Chronic obstructive pulmonary disease (COPD) is a heterogeneous, progressive pulmonary disorder with persistent respiratory symptoms resulting from abnormalities in the airways and/or alveoli and was prevalent globally in 10.3

SCD globally affects over 30 million people and is most prevalent in sub-Saharan Africa, India, the Arabian Peninsula, the Caribbean, and North/South America. Globally, people living with SCD disproportionately suffer premature deaths, hospitalizations due to acute complications, and significant multi-organ complications. Despite vivid similarities with cystic fibrosis (CF), clinical care and research is disproportionately minimal for SCD. Both CF and SCD are inherited, life-limiting, multi-system diseases; however, one mainly affects White people and the other Black people. We aim to describe socio-demographics of SCD populations globally and highlight policy limitations and urgently needed changes to achieve equitable and just SCD care and research. An electronic database search of Ovid MEDLINE (“sickle cell disease and marginalized people” and “policy in sickle cell disease”) was conducted for the period 1947 to May 2022. Additional information was obtained through Google Scholar, gray literature, and back references of relevant articles. Study selection and quality assessment was conducted independently in duplicate. Data were extracted and analyzed from 137 full articles, reports, and gray literature. We propose 5 main actionable items: (1) establish and strengthen national and international screening programs; (2) implement prevention and education programs; (3) enhance collaboration between stakeholders; (4) increase funding for SCD-related research; and (5) promote new models for multidisciplinary and transition care. Globally, social, economic, geographical, and political factors affect access to comprehensive SCD management. Urgent policy changes are needed for equitable, inclusive, and just SCD care with lifespan approach, and research.

Purpose:Race-based correction is widely utilized in clinical practice, but may contribute to overestimation of lung function, underdiagnoses in minority groups, and exclusion of minority groups from research trials. The aim of this systematic review is to examine the usage of race-based correction in pulmonary function testing (PFT) within chronic obstructive lung disease (COPD) research and its impact on the exclusion of minority groups from research trials. Methods:We systematically searched Medline from 2010 to 2022 to identify randomized controlled trials (RCTs) that examine inhaler therapy for COPD. Article screening, critical appraisal, and data extraction were completed in duplicate by independent reviewers. Data regarding study design, inclusion criteria, demographics, and race-based correction were extracted and synthesized narratively. Results:Of the 774 screened articles, we included 21 RCTs in the review, which were multinational trials involving 70696 study participants. All studies had an inclusion criteria of an FEV1 cutoff of 50% to 80%. Racial minorities remained underrepresented in the trials, with the proportion of black participants ranging from <1% to 4.7%. Four studies directly mentioned race-based correction, while the remainder of the studies did not provide any explicit details. After obtaining additional information by contacting authors and reviewing the citations, 15 were estimated to utilize race-based correction. Conclusion:Race-based correction may be frequently utilized in major COPD RCTs, but there remains inconsistent reporting regarding the usage of race-based correction. This may contribute to the exclusion of racialized populations from research trials as there remains significant underrepresentation of racialized populations from research.

Abstract Background Sickle cell disease (SCD) affects over 30 million people and is most prevalent in sub-Saharan Africa, India, the Arabian Peninsula, the Caribbean, and North/South America. Globally, people with SCD disproportionately suffer premature deaths, hospitalizations due to acute complications, and significant multi-organ complications. Despite vivid similarities with Cystic Fibrosis (CF), clinical care and research is disproportionately minimal for SCD. Both CF and SCD are inherited, life-limiting, multi-system diseases; however, one mainly affects white people and the other Black people. Objective We aim to describe socio-demographics of SCD populations globally and highlight policy limitations and urgently needed changes to achieve equitable and just SCD care and research. Methods An electronic database search of Ovid MEDLINE (“sickle cell disease and marginalized people” and “policy in sickle cell disease”) was conducted for the period 1947 to May 2022. Additional information was obtained through Google Scholar, gray literature, and back references of relevant articles. Study selection and quality assessment was conducted independently in duplicate. Results Data were extracted from 137 articles, reports, and gray literature. We propose five main actionable items: 1) establish and strengthen national and international screening programs; 2) implement prevention and education programs; 3) enhance collaboration between stakeholders; 4) increase funding for SCD related research; and 5) promote new models for multidisciplinary care. Conclusions Globally, social, economic, geographical, and political factors affect access to comprehensive SCD management. Urgent policy changes are needed for equitable, inclusive, and just SCD care and research.

