To date, several systematic reviews and meta-analyses have explored associations between commonly used drugs and gastric cancer (GC) risk, with inconsistent conclusions on relationships and methodological quality. No attempts have been made to quantify the credibility of these findings. Hence, it is necessary to compare the results of individual reviews by looking into existing systematic reviews and meta-analyses, providing an overview of the findings of a particular association. This is the first umbrella review to evaluate the validity and credibility of evidence from previously published systematic reviews and meta-analyses on observational studies and to identify associations between commonly used drugs and GC risk and its subtypes.Recently, attention has been paid to some medications and gastric cancer (GC) risk. This review aimed to evaluate associations between commonly used drugs and GC risk and to grade evidence from published systematic reviews and meta-analyses. This umbrella review was registered in PROSPERO (CRD42022320276). The systematic reviews and meta-analyses of observational studies were retrieved by searching Embase, PubMed, and Web of Science. The evidence strength of commonly used drugs and GC risk was categorized into four grades: weak, suggestive, highly suggestive, and strong. Of 19 associations between commonly used drugs and GC risk and its subtypes, none was supported by convincing or highly suggestive evidence. The risk of GC related to non-steroidal anti-inflammatory drugs (NSAIDs), non-aspirin NSAIDs, and acid-suppressive drugs, as well as the risk of non-cardia GC related to NSAIDs and aspirin, was supported by suggestive evidence. The results showed that a reduced GC risk was associated with two drug types (NSAIDs and non-aspirin NSAIDs), and an increased GC risk was associated with acid-suppressing drugs at the suggestive evidence level. Moreover, NSAIDs and aspirin reduced non-cardia GC risk as supported by suggestive evidence. However, the evidence supporting statins or metformin in reducing GC risk was weak, and thus future studies are required to clarify these associations. Globally, it was estimated that over one million new incidences of gastric cancer (GC) and approximately 769,000 deaths were reported in 2020, and GC ranked as the fourth-highest mortality rate and the fifth-highest incidence . AccordiHelicobacter pylori (H. pylori) is a pivotal therapeutic step against GC [H. pylori infection, include family history, salted food, alcohol, and smoking [The eradication of ainst GC . The est smoking ,10,11,12 smoking ,14,15. H smoking ,17, but  smoking ,19. An u smoking ,21; therOverall, this review evaluated the validity and credibility of evidence from previously published systematic reviews and meta-analyses on observational studies and identified associations between commonly used drugs and GC risk.This umbrella review is registered at PROSPERO CRD42022320276). It was conducted following guidelines from the Preferred Reporting Items of Systematic Reviews and Meta-Analyses [320276. IWeb of Science, Embase, and PubMed (last updated on 14 January 2022) were searched to retrieve all systematic reviews and meta-analyses of observational studies focusing on associations between commonly used drugs and GC risk . All refTwo investigators (X.B. and S.-Q.D.) independently screened titles and abstracts, and checked full texts. All disagreements were figured out by three authors  through discussion. Eligibility criteria included: (1) systematic reviews and meta-analyses of observational studies measuring associations between commonly used drugs and GC incidence in any population; (2) results from subgroup analyses stratified by drug type; (3) studies focusing on GC subtypes.Exclusion criteria included: (1) articles that did not examine the use of any commonly drugs; (2) articles that did not assess outcomes of interest ; (3) articles that described some unconventional drugs ; (4) meta-analyses including less than three original studies. In addition, non-English articles, animal studies, and genetic studies were excluded as well. If the same association was examined by two or more meta-analyses, associations in different meta-analyses were considered to be duplicate associations; therefore, the meta-analysis with the largest sample size was selected to avoid overlap, as previously indicated ,24,25.Two authors (X.B. and S.-Q.D.) carried out extraction independently, and three authors  resolved discrepancies by consensus. The first author’s name, year of publication, country, drug type, outcome (GC or its subtypes), comparison, total participants, number of GC cases, and number of included studies were extracted from each eligible meta-analysis. The first author’s name, year of publication, number of subjects and cases, as well as maximally adjusted effect size, including corresponding 95% confidence interval (CI), hazard ratio, odds ratio, and relative risk, were recorded from each primary study included in the meta-analysis for further analysis.A Measurement Tool to Assess Systematic Reviews (AMSTAR) version 2.0, which contained 16 items, was used by two researchers (X.B. and S.-Q.D.) to evaluate the study quality . Disagrep-values for summary effects were calculated at the same time [2 statistics; an I2 > 50% value indicated significant heterogeneity and an I2 > 75% indicated high heterogeneity [First, the effect size of each study included in each meta-analysis was extracted, and a random-effect model was used to assess the effect size with 95% CI for each association. The corresponding ame time . Heterogogeneity ,29. To bogeneity .p-value for Egger’s test < 0.10.Then, Egger’s regression asymmetry tests were used to identify small-study effects, reflecting heterogeneity, genuine opportunity, or other reasons for differences between small and large studies ,32,33. Ap-value for the excess significance test < 0.10, excess significance was considered positive. The STATA version 16.0  was used for all analyses.Excessive significance bias was applied after accounting for publication bias, selective reporting bias and other potential biases. Whether the expected number (E) with significant results was less than the observed number (O) with significant results was compared . A non-cp < 0.05) were rated as four classifications: class I: convincing; class II: highly suggestive; class III: suggestive; class IV: weak.Evidence credibility was assessed using the established criteria from previous umbrella reviews ,37,38,39p < 10−6, number of cases > 1000, p < 0.05 of the largest study, 95% PI excluding the null value, I2 < 50%, p-value for Egger’s test > 0.10, p-value for excess significance test > 0.10.For class I: p < 10−6, number of cases > 1000, p < 0.05 of the largest study.For class II: p < 10−3 and number of cases > 1000.For class III: p < 0.05.For class IV: the summary results of p > 0.05 were ranked as class V with no significance.The summary results of A total of 16,227 studies were screened, and 76 full-text articles were evaluated for eligibility after removing duplicates and screening titles and abstracts. Ultimately, 11 meta-analyses were included in this umbrella review ,48,49,5019 associations were described in 11 eligible meta-analyses, including 147 individual study estimates of GC risk related to exposure to commonly used drugs. The characteristics of these 11 studies and their distributions related to drug type are shown . The incUsing AMSTAR-2, only one (9.1%) meta-analysis was graded as high quality, one (9.1%) was low, and nine (81.8%) were critically low . All stup ≤ 0.05, and only one association (5.3%) between NSAIDs and GC risk reached p < 10−6. Moreover, four associations (21.1%) showed moderate statistical significance (p < 10−3), including non-aspirin NSAIDs and GC risk, NSAIDs and non-cardia GC risk, aspirin and non-cardia GC risk, as well as acid-suppressing drugs and GC risk. The majority of associations that reached statistical significance suggested potential preventative effects on GC risk, including statins, metformin, NSAIDs, aspirin, and non-aspirin NSAIDs. However, acid-suppressing drugs, including H2RAs and PPIs, increased the risk of GC. The effect of the largest study per association indicated that 7 of 19 were significant at p < 0.05.The random-effect model was used to re-perform meta-analyses of 19 associations . Twelve 2 > 75%) was observed in five associations (26.3%) with GC risk: atorvastatin, simvastatin, pravastatin, aspirin, and PPIs. The inter-study heterogeneity was analyzed by calculating the 95% PI value, and only one association (5.3%) between non-aspirin NSAIDs and GC risk excluded the null value  showed significant heterogeneity. Besides, high heterogeneity : any statins and GC risk, simvastatin and GC risk, NSAIDs and GC risk, NSAIDs and non-cardia GC risk, as well as non-aspirin NSAIDs and non-cardia GC risk . HoweverNo evidence of excess significance bias was observed when the plausible effect size was supposed to be equal to the largest study estimate .Of 19 associations between commonly used drugs and GC risk and its subtypes, no association was supported by convincing or highly suggestive evidence. Five associations (26.3%) were supported by suggestive evidence: the association between NSAIDs use, non-aspirin NSAIDs use and decreased GC risk, the association between NSAIDs use, aspirin use and decreased non-cardia GC risk, and the association between acid-suppressing drug use and increased GC risk . NotablyCommonly used drugs may have potential links with various cancer types during the treatment of chronic diseases. To date, several systematic reviews or meta-analyses have explored associations between commonly used drugs and GC risk ,53,54,55In this study, two pieces of suggestive evidence showed that the intake of NSAIDs and non-aspirin NSAIDs could reduce the incidence of GC, while another one showed that the intake of acid-suppressing drugs was positively related to a higher risk of GC. For subtypes of GC, two pieces of suggestive evidence suggested that the increased intake of NSAIDs and aspirin was related to a lower risk of non-cardia GC. Five pieces of weak evidence suggested that the increased intake of aspirin, metformin and any statins was negatively associated with the incidence of GC, while the intake of H2RAs and PPIs was positively associated with a higher risk of GC. Two pieces of weak evidence showed that the increased intake of non-aspirin NSAIDs intake could have a negative correlation with the incidence of both cardia GC and non-cardia GC. The remaining drugs had no association with GC risk. All of these were previously summarized in NSAIDs, including aspirin and non-aspirin NASIDs, are commonly used to treat fever, pain, and inflammation. Recently, the anti-cancer effects of NSAIDs have also been reported in several cancer prevention studies ,57,58. HAcid-suppressing drugs, including H2RAs and PPIs, are primary treatments for peptic ulcer disease, gastroesophageal reflux disease, and other digestive diseases ,70. ThisIn addition to PPIs, the role of statins and metformin in GC development has also been widely studied ,77,78. SThis is the first umbrella review to systematically explore evaluate associations between commonly used drugs and the risk of GC and its subtypes through published systematic reviews and meta-analyses of observational studies. However, there are several limitations to this study. First, the evidence from meta-analyses of observational studies was graded only. Observational studies often have more potential for bias and confounding issues when compared with randomized controlled studies. Thus, the associations identified in observational studies did not necessarily imply causality. Second, the credibility of the umbrella review depended directly on meta-analyses and indirectly on individual studies; therefore, some biases were inevitable. Third, the methodological quality of most systematic reviews and meta-analyses was critically low from the perspective of AMSTAR-2 analyses. Fourth, drug use and the risk of GC subtypes was not comprehensively reviewed due to a lack of data. For example, associations between acid-suppressing drugs and the risk of GC subtypes were not reviewed because the number of GC subtypes from an individual study was not reported . FurtherTo conclude, three associations between GC risk and commonly used drugs  were supported by suggestive evidence. It was found that the intake of NSAIDs or non-aspirin NSAIDs could reduce GC risk, whereas the intake of acid-suppressing drugs could increase GC risk. Moreover, the decreased risk of non-cardia GC associated with NSAIDs or aspirin was also supported by suggestive evidence. However, caution should be exercised when interpreting these relationships, and high-quality studies are required in the future to determine whether these associations have absolute causality.


