Previous studies have identified numerous risk factors of contrast-induced acute kidney injury (CI-AKI) in patients undergoing coronary angiography. However, the association between anemia and CI-AKI remains conflicting. Thus, we conducted a meta-analysis to further clarify the relationship between anemia and CI-AKI. PubMed, EMBASE and Web of Science were systematically searched from inception to June 2020 to identify eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the correlation between anemia and CI-AKI. The potential publication bias was estimated using funnel plot and Begg’s test. A total of 13 studies (five case-control studies and eight cohort studies) comprising 27,135 patients were included. The pooled results showed that anemia was a significant risk factor of CI-AKI . Moreover, the results of subgroup analyses and sensitivity analyses were basically consistent with the overall pooled result. Funnel plot and Begg’s test indicated that there existed potential publication bias, but the result of trim and filled analysis showed that the pooled results kept stable after adding ‘missing’ studies. This meta-analysis suggested that anemia may be correlated with an increased incidence of CI-AKI in patients undergoing coronary angiography. However, our conclusions should be interpreted with caution due to some limitations. Therefore, further high-quality trials should be conducted to confirm our findings.  Coronary angiography has been widely applied in the diagnosis and therapy of coronary artery disease (CAD) for several decades . UnfortuNumerous risk factors of CI-AKI have been identified such as chronic kidney disease, hypertension, hyperuricemia, diabetes mellitus and older age, but most of these factors were irreversible ,9. To deThe association between anemia and CI-AKI remains conclusive. Therefore, in this study we performed a meta-analysis of observational studies to systematically evaluate the correction between anemia and the incidence of CI-AKI, in order to provide the epidemiological evidence on this topic.We searched PubMed, Web of Science and EMBASE databases up to June 2020 using the following keywords: ‘anemia’ or ‘hemoglobin’ and ‘coronary angiography’ or ‘percutaneous coronary intervention’. Patients were searched by ‘anemia’ or ‘hemoglobin’; and ‘coronary angiography’, ‘percutaneous coronary intervention’ or ‘contrast’ for intervention; and ‘kidney failure’ for outcomes. Moreover, we screened the bibliographies of the relevant studies to identify additional articles.The studies meeting all the following criteria were included in this meta-analysis : observaTwo investigators independently assessed the eligibility of all the studies according to the criteria mentioned above. If any disagreement occurred, they removed these issues through a deep discussion. A standardized form was used to extract the following variables from the retrieved studies: first author name, publication year, study design, country of study, period of research, the sex ratio of study population, the age of study population, the number of study population, definition of anemia, definition of CI-AKI, therapy (with or without PCI), outcome measure with the adjusted ORs or RRs with 95% CIs, and the adjusted variables.We assessed the methodological quality of the included studies using the Newcastle-Ottawa Scale (NOS). In this system, three evaluative dimensions aspects were involved: selection of cases and controls, comparability between cases and controls and exposure in cases and controls. Scores from 0 to 9 may be given to a study based on the three dimensions. In the current study, we regarded more than mean score assigned to each study type as a cutoff to determine the quality.2. The formula of calculating I2 is as follows: I2 = 100% x (Q-df)/Q, in which Q represents Cochran’s heterogeneity statistic and df stands for the degree of freedom. The value of I2 ranges from 0% to 100% and I2 value > 50% indicates a dramatical heterogeneity. Considering the unavoidable heterogeneity of observational studies, random-effects model was used to assess the pooled effect. Subgroup analyses were performed based on multiple stratification parameters, including study design type , sample size, methodological quality, definition of anemia and region. Sensitivity analysis was performed by deleting single study in each step. Publication bias was assessed using Begg’s funnel plot. The p-value < 0.05 was considered to be statistically significant. All analyses were carried out using the Stata IC version 15.0 software package .The ORs with 95% CIs were used to estimate the correlation between anemia and the incidence of CI-AKT. The heterogeneity across the included studies was calculated using the Higgins IRelevant studies were identified as the flow diagram illustrated in Baseline characteristics of the included studies are present in 2 = 92.5%) (2 = 73.0%). However, the pooled result of case-control studies showed anemia was not significantly related to CI-AKI . In the subgroup analysis based on study design, the pooled OR/RR of four prospective studies was 1.95 (95% CI = 1.6–2.37), with no evidence of interstudy heterogeneity (I2 = 0), indicating an association between anemia between high incidence of CI-AKI. Similarly, the pooled result of nine retrospective studies also suggested anemia was correlated with increased risk of CI-AKI . In the subgroup analysis by sample size, the pooled result of seven studies with large sample (N ≥ 1000) indicated a significant association between anemia and CI-AKI , with moderate interstudy heterogeneity (I2 = 76.8). However, no statistical significance was observed for the pooled analysis of six studies with small sample size (N < 1000) . The pooled results of six studies with high quality (score ≥ 8)  and seven studies with low quality (score < 8)  suggested there was a close relationship between anemia and CI-AKI. In the subgroup analysis by the definition of anemia, the pooled result of eight studies defining anemia according to the serum hemoglobin , with evidence of high interstudy heterogeneity (I2 = 93.9%), indicated a potential relationship between anemia and CI-AKI. Nevertheless, no significant association between anemia and CI-AKI was found in the pooled analysis of five studies with other definition of anemia . Additionally, we further performed a subgroup analysis based on study region and found an association in Asia  and America , but no relationship in other countries . Then, sensitivity analysis was performed to evaluate the stability of the overall pooled results. As shown in The overall pooled result indicated that anemia was associated with increased risk of CI-CKI , but it was accompanied by a high heterogeneity across the included studies (I= 92.5%) . Subsequ= 92.5%)  were conThe methodological quality of eligible articles was assessed based on NOS criteria. The scores of case-control studies ranged from 6 to 7, and the scores of cohort studies ranged from 7 to 9. A definite cutoff of 8 was applied to determine the quality of a study and six studies were considered high quality (score≥8). The Funnel plot was performed to identify publication bias and its asymmetry was recognized from visual inspection, Then, trimming estimator and filled analyses were applied to analyze and the pooled estimate result was relatively stable .Figure 4In this meta-analysis, the overall pooled result suggested that anemia might be associated with an increased incidence of CI-AKI in patients undergoing coronary angiography. Moreover, the results of subgroup analyses and sensitivity analysis were basically consistent with the overall pooled estimate.Increasing studies showed that CI-AKI has a strong link with adverse clinical outcomes, including cardiovascular complications, renal failure, prolonged hospitalization and death . With thSeveral possible biological mechanisms were considered to explain the association between anemia and CI-AKI. Kidney is a kind of highly oxygen-sensitive organ, so decrease in oxygen transport of blood, reduced blood volume, insufficient effective circulation and blood dilution would increase the consumption of oxygen and injury of oxidative stress in renal tubules cells . BesidesOur study also had several limitations. First, there existed significant heterogeneity across included studies, which might impair the authenticity of pooled effect. However, the results of subgroup analyses and sensitivity analyses were basically consistent with the overall pooled estimate, suggesting that our overall pooled result was robust and reliable. Second, the visual inspection of funnel plot indicated there existed potential publication bias in the meta-analysis, irrespective of the fact that we performed a comprehensive literature search. Interestingly, the result of trim and filled analysis showed that the pooled results kept stable after adding ‘missing’ studies, which indicated that the publication bias might not substantially affect the robustness of our pooled result. Third, although most of the included studies made the definition of anemia on serum hemoglobin level, the cutoff values were not consistent. Moreover, information about the types of anemia was not provided in most eligible studies, so it was hard to exclude the possibility that the pathologies of anemia might be different. Obviously, these potential differences across the included studies may bias our pooled results. Further studies are needed to evaluate the association between anemia and CI-AKI according to different serum hemoglobin level, such as hemoglobin≤13 g/dL, mild (11.1 to 13.0 g/dL), moderate (9.1 to 11.0 g/dL) and severe (7.0 to 9.0 g/dL), as well as the different types of anemia. At last, numerous factors have been considered to be correlated with the incidence of CI-AKI. In this meta-analysis, we found that anemia was a risk factor of CI-AKI, but we could not determine whether anemia is the most important. To ascertain which risk factor is the paramount for predicting CI-AKI, more multi-center clinical studies with large sample size may be performed and multiple credible algorithms should be applied to analyze the relevant data.To sum up, our findings suggested that anemia might be associated with an increased incidence of CI-AKI. However, the conclusion should be interpreted with caution due to some potential confounding factors and heterogeneity. Therefore, further high-quality trials should be performed to further confirm our findings.