IntroductionChronic kidney disease (CKD) demonstrates a complex interaction with tobacco exposure and sex differences, where females and males may experience varying risks and outcomes. This study aims to investigate how sex differences mediate the relationship between tobacco exposure and CKD development, with a secondary focus on regional variability and social determinants of health.Study selection and criteriaComprehensive searches on MEDLINE, EMBASE, clinicaltrials.gov, and MedRxiv until October 6, 2022, were conducted. Eligibility criteria involved any study that reported primary data on the prevalence of CKD, with information pertaining to both sex and tobacco exposure.Data extractionData retrieved include patient socio-demographic characteristics, general study information, diagnostic methods, social determinants of health, and the cause of CKD (e.g., tobacco-related or non-tobacco-related).ResultsStudies were selected through a comprehensive search using key terms such as "chronic kidney disease," "smoking," and "sex differences," which identified 3,025 articles, of which 28 were selected for full texts after screening titles, abstracts. Among the 28 included studies, smoking was consistently identified as a significant risk factor for CKD, with notable disparities related to sex, socioeconomic status, race, and urban versus rural settings. Significant geographical variability in CKD prevalence was observed, ranging from 2.5% to 68.1%, with the highest prevalence in Asia. However, due to high heterogeneity and methodological limitations, a meta-analysis of CKD prevalence stratified by sex and tobacco exposure was not feasible.ConclusionsThe findings emphasize the need for further research to comprehend the intricate relationship between, tobacco exposure, sex, and CKD management, as well as the consideration of cultural, geographical, socioeconomic, political, and structural factors when understanding the pathophysiology and management of CKD.

Objective To systematically identify and narratively synthesize the evidence surrounding liposomal delivery of gene therapy and the outcome for ovarian cancer. Methods An electronic database search of the Embase, MEDLINE and Web of Science from inception until July 7, 2023, was conducted to identify primary studies that investigated the effect of liposomal delivery of gene therapy on ovarian cancer outcomes. Retrieved studies were assessed against the eligibility criteria for inclusion. Results The search yielded 564 studies, of which 75 met the inclusion criteria. Four major types of liposomes were identified: cationic, neutral, polymer-coated, and ligand-targeted liposomes. The liposome with the most evidence involved cationic liposomes which are characterized by their positively charged phospholipids (n = 37, 49.3%). Similarly, those with neutrally charged phospholipids, such as 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine, were highly researched as well (n = 25, 33.3%). Eight areas of gene therapy research were identified, evaluating either target proteins/transcripts or molecular pathways: microRNAs, ephrin type-A receptor 2 (EphA2), interleukins, mitogen-activated protein kinase (MAPK), human-telomerase reverse transcriptase/E1A (hTERT/EA1), suicide gene, p53, and multidrug resistance mutation 1 (MDR1). Conclusion Liposomal delivery of gene therapy for ovarian cancer shows promise in many in vivo studies. Emerging polymer-coated and ligand-targeted liposomes have been gaining interest as they have been shown to have more stability and specificity. We found that gene therapy involving microRNAs was the most frequently studied. Overall, liposomal genetic therapy has been shown to reduce tumor size and weight and improve survivability. More research involving the delivery and targets of gene therapy for ovarian cancer may be a promising avenue to improve patient outcomes.

OBJECTIVES:To create a comprehensive list of all openly available online trainings in scholarly peer review and to analyze their characteristics. STUDY DESIGN AND SETTING:A systematic review of online training material in scholarly peer review openly accessible between 2012 and 2022. Training characteristics were presented in evidence tables and summarized narratively. A risk of bias tool was purpose-built for this study to evaluate the included training material as evidence-based. RESULTS:Fourty-two training opportunities in manuscript peer review were identified, of which only twenty were openly accessible. Most were online modules (n = 12, 60%) with an estimated completion time of less than 1 hour (n = 13, 65%). Using our ad hoc risk of bias tool, four sources (20%) met our criteria of evidence-based. CONCLUSION:Our comprehensive search of the literature identified 20 openly accessible online training materials in manuscript peer review. For such a crucial step in the dissemination of literature, a lack of training could potentially explain disparities in the quality of scholarly publishing.