Subgroup comparisons did not find a statistically significant difference in the levels of Hcy between AD and PD patients. The overall risk of bias for the analyzed studies was low, with some moderate risk of bias across select domains. This meta-analysis determined that compared to females, males with either AD or PD have higher levels of Hcy. These findings suggest that Hcy could be a useful biomarker for predicting neurodegenerative diseases in males; however, further studies are needed to confirm the clinical utility of this suggestion.Although recent studies suggest homocysteine (Hcy) is an independent risk factor for neurodegenerative disorders, little is known about sex differences in the levels of Hcy. In this study, we conducted a comparative meta-analysis to investigate sex differences in the levels of Hcy in both Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients. Reports of Hcy stratified by sex in both AD and PD patients were obtained from electronic databases. From the initial 1595 records, 921 were assessed for eligibility, of which 16 sufficiently reported sex differences. Standardized mean difference (SMDs) using random effects together with tests of heterogeneity and quality assessment were applied in this meta-analysis. Data from 3082 diagnosed patients  were included. There were statistically significant differences in the levels of Hcy between sexes in AD and PD patients, with an SMD of 0.291 ,  Alzheimer’s disease (AD) and Parkinson’s disease (PD) are chronic neurodegenerative disorders that involve the loss of neurons and synapses and the deposition of aberrant proteins ,2. AD, tCommon neuropathological hallmarks of AD include the deposition of the extracellular amyloid plaques and intracellular neurofibrillary tangles which compromise cellular pathways, leading to neuronal apoptosis and progressive changes in brain structure and function ,4,5. TheThe main neuropathological features of PD include loss of dopaminergic neuronal cells in the substantia nigra and substantial deposition of intracellular proteins or Lewy bodies consisting of aggregates of α-synuclein proteins . The etiHomocysteine (Hcy) is a sulfur-containing amino acid metabolite produced by the trans-methylation of methionine ,11. ExteSex is one of the predominant and unmodifiable risk factors in the development of neurodegenerative disorders . FemalesThis meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles were identified by searching Medline Ovid (1946-Present), Embase Ovid (1947-Present), Web of Science (1900-Present), PsycINFO (1806-Present), and Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (2000-present). Articles were reviewed by two independent raters and in the case of conflicts, final consensus was reached by a third rater.Diagnostic and Statistical Manual of Mental Disorders, DSM-5/American Psychiatric Association). There were no limitations on age and patients could have pharmacological and surgical interventions or co-morbidities. Pre-clinical trials and non-peer-reviewed studies were excluded.We included studies from English-language peer-reviewed journals that (1) reported Hcy levels by sex/gender  and (2) included patients who were diagnosed with AD or PD ), age, study design, and type of diagnosis.Standard mean differences (SMD) or Cohen’s d effect size and 95% confidence level (CI) were used in this meta-analysis in that Hcy concentration levels could be measured by different instruments. Random-effects model was applied to account for statistical heterogeneity as diversity across sample sizes and distribution of sexes among studies was expected . The magSMD of 0.2 represents a small effect;SMD of 0.5 represents a medium effect;SMD of 0.8 represents a large effect.2 statistic (I2) [2) was as follows:Measurement of heterogeneity based on chi-square test (Q) was included in forest plots . To quantic (I2) . An inte2 < 60% is regarded as moderateI2 from 50% to 90% is considered substantialI2 from 75% to 100% is considerableIEvaluation of publication bias across studies was visually quantified using funnel plots and Egger’s test . Lastly,The selection process of studies was guided by The Preferred Reporting Items for Systematic Reviews and Meta-analyses and is summarized in the flowchart shown in p < 0.05, 95% CI. The test of heterogeneity using Chi2 statistic revealed moderate heterogeneity across studies, I2 = 46.84%, Q  = 24.5, p > 0.05. Of the 16 studies, four studies  reported significant differences in the levels of Hcy stratified by sex [The results of the meta-analysis are presented in d by sex ,30,32,34p > 0.05. Overall heterogeneity across AD and PD remained moderate, I2 = 45.08%, Q (14) = 22.61, p > 0.05. However, subgroup analysis of the seven PD studies was found to have substantial heterogeneity, I2 = 56.43%, Q(6) = 4.82, p < 0.05.A between-study subgroup analysis was performed to evaluate the sex differences in Hcy between individuals diagnosed with AD and PD. The risk of bias was assessed in each of the 16 included studies using the Newcastle Ottawa Scale and the Cochrane Collaboration’s risk of bias assessment items. We established that all papers had either a low or unclear risk of bias in four domains: random sequence generation, allocation concealment, blinding of participants, and blinding of outcome assessment. Since most studies were neither randomized controlled trials (RCT) nor interventional, there was a low likelihood of both performance and detection bias across studies. Two studies were determined to have a high risk of selection bias (Guidi 2006 and Wu 2020) ,23, and Neurodegenerative diseases are common pathologies seen in the elderly, resulting in significant poor health outcomes ,2. PreviA study published in 2020 investigating the levels of Hcy in 7872 healthy participants found that there was a significant difference in the levels of Hcy by sex for all age ranges from 20 to 80 years of age . In the In addition to an increased prevalence of AD in females, sex differences have also been reported for clinical symptoms, disease progression, and prognosis [reviewed in . SeveralSex differences in PD also include different clinical manifestations of the disease. The incidence ratio of developing PD for males versus females was found to vary from 1.37 to 3.7 . In addiBased on the results of this meta-analysis and previous research into the different clinical presentations of neurodegenerative diseases by gender ,42, we sOur study had limitations. First, most studies included in the quantitative analysis were retrospective and observational, which prevents the establishment of a causal relationship between the severity of the disorders and elevated levels of Hcy. In addition, sex differences in symptom severity were not reported in a sufficient number of the studies analyzed, and thus Hcy levels were not compared to the scores obtained for mental status or mobility. Second, certain medications and co-morbidity may have contributed to the different levels of Hcy; factors that were not explored in this study. For example, both cardiovascular and cerebrovascular diseases are associated with hyperhomocysteinemia ,25. NeurThe current study assessed sex differences in the levels of Hcy in patients with AD and PD. To our knowledge, this is the first meta-analysis reporting elevated Hcy levels in male patients with AD and PD. This supports the exploration of Hcy as a risk factor and potential biomarker for the development and progression of neurodegenerative diseases such as AD and PD. Although the results contribute to our understanding of sex differences in neurodegenerative conditions, additional preclinical and clinical investigations are required to further confirm the results of this study.


