgins’ I 2 was 32.0%. In the subgroup analysis by outcome measures, the SMDs were -0.21 (95% CI; -0.42, -0.01) for medication or system injection, -0.49 (95% CI; -0.85, -0.13) for intravesical injection, and -0.39 (95% CI; -0.69, -0.08) for others. All statistical analysis results were based on clinical practice. (Fig. 3 ).

Forest plots for individual symptoms of pain, frequency, urgency, and nocturia (clockwise) in pairwise meta-analysis. SMD, standardized mean difference; CI, confidence interval; PPS, pentosane polysulfate; MPD, monophosphate dehydrogenase; HA, hyaluronic acid; CS, chondroitin sulfate; HL, heparin sodium-lidocaine; BTX, botulinum toxin

Forest plots for structured questionnaires of ICPI, ICSI, PUF, and FBV (clockwise) in pairwise meta-analysis. SMD, standardized mean difference; CI, confidence interval; PPS, pentosane polysulfate; MPD, monophosphate dehydrogenase; HA, hyaluronic acid; CS, chondroitin sulfate; HL, heparin sodium-lidocaine; BTX, botulinum toxin; ICPI, interstitial cystitis problem index; ICSI, interstitial cystitis symptom index; PUF, pelvic pain – urgency - frequency symptom scale; FBV, functional bladder volume

Outcome findings from NMA

Using a Bayesian network meta-analysis to simultaneously examine the differences in each treatment for each outcome measure, the study found that no specific treatment showed statistically significant improvement compared to the control group in all outcomes (pain, frequency, urgency, nocturia, ICPI, ICSI, PUF and FBV) (Fig. 4 , and eFigure 1 to 6 in the Supplement). The consistency test showed that the direct and indirect comparison of all outcomes was consistent, so we applied the consistency model in this study (all P > 0.05). All statistical analysis results were based on clinical practice.

Network plots, forest plots, and SUCRA values of pain in network meta-analysis

Moderator analysis

The study also considered the potential moderating roles of the following variables using meta-regression analysis (Table 1 and eTable 5 in the Supplement). With increasing age, a statistically significant increase was found in nocturia ( β = 0.063, P = 0.005 ) , worsening by 3.6%. With an increasing follow-up period, a statistically significant decrease in frequency ( β = -0.040, P = 0.014 ) was found, improving by approximately 2.3%.

Publication bias

The statistical approaches for the detection of publication bias or a small-study effect are shown in eFigure 7 in the Supplement. Individual symptoms (pain, frequency, urgency and nocturia) showed visual asymmetric graphics in funnel plots, and Egger’s regression also suggested publication bias (all P < .05). However, the structured questionnaires (ICPI, ICSI, PUF and FBV) showed symmetry, and Egger’s regression did not support publication bias or a small-study effect (all P > 0.05).

Quality assessment

The seventy studies were evaluated using the five RoB 2.0 domains to determine the risk of bias. In D1, forty-seven studies and twenty-three were classified as “Some concerns” and “Low”. In D2 & D4, one study was classified as “igh”. In D3, nine studies were classified as “Some concerns”. In D5, all studies were classified as “Low”. Based on these evaluations, nineteen studies were classified as “Low”, fifty studies as “Some concerns” and one study (Hsieh et al. 2012) as “High” (eFigure 8 in the Supplement).

Through our research, we have revealed for the first time that it is appropriate to try a combination of multiple treatments clinically rather than just one treatment in treating the difficult-to-overcome disease called interstitial cystitis. Even though the outcomes of the NMA were in keeping with the data published in the Cochrane review [ 9 ], the former highlighted an alternative perspective in that in comparison to a placebo, the overall effects of treatment for discomfort, nocturia, ICPI and ICSI were greater. The types of therapy applied included intravesical instillation or injection, and additional strategies, such as diet modification and hyperbaric oxygen. The meta-regression analysis demonstrated that for frequency, the longer the follow-up duration, the more improved the clinical results. Ageing was identified as a negative moderator associated with a poorer end result in nocturia. The NMA showed that in comparison to a placebo, no single therapy offered any benefit to patients with IC. However, where more than one therapeutic approach was applied, such as an adjunctive immune modulator, intravesical injection, intravesical instillation with BTX or HA, or HA and CS, or changes in diet, more positive outcomes could be anticipated which could be demonstrated in the future by RCTs.