Associations between endogenous estrogen exposure indicators and risk of subtypes of dementia have been unclear.Databases  were searched electronically on 1st July and updated regularly until 12nd November 2021. Observational studies of English language were selected if reported an effect estimate  and 95% CI for the association between any exposure  and any endpoint variable . Random-effects models and dose-response meta-analyses were used to calculate estimates and to show the linear/nonlinear relationship. PROSPERO CRD42021274827.2=56.0%), AD , VD  and CI  in categorical meta-analysis, showing similar results in dose-response meta-analyses. An inverse relationship between longer reproductive duration (≥35 vs <35 years) and dementia was observed in dose-response meta-analysis. In addition, estradiol levels after menopause were inversely correlated with the risk of AD and CI.We included 22 studies (475 9764 women) in this analysis. We found no clear relationship between late menarche (≥14 vs <14 years) and dementia, CI in categorical meta-analysis compared to a J-shape relationship in dose-response meta-analyses. Later menopause (≥45 vs <45 years) was consistently associated with a lower risk of all-cause dementia (pooled RR: 0.87, 95%CI: 0.78–0.97, IIn this study, later menopause and longer reproductive period were associated with a lower risk of dementia, while the relationship for menarchal age was J-shaped. There was an inverse relationship between higher postmenopausal estrogen levels and risk of AD and CI. Longitudinal study are needed to further explore the association between life-time estrogen exposure and risk of subtypes of dementia.Start-up Foundation for Scientific Research in Shandong University. Previous studies have shown inconsistent findings on the associations between age at menopause, length of reproductive period and risk of dementia.Compared with previous studies, we included both pre- and postmenopausal estrogen exposures in the present review, providing a life-course perspective into understanding the relationship between endogenous estrogen exposure and subtypes of dementia. Methodologically, besides using categorized meta-analyses, we also used dose-response meta-analyses to show the linear/non-linear relationship between the exposure and outcome across a continuous exposure spectrum.Later menopause and longer reproductive period were associated with a lower risk of dementia, while the relationship for menarchal age was J-shaped. Higher concentration of endogenous estradiol after menopause was linked to lower risk of AD and CI. Longitudinal, repeat measure designs are needed to examine the association between life-time estrogen exposure and risk of subtypes of dementia using direct measure of serum level of endogenous estrogen before and after menopause.Alt-text: Unlabelled box,Sex differences have been shown in the epidemiology of dementia.,,,,,,,,22Age at menopause, age at menarche and reproductive period are all indicators of endogenous estrogen exposure before menopause. Previous studies have shown inconsistent findings on the associations between these indicators and risk of dementia. Late age at menarche had been linked to poor cognitive function or elevated risk of dementia,The aim of this study was to synthesize and quantify the association of reproductive factors: age at menarche, age at menopause, reproductive period, postmenopausal level of estrogen with risk of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VD), and CI.We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. This study was registered with PROSPERO, CRD42021274827.Three online databases, PubMed, EMBASE and Web of Science were searched using a combination of search terms as following up to 1st July 2021.The search strategy included combined terms on: (1) terms related to menarche ; (2) terms related to menopause ; (3) terms related to reproductive period ; (4) terms related to estrogen exposure ; (5) terms related to cognitive impairment . The detailed search strategy for each database was listed in eMethods in the Supplement.First, we imported all searched literature into Endnote and excluded duplicates. The search was limited to studies on human beings and were published in English. Then two investigators screened the titles and abstracts independently and selected the final list of studies in consensus (WTH and CYF). Finally, we extracted the first author's name, country, study design, exposure variables, outcome variables, covariates adjusted, estimates , relative risk (RR) or hazard ratio (HR)) and their 95% CIs. The search was updated on 12nd November 2021.We included studies if they met the following inclusion criteria. (1) Observational studies. (2) Exposure variable was at least one of the following: age at menarche, age at menopause, reproductive duration, or concentration of endogenous estrogen after menopause. (3) The endpoint of interest was all-cause dementia, AD, VD, or CI. (4) The study reported an effect estimate  and the corresponding 95% confidence interval (95% CI) for the association between exposure and endpoint variable.We defined four exposure variables of interest: (1) Age at menarche was the occurrence of a first menstrual period in female adolescenceThe outcomes of interest were the following: all-cause dementia, AD, VD and CI. The presence of dementia, AD and VD was determined by self-reported dementia or AD or VD diagnosed by a doctor, ascertained by medical records. The presence of CI (including MCI) or not was assessed by using scales of Mini-mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA). MMSE<24 or education-specific cut-off points of MMSE , and MoCA<26 were used to define CI. MMSE<27 was used to define MCI.The Newcastle-Ottawa Scale (NOS) was used to assess risk of bias for systematic review of observational studies.,Given the lower than 10% incidence of dementia or MCI  to yield a pooled estimate of the association of menarchal age, menopausal age, reproduction duration with each outcome , respectively. Forest plots were used to show results. As categories of exposure variables differed in individual studies and lacked a uniform reference, we recombined the original categories into simplified categories to pool the effect estimates. For example, age at menopause categories: <40, 40–44, 45–49, 50–54, ≥55 years were combined as <45 and ≥45 years. Categorical meta-analysis was not conducted for estradiol level due to large variation between studies. Limited studies precluded further analysis of the association between reproductive factors and VD.2χ and p-value calculated in step one, we determined whether a linear (P>0.05) or non-linear (P<0.05) dose-response meta-analysis should be adopted. The Q and 2I statistics were used to evaluate the heterogeneity among studies. Higgins et al. (2003) suggested that heterogeneity could be quantified as low, moderate, and high to I2 values of 25%, 50%, and 75%, respectively.Second, we conducted a dose-response meta-analysis for each exposure-outcome relationship. Step one, we performed a non-linear dose-response meta-analysis for each exposure-outcome relationship, then based on the Finally, we performed subgroup analyses based on study design (case-control or cohort) and race (white and non-white). Additionally, to address potential bias and verify our results, we performed various sensitivity analyses by (1) excluding low-quality studies, (2) using a leave-one-out method, (3) Mantel-Haenszel weighting. To investigate the risk of publication bias, we applied the Egger test and visually inspected the funnel plots.All analyses were carried out using Review Manager, version 5.4 (Nordic Cochrane center), complemented by STATA statistical software, version 15.0 (StataCorp). Generalized least squares for trend estimation (GLST) function was used to conduct dose-response meta-analysis. All statistical tests were based on the two-sided 5% level of significance.The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and final responsibility for the decision to submit for publication.,13,18,,,We identified 7 857 studies from various databases initially. Among them, 7523 were excluded for duplication or for not meeting our inclusion criteria. Thus, 64 studies were left for full paper assessment. Of them, 19 43.2%) studies lacked information of effect sizes cannot be calculated based on the data provided, 16 (36.3%) were not related to the topic, three (6.8%) had abstract only, three (6.8%) included women using exogenous estrogen therapy, one (2.2%) was a duplicate publication..2% studiOverall, the 22 studies included 475 9764 women. Studies were published between 1994 and 2020, with women's age 40 years or older at baseline. Of these studies, seven were done in Asian , six in the USA, eight in Europe , and one contained women from mixed countries . Fourteen were case-control studies, six were cohort studies and two were cross-sectional studies  based on NOS quality assessment tool, and only two studies were rated moderate quality (with a score of six). AHRQ scale for cross-sectional studies also showed that both the two studies were with a high quality (appendix pp 22–23).2=4.8%), while no clear association with AD (2=0.0%) (Compared to women with earlier age at menarche (≤12 years), categorized meta-analysis showed that menarchal age 13–14 years was borderline associated with lower risk of all-cause dementia  . Dose-re2=56.0%), AD , VD  and CI  (Compared to women with earlier menopause (<45 years), later menopause (≥45 years) was linked to a decreased risk of all-cause dementia  (Pooled RRs (95% CI) from categorized meta-analyses showed no association between reproductive duration (≥35 years vs <35 years) and risk of all-cause dementia and AD , while lAn inverse linear association was observed between postmenopausal estradiol concentration and risk of AD and CI . As to the link with all-cause dementia, due to the estradiol levels in available studies were all in a lower level (less then 45 pmol/L), we did not find a clear relationship between them . Although no significance was observed with VD, there was a trend that higher postmenopausal concentration of estradiol might be related to increased risk of VD (Supplementary eTable 2).2=62%), and the pooled