Scopus and PubMed databases were systematically searched from their inception to November 2021 to obtain pertinent studies. Standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the difference in Hg levels between people with and without T2DM. The association of the Hg exposure with T2DM was assessed using a random-effects model by pooling the odds ratios (ORs) and 95% CIs. P ≤ 0.001), with significant heterogeneity across studies . No significant association was found between Hg exposure and risk of T2DM in the overall analysis and subgroup analysis based on the source of sample and study design. However, higher exposure to Hg was related to reduced risk of T2DM in men , but not in women. No significant evidence for publication bias was detected.  A total of 17 studies, with 42,917 participants, aged ≥18 years, were analyzed. Overall, Hg levels were significantly higher in T2DM patients compared with non-T2DM controls (SMD = 1.07; 95%CI = 0.59 to 1.55,  Although the Hg level in T2DM is significantly higher than that of nondiabetics, there was no association between Hg exposure and the overall risk of T2DM. Nevertheless, our study shows that higher exposure to Hg might reduce the risk of T2DM in men. Type 2 diabetes mellitus (T2DM) is a worldwide health concern . This di0) and mercurous (Hg2++) or mercuric (Hg++) salts, while organic Hg includes compounds in which Hg is bonded to a structure containing carbon atoms  ) OR (Mercury[Title/Abstract])) OR (methyl Mercury[Title/Abstract])) OR (Quicksilver[Title/Abstract])) OR (dimethylmercury[Title/Abstract])) OR ) AND  OR (diabetes[Title/Abstract])) OR (“type 2 diabetes mellitus”[Title/Abstract])) OR (T2DM[Title/Abstract])) OR (“noninsulin-dependent diabetes mellitus”[Title/Abstract])). Only English studies were reviewed. All review articles and study references were checked to minimize the possibility of losing studies. To speed up the screening process, all identified studies were imported into an EndNote library, and duplicates were removed. The selection of eligible studies was independently reviewed by two researchers. First, the titles and abstracts of the studies were evaluated, and then the full text of the remaining publications was independently reviewed.The criteria for including eligible articles in this systematic review and meta-analysis were defined as follows: (A) cohort studies, cross-sectional, or case-control studies, (B) having a nondiabetic control group, (C) studies that reported odds ratios (ORs), hazard ratios (HRs), or relative risks (RRs) and the corresponding 95% confidence interval (CI) for the association of the Hg exposure in the blood, urine, hair, and nails with T2DM, (D) studies reported the mean and standard deviation (SD) of Hg in patients with T2DM and healthy controls, (E) the full text of the article was available in English, and (F) studies were conducted on adults (aged ≥18 years). Case reports, book chapters, conference papers, letters, editorial papers, and animal and cell culture studies were excluded.Two researchers independently reviewed the full text of the studies and extracted the data and resolved the differences through discussion with the third independent researcher. The following information was extracted: (1) study characteristics , (2) mean and SD of Hg, and (3) relevant reported risk estimates  and the corresponding 95% CIs.In this meta-analysis, the Newcastle–Ottawa Scale (NOS) questionnaire was used to evaluate the quality of studies in three areas  . StudiesI2 statistics. Heterogeneity was considered significant if I2 >50% (P < 0.1). Funnel diagrams and Egger's test were used to assess publication bias. Subgroup analysis was performed according to the type of study (prospective cohort vs. case-control), gender , and sample source . STATA  was used to perform all statistical tests for the current meta-analysis. P value <0.05 was considered statistically significant for all statistical analyzes.In this meta-analysis, a random effects model was used to test the effect of interest. Mean differences in Hg levels between the patients with T2DM and healthy controls were reported as standardized mean difference (SMD) and 95%CI. Standardized mean differences (SMD) for each original study were derived using the method of Cohen's d  as the dn = 168) and unrelated studies by titles/abstracts (n = 559), 51 publications underwent full-text screening, of which 17 studies [The systematic search of databases yielded a total of 778 studies. After excluding duplicate publications n = 8 and unr studies , 40–44,  studies , 44, and studies , 42–44 r studies , 36, 41, studies , 1 study studies , and theP ≤ 0.001) (P=≤0.001). In the stratified analysis by type of sample, compared with healthy controls, Hg levels were also significantly higher in blood  and hair  of patients with T2DM, but not in urine samples  , with a  studies –42, 44,  studies , 33, 41, 1 study )   and studEgger test and funnel plot detected no significant evidence for publication bias in studies investigating the relation of Hg exposure to the risk of T2DM .The current study is the first systematic review and meta-analysis which aimed to investigate the association of Hg levels in different body samples with the risk of T2DM. Overall, we found consistent epidemiological evidence that Hg levels in the blood and hair samples of diabetic patients were considerably higher than in the nondiabetic control group. Nevertheless, overall, the findings of this study revealed no significant association between Hg exposure and the risk of T2DM. However, Hg exposure in the male subgroup might reduce the risk of T2DM.The findings of the current meta-analysis demonstrated no significant association between Hg exposure and the risk of T2DM. This lack of association was even observed in the subgroups by sample source  and the type of study (case-control vs. prospective cohort). A cross-sectional study conducted on 1588 men and 1596 women with age ≥30 years in the general population in South Korea indicated that blood Pb, Hg, and Cd concentrations in diabetic patients were slightly higher than the nondiabetic individuals; this difference, nonetheless, was not significant . Even afAlthough, in the overall analysis, the current study demonstrated no association between Hg exposure and the risk of diabetes, the results of the gender-based analysis revealed that more exposure to Hg among the subgroup of men might be associated with a lower risk of T2DM. This finding resulted from the pooled analysis of only three studies , 35, 36;The current study is the first meta-analysis examining the association between blood, hair, toenail, and urine Hg levels and the risk of T2DM. As strength, no evidence for publication bias was identified. However, some limitations of this meta-analysis should be declared. First, significant heterogeneity was found across studies; we identified that this heterogeneity did not originate from the sample type or study design, but the gender of participants. Second, the majority of the included studies were case-control in design that might be affected by the unexamined confounding factors and suffer from a higher probability of bias than cohort studies. Other weaknesses of the present study include the difference in Hg concentration of various body samples, the difference in the methods of measuring Hg levels, and the biomarkers' measurement precision. Hg levels in hair, nail, and urine are usually reflective of longer aggregation, and its levels in the blood sample are usually indicative of short-term exposure, which this could be a source of the observed heterogeneity .Overall, this meta-analysis indicated that although the Hg level in diabetic individuals is significantly higher than the nondiabetics, there existed no association between Hg exposure and the risk of T2DM. However, exposure to Hg in men might reduce the risk of T2DM; however, additional studies are required to confirm this finding.


Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides.We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use.We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC , squamous cell carcinoma (SCC) , and melanoma . The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide . Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading , nodular , and lentigo maligna melanoma . Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide.Hydrochlorothiazide is associated with an increased risk for NMSC  and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions.CRD42021234317.PROSPERO The online version contains supplementary material available at 10.1186/s12916-022-02419-9. According to the Global Burden of Disease Study, the incidences of basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and melanoma have increased by 77%, 309%, and 161%, respectively, from 1990 to 2017 [Among first-line antihypertensives , thiazidWe followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines , 16. TwoWe searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies published from inception to January 5, 2022. We also screened the bibliographies of included studies and consulted experts for relevant unpublished studies. Additional file We developed the participants (P), interventions (I) or exposures (E), comparators (C), and outcomes (O) framework for study selection. For RCTs or cohort studies, the PICO included P: patients without skin cancers; I: any individual thiazide use; C: no thiazide use or controls; O: skin cancers. For case-control studies, the PECO included P: patients with skin cancers; E: any individual thiazide use; C: no thiazide use or controls; O: skin cancers. The skin cancers were defined as NMSC , 18 (incThe exclusion criteria were as follows: (1) other types of publications ; (2) studies from spontaneous adverse drug reaction reports databases; (3) studies on transplant populations receiving immunosuppressants with increased risk for skin cancers ; (4) dupWe examined the author lists in the included studies, and contacted the expert (AP) who was most frequently listed in this field for unpublished or missing literature and for discussion of the severe methodological weaknesses in the included studies.The following data were extracted: study design, first author, publication year, country, mean age, sex, photosensitive co-medications, comorbidities, and risk estimates on the association of thiazide use with skin cancers. For studies lacking relevant outcome data, we contacted the authors for clarification.The RoB in the included observational studies and RCTs was assessed using the Newcastle-Ottawa Scale (NOS) and Cochrane RoB 2.0 tool, respectively –25. We cI2 statistic was used to quantify statistical heterogeneity across the included studies, whereby substantial heterogeneity was considered when the I2 statistic exceeded 50% [If a study provided multiple risk estimates, those with the most fully adjusted confounders were adopted. The meta-analysis was conducted using Review Manager Version 5.4  to investigate the associations of different thiazides with skin cancers, and the risk for NMSC  and melanoma was calculated. The pooled risk ratio (RR) with 95% confidence interval (CI) was calculated for RCTs and pooled odds ratio (OR) with 95% CI for case-control studies. Incidence rate ratio was considered hazard ratio (HR), and pooled HR with 95% CI were calculated for cohort studies . The I2 eded 50% . Anticipeded 50% . HoweverFigure The RoB in the included studies is summarized in Table I2 = 96%) and cohort studies   was found. However, no increased risk for hydrochlorothiazide-associated BCC  and MCC  was found. The dose-response analyses  and 1.20-fold (95% CI 1.00–0.45) increased risks for SCC associated with high cumulative doses of hydrochlorothiazide in case-control and cohort studies, respectively. The 1.23-fold  increased risk for BCC associated with high cumulative doses of hydrochlorothiazide was only found in case-control studies, while there was no dose–response for BCC in cohort studies. We also found 3.30-fold (95% CI 1.31–8.31) increased risk for MCC associated with high cumulative doses of hydrochlorothiazide in one case-control study. However, one cohort study found no dose-response for unspecified NMSC  in case-control studies, whereas no significant differences were observed in the cohort studies  , medium , and low  cumulative doses , nodular , and lentigo maligna melanomas . These were all non-Asian studies  in case-control studies, whereas a significantly increased risk was observed in cohort studies   , BCC  and MCC  was found. The dose-response analyses on case-control studies found no significant or clinically meaningful increase in the risk for SCC, BCC, and MCC associated with higher cumulative doses of bendroflumethiazide  and cohort  studies , as did another cohort study from the UK   was similar to that for BCC . The dose-response analyses found no significant risk for SCC and BCC associated with higher cumulative doses of indapamide use  Fig. A, B. TheI2 = 66%), whereas one UK cohort study indicated a 43% risk increase   Non-Asian countries (B) Asian countries. Figure S8. Forest Plot for the Subgroup Analysis According to Geographic Regions of Nonmelanoma Skin Cancer in Cohort Studies of Hydrochlorothiazide (A) Non-Asian countries (B) Asian countries. Figure S9. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Hydrochlorothiazide and Melanoma in Case-Control studies. Figure S10. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Hydrochlorothiazide and Melanoma in Cohort studies. Figure S11. Forest Plot for the Subgroup Analysis According to Geographic Regions of Melanoma in Case-Control Studies of Hydrochlorothiazide. Figure S12. Forest Plot for the Subgroup Analysis According to Geographic Regions of Melanoma in Cohort Studies of Hydrochlorothiazide. Figure S13. Forest Plot for the Subgroup Analysis According to Melanoma Subtypes in Case-Control Studies of Hydrochlorothiazide. Figure S14. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Bendroflumethiazide and Basal Cell Carcinoma in Case-Control Studies. Figure S15. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Bendroflumethiazide and Squamous Cell Carcinoma in Case-Control Studies. Figure S16. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Bendroflumethiazide and Merkel Cell Carcinoma in Case-Control Studies. Figure S17. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Indapamide and Basal Cell Carcinoma in Case-Control Studies. Figure S18. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Indapamide and Squamous Cell Carcinoma in Case-Control Studies. Figure S19. Forest Plot for the Subgroup Analysis of the Association between Cumulative Doses of Indapamide and Melanoma in Case-Control Studies. Table S1. Search Strategy. Table S2. Studies with Overlapping Populations. Table S3. Exposures for Thiazide Use in the Included Studies. Table S4. Other Characteristics of Included Studies. Table S5. The Relationship Between Cumulative Duration of Individual Thiazide Uses and Skin Cancer Risk. Table S6. Risk-of-bias Assessment of Included Case-Control Studies Based on Newcastle Ottawa Quality Assessment Scale. Table S7. Risk-of-bias Assessment of Included Cohort Studies Based on Newcastle Ottawa Quality Assessment Scale. Table S8. Comparisons of the Results between the Main and Sensitivity Analyses. Table S9. Sensitivity Analysis By Including Only Low Risk-of-bias Case-Control Studies.


I2 = 2%) indicated that the use of HRT was associated with a 28% reduction in risk of gastric cancer compared with those who had no HRT exposure. The narrow prediction interval (0.62–0.84) for gastric cancer risk suggested a low between-study variance. In subgroup analysis defined by HRT formulation, there were reduction in risks of gastric cancer after the use of estrogen-only therapy  and estrogen-progestin therapy , as compared with non-users. In this systematic review and meta-analysis, the use of HRT was associated with a reduced gastric cancer risk regardless of HRT formulation. Further investigations are warranted to confirm underlying mechanisms.Hormone replacement therapy (HRT) is widely used to relieve menopausal symptoms; however, it remains unclear whether the use of HRT was associated with gastric cancer. We conducted a systematic review and meta-analysis to synthesize available evidence. This study followed the PRISMA guideline to report meta-analysis. PubMed, Embase, and Cochrane library were searched from conception through 23 February 2022. Eligible studies reporting risk of gastric cancer after HRT were screened and accessed by two independent reviewers. Random-effects meta-analysis was used to calculate pooled risk estimate as relative risk . Pre-established review protocol was registered in PROSPERO (CRD42021281260). Among the 1095 articles identified, we included 11 studies with 1,919,089 women in this meta-analysis. The combined risk estimate (RR, 0.72; 95% CI 0.64–0.81;  Albeit recent efforts shed light on the reduction of gastric cancer burden4 and the present decreasing trend in incidence rate has been projected to continue5, it was estimated that there will be 1,596,319 gastric cancer cases in 20356.Gastric cancer was the sixth commonly diagnosed cancer globally, responsible for 768,793 cancer deaths in 20207. The use of HRT was also linked to osteoporosis prevention8. Previous studies suggested that the use of HRT may be associated with an increased risk of breast cancer and ovarian cancer10. On the other hand, several studies have shown a reduction in the risk of esophageal cancer and colorectal cancer in women with HRT15.Hormone replacement therapy (HRT), including various estrogen-only and estrogen–progestin combined regimens, is widely prescribed to relieve menopausal symptoms, such as night sweats, hot flushes and mood swings16. Since then, more studies have been published but the results were inconsistent19. In addition, different hormone combinations are available, resulting in concerns about benefits and harms of specific formulations. However, little is known about the associations of different formulations of HRT with the risk of gastric cancer. Achieving individualised treatment and making informed decisions among women with menopausal symptoms require clear and consistent evidence, and therefore, further assessment of gastric cancer risk associated with specific types of HRT are needed. In this study, we sought to perform a systematic review and meta-analysis to summarize the association of HRT use with gastric cancer incidence.In 2012, a meta-analysis reported an inverse association between the overall use of HRT and gastric cancer riskWe performed this systematic review and meta-analysis in accordance with the pre-established review protocol registered in PROSPERO CRD42021281260). This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline (see Supplementary file 281260. TTwo reviewers (CYL and HLH) systematically searched human studies reporting the association of hormone replacement therapy and the risk of gastric cancer on the following electronic databases from inception to 23 February 2022: PubMed, Embase, and Cochrane library (the detailed search strategy is described in Supplementary file We included studies if they met the prespecificed criteria: (1) published original researches in human who had no prior cancer diagnosis with data on the use of hormone replacement therapy in relation to the risk of gastric cancer; and (2) study designs were randomised controlled trials, cohort studies, or case–control studies. Exclusion criteria included studies assessing hormone replacement therapy and cancer mortality; and cross-sectional studies, reviews, case reports, letters, and animal studies. We applied no restrictions on the route of hormone replacement therapy administration. The primary outcome was risk of gastric cancer after hormone replacement therapy. In this review, only studies that provided hazard ratio (HR), relative risk (RR), or odds ratio (OR) with 95% confidence intervals (CIs); or provide sufficient data that would allow the risk estimate to be calculated were eligible for inclusion.20.Two reviewers (CYL and HLH) independently reviewed all identified articles to extract the following data using a standardised observation form: name of first author, publication year, country, study design, study period, age, sample size, information on hormone replacement therapy, numbers of outcomes, adjustment, and risk estimates. A third reviewer (YCJ) performed verification. The Newcastle–Ottawa Quality Assessment Scale (NOS) was used to assess the methodological quality of all included studiesI2 statistic to quantify the percentage of variation attributable to between-study heterogeneity. The I2 was categorised as low (≤ 50%), moderate (51–75%), and high (> 75%) heterogeneity21. Predictive intervals describing the heterogeneity in random-effects meta-analysis were estimated to inform the potential future treatment effect in 95% of all populations22. Visual inspection of Begg funnel plot and Egger test were performed to evaluate potential publication bias and small-study effects23. Trim and fill method was performed if publication bias existed24. Subgroup analyses were performed based on different types of HRT (estrogen-only HRT or estrogen-progestin HRT) for the risk of gastric cancer. Additional sensitivity analysis was performed to assess the robustness of the primary meta-analysis by using a fixed effect model to rerun the analysis. To assess the impact of individual studies on primary analysis, we conducted leave-one-out meta-analysis by omitting one study at a time25. In the present study, exact p values are provided unless p < 0.0001. Data were analysed using STATA version 16.1 .In this study, pooled estimates of relative risks were synthesised using random-effects meta-analysis, considering both within- and between-study variation. Methodological and clinical heterogeneity was assessed by 26, leaving 13 articles for full-text review. An additional two studies were excluded because of overlapping data sources28. Of studies with the same data source, the study with longer duration was included in the analysis. Finally, 11 studies were included in qualitative assessment and meta-analysis35.As shown in Fig. 32, three case–control studies35, and one nested case–control study33 were eligible for inclusion in the meta-analysis. The studies were published between 2003 and 2021 and included cohorts from 16 countries . The participant number ranged from 652 to 1,160,351, which resulted in a total of 1,919,089 participants included in this meta-analysis. Study quality scores, assessed by NOS, were between low and high. Table Table I2 = 2%) of gastric cancer  for individuals who had estrogen-only HRT, comparing with non-users   Fig. B.Figure I2 = 0%)  of the association between the use of HRT and risk of gastric cancer suggested that there was no publication bias and small-study effects; and therefore, trim-and-fill method was not conducted.In additional analysis, the risk estimate was generally consistent after we reran the meta-analysis with a fixed-effect model  Figure . In leav) Figure . The fun) Figure  and EggeIn this study, we used non-overlapping data from ten studies comprising 1,919,089 women