The study NMA objective was to evaluate the effectiveness of any drug treatments available for IC. Although the underlying causes of IC remain poorly defined, there are some data to suggest that in this condition, there is an aberrant immune response. Thus, controlling the intravesical immune response could be a potential therapeutic strategy.

Injection into the bladder was also categorized during this work. Out of a range of possible treatments, intravesical instillation or injection was shown to be an efficacious therapy in pairwise meta-analysis. Recommendations published by the American Urological Association (AUA) state that this procedure should be performed following the failure of first-line approaches and alongside oral treatments and physiotherapy [ 3 ].

Since IC is a chronic condition, therapy and monitoring should be carried out over the long term [ 19 ]. Current therapeutic options may not offer a cure; however, in a number of patients, there may be spontaneous recovery, ultimately leading to complete relief from symptoms [ 3 , 19 ]. An adverse prognostic factor for IC is age. Additionally, increased frequencies of diabetes mellitus, high blood pressure, kidney pathologies, coronary artery disease and raised serum lipids were identified [ 20 ]. Psychological symptoms were also demonstrated to be more common in this cohort, with anxiety and depression recognized in 14–52% and 16–70% of patients with IC, respectively [ 21 ]. Frequent monitoring and therapy were observed over the preceding five years in 76.3% of patients studied by Yeh et al. [ 22 ]. This group had a higher prevalence of chronic pathologies, which could impact the ongoing degree of IC. The majority of individuals who were under frequent review and who had been offered a range of therapies continued to present with bladder discomfort symptoms and were seeking novel therapeutic options. Those who no longer attended review appointments during the preceding five years had been less symptomatic following their early therapy. The current meta-regression analysis demonstrated that the more prolonged the follow-up period, the more likely frequency was to improve. Advancing years were associated with poorer clinical endpoints, e.g. nocturia; in general, each additional year of age was associated with a 3.4% deterioration in symptom score.

Although a single treatment study has been reported that BTX is effective in pain relief and that PPS helps improve subjective symptoms in patients [ 23 , 24 ], the strength of the current NMA is that a de novo combination of therapy is proposed. Despite the lack of statistical evidence for the efficacy of each therapy alone in comparison to a placebo, the therapy with the highest rank for its modality was indicated by the SUCRA ranking analysis. Therapeutic combinations which are anticipated include the use of an immune moderator, injections or instillations into the bladder, e.g. with BTX, HA, or HA and CS, and diet modification.

Immune cells liberate tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine that has been implicated in the inflammatory responses associated with IC. In urothelial cells from the bladder of individuals with ulcerative IC, amplified expression of TNF-α has been observed. Additionally, serum TNF-α titers, as well as levels of additional proinflammatory cytokines, are higher in patients with IC than in control subjects. These data suggest that in addition to the activation of mast cells, these cytokines are key inflammatory mediators in the disease processes underlying IC [ 25 ].

In vivo models of autoimmune cystitis have been used to experimentally show that inhibition of TNF-α diminishes inflammation within the bladder by disrupting the triggering of mast cells [ 26 , 27 , 28 ]. In this context, vesical inflammation related to IC and the associated symptoms could be relieved by TNF-α inhibition and suppression of mast cell activation using agents that oppose the actions of TNF-α, e.g. adalimumab and certolizumab pegol. Clinical endpoints were enhanced following therapy with adalimumab in individuals with a moderate to severe degree of discomfort from IC [ 29 ]. However, as the placebo effect was significant, a positive proof of concept with respect to adalimumab could not be demonstrated. A further study documented that the use of certolizumab pegol in female subjects with moderate to severe unremitting IC offered greater symptom relief than a placebo [ 30 ].

In the course of development, nerve growth factor (NGF) is a key requisite for sensory and sympathetic nerve cell survival. It has also been determined that NGF is a peripheral mediator in a number of inflammatory disorders associated with pain [ 31 ]. As a humanized monoclonal antibody against NGF, tanezumab has a high affinity and specificity for bonding with NGF, thus blocking the mediator from engaging with nociceptive nerve cell receptors. The latter comprises the high- and low-affinity receptors, tropomyosin-related kinase A and p75 [ 32 ]. Following the use of tanezumab, a clinical trial reported an improvement in pain scores as well as enhanced function and overall evaluation outcomes in individuals with chronic painful disorders, not including IC [ 33 , 34 , 35 ]. The initial effectiveness of pain relief following pain therapy in IC was documented by Evans et al. [ 36 ], but these data were too ambiguous to be incorporated within the current meta-analysis or NMA.