RR (95% CI) in cohort studies was 0.89  .Overall, the associations of exposures with outcomes in this study were marginally moderated by study design. Taking age at menopause (≥ 45 vs <45 years) and all-cause dementia for instance, the pooled OR (95% CI) in case-control studies was 0.79 , while in non-white population, longer reproductive period was linked to lower risk of all-cause dementia  .In white population, no significant association was observed between reproductive period and all-cause dementia . Restriction of the analyses to high-quality studies did not substantially change the pooled estimates . Mantel-Haenszel weighting also yielded similar results .Limited by the number of studies for exposure-outcome relationship, we only conducted Egger test and visualize funnel plot for studies of age at menarche, age at menopause and all-cause dementia. We observed no evidence of publication bias with inspection of the funnel plot or with the Egger test .Our findings showed that in categorized meta-analyses, later menopausal age was associated with decreased risk of all-cause dementia, AD, VD and CI. Later menarcheal age was linked to higher risk of VD. Longer reproductive duration was related to lower risk of VD and CI. No clear relationship was observed between age at menarche, reproductive duration and risk of AD. In dose-response analyses, there was a J-shape relationship between menarchal age and risk of all-cause dementia and AD, and an inverse linear relationship between menopausal age, reproductive duration, postmenopausal estradiol level and risk of all-cause dementia, AD and CI.In a systematic review published in 2016, Marios et al. found no association of age at menopause, reproductive duration with dementia and CI.By using a standard classification of menopausal age, we found later menopause (≥45 years vs <45 years) was associated with decreased risk of all-cause dementia , AD, VD. Further, when CI was used as an outcome, later menopause and longer reproductive duration (>39 years vs <35 years) were linked to lower risk of CI, consistent with the findings from the previous review.,,,,,,,Past studies indicated that compared to pre- and perimenopausal women, dramatic decrease in estrogen level after menopause was linked with declined cognitive performance in postmenopausal women.2+homeostasis and regulating the function of l-type calcium channel, thereby relating to synaptic function and pathological changes of the AD.,Several mechanisms have been proposed to explain why lengths and levels of endogenous estrogen exposure affect the cognitive function decline. First, estrogen can remove oxygen free radicals. Estrogen increases the energy production efficiency of mitochondria, thereby inhibiting the mitochondrial production of free radical oxygen molecules.,,Our review has several strengths. Previous reviewsOur review also has several limitations. First, moderate or high heterogeneity among studies was observed when pooled estimates for age at menopause and dementia, or reproductive duration and dementia was calculated. The women's age differed in individual studies, raising the possibility of heterogeneity based on age. Nonetheless, I-square values in this review were in the acceptable range, given the use of random-effects models that account for heterogeneity and yield more conservative effect. In addition, although majorities of studies were adjusted for key potential confounders: education, BMI, smoking and postmenopausal HRT status, other confounding factors affecting lifetime estrogen exposure, such as parity, breastfeeding and oral contraceptive use could not be adjusted in most of the studies. Third, dose-response relationship between postmenopausal estradiol level and CI were from cross-sectional studies and may only reflect a cross-sectional association. Fourth, as to postmenopausal estradiol level, although most included studies detected serum estrogen level using fasting blood at 8–11 am, due to the lack of unified detection methods, the estrogen concentration might fluctuate across studies. Last, limited by the number of studies included, publication bias (using funnel plots) were only assessed for the associations of menopausal age, menarchal age and all-cause dementia.Later menopause was consistently linked to lower risk of dementia and CI, while menarchal age showed a J-shape relationship with dementia. There was an inverse relationship between higher concentration of postmenopausal estrogen level and risk of AD and CI. Our findings may support the hypothesis that endogenous estrogen loss at menopause confers increased vulnerability to AD in women. Our findings also indicated estrogen exposure indicators before or after menopause might have different effect on VD, with former protective and latter non or harmful. Longitudinal, repeat measure designs are needed to examine the association between life-time estrogen exposure and risk of subtypes of dementia using direct measure of serum level of endogenous estrogen before and after menopause.Start-up Foundation for Scientific Research in Shandong University.CF and WH searched databases, extracted data, did statistical analyses, and drafted the manuscript. NS, SSV, SRM, and DZ contributed to critical revision of the manuscript. DZ was the study supervisor and conceived the study design and contributed to interpretation of the results.Dr. Virani reports grants from Department of Veterans Affairs, NIH, World Heart Federation, Tahir and Jooma Family, other from being an associate editor for Innovations of American College of Cardiology(acc.org), outside the submitted work. All the other authors report no conflicts.


ABCA1 gene polymorphisms may be associated with the plasma lipid concentration, the literature has not shown a consistent pattern. In this study, we attempted to elucidate the association between the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms and the plasma lipid concentration through a systematic review and meta-analysis. Methods: We selected studies published up to October 2020 in the PubMed, Web of Science, and Embase databases according to inclusion and exclusion criteria. The mean difference (MD) and 95% confidence interval (CI) were used to assess the relationship between the presence of ABCA1 69C>T, 825V>I, and 230R>C and plasma lipid levels. Meta-analysis was performed using Review Manager (version 5.3). Both Begg’s test and Egger’s regression test of the funnel plot were performed using R Studio software (version 3.6.0) to identify publication bias. Results: We analyzed the data on the ABCA1 69C>T polymorphism involving 14,843 subjects in 11 studies, 825V>I polymorphism involving 2580 subjects in 5 studies, and 230R>C polymorphism involving 4834 subjects in 4 studies. The T allele carriers in 69C>T, II carriers in 825V>I, and C carriers in 230R>C had lower high-density lipoprotein cholesterol levels; the MD (95% CI) was −0.05 mmol/L , −0.05 mmol/L , and −0.1 mmol/mL , respectively. In the case of 230R>C, the serum total cholesterol concentration of C carriers was significantly lower than that of RR carriers . Conclusion: This meta-analysis demonstrates that the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms could affect the plasma lipid concentration. As the plasma lipid concentration may be related to various diseases, ABCA1 genotyping could be useful for the management of lipid levels.Background: Although  Coronary heart disease (CHD) is a common disease with high morbidity and mortality . AlthougATP-binding cassette transporter A1 (ABCA1) is a cell membrane transport protein composed of 2261 amino acids. One of its main functions is to promote the efflux of cellular cholesterol and phospholipids . They coABCA1 gene is a highly polymorphic gene located on chromosome 9 [ABCA1 have been found in the intron, exon, or promoter region, which can affect the function of ABCA1. Defects in the reverse cholesterol transport process caused by ABCA1 genetic mutations can cause Tangier’s disease or familial HDL deficiency by reducing HDL-C levels [The mosome 9 ,11. SomeC levels .ABCA1 genetic polymorphisms and the plasma lipid concentration, including ABCA1 69C>T, 825V>I, and 230R>C [ABCA1 69C>T is located in the 5ʹ untranslated region, and 825V>I and 230R>C are missense mutations; thus, they may have a greater effect on the expression and function of ABCA1. However, previously published studies on the relationship between these ABCA1 gene polymorphisms and the plasma lipid concentration showed inconsistent results.Several studies have demonstrated the relationship between d 230R>C ,14,15. AABCA1 69C>T, 825V>I, and 230R>C polymorphisms through a systematic review and meta-analysis of previous studies.Therefore, the aim of this study was to investigate the correlation between the plasma lipid concentration and the This meta-analysis was conducted according to the checklist outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . Two revABCA1 69C>T, 825V>I, and 230R>C with the lipid levels (mmol/L) of adults. The language of the articles was limited to English. Studies were excluded if (i) they were editorials, notes, abstracts, reviews, comments, letters, news, or editorials; (ii) they were in vitro or in vivo studies; (iii) extraction of the data was not possible; or (iv) sample size was less than 20. If there were overlapping data, only the most recent and comprehensive data were included in the meta-analysis.Studies were included if they evaluated the relationship of Two reviewers extracted the data independently, and discrepancies were resolved by consensus. Extracted data included the following information: name of the first author, publication year, country, disease, study design, number of subjects, mean age, percentage of females, genotyping method, studied lipid types, and lipid levels by genotype.Two researchers independently assessed the selected studies based on the Newcastle–Ottawa scale (NOS) for cohort studies and case–control studies . The NOSABCA1 69C>T, 825V>I, and 230R>C and lipid levels. For studies reporting only medians and interquartile ranges, we retrieved the mean and variance values from the authors of the original reports or used appropriate formulas to calculate the mean and variance, making no assumption