to conduct a systematic review and meta-analysis and examine the association between HRT use and the risk of gastric cancer. The pooled results showed that women who used HRT were at a 28% lower risk of gastric cancer, compared to non-users. Estrogen-only therapy was associated with a 37% reduction in gastric cancer incidence and combined estrogen-progestin therapy reduced gastric cancer risk by 30%. The estimations for prediction intervals were in line with the main analysis. In sensitivity analysis, the results did not change substantially when using the fixed-effect meta-analysis.16. The current meta-analysis incorporated the most updated evidence and conducted stratified analysis according to specific types of HRT, which were not considered in the previous meta-analysis. Our results suggested that both estrogen-only therapy and combined estrogen–progestin therapy were associated with lower gastric cancer incidence, providing new insight to the assessment of benefits and risks among individuals who had been prescribed with estrogen-only HRT after hysterectomy. The prevalence of HRT use has reduced significantly after the Women’s Health Initiative study suggested that HRT use was associated with a number of adverse health outcomes36. Despite the fact that HRT remains a management option for women with menopausal symptoms and its benefits may outweigh the harms38, many may focus on side effects without considering all the available evidence when making choices. Nevertheless, our findings that HRT was associated with a lower risk of gastric cancer does not ipso facto imply that HRT should be prescribed as primary preventive measure. Finally, due to paucity of data, we were unable to perform analysis stratified by dosage and duration. Given that stomach cancer is the seventh most common cancer in women, affecting 1 in 80 women during their lifetime39, our findings justify further preclinical research and explorations on the link between HRT use and gastric cancer risk according to the dosage and duration of use.Our findings are broadly in line with the previous meta-analysis, including seven studies published before 201140, and exogenous hormone binding could result in inhibition of cancer cell growth and induce apoptosis41. The findings of a Korea study using human gastric cancer cell lines implied inhibitory effects of HRT on the ERβ-positive gastric cancer42. Indeed, loss of ERβ expression was associated with poor gastric cancer survival40. In addition, a selective estrogen receptor modulator was suggested to promote gastric carcinogenesis via antiestrogenic effects in breast cancer survivors43. A previous study using data from the Swedish Cancer Registry showed a shorter latency of gastric cancer development in breast cancer survivors who had tamoxifen, as compared with non-users44.Although the causal pathway has not been well established, our findings provided evidence that hormone use may lead to a favourable outcome for primary gastric cancer prevention. There are several mechanisms through which exposure to HRT may lead to a reduction of gastric cancer risk. The presence of estrogen receptors-beta (ERβ) have been demonstrated in gastric adenocarcinoma35. However, among these eight studies, five studies were prospective design, which may minimize the bias from misclassification since any misreporting may be random and unrelated to outcomes. Second, observational studies are susceptible to residual confounding. In this analysis, the majority of the included studies adjusted for major risk factors for gastric cancer: cigarette smoking was adjusted in nine out of 11 studies35, alcohol consumption was adjusted in five studies35, and body mass index (BMI) or obesity was adjusted in eight studies35. Third, despite rigorously searching for the literature, only three of 11 studies included were from gastric cancer high incidence countries 32. Third, the relatively small cancer case number of the included studies may limit statistical power. Nevertheless, we provided prediction intervals indicating the potential findings of future studies. Fourth, the current available evidence does not allow us to conduct subgroup analysis based on cancer histology, location or H. pylori infection status. Given the heterogeneity in gastric cancer, the results of the present study may not represent a specific type of gastric cancer. Lastly, the possibility of health user bias cannot be entirely excluded, in which HRT users may have different lifestyle behaviors from non-users. The adjustment for cigarette smoking, alcohol consumption, and BMI in most included studies may lessen the concerns regarding health user bias. While the current evidence suggests that HRT may be of clinical benefit in the reduction of gastric cancer risk, the findings do not necessarily support HRT use for the purpose of cancer prevention. Further clinical assessment is needed to consider the balance between benefits and harms of HRT use in the setting of chronic disease prevention.To our knowledge, this study is the most updated and comprehensive meta-analysis that examines the association of HRT use with the risk of gastric cancer. The present study is also the first to provide subgroup analyses based on HRT formulation. This meta-analysis has some limitations. First, eight of the 11 included studies used self-reported questionnaires to assess the usage of HRTIn conclusion, this meta-analysis of observational studies showed that the use of HRT was associated with a lower risk of gastric cancer regardless of HRT formulation. Further studies are needed to investigate the mechanisms and to explore the associations by various dosage and duration.Supplementary Information.


We read with great interest the article, “Evaluating the Effectiveness of Gamification on Physical Activity: Systematic Review and Meta-analysis of Randomized Controlled Trials” by Mazeas et al . The autFirst, Paul et al  was not Second, the total number of hours of gamification performed can make a significant difference. Although the authors have conducted a subgroup analysis of the duration of gamification (short- and long-term interventions), each type of gamification is different, and we do not know the number of minutes of gamification performed per day. The total number of hours of gamification performed can vary greatly across the different studies. We believe this could be a potential source of heterogeneity.Third, this meta-analysis may not apply to older adults. The mean age of participants in the selected studies was 35.7 years, and most of the studies were conducted on participants aged <65 years. The American College of Sports Medicine suggests that the population most in need of exercise may be older adults . In a prIn conclusion, we believe that clarification of the above points can strengthen the interpretation of the study results. The authors have analyzed an important issue. A better understanding of the effects of gamification mechanisms on PA is critical for clinicians.


The objective is to identify the risk factors for necrotizing enterocolitis (NEC) in neonates by a meta-analysis, and to provide a reference for the prevention of NEC.The databases, including Chinese Biomedical Literature Datebase, China National Knowledge Infrastructure, Wanfang database, and Weipu Periodical database, PubMed, Web of Science, Embase, Cochrane Library, were searched for studies on the risk factors for NEC in neonates. The meta-analysis was carried out with the aid of Stata software.A total of 52 studies were included, with 48 case-control studies and 4 cohort studies. There were 166,580 neonates in total, with 33,522 neonates in the case group and 133,058 neonates in the control group. The meta-analysis showed that gestational diabetes , premature rupture of membranes , low birth weight , small for gestational age , septicemia , blood transfusion , congenital heart disease , respiratory distress syndrome , premature birth , pneumonia  were risk factors for NEC in neonates. Breastfeeding , take probiotics , prenatal use of glucocorticoids , Hyperbilirubinemia  were protective factors for NEC in neonates.Gestational diabetes, premature rupture of membranes, low birth weight, small for gestational age, septicemia, blood transfusion, congenital heart disease, respiratory distress syndrome, premature birth, and pneumonia may increase the risk of NEC in neonates. Breastfeeding, taking probiotics, prenatal use of glucocorticoids, and Hyperbilirubinemia may reduce the risk of NEC in neonates. Necrotizing enterocolitis (NEC) in neonates is a severe muti-factorial disease characterized by intestinal necrosis in the ileum, jejunum, and colon. It is one of the leading causes of morbidity and mortality in preterm infants , with whChina National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Chinese Journal Database, Chinese Biomedical Literature Database, PubMed, Web of Science, Embase and Cochrane Library were searched to systematically collect published studies on risk factors of NEC in neonates. The search strategy of combining keywords and subject terms was adopted. The Chinese search terms were “newborn”, “necrotizing enterocolitis”, “risk factors”, “case-control study”, “cohort study”, etc. English search words “Enterocolitis, Necrotizing”, “Infant, Newborn”, “relative risk”, “cohort”, etc., supplemented by manual search and literature tracing.Inclusion criteria: 1. The diagnosis of NEC is clear; 2. The study type was a case-control study or cohort study; 3. The subjects were neonates (<28 days); 4. The original data is available. The OR (odds ratio) value and 95% confidence interval (CI) are provided, or the OR value and 95% CI can be calculated from the data.Exclusion criteria: 1. Conference summary, comments and review articles; 2. Unable to extract effective outcome indicators from the literature; 3. The experimental design is not rigorous ; 4. Unable to get a full text; 5. The sample size is too small.Two researchers strictly followed the inclusion and exclusion criteria to independently conduct literature screening, quality evaluation, data extraction, and discuss possible differences to reach an agreement. The final results were confirmed by more senior researchers. The Newcastle-Ottawa Scale (NOS)  was used2 statistic were used to evaluate the heterogeneity, and the test level was set as 0.1. If the heterogeneity test results were P > 0.1 and I2 < 50%, the pooled effect size OR and 95% CI were calculated using the fixed effects model. Otherwise, the random effect model is used to calculate; Sensitivity analysis uses different models to analyze the same data. Egger's or Begg's test was used to evaluate publication bias, and Stata12.0 was used for statistical analysis.The Q test and IA total of 5,728 relevant articles were obtained through preliminary screening, and 3,931 articles remained after being re-selected by Endnote software. Ulteriorly, 3,475 articles were excluded after reading the title and abstract, and 117 articles remained for further evaluation. Finally, after reading the full text, 52 articles were included according to the inclusion and exclusion criteria, as shown in According to the risk factors involved in the included literature, gestational diabetes, premature rupture of membranes, cesarean section, low birth weight, small for gestational age, sepsis, blood transfusion, congenital heart disease, respiratory distress syndrome, mechanical ventilation, breast feeding, probiotics, preterm delivery, pneumonia, prenatal use of glucocorticoids, hyperbilirubinemia, ect., were selected for analysis. Heterogeneity test results showed that there was