ObjectivesTo identify, summarize, and analyse comments on the core reporting guidelines for protocols of randomized trials (Standard Protocol Items: Recommendations for Interventional Trials [SPIRIT] 2013) and for completed trials (Consolidated Standards of Reporting Trials [CONSORT] 2010), with special emphasis on suggestions for guideline modifications.MethodsWe included documents written in English and published after 2010 that explicitly commented on SPIRIT 2013 or CONSORT 2010. We searched four bibliographic databases (Embase and MEDLINE to June 2022; Web of Science and Google Scholar to April 2022) and other sources (e.g., the EQUATOR Network website, the BMC Blog Network, and the BMJ rapid response section). Two authors independently assessed documents for eligibility and extracted data on basic characteristics and the wording of the main comments. We categorized comments as 'suggestion for modification to the wording of an existing guideline item,' 'suggestion for a new item,' or 'reflections on challenges or strengths.' We provided a summary and examples of the proposed suggestions and categorized comments into those that were directly linked to empirical investigations, were continuations of previous methodological discussions, or reflected new methodological developments.ResultsWe assessed full text of 2,320 potentially eligible documents and included 93 documents with 114 comments. In total, 37 comments suggested modifications to existing guideline items. The participant flow section of CONSORT 2010 received the most comments (eight comments made different suggestions, e.g., one comment suggested to add numbers on nonrandomized screened participants). There were 46 comments suggesting new items. Multiple suggestions were related to trial interventions (eight comments made different suggestions, e.g., one comment suggested to add content on cointerventions), blinding (six comments suggested to add content on risk of unblinding), statistical methods (five comments made different suggestions, e.g., one comment suggested to add content on blinding of statisticians), and participant flow (seven comments made different suggestions, e.g., three comments suggested to add content on missing data). Half (53%) of the suggestions were directly linked to empirical investigations. Six (7%) suggestions were continuations of previous methodological discussions and five (6%) suggestions reflected new methodological developments related to conflicts of interest and funding, data sharing, and patient and public involvement.ConclusionThe issues raised provide context to authors, peer reviewers, editors, and readers of trials using SPIRIT 2013 and CONSORT 2010 and inform the planned updates of the core guidelines.

Adherence to study registration and reporting best practices is vital to fostering evidence-based medicine. All registered clinical trials on ClinicalTrials.gov conducted in Canada as of 2009 and completed by 2019 were identified. A cross-sectional analysis of those trials assessed prospective registration, subsequent result reporting in the registry, and subsequent publication of study findings. The lead sponsor, phase of study, clinical trial site location, total patient enrollment, number of arms, type of masking, type of allocation, year of completion, and patient demographics were examined as potential effect modifiers to these best practices. A total of 6720 trials were identified. From 2009 to 2019, 59% (n = 3,967) of them were registered prospectively, and 32% (n = 2138) had neither their results reported nor their findings published. Of the 3763 trials conducted exclusively in Canada, 3% (n = 123) met all three criteria of prospective registration, reporting in the registry, and publishing findings. Overall, the odds of having adherence to all three practices concurrently in Canadian trials decrease by 95% when compared with international trials. Canadian clinical trials substantially lacked adherence to study registration and reporting best practices. Knowledge of this widespread non-compliance should motivate stakeholders in the Canadian clinical trial ecosystem to address and continue to monitor this problem.

Collectively, these results showed that HSV-2 is taken up by human vaginal epithelial cells through an endosomal-lysosomal pathway in association with LAMP3, which plays a crucial role in the enhancement of HSV-2 replication. These findings provide the basis for the future design of antiviral agents for prophylactic measures against HSV-2 infection.