Fulranumab is a human recombinant monoclonal antibody and a powerful human NGF inhibitor. A positive dose effect has been demonstrated in painful disorders, including the neuropathy associated with diabetes. Additionally, mixed data regarding its efficacy in comparison with a placebo have been presented. In patients with osteoarthritic symptoms, fulranumab demonstrated greater efficacy than an opiate, although, in low back pain, no benefit over a placebo was seen [ 32 ]. A study by Wang et al. [ 37 ] failed to show any positive effects from one dose, but the sample size was restricted and the study had insufficient statistical power. The clinical observations from these studies suggest that it would be valuable to carry out a clinical study in larger or more selected populations to establish whether fulranumab would be effective as a treatment for the refractory pain experienced by patients with IC. Additional possible treatment strategies include options from complementary and alternative medicine. These include behavioural and physical therapies approaches to ameliorate stress and modification of the diet [ 4 , 6 ]. In patients who were symptomatic with IC, an intense and systematic alteration of the diet was associated with symptom relief within three months; this benefit continued for a minimum of 12 months [ 38 ].

There are several limitations associated with this study. Firstly, despite the numerous studies encompassed, there is a surplus of specific therapeutic strategies and the study populations for the individual approaches are small. Secondly, the only first-line therapy evaluated was diet modification. AUA guidelines suggest that patient education, patient self-efficacy, behavioural changes and stress reduction should be first-line therapies in individuals with IC [ 3 ]. Finally, the large number of therapeutic possibilities evaluated precluded their concurrent analysis in the NMA.

Conclusions

In patients with IC, therapy is not straightforward. The current work has led to the recognition of a therapeutic combination for this condition that could be anticipated to have a positive clinical outcome. It was established that ongoing therapy is of value, and that the efficacy of treatments is diminished in individuals of advancing years. Additional RCTs are required to ascertain the efficacy of combined therapeutic approaches, such as immunomodulatory compounds, intravesical injection or instillation with BTX or HA, or HA and CS and diet modification.

Availability of data and materials

Data are publicly available. The data supporting this study’s findings are available from the corresponding author upon reasonable request.

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This work was supported by Soonchunhyang University Research Fund. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Jae Joon Park and Kwang Taek Kim are the co-first authors.

Authors and Affiliations

Department of Urology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsangu, Seoul, 04401, Republic of Korea

Jae Joon Park, Joey Chun, Serin Lee & Jae Heon Kim

Department of Urology, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea

Kwang Taek Kim

Department of Radiology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea

Cranbrook Kingswood Upper School, Bloomfield Hills, Michigan, United States

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States

Department of Biomedical Informatics, College of Medicine, Konyang University, 158 Gwanjeodong-ro, Seo-gu, Daejeon, 35365, Republic of Korea

Sung Ryul Shim

Konyang Medical data Research group-KYMERA, Konyang University Hospital, Daejeon, Republic of Korea

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Contributions

Study concept and design: Shim SR and Kim JH; Data acquisition and statistical analyses: Park JJ, Lee EJ, Kim KT, Chun J, Lee SR & Shim SR; Interpretation of data: All authors; Drafting of manuscript: Kim JH, Lee EJ, Shim SR, & Park JJ; Critical revision of manuscript for important intellectual content: All authors; Supervision: Shim SR, Kim JH, & Park JJ. Kim JH and Park JJ are co-first authors. Shim SR had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Sung Ryul Shim or Jae Heon Kim .

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Park, J.J., Kim, K.T., Lee, E.J. et al. Current updates relating to treatment for interstitial cystitis/bladder pain syndrome: systematic review and network meta-analysis. BMC Urol 24 , 95 (2024). https://doi.org/10.1186/s12894-024-01485-w

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Received : 12 November 2023

Accepted : 16 April 2024

Published : 24 April 2024

DOI : https://doi.org/10.1186/s12894-024-01485-w

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• Interstitial
• Lower Urinary Tract Symptoms
• Urinary Bladder
• Medication Therapy Management
• Administration
• Intravesical
• Physical Therapy Modalities

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