heterogeneity among the studies of diabetes in pregnancy, premature rupture of membranes, cesarean section, small for gestational age, sepsis, blood transfusion, congenital heart disease, respiratory distress syndrome, mechanical ventilation, breast-feeding, probiotics, preterm delivery, pneumonia and hyperbilirubinemia, and the random effect model was used to combine the effect amount. In contrast, there is no heterogeneity in other related factors, and the fixed effect model is used to combine the effects. The meta-analysis results demonstrates that: Cesarean section and mechanical ventilation were not statistically significant with NEC in neonates. Gestational diabetes mellitus, premature rupture of membranes, low birth weight, small for gestational age, sepsis, blood transfusion, congenital heart disease, respiratory distress syndrome, premature birth and pneumonia were risk factors for NEC in neonates. Breastfeeding, probiotics, prenatal glucocorticoid use, and hyperbilirubinemia were protective factors for NEC in neonates, as shown in P < 0.05), as shown in For the screened risk factors, the fixed effect and random effect models were used to recalculate the combined effect size. The calculation results of these two models were basically consistent, indicating that the results of this study were basically reliable. However, the results of premature rupture of membranes are not robust enough and should be treated with caution. The results of Egger's or Begg's test suggest that the results of sepsis, probiotics, and pneumonia are biased  Due to the immature intestinal function and slow intestinal peristalsis of low birth weight infants, food residues are easy to be detained and fermented, providing a good environment for bacterial growth, leading to a large number of bacterial proliferation; (2) The intestinal microbiota of low birth weight infants is very immature, and direct contact with pathogenic microorganisms will cause inflammation related to mucosal damage, leading to NEC .This meta-analysis showed that small for gestational age (SGA) was a risk factor for NEC. SGA infants have a high probability of NEC, neonatal asphyxia, brain injury and respiratory distress syndrome . One stuThis meta-analysis showed that septicemia, congenital heart disease, respiratory distress syndrome, and pneumonia were risk factors for NEC. In severe infection, the body is in a state of inflammation activation, producing a variety of inflammatory transmitters. These substances directly or indirectly cause damage to the intestinal mucosa, and then participate in the occurrence and development of NEC , 63. MeaThis meta-analysis showed that blood transfusion was a risk factor for NEC. The possible pathogenesis of NEC is as follows: the inflammatory mediators such as TNF-α, IL-6, and PAF produced during the processing of whole blood and the storage of red blood cells, and the residual white blood cells, free hemoglobin, red cell membrane fragments, etc. promote the occurrence of NEC. The pathological changes of red blood cells occurred during storage, including decreased erythrocyte deformability, increased oxygen affinity ability and decreased nitric oxide resulting in the loss of vasodilator activity, etc., resulting in the failure to improve intestinal microcirculation perfusion flow after blood transfusion; NEC may be caused by anemia .This meta-analysis showed that preterm birth was a risk factor for NEC. Due to the unsound development of the enteric nervous system and poor regularity of small intestinal peristalsis, premature infants are prone to excessive bacterial growth and gas after food fermentation, and are prone to NEC .This meta-analysis showed that breastfeeding, probiotics, prenatal glucocorticoid use, and hyperbilirubinemia were protective factors for NEC. Breast milk is known as the most natural and safe natural food for infants and young children, containing nutrients and antibodies necessary for the development of organized organs, especially beneficial antibodies, which can help maintain the immune function of newborns, inhibit the inflammatory reaction, and speed up the repair of the damaged intestinal mucosa . CompareThis study has some limitations: First, sensitivity analysis found that the results of premature rupture of membranes were not robust enough. Therefore, the relationship between premature rupture of membranes and NEC in neonates needs further study. Secondly, there exist differences in sample size, case selection, and definition of exposure factors among the studies, which may lead to heterogeneity among the studies and have a certain impact on the results. Finally, only Chinese and English literature ware included in the included study, and literature published in other languages could not be analyzed, which may result in language bias.We conducted a meta-analysis to evaluate the risk factors of NEC. This meta-analysis showed that gestational diabetes mellitus, premature rupture of membranes, low birth weight, small for gestational age, sepsis, blood transfusion, congenital heart disease, respiratory distress syndrome, premature birth, and pneumonia maght increase the risk of NEC in neonates. Therefore, perinatal health care should be strengthened to reduce the incidence of neonatal complications, so as to prevent the occurrence of NEC in neonates.


Brain cancer is one of the most aggressive cancer types owing to poor treatment effects. Epidemiological studies have demonstrated that allergies may increase the disease risk. Therefore, this study evaluated the association between eczema and the risk of various brain cancers.We systematically searched the PubMed and Embase databases from their inception until June 23, 2022. Two reviewers independently reviewed and screened the articles, extracted data, assessed the study quality, and pooled the results. Stata software was used to generate pooled odds ratios and 95% confidence intervals (CIs).We included 20 studies comprising 5,117,222 patients that investigated the relationship between eczema and brain cancer. Eczema was significantly inversely associated with the risk of brain cancer , glioma , meningioma , and acoustic neuroma . Interesting, The strong correlation between eczema and the reduced risk of brain cancer was observed in people over 16 years old , but not in those under 16 years old . In addition, subgroup analyses found that eczema significantly decreased the glioma risk in Europeans  but not Australians  or Americans .Eczema may be considered as a potential protective factor of brain cancer in population aged over 16 years. However, this relationship requires verification using large-scale clinical data.The online version contains supplementary material available at 10.1186/s12885-022-10471-0. Brain cancer is one of the most aggressive tumors owing to poor treatment effects , 2. MoreEczema is a common chronic cutaneous inflammatory disease affecting 10–30% of children and 2–10% of adults worldwide . Some reThis meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)  and the The inclusion criteria were: a) human studies; b) observational studies including cohort and case-control study designs; c) published in English; and d) studies focusing on the relationship between eczema and the risk of brain tumors.The exclusion criteria were: a) reviews, animal studies, abstracts, or conference proceedings; b) unpublished data or case reports; c) duplicate literature and duplicate data; and d) studies lacking specific data on exposure (eczema) and endpoints (brain tumors).The following relevant information was independently extracted by two reviewers (XSL and XYD) from the included studies: first author’s name, country of origin, publication year, study design, sample size, age, percentage of females, tumor type, number of patients, years of follow-up, and odds ratios (ORs) with 95% confidence intervals (CIs). For this meta-analysis, we defined eczema as the exposure factor and the occurrence of various brain tumors as the outcome. Data not directly obtainable from the text were extracted from the associated information . The corresponding authors were contacted to retrieve missing data.Two authors (TYR and YWM) used the Newcastle-Ottawa Scale (NOS)  to evalu2 value. A P-value of > 0.1 and I2 value of < 50% indicated acceptable heterogeneity, and then a fixed effects model was used to calculate pooled ORs and 95% CIs [Stata software  was used for the meta-analysis. The heterogeneity of the included papers was estimated using a homogeneity test (Q test) and the I 95% CIs ; otherwi 95% CIs . SubgrouWe retrieved 9382 records that included 5,117,222 patients. After screening the titles and abstracts, 9148 studies were removed. After assessing the full text of the remaining articles and relevant articles in their bibliographies, 20 studies –35 were P = 0.004, I2 = 48.1%; Fig. P > |z| = 0.362; Egger’s: P = 0.183, 95% CI: − 1.900–0.384; Fig. Eczema was significantly associated with a decreased brain cancer risk in the analysis with all 20 studies –35  but no association for those under 16 years old . However, the relationship between eczema and glioma risk was statistically insignificant for Australians  and Americans  ; the analysis included nine studies , 30, 33.P = 0.366, I2 = 0.0%; Fig. Eczema was significantly associated with a decreased risk of acoustic neuroma ; the analysis included two studies , 30. TheThis meta-analysis aimed to advance our understanding of the association between eczema and brain cancer by analyzing 20 related papers. The strong correlation between eczema and the reduced risk of brain cancer was observed in people over the age of 16, but not in the age of 16, which indicated that eczema may be considered as a potential protective factor when assessing the risk of brain cancer in population aged over 16 years. At the same time, eczema was significantly associated with a decreased risk of glioma, meningioma, and acoustic neuroma. However, the relationship between eczema and the risk of glioma differed regionally. Specifically, eczema significantly decreased the glioma risk in the European subgroup without heterogeneity but not in the Australian and American subgroups.Many previous studies have investigated associations between allergic diseases and the risk of various cancers , 36, 37 Numerous studies have reported inverse associations between eczema and several cancer sites , 38, 39.This study had some limitations. First, some of our results had heterogeneity, which might affect their reliability. However, heterogeneity did not exist between eczema and meningiomas and acoustic neuromas; the relationship between eczema and glioma was an exception. Therefore, heterogeneity minimally affected our conclusions. Second, our study population spanned a wide age range, but data limitations prevented us from investigating the effects of age on the results; we could only evaluate associations. Finally, we did not find publication bias in our analyses because researchers only reported positive results. Therefore, we inevitably could not assess the effects of unpublished studies with negative results. Nonetheless, our study included many patients and individually eliminated studies to evaluate sensitivity, making our results more comprehensive and reliable.Eczema was significantly inversely associated with the risk of brain cancer, including glioma, meningioma, and acoustic neuroma. Therefore, eczema is a promising predictor of brain tumor risk. However, the study location affects this relationship. Therefore, these results require validation in large randomized controlled trials.Additional file 1. Supplementary Material.