Objective: To identify, summarise, and analyse comments on the core reporting guidelines for protocols of randomised trials (SPIRIT 2013) and for completed trials (CONSORT 2010), with special emphasis on suggestions for guideline modifications.Methods: We included documents written in English and published after 2010 that explicitly commented on SPIRIT 2013 or CONSORT 2010. We searched four bibliographic databases (Embase and MEDLINE to June 2022; Web of Science and Google Scholar to April 2022) and other sources (e.g., the EQUATOR Network web-site, the BMC Blog Network, and the BMJ rapid response section). Two authors independently assessed documents for eligibility and extracted data on basic characteristics and the wording of the main comments. We categorized comments as ‘suggestion for modification to the wording of an existing guideline item’, ‘suggestion for a new item’, or ‘reflections on challenges or strengths’. We provided a summary and examples of the proposed suggestions and categorised comments into those that were directly linked to empirical investigations, were continuations of previous methodological discussions, or reflected new methodological developments.Results: We assessed full text of 2320 potentially eligible documents and included 93 documents with 114 comments. In total, 37 comments suggested modifications to existing guideline items. The participant flow section of CONSORT 2010 received the most comments (eight comments made different suggestions, e.g., one comment suggested to add numbers on non-randomised screened participants). There were 46 comments suggesting new items. Multiple suggestions were related to trial interventions (eight comments made different suggestions, e.g., one comment suggested to add content on co-interventions), blinding (six comments suggested to add content on risk of unblinding), statistical methods (five comments made different suggestions, e.g., one comment suggested to add content on blinding of statisticians), and participant flow (seven comments made different suggestions, e.g., three comments suggested to add content on missing data). Half (53%) of the suggestions were directly linked to empirical investigations. Six (7%) suggestions were continuations of previous methodological discussions, and five (6%) suggestions reflected new methodological developments related to conflicts of interest and funding, data sharing, and patient and public involvement.Conclusion: The issues raised provide context to authors, peer reviewers, editors and readers of trials using SPIRIT 2013 and CONSORT 2010 and inform the planned updates of the core guidelines.

Objective: Premenstrual syndrome (PMS) is a very prevalent condition that affects premenopausal women and can result in monthly debilitating emotional and physical symptoms. The objective of this systematic review was to determine which predictive factors were associated with an increased amount of bias in non-randomized studies (NRSs) of PMS. Materials and methods: A search of the EMBASE and Medline electronic databases was completed from January 1, 2010 to December 2021. The methodological quality of the included studies was independently evaluated and critically appraised using the Risk of Bias in Non-Randomized Studies - of Interventions (ROBINS-1) tool. Associations of different factors with the risk of bias levels were assessed using a univariate logistic regression. Odds ratio and 95% confidence interval (CI) were reported. Results: Of the 1668 studies, 38 were determined to be eligible for inclusion. The ROBINS-1 tool identified that 12 studies were of low/moderate risk of bias (31.6%) and 26 were of serious/critical risk (68.4%). Evidence of relationships between the ROBINS-1 score and impact factor (OR=0.20; 95% CI, 0.07 to 0.57; p= 0.003) and number of authors (OR=0.65; 95% CI, 0.43 to 0.99; p= 0.046) were identified, whereas no relationships were found with the number of citations, the sample size, the funding type, or the conflict-of-interest statement. Conclusion: The systematic review concludes that the methodological rigor of non-randomized studies of PMS can vary, with fewer authors and a lower impact factor showing evidence of association with a decreased quality of evidence.