on the distribution of the underlying data [Meta-analysis was performed using Review Manager . The mean difference (MD) and 95% confidence interval (CI) were used to assess the relationship between the presence of ing data . The uniI2 statistic. An I2 value of ≥50% was considered to indicate significant heterogeneity. The selection of the proper effect model was based on the analysis results; the fixed effect model was used if I2 < 50%, and the random effect model was used if I2 ≥ 50% [p-value < 0.05 was considered statistically significant.The heterogeneity across studies was estimated by the chi-square test and I2 ≥ 50% . Both BeI2 ≥ 50% ,21. A p-n = 73); there was no ABCA1 polymorphism-grouped lipid outcome (n = 52); there was no lipid outcome (n = 19); the study was not a clinical trial (n = 10); the sample size was less than 20 (n = 8); the study involved children (n = 4); there was an overlapping cohort (n = 2); the study was not in English (n = 1). Therefore, 18 articles were identified for this systematic review [A detailed flow chart of the study selection process is presented in c review ,33,34,35The characteristics of the included studies are presented in ABCA1 69C>T with the plasma lipid concentration, 11 studies with a total of 14,843 subjects were included in the meta-analysis. As shown in p = 0.02) compared with the concentration of wild-type homozygote carriers (CC). High heterogeneity was detected among the studies . There were no significant differences in LDL-C, TG, and TC levels between genotypes  compared with the concentration of subjects with the VI and VV genotypes based on a meta-analysis of five studies. Low heterogeneity was observed . The association between the 825V>I polymorphism and plasma LDL-C, TG, and TC levels was not statistically significant  compared with the concentration of non-carriers. Low heterogeneity was observed among the studies . The TC concentration of variant C carriers was significantly lower than that of wild-type homozygote carriers (RR) by 0.2 mmol/L  . There were no differences in LDL-C and TG levels between genotypes  D. No hetThis meta-analysis showed that the T allele carriers in 69C>T, II carriers in 825V>I, and C carriers in 230R>C had significantly lower HDL-C levels. In the 230R>C polymorphism, TC levels were significantly lower among C carriers compared with wild-type homozygote carriers.ABCA1 transfers excess intracellular cholesterol and phospholipids to apolipoprotein AI, producing an early form of HDL-C . This inThe results of our meta-analysis are consistent with those of previous studies on the risk of developing lipid-related diseases such as atherosclerosis (AS) and CAD, in which abnormal lipid levels are the main cause of the diseases. The relationship between the 69C>T polymorphism and AS was examined in a previous study . This meABCA1 gene polymorphisms may play different roles in different atherosclerotic diseases, they can be related to the onset of AS.In the case of the 825V>I polymorphism, the aforementioned study failed to show a significant association with the development of AS; this is different from the results of our study, in which the level of HDL-C was significantly lower in II genotype carriers than in VI and VV genotype carriers . HoweverABCA1 230R>C revealed that C carriers had both lower HDL-C and lower TC plasma levels compared with the levels of non-carriers in our study, which were controversial in explaining the association of ABCA1 polymorphisms and the development of lipid-related diseases such as AS and CAD. Similar results were also reported in a previous study conducted in Mexico on the association between the 230R>C polymorphism and early CAD [ABCA1 230R>C polymorphism may also affect other functions, thus contributing to the inconsistency between lipid levels and the risk of developing lipid-related diseases [Analysis of arly CAD . Particiarly CAD . As ABCAdiseases ,42.ABCA1 gene polymorphisms  and abnormal lipid levels. However, this study has several limitations. First, this study did not consider that there may be differences in the plasma lipid concentration of patients with underlying diseases such as familial hypercholesterolemia or diabetes mellitus. Second, only published studies in English were included. Lastly, in addition to genetic factors, various risk factors that can affect the plasma lipid concentration  were not considered.This study is the first meta-analysis to reveal an association between ABCA1 gene polymorphisms  may be associated with lower HDL-C levels. In addition, a significant association was found between the 230R>C polymorphism and lower TC levels. To the best of our knowledge, this is the first meta-analysis to show an association between the ABCA1 69C>T, 825V>I, and 230R>C polymorphisms and the plasma lipid concentration. Further studies with a large population and analysis of related risk factors are needed to confirm our findings.This meta-analysis demonstrates that


Background. Actinic cheilitis (AC) is a potentially malignant disorder characterized by chronic lip inflammation, especially the lower lip, associated with accumulative exposure to solar radiation. The present study aimed to assess the possible risk factors related to AC.Methods. A search for studies on AC risk factors was conducted in the following databases: PubMed , Web of Science (WoS), and Google Scholar. For dichotomous outcomes, the estimates of the effects of intervention were expressed as odds ratios (ORs) using Mantel-Haenszel (M-H) method, and for continuous outcomes, the estimates of the effects of intervention were expressed as mean difference (MD) using the inverse variance (IV) method, both with 95% confidence intervals.Results. Twelve studies were considered in this meta-analysis. The factors from the highest to lowest risk of AC were having a low skin phototype (OR: 3.30), age >50 years (OR: 3.01), having high sun exposure, cumulative throughout life (OR: 2.13) as daily (OR: 2.00), being male (OR: 1.78), and being a drinker (OR: 1.56) or smoker (OR: 1.32). However, the use of sunscreen creams and caps/hats to protect against the sun were factors with no significant influence on the AC risk.Conclusion. Chronic sun exposure in subjects with low skin phototypes is the main risk factor for AC. Clinically, AC is characterized by areas of erythema, atrophy, edema, and desquamation that can evolve into erosions or white patches in advanced cases. A diffuse border between lip skin and labial semimucosa might also be seen. Histologically, AC exhibits atypia and loss of polarity of the keratinocytes, chronic inflammatory infiltrate, and elastosis in the connective tissue due to basophilic degeneration of the extracellular matrix (solar elastosis). In advanced cases, dysplastic changes might be observed.Actinic cheilitis (AC) is a potentially malignant disorder characterized by chronic inflammation of the lip, especially the lower lip, which is associated with chronic and cumulative exposure to ultraviolet (UV) radiation. The prevalence of AC ranges between 0.4% and 2.4% of the general population, although in susceptible groups with outdoor activities, it might reach 43.2%.The main risk factor for AC is chronic and cumulative exposure to solar radiation. Other related risk factors include long outdoor work and activities, smoking habits, lighter skin tones, and immunosuppression. Fair-skinned subjects (low skin phototypes) are more susceptible to sun damage and more prone to developing AC. The process of malignant transformation of AC into lip carcinoma is usually very slow (1–30 years), with a transformation rate of 3‒16.9%. Therefore, early diagnosis and treatment of AC are of great importance to prevent its progression to lip carcinoma.The present study aimed to assess the potential risk factors related to AC. c) articles without a control group (n = 194), and d) studies with non-usable data (n = 78). After applying these criteria, 12 studies were included in this meta-analysis , Web of Science (WoS), and Google Scholar (Google Scholar). A combination of Medical Subjects Headings (MeSH) and free-text terms were used as search strategies. The search terms were the following: (“cheilitis” [MeSH Terms] OR “lip diseases” [MeSH Terms]) AND “sunlight” [MeSH Terms]; (“actinic cheilitis” OR “actinic cheilosis”); allintitle: “actinic” AND (“cheilitis” OR “cheilosis”). After this initial search, 795 articles were found  from 1952 to 2020, 299 of which were duplicates, leaving 496 eligible articles. The two authors jointly agreed upon the study selection process for the meta-analysis. The exclusion criteria were: a) articles without full-text availability (n = 145), b) articles with a score of <6 stars out of a maximum of 9 on the Newcastle-Ottawa methodological quality assessment scale (n = 67),analysis .P values and the Higgins statistic (I2). A random-effects model was applied when the heterogeneity was high (I2 > 50%). A P value < 0.05 was considered statistically significant.The data were processed with the RevMan 5.4 software for meta-analysis . For dichotomous outcomes, the estimates of effects of the intervention were expressed as odds ratios (ORs) using Mantel-Haenszel (M-H) method. For continuous outcomes, the estimates of the effects of intervention were expressed as mean difference (MD) using the inverse variance (IV) method, both with 95% confidence intervals. Heterogeneity was determined according to the  only articles with low to moderate risk of bias (≥6 stars) were included in the present study. Nine articles (75.0%) achieved 7 points on the NOS scale, while the other three (25.0%) had 6 points.A total of 3798 individuals, 1084 patients (28.6%) with AC and 2714 (71.4%) without this lip lesion were recorded in these studies. By gender, 679 males (62.6%) and 405 females (37.4%) were found in the group of AC patients, with 1406 males (51.8%) and 1308 females (48.2%) in non-AC subjects. Considering the Newcastle-Ottawa (NOS) quality scale,The analyses of different AC risk factors are presented in  analyzed whether being older or younger than 50 could influence the risk of developing AC. Patients >50 years of age were 3.01 times more likely to develop AC with a highly significant statistical relationship . Four studies