In this meta-analysis, 9 studies enrolled a total number of 943 participants, including 534 (56.63%) patients with CHD and 409 controls (43.37%). We found that patients with CHD showed a significantly lower FMD than the controls  with high heterogeneity. In addition, funnel plot analysis suggested asymmetry that could be evidence of publication bias. But sensitivity analyses show that there were no influential studies. This meta-analysis provides evidence that patients with CHD show a significantly lower FMD than controls and highlights the literature on FMD as a hallmark in CHD diseases.Endothelial dysfunction may contribute to the increased morbidity and mortality associated with coronary heart disease (CHD). Flow-mediated dilatation (FMD) is the most popular noninvasive method for vascular endothelial function evaluation. This meta-analysis aimed to investigate the association between FMD and CHD. We searched the publications listed in the PubMed, Web of Science, Scopus, and Embase databases. Stata 14 software was used to analyze the data. Standardized mean difference (SMD) was used to calculate FMD levels, and the effect sizes were expressed with a 95% confidence interval (CI). I The vascular endothelium plays an essential role in various pathological and physiological processes, for instance, regulating vascular homeostasis, vasoconstriction and dilation, thrombosis, fibrinolysis, inhibition of inflammation, and smooth muscle cell function . An imbaCurrently, invasive and noninvasive methods are commonly used to evaluate vascular function. Invasive tests require the injection of acetylcholine into human coronary arteries, but their clinical application is limited because they are invasive, time-consuming, and expensive, and they are not recommended for healthy or asymptomatic patients . The nonMany large prospective cohort studies have accepted FMD as an adjunctive marker of coronary heart disease (CHD). Several studies found that a decreased FMD could increase the risk of CHD , 9. HoweThis meta-analysis followed the guidelines of the preferred reporting items. We searched the publications listed in the electronic databases MEDLINE  and Embase  using the following text and keywords in combination both as MeSH terms and text word: “flow-mediated dilatation” and ‘‘coronary artery disease” or “coronary heart disease” or “coronary vascular disease.”Inclusion criteria of this study were as follows: patients with coronary heart disease; FMD brachial artery in CHD and control was detected by high-resolution ultrasound methods, and the brachial artery FMD was calculated as [/baseline diameter × 100%]; and the enrolled studies were prospectively or retrospectively designed. Exclusion criteria were as follows: patients with infections, tumors, and immune disease; incomplete FMD data; literature that was duplicated and poorly designed; and reviews.Two investigators independently screened the titles and abstracts of the studies and excluded those that did not meet the inclusion criteria. After screening the full text, the studies that met the requirements were selected according to the inclusion and exclusion criteria. If two authors had objections to the extracted literature, a third investigator was invited to arrive at the final conclusion. Finally, the articles were written according to the systematic reviews and meta-analyses guidelines.Q test and the I2 statistic were used to assess the heterogeneity between studies. In detail, if there was no heterogeneity , the fixed-effects model was used for analysis. If heterogeneity existed , the random-effects model was used for analysis. Sensitivity analysis was conducted to determine the stability and credibility of the results. Funnel plots and shear complement methods were used to detect publication biases.Stata 14 software was used to analyze the data. Standardized mean difference (SMD) was used to calculate FMD levels, and the effect sizes were expressed with a 95% confidence interval (CI). Chi-square Cochran's The results of the literature search are shown in All included studies were observational and were prospectively designed. As shown in 2 = 71.2% and P=0.001, suggesting heterogeneity was statistically significant among these studies. Therefore, a random-effects model was used to analyze the data in this meta-analysis. As shown in P=0.001), suggesting that endothelial dysfunction correlates with coronary heart diseases.In 9 studies, heterogeneity was IPublication bias was assessed using a funnel plot analysis. As shown in Endothelial cell damage and dysfunction play an important role in developing the process . StudiesP=0.001), indicating that patients with CHD show a reduced vasodilatory response and endothelial function. Therefore, evaluation of FMD can be a useful noninvasive diagnostic tool for CHD risk assessment.The present meta-analysis results consistently showed that CHDs might be associated with endothelial dysfunction, as evaluated by ultrasound-based FMD of the brachial artery. In particular, we demonstrated that 534 patients with CHD showed a significantly lower FMD than the 409 controls (SMD −0.690%; 95% CI: −0.981, −0.398; Many cardiovascular risk factors affect endothelial function, such as race, age, estrogen, hypertension, diabetes, and smoking . AlthougThe funnel plot analysis confirmed the existence of significant publication bias. However, we obtained a similar SMD by the trim and fill method, and there was no obvious difference compared with previous results, possibly because of low power due to the small number of studies . In addiAccumulating evidence indicates that early endothelial dysfunction is a reversible disorder, and several interventions, such as exercise and bilirubin or other medicine, can increase endothelial function and reduce CVD risk , 25. If Some potential limitations of our study must be discussed. First, there was a publication bias in this meta-analysis. However, the combined SMD was consistent with the uncut and complemented conclusions, indicating that although there was a certain publication bias, the results were stable and reliable. Second, heterogeneity among the studies was generally significant, and it was not possible to conclusively ascertain sources of heterogeneity. Finally, the small number of studies and participants limited the accuracy of the results. Further efforts will be made to conduct further studies in the future.In conclusion, this meta-analysis provides evidence that patients with CHD show a significantly lower FMD than controls and highlights the literature on FMD as a hallmark in CHD diseases. Although limited in number, these studies provide important evidence that FMD should be considered a worthy biomarker for assessment in future research.


Ovarian cancer is the most lethal cancer of the female genital tract despite major advances in both surgical and oncological treatments. This is in part due to difficulties in identifying those most at risk of developing ovarian cancer, and that there are currently no effective screening strategies. Whilst 20% of cases have a genetic component, the majority have no obvious cause. Many risk factors have been associated with ovarian cancer, although the strength of this evidence remains unclear. This umbrella review attempts to review the validity of associations between non-genetic risk factors and the risk of developing or dying from ovarian cancer. There were six associations that were supported by strong evidence. Greater height, BMI and use of HRT increased the risk, whilst the use of oral contraceptive pill reduced that risk. This review will enable further research into these areas and may promote identification of individuals at high risk.2 versus normal 1.27, 95% CI 1.17–1.38) and three exposures of varying preparations and usage related to hormone replacement therapy (HRT) use increased the risk of developing ovarian cancer. Use of oral contraceptive pill reduced the risk . Refining the significance of genuine risk factors for the development of ovarian cancer may potentially increase awareness in women at risk, aid prevention and early detection.Several non-genetic factors have been associated with ovarian cancer incidence or mortality. To evaluate the strength and validity of the evidence we conducted an umbrella review of the literature that included systematic reviews/meta-analyses that evaluated the link between non-genetic risk factors and ovarian cancer incidence and mortality. We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews and performed a manual screening of references. Evidence was graded into strong, highly suggestive, suggestive or weak based on statistical significance of the random effects summary estimate and the largest study in a meta-analysis, the number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, and presence of excess significance bias. We identified 212 meta-analyses, investigating 55 non-genetic risk factors for ovarian cancer. Risk factors were grouped in eight broad categories: anthropometric indices, dietary intake, physical activity, pre-existing medical conditions, past drug history, biochemical markers, past gynaecological history and smoking. Of the 174 meta-analyses of cohort studies assessing 44 factors, six associations were graded with strong evidence. Greater height  1.11–1.20), body mass index (BMI) (RR ≥ 30 kg/m Ovarian cancer is the most lethal gynaecological malignancy in high-income countries . WorldwiAlthough approximately 20% of the cases of ovarian cancer have been associated with genetic mutations in Breast Cancer (BRCA)1 and BRCA2 , the majIn this study, we present an umbrella review of systematic reviews and meta-analyses of observational studies to systematically appraise the evidence and validity of associations between non-genetic risk factors and the risk of developing or dying from ovarian cancer. We searched PubMed, EMBASE and the Cochrane Database of Systematic Reviews from inception to September 2019 , and studies assessing genetic factors as the exposure of interest, as well as studies investigating the prognostic ability of factors on survival of patients previously diagnosed with ovarian cancer . We furtIn the event of multiple meta-analysis reporting on the same exposure-outcome associations, we selected the one with the largest number of studies to preclude duplication of the original studies. Hand searches were performed to ensure primary studies were not included in more than one systematic review that formed the evidence base. p-value; p-value of largest study in meta-analysis; number of cases; between-study heterogeneity; 95% prediction interval; small study effects; excess significance bias. Full details of the statistical analysis and grading is presented in the Each identified risk factor and ovarian cancer association was graded into four groups; strong, highly suggestive, suggestive and weak evidence using a series of criteria described previously ,20,21,22The strength and quality of all included meta-analyses was assessed using the AMSTAR 2 tool, which uses 16 measures to appraise the methodological