ABSTRACT 1. Background Peer review plays an integral role in scientific publishing. Despite this, there is no training standard for peer reviewers and review guidelines tend to vary between journals. The purpose of this study was to conduct a systematic review of all openly available online training in scholarly peer review and to analyze their characteristics. 2. Methods MEDLINE, PsycINFO, Embase, ERIC, and Web of Science were systematically searched. Additional grey literature searches were conducted on Google, YouTube, university library websites, publisher websites and the websites of peer review related events and groups. All English or French training material in scholarly peer review of biomedical manuscripts openly accessible online on the search date (September 12, 2021) were included. Sources created prior to 2012 were excluded. Screening was conducted in duplicate in two separate phases: title and abstract followed by full text. Data extraction was conducted by one reviewer and verified by a second. Conflicts were resolved by third-party at both stages. Characteristics were reported using frequencies and percentages. A direct content analysis was preformed using pre-defined topics of interest based on existing checklists for peer reviewers. A risk of bias tool was purpose-built for this study to evaluate the included training material as evidence-based. The tool was used in duplicate with conflicts resolved through discussion between the two reviewers. 3. Results After screening 1244 records, there were 43 sources that met the inclusion criteria; however, 23 of 45 (51%) were not able to be fully accessed for data extraction. The most common barriers to access were membership requirements (n = 11 of 23, 48%), availability for a limited time (n = 8, 35%), and paywalls with an average cost of $99 USD (n = 7, 30%). The remaining 20 sources were included in the data analysis. All sources were published in English. Half of the sources were created in the last five years (n = 10, 50%). The most common training format was an online module (n = 12, 60%) with an estimated completion time of less than one hour (n = 13, 65%). The most frequently covered topics included how to write a peer review report (n = 18, 90%), critical appraisal of data and results (n = 16, 80%), and a definition of peer review (n = 16, 80%). Critical appraisal of reporting guidelines (n = 9, 45%), clinical trials (n = 3, 15%), and statistical analysis (n = 3, 15%) were less commonly covered. Using our ad-hoc risk of bias tool, four sources (20%) met our criteria for evidence-based. 4. Conclusion Our comprehensive search of the literature identified 20 openly accessible online training materials in manuscript peer review. For such a crucial step in the dissemination of literature, a lack of training could potentially explain disparities in the quality of scholarly publishing. Future efforts should be focused on creating a more unified openly accessible online manuscript peer review training program.

Background Adherence to study registration and reporting best practices are vital to foster evidence-based medicine. Poor adherence to these standards in clinical trials conducted in Canada would be detrimental to patients, researchers, and the public alike. Methods All registered clinical trials on [ClinicalTrials.gov][1] conducted in Canada as of 2009 and completed by 2019 were identified. A cross-sectional analysis of those trials assessed prospective registration, subsequent result reporting in the registry, and subsequent publication of study findings. The lead sponsor, phase of study, clinical trial site location, total patient enrollment, number of arms, type of masking, type of allocation, year of completion, and patient demographics were examined as potential effect modifiers to these best practices. Results A total of 6,720 trials met the inclusion criteria. From 2009-2019, 59% (n=3,967) of them were registered prospectively and 39% (n=2,642) reported their results in the registry. Of the trials registered between 2009-2014, 55% (n=1,482) were subsequently published in an academic journal. Of the 3,763 trials conducted exclusively in Canada, 3% (n=123) met all 3 criteria of: prospective registration, reporting in the registry, and publishing findings. In contrast, of the remaining 2,957 trials with both Canadian and international sites, 41% (n=1,238) had an overall compliance to these three criteria. Overall, the odds of having adherence to all three practices concurrently in Canadian trials decreases by 95% when compared to international trials (OR = 0.05; 95CI: 0.04 – 0.06). Conclusion Canadian clinical trials substantially lacked adherence to study registration and reporting best practices. Knowledge of this widespread non-compliance should motivate stakeholders in the Canadian clinical trials ecosystem to address and continue to monitor this problem. The data presented provides a baseline against which to compare any improvement in the registration and reporting of clinical trials in Canada. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This work was funded by the Summer Studentship Program from the University of Ottawa, Faculty of Medicine. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data referred to in the manuscript are available online at https://osf.io/kb4nf/ [1]: http://ClinicalTrials.gov