considered the mean age of AC patients and controls, reporting a mean age of 8.13 years higher in AC patients. Statistical analysis revealed a highly significant association . Regarding gender, 11 studies evaluated this parameter as a risk factor, reporting a 1.78-times higher probability of AC in men than in women, with statistically significant differences .Seven studies considered that smoking increased the risk of developing AC 1.32 times, with a statistically significant relationship .Harmful habits (smoking and drinking) were also examined in AC patients compared to the controls without AC. Twelve studies alcohol beverage intake was assessed in AC patients and controls, demonstrating that drinkers had 1.56 times more risk of AC. Statistical analysis indicated a highly significant association .In seven studies, reviewed the possible implication of accumulated sun exposure during life. AC patients were 2.13 times more likely to have high sun exposure, with highly significant statistical differences . Five studies evaluated daily sun exposure, reporting a two-fold probability of presenting high daily exposure in AC patients (≥4 hours a day). The statistical analysis showed a significant association . Three studies investigated the mean number of hours of sun exposure as a possible risk factor, showing, on average, 9.25 more hours of sun exposure in AC patients, with a statistically significant relationship .Eight studies analyzed the possible influence of the skin phototype on the AC risk. Subjects with low skin phototypes  exhibited 3.30 times higher AC risk with a highly significant statistical relationship .Ten studies considered the use of sunscreens, finding no relevant impact of their use on the AC risk . Other four studies detailed the use of lipstick, verifying that it did not reduce the AC risk. Statistically significant differences were observed . Finally, five studies examined the use of a cap/hat, reporting no effect on the AC risk. The statistical analysis did not reveal a statistically significant relationship .Seven studiesTwelve studies on the possible risk factors for AC were included in the present meta-analysis.AC is a potentially malignant oral disorder characterized by chronic inflammation of the lip, most commonly affecting the lower lip, resulting from excessive and cumulative sun exposure. The rate of malignant transformation of AC to lip squamous cell carcinoma is around 3%.P < 0.001). The seven studies that analyzed this parameter coincided in pointing out this higher AC frequency with aging. Older age is a variable strongly associated with the development of AC. The relationship between an increase in age and the presence of AC tends to be directly proportional to the accumulated UV radiation exposure during life, especially in people with fair skin. Most cases of AC appear in people over 50 years of age who have a longer time of sun exposure and more severe lip clinicopathological changes. In this investigation, the AC patients had a mean age of 8.13 years older than the controls with a highly significant statistical relationship (P < 0.001). All the studies indicated this higher mean age in AC patients closely associated with a higher mean number of years of exposure to solar radiation.In the present study, subjects >50 years of age had a 3-fold higher probability of developing AC with highly significant differences (P < 0.01). Of the eleven studies that considered gender, ten studies consistently indicated a predilection for the male gender. At the same time, only one did not observe this higher prevalence in men, although without statistically significant results. This higher prevalence of AC in men could be explained by their greater exposure to solar radiation derived from professional outdoor activities  and by the lack of solar protective measures. All this contributes to the development of chronic lip lesions. In the case of women, several reasons justify this lower predisposition to AC: a higher frequency of using sunscreen lipsticks and other protective measures, a lower percentage of outdoor workers, or a retirement age lower than that of men.In the present paper, AC was more frequent in men than in women, with a statistically significant association (P = 0.04). Of the 12 studies that evaluated the smoking habit, nine confirmed the impact of tobacco consumption, while the remaining three noted a higher frequency of AC in non-smokers. The placement of the cigarette on the lip and the continuous exposure to the heat generated by the smoke seem to enhance the lip changes induced by chronic exposure to solar radiation, also increasing the probability of malignant degeneration due to a synergistic action of several carcinogens. It is important to discourage smoking, especially among people exposed to more than one risk factor involved in lip and oral carcinogenesis.Harmful habits such as smoking and/or drinking were also analyzed. In this study, smokers had 1.32 times more AC risk with statistically significant differences (P < 0.001). The seven studies that assessed this parameter confirmed the relevance of alcohol intake as a possible causal agent of AC. Although there is no consensus regarding the influence of alcohol on the development of AC due to the difficulty for an adequate quantification of this parameter, alcohol consumption and other factors, especially smoking, favor the development of these labial lesions. This higher AC prevalence in drinkers might be associated with other risk factors such as more frequent smoking in men, outdoor activities with greater exposure to solar radiation, and the lower use of lip protection factors.Similarly, drinking increased the probability of AC 1.56 times, with a highly significant statistical association (P < 0.01). Six studies highlighted the relevance of accumulated sun exposure as a causal agent of AC. Individuals who are regularly sun-exposed at an early age and with a history of accumulated sun exposure during their life are the most susceptible to developing AC. Likewise, in the present study, patients with high daily sun exposure were twice as likely to present AC with a statistically significant association (P = 0.04). The five studies that examined daily hours of sun exposure confirmed this increased AC risk. Sun exposure of more than 4 hours a day is directly associated with an increased AC risk, especially in those who do not use sunscreens. On the other hand, in this investigation, it was also found that AC patients had a mean number of 9.25 hours more sun exposure than subjects without AC, with statistically significant differences (P < 0.01). All the studies that estimated the number of hours confirmed this increased AC risk as the number of hours of sun exposure increases. In AC, the tissue damage induced by sun exposure is cumulative, showing the chronicity of the lip lesion.Cumulative sun exposure, both in the number of hours per day and throughout life, is considered the most important etiological agent in the appearance of AC. In this study, greater sun exposure doubled the AC risk with a statistically significant relationship (P < 0.001). The ten studies that investigated the phototype indicated this increased AC risk in fair-skinned individuals. The lower the skin phototype, the lower the melanin concentration at the level of the basal layer of keratinocytes, the natural pigment with a protective effect against UV radiation. Besides, subjects with low phototypes have a less effective mechanism for cellular repair of the damage induced by sun exposure. There is an inverse relationship between the amount of melanin and DNA damage induced by exposure to UV radiation. Furthermore, white-skinned subjects do not present UV-induced apoptosis. In contrast, darker-skinned subjects do show relevant apoptosis, demonstrating the efficient elimination of cells damaged by UV rays in individuals with higher skin phototypes.In the present meta-analysis, people with low skin phototype  increased the probability of having AC 3.30 times, with a highly significant statistical relationship (P = 0.91). Of the seven studies that assessed this parameter, four observed AC in the sunscreen users, while the remaining three found AC in those who did not use sunscreens. Sunscreens protect the facial skin against solar keratosis; however, since they are not applied to the lips, they do not have any protective effect on them and do not prevent AC in susceptible individuals.In this study, the use of sunscreen creams did not influence the risk of AC, without a statistically significant association (P = 0.02). The four studies that analyzed this variable confirmed the unexpected ineffectiveness of lipsticks as a protective factor against AC. A possible explanation for this contradictory result could be in the type of population considered in these studies. The majority were rural male workers with little awareness of the use of lipsticks and other protective measures against solar radiation.The specific use of lipstick as a protection measure was also verified, surprisingly showing that it did not reduce the AC risk with a statistically significant result (P = 0.91). Only two of the five studies indicated a protective effect of the cap/hat against AC. On many occasions, the use of a cap/hat creates a false sense of protection when some of these clothes, due to their design, do not cover the lower third of the face, exposing the lips, especially the lower lip, to the action of solar radiation, facilitating the development of AC.Finally, the use of a cap/hat as an element of protection was evaluated, and as with the rest of the protective measures (photoprotective creams and lipsticks), it did not affect the AC risk in a relevant way, without statistically significant differences , age >50 years (OR: 3.01), having high sun exposure, both cumulative throughout of life (OR: 2.13) and daily (OR: 2.00), being male (OR: 1.78) and being a drinker (OR: 1.56) or smoker (OR: 1.32). However, the use of sunscreen creams and caps/hats to protect against the sun were factors with no significant influence on the AC risk.ARA and AIB contributed equally in concept, design, data collection, and interpretation and preparation of the final manuscript.None.None.None.Not applicable.