quality of systematic reviews  into higOur primary analysis focused on cohort studies as these studies provide most robust evidence among observational studies. We also conducted sensitivity analyses afterwards including case-control studies.We performed further sensitivity analyses and applied the credibility ceilings threshold to account that a single observational study cannot give more than a maximum certainty, c% (credibility ceiling), that the true effect size is in a different direction from the one suggested by the point estimate . The conp values were two tailed.The complete statistical analyses were performed using Stata version 15  (StataCorp 2015) , all p vThere was no patient involvement.This project is registered on Open Science Framework (DOI: 10.17605/OSF.IO/YMDSQ). We identified 72 eligible publications that included 212 meta-analyses of 1853 individual study estimates exploring associations between non-genetic risk factors and the risk of developing or dying from ovarian cancer  8,19,26,96,97,98A total of 55 risk factors were studied in the 212 meta-analyses, belonging broadly to eight categories; seven anthropometric indices, 17 dietary factors, two risk factors including physical activity and sedentary behaviour, three risk factors associated with pre-existing medical conditions or interventions, nine factors related to past drug history, four biomarkers, 11 risk factors related to past gynaecological history and three carcinogens. Full details of the risk factors in each category are found in the Of the 212 meta-analyses, 174 included at least two cohort studies examining 44 risk factors and were included in the main analysis. Eight of the 174 meta-analyses reported on ovarian cancer incidence and mortality, one meta-analysis reported on ovarian cancer mortality only, and the remaining meta-analysis reported on ovarian cancer incidence.p < 0.05 as the threshold of statistical significance, the summary fixed and random effects estimates were significant in 39 (22%) and 40 (23%) out of the 174 meta-analyses of cohort studies, respectively  and 17 (10%) meta-analyses produced significant summary results using the fixed and random effects model, respectively. At p < 10−6, summary fixed effects estimates were significant in 14 (8%) meta-analyses and summary random effects were significant in 10 (6%) meta-analyses. Of the 10 meta-analyses with highly statistically significant summary random effect estimates, eight described an increased risk of ovarian cancer incidence or mortality for the following risk factors: obesity, height, hormone replacement therapy (HRT), endometriosis and asbestos exposure. Two meta-analyses including exposure to the oral contraceptive pill (OCP) and metformin demonstrated a decreased risk of ovarian cancer incidence. With ectively . At p < p < 0.05, as previously performed by He and colleagues [Assessment of between-study heterogeneity, 95% prediction intervals, small study effects, and excess significance bias were performed only on those meta-analyses that demonstrated statistically significant results i.e., lleagues . The metThe association of the largest study included in each meta-analysis was nominally statistically significant in 20 of the 40 statistically significant meta-analyses (50%), and the relative risks of the largest studies were more conservative than the summary random effects in 28 (70%) meta-analyses.p ≤ 0.10 using the Cochran’s Q test. Large heterogeneity (I2 = 50–75%) was found in five (13%) meta-analyses and very large heterogeneity (I2 > 75%) in two (5%) meta-analyses for five risk factors including endometriosis, diabetes mellitus, HRT, in vitro fertilisation (IVF) and pelvic inflammatory disease (PID) (Seven (18%) of the 40 meta-analyses presented significant evidence of between-study heterogeneity at se (PID) .p < 0.10 with more conservative effects in the largest study of a meta-analysis compared to the summary random effects estimate) for endometriosis, HRT and BMI.  reported small study effects (Egger’s test at and BMI. . p < 0.10). These included varying exposures, namely endometriosis, BMI, asbestos exposure, and breastfeeding. Using either the summary fixed or random effects estimates instead of the largest study estimate did not highlight any further meta-analyses with excess significance bias (Five (12.5%) meta-analyses demonstrated evidence of excess significance bias using the largest study estimate as the plausible effect size , and three associations for use of HRT  were associated with a higher risk of ovarian cancer. Use of OCP was strongly associated with lower risk of developing ovarian cancer   .Only three meta-analyses  fulfilled the criteria for highly suggestive evidence. Two of them  reported an increased ovarian cancer incidence for use of HRT  and endometriosis . Metformin use was associated with a lower risk of ovarian cancer incidence  . There wFive meta-analyses  received a suggestive evidence grade and 26  meta-analyses had weak evidence, whereas the rest  had a nominal insignificant association.Thirty-five percent of all the included papers were graded as high  or moderate  quality, whilst 26% (19/72) and 39% (28/72) were graded as low or critically low . Papers Only five included publications ,67,101 wThe three meta-analyses that received highly suggestive evidence had high quality (endometriosis) , or modeNone of the associations that received strong evidence grading were downgraded when cohort and case-control studies were both included . Two sta2 versus normal, all three HRT risk factors and OCP use) remained nominally statistically significant in the main analysis until a 15% credibility ceiling was applied. The three risk factors found to have highly suggestive evidence remained nominally statistically significant until a 10% credibility ceiling was applied . For most of the duplicate meta-analyses (n = 38/41 93%) there was concordance in direction, magnitude and statistical significance of the summary associations between them  and in the WHO/IARC World Cancer Report (WCR) 2020 . No MendThe mechanisms that underpin these associations are complex. The concept of the ‘incessant ovulation’ supports the notion that recurrent minor trauma caused to the ovarian epithelial surface as a result of ovulation increases the risk of malignant transformation. This process may explain the reduction in risk with OCP, breastfeeding and parity as they are associated with fewer ovulatory cycles ,112,113.Several advances have been made since the theory of ‘incessant ovulation’ as a causative factor in ovarian cancer was first postulated in the 1970′s. One such concept includes that of extra-ovarian origins of ovarian cancer, the most common of which is that of fallopian tube cancers, considered to be the origin of many ovarian high grade serous ovarian cancers (HGSOC), along with serous tubal intraepithelial carcinoma (STIC) lesions found in fallopian tubes removed prophylactically in BRCA-positive patients. The pro-inflammatory environment of repeated ovulation has also been demonstrated to affect the fallopian tubes, with the resulting pro-repair environment providing tumorigenic factors which potentially supports malignant transformation. Other extra-ovarian sites include mucinous tumours originating from the gastrointestinal tract or cervix, and clear cell and endometrioid ovarian cancers being linked with endometriosis ,123,124.PTEN and ARID1A, caused by oxidative stress from iron-rich endometriotic cysts have been found in both EAOC tumours and adjacent endometriotic tissue [The positive association of endometriosis with ovarian cancer was supported by highly suggestive evidence when using only cohort studies, and it was upgraded to strong evidence when case-control studies were included. Endometriosis has been primarily associated with clear cell   and endoc tissue . ‘Retrogc tissue . This coOur umbrella review revealed suggestive evidence that diabetes increases the risk of ovarian cancer incidence , which iThere has been intense debate as to whether talcum powder use increases the risk of ovarian cancer . The mulIn this umbrella review, we have presented the most extensive critical appraisal of published associations to date. A wide array of statistical tests and sensitivity analysis were used to assess evidence strength and validity in an attempt to create a systematic and transparent method of evidence appraisal of the literature.Several limitations and caveats should also be considered when interpreting our findings. Although some individual studies may have been missed in the literature search of the original meta-analyses, this is not expected to have altered our inference as duplicate meta-analyses on the same exposure-outcome pairs gave similar results. The quality of the original studies included in the meta-analyses was also not assessed and was beyond the scope of this umbrella review, but we did assess the quality of the meta-analyses. Furthermore, the statistical tests used can ‘hint’ the presence of possible bias but are unable to confirm its definitive presence and source. The analysis was further restricted by the inability to explore the impact of risk factors separately on pre- and post-menopausal women, for different histological subtypes  , the preThe positive associations of height, obesity and use of HRT with ovarian cancer risk, and the inverse association of OCP use with disease risk were supported by strong evidence. There was further highly suggestive evidence that endometriosis increases disease risk, whilst metformin reduces it. Although further exposures may be also associated with ovarian cancer, the evidence is less certain and further research is required.The description of potentially genuine risk factors found to alter ovarian cancer incidence and mortality is of great interest to the scientific community, clinicians and the public given the dearth of preventative strategies for ovarian cancer. Information on hormonal modifiable risk factors such as HRT and OCP use could be used in the counselling of women considering their use and how this may theoretically positively or inversely affect their risk, whilst further research on the mechanisms that promote reduction in risk in exposures such as the oral contraceptive pill is required. Drugs such as metformin or others working on similar metabolic pathways may be further used and are possible chemopreventative targets. The development of successful methods of screening for ovarian cancer is an ongoing effort and effective preventative measures are yet to be discovered. Whilst the use of risk factors to determine level of risk clinically may be challenging, their recognition is a useful and necessary contribution to the continuing exploration of the non-genetic causes associated with ovarian cancer. Whilst acknowledging that further research is required, in the absence of efficient screening and prevention, evidence on the strength of previously proposed associations may enhance awareness of individuals at higher risk of ovarian cancer and promote prevention or early detection.