Objectives: The objective of this study was to evaluate the extent, type, and severity of spin in randomized controlled trials (RCTs) in obstetrics and gynecology.Data Sources: The top five highest impact journals in obstetrics and gynecology were systematically searched for RCTs with non-significant primary outcomes published between January 1, 2019, and December 31, 2020.Methods: Study selection and data extraction assessment were conducted independently and in duplicate. The extent, type, and severity of spin was identified and reported with previously established methodology, and risk of bias was assessed with the Cochrane Risk-of-Bias 2 Tool independently and in duplicate. Fisher's exact tests were used to evaluate the association between study characteristics, risk of bias, and spin.Results: We identified 1475 publications, of which 59 met our inclusion criteria. Articles evaluated interventions in obstetrics (n = 37, 63%) and gynecology (n = 22, 37%). Spin was not detected in 28 (47%) of the articles: Three (5%) had one, 10 (17%) had two, and 18 (31%) had greater than two occurrences of spin. Compared with articles where no spin was detected, spin was associated with the Cochrane Risk-of-Bias domain pertaining to missing data (p < 0.05). No association was observed with the journal, funding source, number of authors, types of interventions, and whether the study involved gynecology or obstetrics.Conclusions: Spin was detected in nearly half of 1:1 parallel two-arm RCTs in obstetrics and gynecology, highlighting the need for caution in the interpretation of RCT findings, particularly when the primary outcome is nonsignificant.

Purpose Induction of labour has become more common over the last decade, together with an increase in the number of systematic reviews of the subject. However, with multiple systematic reviews it is necessary to evaluate the methodological rigor to ensure the reliability of conclusions and recommendations for clinical practice. Therefore, the aim of this study was to appraise the quality of systematic reviews that examined the efficacy and/or safety of labour induction methods. Methods An electronic search of MEDLINE, Embase, and the Cochrane Library from 2000 to 2020 was conducted. Study selection, data extraction and quality assessment were conducted using A Measurement Tool to Assess Systematic Reviews (AMSTAR) by two independent reviewers, in duplicate. Results The search identified 387 publications, of which 48 studies (13%) met the a priori inclusion criteria. No significant relationships were found between study quality and number of citations, journal impact factor, or publication year. Conclusion Methodological quality for systematic reviews on the induction of labour were ranked as moderate with no significant changes in quality over the past 2 decades. Publication characteristics are not significantly associated with methodological quality, indicating that healthcare professionals should critically appraise studies before applying them to practice.

Abstract Background Postpartum depression (PPD) is a highly prevalent mental health problem that affects parental health with implications for child health in infancy, childhood, adolescence and beyond. The primary aim of this study was to critically appraise available systematic reviews describing interventions for PPD. The secondary aim was to evaluate the methodological quality of the included systematic reviews and their conclusions. Methods An electronic database search of MEDLINE, Embase, and the Cochrane Library from 2000 to 2020 was conducted to identify systematic reviews that examined an intervention for PPD. A Measurement Tool to Assess Systematic Reviews was utilized to independently score each included systematic review which was then critically appraised to better define the most effective therapeutic options for PPD. Results Of the 842 studies identified, 83 met the a priori criteria for inclusion. Based on the systematic reviews with the highest methodological quality, we found that use of antidepressants and telemedicine were the most effective treatments for PPD. Symptoms of PPD were also improved by traditional herbal medicine and aromatherapy. Current evidence for physical exercise and cognitive behavioural therapy in treating PPD remains equivocal. A significant, but weak relationship between AMSTAR score and journal impact factor was observed (p = 0.03, r = 0.24; 95% CI, 0.02 to 0.43) whilst no relationship was found between the number of total citations (p = 0.27, r = 0.12; 95% CI, − 0.09 to 0.34), or source of funding (p = 0.19). Conclusion Overall the systematic reviews on interventions for PPD are of low-moderate quality and are not improving over time. Antidepressants and telemedicine were the most effective therapeutic interventions for PPD treatment.