Autoimmune thyroid disease (AITD) is characterized by thyroid dysfunction and deficits in the autoimmune system. Growing attention has been paid toward the field of gut microbiota over the last few decades. Several recent studies have found that gut microbiota composition in patients with AITD has altered, but no studies have conducted systematic reviews on the association between gut microbiota and ATID.We searched PubMed, Web of Science, Embase, and Cochrane databases without language restrictions and conducted a systematic review and meta-analysis of eight studies, including 196 patients with AITD.Bifidobacterium and Lactobacillus were decreased in the AITD group, and harmful microbiota like Bacteroides fragilis was significantly increased compared with the controls. Furthermore, the percentage of relevant abundance of other commensal bacteria such as Bacteroidetes, Bacteroides, and Lachnospiraceae was increased compared with the controls.The meta-analysis showed that the alpha diversity and abundance of certain gut microbiota were changed in patients with AITD compared to the controls. Chao1,the index of the microflora richness, was increased in the Hashimoto’s thyroiditis group compared to controls , while it was decreased in the Graves’ disease group . In addition, we found that some beneficial bacteria like This meta-analysis indicates an association between AITD and alteration of microbiota composition at the family, genus, and species levels.PROSPERO, identifier CRD42021251557. Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the main types of autoimmune thyroid disease (AITD). AITDs are the most common organ-specific autoimmune disorders. Although the clinical manifestations of GD and HT are different, such as hyperthyroidism and hypothyroidism, respectively, GD and HT share similar immune-mediated mechanisms of disease, even alternating from one to the other , 2. Manyvia GPR109A  AND .Studies were considered eligible if they met the following criteria: 1) investigating the gut microbiota and patients diagnosed with AITD. 2) providing sufficient data on the relationship between AITD and intestinal microbiota and could be extracted to analyze the 95% confidence interval (CI). 3) written in English. 4) full-text availability. However, comments, animal model subjects, conference abstract, and reviews were excluded. We also excluded studies with incomplete outcome data on the percentages or relative abundance of gut microbiota and studies with fewer than 20 participants.Three reviewers independently extracted the following data from each study: authors, publication year, country of population, population age, clinical parameters of thyroid function, diagnosis of AITD, and microbiology assessment methods.Two reviewers completed the quality assessment using the Newcastle-Ottawa scale (NOS) to evaluate all the included studies, comprising the trial group selection, comparability, and exposure. The total score ranged from 5−9, where a higher score represents a higher quality of assessment. All the discrepancies or poor agreement were resolved through a consensus discussion with a third author.Standardized mean differences (SMD) were calculated between the HT and GD groups to assess the bacterial alpha diversity indices (Chao1). SMD >0 indicates that participants with HT have a higher level of richness in the intestinal microflora. A fixed- and random-effects were used to assess the percentages or relative abundances of certain gut microbiota with AITD compared with the healthy controls. We examined the statistical heterogeneity using the I2 statistic. I2 values of 25%, 50%, and 75% were related to low, moderate, and high heterogeneity, respectively. A Random-effects model was used to pool the results when high heterogeneity (I2>50%) existed. Additionally, the fixed-effects model was used if the heterogeneity was low. Furthermore, we performed a sensitivity analysis as well as Begg’s test to assess the potential influences of bias. All statistical analyses were performed using Stata software (version 12.0). and richness indices (ACE and Chao1). The Chao1 index was a reflex of microflora richness. The meta-analysis of four studies reported data about the Chao1 index between patients with AITD and healthy controls. We found that the Chao1 index was significantly different between the HT and GD groups compared with the controls. To explore the source of heterogeneity, we divided these four articles into two subgroups based on the entities of AITD. The random-effects model of subgroup meta-analysis showed that the Chao1 index was increased in the HT group compared to the controls , while it was decreased in the GD group . The effect size  was relatively small. There was no evidence of between-study heterogeneity I2 = 0%; Figure 2Firmicutes, one of the predominant phyla of the human gut microbiota, showed a lower abundance in patients with AITD than the controls (Firmicutes in the detected sample of HT was 48.3% (95%CI: 0.080 to 0.885) and 55.1% , slightly higher than that in the control group 35.2% , while the control group was 34.1% , while the percentage in healthy control was 14.5%  and 18% , whereas that in healthy controls was 17.8%  in patients with AITD and 0.1% (95%CI: 0.001−0.002) in healthy controls. The heterogeneity within the AITD group was low  compared to 0.4% in control group ,higher than the healthy controls , Dorea , Faecalibacterium , Synergistetes ,and Coprococcus  were negatively correlated with TPO-Ab or TR-Ab. In contrast, other commercial bacteria like Blautia, Lactobacillus, Alistipes, Ruminococcaceae, and Enterobacteriaceae were positively correlated with TPO-Ab.Several studies have revealed the significant correlations between clinical thyroid-related antibodies like TPO-Ab and TR-Ab, and different bacterial abundances by Spearman’s correlation distance. The Spearman correlation coefficient R-value between microbiota and immune indices, including TPO-Ab and TR-Ab, demonstrated that certain microbiota significantly correlated with thyroid function tests Table 3.To the best of our knowledge, this is the first meta-analysis to demonstrate the association between gut microbiota and AITD. This association has become a very popular topic and field in recent years. Many researchers want to illuminate the association and underlying mechanism linking AITD and microbiota, expecting to discover a novel target for early diagnosis or reversal of the host’s disordered immune system through fecal microbiota transplantation. Owing to the development of 16SrRNA sequencing technologies, significant alterations of the abundance and composition of gut microbiota have been found between AITD and healthy controls, suggesting that the gut-thyroid axis may play a pivotal role in the development and progress of AITD .Though HT and GD are considered the most common two forms of AITD, the pathogenesis and hallmark of HT and GD are quite different. The hallmark of HT is the high rate of TPO-Ab, and TG-Ab, while high TR-Ab level was detected in patients with GD . BesidesFirmicutes and Bacteroidetes are the main dominant microbiota at the phyla level. Traditionally, the ratio of Firmicutes and Bacteroidetes has been implicated in the predisposition of disease conditions. In our meta-analysis, the rate of Firmicutes and Bacteroidetes ratio of patients with AITD showed a lower level than their healthy counterparts. Besides, AITD patients showed a notable alteration in gut microbiota composition as compared to the controls. A random-effect model indicates that people with AITD showed a significantly increased relative abundance of pathogenic bacteria and a decreased proportion of beneficial bacteria such as Lactobacillus and Bifidobacterium. Lactobacillus and Bifidobacterium could be used as a probiotic to modulate the immune response and have no adverse effect on developing an experimental autoimmune thyroiditis mice model  or DAMPs (damage-associated molecular pattern molecules (DAMPs) patterns. Notably, the IL-1β, the subsequent effector molecules downstream of inflammasomes, can modulate the microbiota by regulating the production of antimicrobial peptides (AMPs)  . In addis (AMPs) . A studynd NF-kB , 46. MorRuminococcaceae, Blautia, and Alistipes, were significantly positively correlated with TPO-Ab. In contrast, other bacteria such as Bacteroides and Synergistetes were negatively correlated with TPO-Ab or TR-Ab. Furthermore, the gut microbiota is correlated with cell functions such as membrane transport, genetic information, or other cellular processes  of thyroid may provide guidance for the future study or diagnosis of AITD. We found that some intestinal microbiota, such as rocesses . Notablyrocesses , 48. TheSeveral limitations of this meta-analysis should be considered. First, most studies did not consider the effect of dietary habits. The consumption of various food or fiber can influence the composition of the commensal microbiota and its metabolites, SCFA . Second,Bifidobacterium and Lactobacillus, may be associated with the development of AITD to some extent. However, the way how microbiome affects the progress of AITD is still controversial, and the research data is limited. Therefore, a further multicenter approach is needed to clarify the underlying pathogenesis and progress of intestinal microbiota dysbiosis in AITD.This meta-analysis shows the interactions between the gut microbiota and the pathogenesis of AITD. Furthermore, certain beneficial intestinal bacteria decrease, such as The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.BG and ZS conceived the study. CW, FM, HW, and YY participated in the statistical analysis. BG and BS drafted the article. All authors read and approved the final version of the manuscript.This study was supported by the Department of Education in Liaoning Province, China (LJKZ0742).