Abstract Study question Is there an association between exposure to certain environmental toxins and the prevalence of uterine leiomyoma in women? Summary answer Some evidence was obtained to suggest an association between phthalate esters, bisphenol A, heavy metals, persistent organic pollutants and the prevalence of uterine fibroids. What is known already Environmental toxins are naturally occurring, or human made chemicals that can act as endocrine disrupting chemicals (EDCs) by binding and activating estrogen receptors in the body. Uterine fibroids, often called leiomyoma are non-cancerous growths occurring in the uterus. Though often asymptomatic, they can cause pain, infertility, pregnancy complications and are a leading cause for hysterectomy. The aetiology of leiomyoma is not fully understood but both estrogen and progesterone have been implicated in their growth. We aimed to investigate the epidemiological evidence for the association between EDCs and the prevalence of fibroids. Study design, size, duration We undertook a systematic review and in keeping with PRISMA guidelines, a structured search of Medline, Embase, Scopus, and Web of Science was conducted (to October 2020). Case-control, cross-sectional, cohort and experimental studies were included. Participants/materials, setting, methods The included studies analyzed the association between one or more toxins and the occurrence, or growth of leiomyoma in humans, including human cell lines. The types of toxins, patient characteristics, association and outcome, body concentration of toxin and confounding variables were extracted and analyzed. Quality assessment was performed using the Newcastle-Ottawa Scale. Main results and the role of chance In total, 34 studies were included. The majority (76%) of studies revealed a significant association between the exposure studied and the prevalence of uterine leiomyoma. In examining body burden in cases vs controls, phthalate esters showed an association with increased odds of uterine leiomyoma, except in one case where a negative association was observed. In vitro experimental studies examining the effect of alkyl-phenols such as bisphenol A (BPA), octylphenol (OP) and nonylphenol (NP) demonstrated that these environmental estrogens can act to promote the proliferation of leiomyoma cells through a number of mechanisms, typically including the estrogen receptor alpha (ERa) signalling pathway. There were conflicting results for the association between alkyl-phenols and fibroids in case-control studies. A positive association between cadmium was demonstrated in only two studies. There were conflicting results for the association between lead, mercury, arsenic and uterine fibroids. Several metabolites of organophosphate esters, alternative plasticizers, and persistent organic pollutants were associated with an increased risk of uterine fibroids. Limitations, reasons for caution Separating these exposures from the multiple other factors that could affect the outcome of leiomyoma is challenging, but an important issue for future research. Wider implications of the findings The link between some environmental toxins and uterine fibroids discussed is in agreement with previous literature. However, our review provides a more in depth analysis on specific dosage effects, odds ratios, and potential gene mechanisms of the exposures. This information could contribute to more accurate preventative measures. Trial registration number not applicable

Study Objective Uterine leiomyoma, often called fibroids, are benign tumours in the uterus and are prevalent in up to 70% of women. Environmental toxicants that can mimic and disrupt estrogen signaling have led to the hypothesis that toxicants may be associated with increased prevalence of leiomyoma. Our objective was to systematically review the literature examining this association. Design A systematic search of MEDLINE, EMBASE, SCOPUS, and Web of Science was conducted (to October 2020) to identify primary literature reporting toxicant exposure on leiomyoma. Only human or human cell studies in English were included. Data extracted included type of exposure, dosage and effect size. Quality assessment was done using the Newcastle-Ottawa Scale. Setting N/A. Patients or Participants N/A. Interventions N/A. Measurements and Main Results Thirty-three studies (24 patient and 9 in-vitro) were included. Patient studies examined plasticizers (phthalates, n=9; others, n = 3), bisphenol A (n = 7), phenols (n=5), organohalogen compounds (n = 5), heavy metals (n = 3), polycyclic aromatic hydrocarbons (n=1), and hair relaxers (n=1). Positive associations were identified for each group of toxicants, though results were often conflicting. Specific compounds most commonly positively associated with fibroids were di (2- ethylhexyl) phthalate (DEHP) metabolites (phthalates; n=5); nonylphenol (phenols; n=5), and bisphenol A (n=4). The majority of in vitro studies (n=6) reported effects of bisphenol A on leiomyoma growth and half of these suggested mediation through the estrogen receptor alpha signaling pathway. Studies that measured toxicants in urine had more positive outcomes than studies examining the same toxicants in the serum. Conclusion Review of the literature supports environmental toxicants as potential contributors in leiomyoma prevalence. We found that DEHP, bisphenol A, and nonylphenol were often positively associated with leiomyoma. Additionally, we found differential outcomes based on the tissue which the exposure was drawn from. The cause-effect relationship of toxicant exposure on leiomyoma will be an imperative topic for future research.