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Low Geriatric Nutritional Risk Index has been identified as an index of impaired nutritional state. The objective of the meta-analysis was to assess the association of the Geriatric Nutritional Risk Index (GNRI) with adverse outcomes in patients with coronary artery disease (CAD).Methods: Relevant studies were identified by comprehensively searching PubMed and Embase databases in May 2021. Studies assessing the association of GNRI with all-cause mortality or major adverse cardiovascular events (MACEs) in patients with CAD were included. The predictive value of GNRI was summarized by pooling multivariable adjusted risk ratios (RR) with 95% confidence intervals (CI) per GNRI point decrease or the lowest vs. the highest GNRI group.Results: A total of eight studies involving 9277 patients with CAD were analyzed. Meta-analysis showed that the lowest GNRI was associated with a higher risk of all-cause mortality  and MACEs , respectively. Furthermore, per point decrease in GNRI was associated with 8 and 10% additional risk of all-cause mortality and MACEs. Subgroup analysis indicated that the value of low GNRI in predicting all-cause mortality was not affected by subtype of patients or follow-up duration.Conclusion: Low GNRI score at baseline was associated with a higher risk of all-cause mortality and cardiovascular events in patients with CAD. The nutritional state estimated by the GNRI score could provide important predictive information in patients with CAD. Geriatric Nutritional Risk Index, created by Bouillanne et al., was calculated by serum albumin level and the ratio of actual to ideal body weight . This neDespite the prevalence of nutritional deficiency remaining unclear in patients with coronary artery disease (CAD), malnutrition was reported to be at 38.7% with Controlling Nutritional status (CONUT) scores and 64% with GNRI scores among non-ST-elevated myocardial infarction (NSTEMI) , and varThere is no previous meta-analysis specifically focused on the predictive value of GNRI in patients with CAD. We hypothesized that low GNRI scores may be associated with adverse outcomes. To summarize the available evidence, we performed this meta-analysis to assess the value of baseline GNRI in predicting adverse outcomes in patients with CAD in terms of all-cause mortality and major adverse cardiovascular events (MACEs).This study was reported according to the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . RelevanStudies satisfying all the following criteria were included: (1) cohort studies recruiting patients with stable or acute CAD, (2) assessing the association of GNRI with all-cause mortality or major adverse cardiovascular events , and (3) providing multivariable adjusted risk ratio (RR), hazard ratio (HR), or odds ratio (OR) with 95% confidence intervals (CI) per GNRI point decrease or the lowest vs. the highest GNRI group.Studies reporting in-hospital outcomes were excluded.The following information was collected from the included studies: the surname of the first author, published year, region, study design, subtypes of patients, sample sizes, percentage of men, age at baseline, cutoff value of the highest GNRI, definition of MACEs, time of follow-up, endpoints, most comprehensively adjusted risk summary, and adjusted confounders. The methodological quality of included studies was judged using the Newcastle–Ottawa Scale (NOS) . StudiesI2 statistic and the Cochrane Q test were used to judge the heterogeneity, with statistical significance set at I2 ≥ 50% or p <0.10. We chose a random effects model in case of significant heterogeneity. Otherwise, a fixed-effect model was selected. To investigate the robustness of the pooling risk estimate, we conducted the sensitivity analysis by sequentially removing each study to recalculate the risk summary. Meanwhile, we performed the subgroup analyses according to the subtypes of patients with CAD, sample sizes, median or mean age, and length of follow-up. Both Begg's test  was applied to perform the meta-analysis. The predictive value of GNRI was calculated by pooling multivariable adjusted RR with 95% CI per point decrease in GNRI or the lowest vs. the highest category of GNRI. The g's test  and Eggeg's test  were plaI2 = 0%; p =0.771). The adjusted pooled RR of all-cause mortality was 2.10 (95% CI 1.68–2.63) when compared the lowest to the highest GNRI category. The value of the lowest GNRI in predicting all-cause mortality was consistently observed across multiple subgroups . Sensitivity analysis indicated that removal of individual study each time did not significantly alter the originally statistical significance of the pooling risk estimate (data not shown).The predictive value of GNRI by categorical analysis for all-cause mortality was available in six studies , 17, 18.ubgroups . In addiubgroups , 17 asseI2 = 75.3%; p = 0.018). The adjusted pooled RR of MACEs was 2.84 (95% CI 1.56–5.16) when compared the lowest to the highest GNRI category. In addition, three studies . Sensitivity analysis suggested that the originally statistical significance of the pooling risk estimate did not significantly change when excluded from the individual study each time (data not shown).The predictive value of GNRI for MACEs by categorical analysis was available in three studies , 12, 18. studies , 12, 17 We did not conduct the Begg's test and the Egger's test to check the publication bias because of the less than recommended arbitrary number of 10 studies .This is the first meta-analysis to evaluate the predictive value of GNRI in patients with CAD. The main findings of our meta-analysis indicated that a low GNRI score was an independent predictor risk all-cause mortality and MACEs in patients with CAD. The patients with CAD who had the lowest GNRI score had a 2.84-fold and 2.10-fold increased risk of MACEs and all-cause mortality, respectively. Moreover, per point decrease in GNRI score was associated with 10 and 8% higher risk of MACEs and all-cause mortality, respectively. Together with these findings, the nutritional status, estimated by the GNRI, may provide important predictive value in patients with CAD.Geriatric Nutritional Risk Index score was also associated with a 3.16-fold higher risk of bleeding event in patients undergoing percutaneous coronary intervention (PCI) with an oral anticoagulant during a 3-year follow-up . In addiSeveral nutritional scoring systems, including the prognostic nutritional index (PNI), CONUT, triglycerides-total cholesterol-body weight index (TCBI), Mini Nutritional Assessment (MSA), Graz Malnutrition Screening (GMS), and GNRI have been introduced for evaluating nutritional state in clinical practice. Malnutrition determined by the PNI , TCBI 2, 25, andCoronary artery disease includes a heterogeneous population. Results of subgroup analysis suggested that the association between low GNRI and all-cause mortality was stronger in patients with acute coronary syndrome (ACS) compared with those with stable CAD. The value of low GNRI in predicting all-cause mortality weakened with the lengthening of the follow-up time in the subgroup analysis. It is noteworthy that these results were established on the small number of studies analyzed. Future studies are necessary to confirm the present findings.Despite diet nutrition being recommended in patients with CAD as secondary prevention, nutritional support is often neglected by physicians . This meThere are several potential limitations in the current meta-analysis. First, the majority of the analyzed studies adopted the retrospective design, and selection bias of this type of study may have been committed. Second, the included studies selected different thresholds of low GNRI scores, which makes it difficult for clinicians to identify those in need of nutritional supplementation. Third, there was significant heterogeneity in pooling MACE subtypes. Different subtypes of patients with CAD, thresholds of low GNRI score, definitions of MACEs, or intervals of follow-up duration may be correlated to the observed heterogeneity. Fourth, GNRI score of 92–98, 82–91, and <82 reflects the mild, moderate, and severe malnutrition, respectively. However, most of the included studies reported the predictive value of GNRI based on the single cutoff and not by nutritional status, which prevents the evaluation of the prediction of malnutrition defined by GNRI <92. Future studies should further assess the association of the different degrees of malnutrition with adverse outcomes in patients with CAD. Fifth, considering all patients were from East Asia, generalization of the current findings to western countries should be done with caution. Finally, we did not examine the publication bias tests due to the less than recommended arbitrary minimum number of studies.This meta-analysis consolidates the growing evidence that a lower GNRI score at baseline is an independent predictor of all-cause mortality and MACEs in patients with CAD regardless of the acute stage of stable phase. Nutritional status estimated by the GNRI score may play an important role in the risk classification of patients with CAD.The original contributions presented in the study are included in the article/CFM: study conception, design, and revising the article critically for important intellectual content. YF and LH: acquisition of data, analysis, and interpretation of data. YF and YJZ: statistical analysis. YF: drafting the article. All authors read and approved the final version of the study to be published.This study was supported by (1) Jiangsu Innovative Team Leading Talent Fund , (2) Jiangsu 333 Talent Fund (BRA2020016), and (3) Suqian Science and Technology Support Project Fund (K201907).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The pooled ORs showed a significant association between specific tumor-related genes and HNC risk: p16 , MGMT , DAPK , TIMP3 , and RASSF1A . Overall, our meta-analysis provides precise evidence on the association between salivary DNA promoter hypermethylation and HNC risk. Thus, detection of promoter DNA methylation in saliva is a potential biomarker for predicting HNC risk.Aberrant methylation of tumor suppressor genes has been reported as an important epigenetic silencer in head and neck cancer (HNC) pathogenesis. Here, we performed a comprehensive meta-analysis to evaluate the overall and specific impact of salivary gene promoter methylation on HNC risk. The methodological quality was assessed using the Newcastle–Ottawa scale (NOS). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association and Egger’s and Begg’s tests were applied to detect publication bias. The frequency of salivary DNA promoter methylation was significantly higher in HNC patients than in healthy controls (OR: 8.34 (95% CI = 6.10–11.39;  CDKN2A), E-cadherin (CDH1), death-associated protein kinase (DAPK), phosphatase and tensin homolog (PTEN), and O6-methylguanine-DNA methyltransferase (MGMT), have been reported in HNC [The important role of epigenetic mechanisms in carcinogenesis has been widely reported. Identification of specific genes that are altered by aberrant epigenetic processes contributes to better understanding molecular pathogenesis in HNC . As one d in HNC . Likewisd in HNC ,10,11. AThis study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines , and theThe search strategy and data extraction were previously described in Part I .The inclusion criteria were as follows: (1) case-control studies; (2) studies based on salivary DNA hypermethylation biomarkers for HNC; and (3) sufficient data to calculate odds ratios (ORs) and corresponding 95% confidential intervals (CIs). The exclusion criteria were as follows: (1) reviews, letters, personal opinions, book chapters, case reports, conference abstracts, and meetings; (2) duplicate publications; (3) incomplete data; and (4) in vitro or in vivo animal experiments. Independent investigators evaluated methodological quality by applying the Newcastle–Ottawa scale (NOS)  to each https://www.r-project.org, accessed 30 November 2020). The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to assess the strength of the association between salivary promoter methylation and HNC. To evaluate the statistical model applied to the meta analytic database, heterogeneity was assessed on the basis of I-square (I2) value and Cochran’s Q statistic test-based Chi-squared test. Heterogeneity was considered significant when I2 > 50% and/or presence of a p < 0.10 for the Cochran’s Q test. If significant heterogeneity was detected, the DerSimonian and Laird random-effects model was applied to calculate the pooled OR with 95% CIs; otherwise, the Mantel–Haenszel fixed-effects model was used. Meta-regression and subgroup analyses were performed to explore the potential sources of heterogeneity among studies insofar as anatomic tumor location, sample type, sample size, DNA methylation method, and methylation gene profiling. Publication bias was assessed by Begg’s and Egger’s tests, and funnel plot inspection [Statistical analysis was conducted using the meta package of free R software . A random-effects model was used because heterogeneity among the 18 studies (I2 = 72%) was identified. The shape of the Begg’s funnel plot did not reveal potential asymmetry (p = 0.271), although publication bias was detected by Egger’s test (p = 0.002)  . p = 0.128), sample size (p = 0.349), and DNA methylation method (p = 0.275) were not significant sources of heterogeneity. However, anatomic tumor location (p = 0.002) and gene profiling (p < 0.001) were, in fact, potential sources of heterogeneity in this study . The shape of the Begg’s funnel plot did not reveal potential asymmetry (p = 1), although publication bias was detected by Egger’s test (p = 0.040)  .MGMT promoter hypermethylation on HNC risk. As shown in MGMT promoter hypermethylation was associated with an increased HNC risk . Visual analysis of the funnel plot revealed a symmetrical distribution of the studies , indicating no evidence of publication bias . Visual examination of the funnel plot revealed a symmetrical distribution of the studies , indicating no evidence of publication bias . Visual inspection of the funnel plot revealed a symmetrical distribution of the studies , indicating no evidence of publication bias . Visual examination of the funnel plot revealed a symmetrical distribution of the studies , indicating no evidence of publication bias . Visual examination of the funnel plot revealed no potential asymmetry , indicating no evidence of publication bias . In addition, the qualitative nature and lower specificity of MSP could lead to an overestimation of methylation data compared to qMSP methods . Howeverp16, DAPK, TIMP3, MGMT, and RASSF1A was significantly higher in HNC patients compared to controls, suggesting that the methylation of these tumor suppressor genes may play an important role in head and neck carcinogenesis. The p16 gene acts as a negative cell cycle regulator that prevents the inactivation of retinoblastoma (Rb) protein by inhibiting the cyclin-dependent kinases and, therefore, cell cycle progression at G1/S phase [p16 promoter has been reported as a frequent epigenetic event in oral carcinogenesis [p16 promoter was significantly associated with a 3.75-fold increase in HNC risk, which is consistent with the study by Shi et al. (OR: 3.37) based on tissue and liquid biopsy methylation data [p16 gene promoter in saliva could be a predictive biomarker for HNC risk. The MGMT gene is involved in the repair of O6-methylguanine in DNA sequences originating from the carcinogenic effects of alkylating agents [MGMT promoter by aberrant hypermethylation has been associated with an increased frequency of GC > AT transition mutations in TP53 and in KRAS oncogene, contributing to carcinogenesis and tumor progression [MGMT promoter leads to a 5.72-fold increase in HNC risk. DAPK plays a critical role in the apoptotic process triggered by interferon-gamma (IFN-γ), tumor necrosis factor (TNF)-alpha, Fas ligand, and detachment from extracellular matrix [DAPK gene promoter is a frequent alteration in HNC [DAPK gene promoter had a 5.34-fold higher HNC risk. A previous meta-analysis also showed that the frequency of DAPK promoter methylation was significantly higher in HNC vs. control groups (OR: 6.72) [TIMP3 gene is a tissue inhibitor of matrix metalloproteinases, which acts as a potential anticancer agent by inducing apoptosis and inhibiting proliferation, angiogenesis, and metastasis [TIMP3 promoter has been associated with HNC [TIMP3 promoter methylation and HNC with an OR of 3.42. The RASSF1A gene prevents tumorigenesis through multiple cellular process, such as cell cycle arrest, migration, microtubular stabilization, and apoptosis promotion [RASSF1A by hypermethylation has been observed in various cancers, including HNC [RASSF1A promoter led to a 7.69-fold increase in HNC risk compared to the control group. In a previous study, Meng et al. evaluated the methylation prevalence of RASSF1A between cancerous tissues and controls, finding a significant association (OR: 2.93) between aberrant methylation of RASSF1A and HNC [APC gene acts as a negative regulator in the Wnt/beta-catenin signaling pathway and its dysfunction leads to increased β-catenin transcriptional activity, promoting the activation of downstream targets involved in tumorigenesis, such as cyclin D1 and Myc [APC promoter has been reported as a mechanism for APC-gene inactivation in oral carcinogenesis [APC promoter hypermethylation and HNC, which could be explained by the low APC-gene methylation rates detected in saliva from HNC patients. Until now, few studies have reported APC hypermethylation in saliva from HNC patients [p16, DAPK, TIMP3, MGMT, and RASSF1A plays an important role in the carcinogenesis of various tumors, such as lung, breast, colorectal, renal, or gastric [We also explored the association between gene-specific promoter DNA methylation and HNC risk by analyzing the methylation frequency of genes reported in at least three studies. Thus, promoter hypermethylation of /S phase . Hypermeogenesis ,22. In tion data . In lineion data . Overallg agents . The inagression ,27. In fr matrix . Hypermen in HNC ,30. The R: 6.72) . The TIMtastasis . The metwith HNC ,34. Interomotion . Epigeneding HNC . Our datl. OR: 3. based on and Myc . Hypermeogenesis . Our stupatients ,41,42; hpatients ,39,43,44 gastric ,48,49,50 gastric ,53,54,55The present study has several strengths. It is the first meta-analysis highlighting the association between salivary DNA promoter hypermethylation and HNC. It explores the magnitude of the association both overall and by specific hypermethylated gene. In addition, it involved a comprehensive literature review without language restrictions. However, our study is not exempt from limitations. Firstly, all included research involved case-control retrospective studies, which could lead to selection bias. Some bias could also stem from the fact that cases and controls were not matched for demographic variables, such as age, sex, and lifestyle habits. Secondly, significant heterogeneity was found among studies. Despite performing subgroup analysis by anatomic tumor location, sample type, sample size, DNA methylation method, and methylation gene profiling, we were unable to elucidate the potential sources of this heterogeneity. Further subgroup analysis was hindered by the lack of original data regarding lifestyle habits or ethnicity. Thirdly, the association of salivary DNA promoter hypermethylation and clinicopathological variables  was not explored due to insufficient data. Therefore, well-designed prospective clinical studies with large sample sizes are necessary to validate the results of this meta-analysis.p16, MGMT, DAPK, TIMP3, and RASSF1A showed an important role in HNC development. Thus, saliva could be used as a potential source of epigenetic biomarkers for predicting HNC. The development of HNC screening programs based on the combination of these 5-methylated genes in saliva could be useful for identifying high-risk patients and for detecting cancer before the occurrence of initial clinical symptoms. The clinical implementation of this salivary panel would represent the beginning of precision medicine for HNC. To attain this, prospective and multicenter studies should be carried out in order to validate the present results.Overall, the findings from this meta-analysis showed that salivary DNA promoter hypermethylation was associated with HNC risk. Salivary hypermethylation of


Background: The association between a diverse array of environmental risk factors and the risk of endometriosis is contradictory.Objective: To summarize the evidence of associations between environmental risk factors and the risk of endometriosis.Methods: Databases such as PubMed, EMBASE, Web of Science, and ClinicalTrial.gov were systematically searched in June 2020. Meta-analyses of observational studies investigated any environmental exposure (non-genetic) and endometriosis risk. For each article, we estimated the summary effect size, 95% CIs, and the 95% prediction interval (PI). We also estimated the between-study heterogeneity expressed by I2, evidence for small-study effects, and evidence of excess significance bias.Results: About 12 eligible articles  yielded data on 40 unique environmental risk factors, including life styles (n = 16), reproductive factors (n = 3), early life factors (n = 4), and a range of other risk factors . About 25 of these 40 associations (62.5%) were statistically significant (p < 0.05) under random-effects models. Evidence for an association was indicated for alcohol intake  and the exposure to endocrine disruptor chemicals (EDCs)  while 15 associations presented only weak evidence.Conclusions: Our analyses showed that alcohol intake and exposure to endocrine-disrupting chemicals may be potential risk factors for endometriosis and supported by suggestive epidemiological evidence. However, it was evident that there was substantial heterogeneity and/or bias between the different studies featured in various meta-analyses included in this review; therefore, the outcomes of our analysis should be interpreted cautiously. Endometriosis is a chronic condition associated with pelvic pain, dyspareunia, and infertility and is thought to affect 6–10% of women of reproductive age . These dBiologically, endometriosis is an estrogen-dependent, chronic, and inflammatory gynecological condition that is characterized by the proliferation of a functional endometrial tissue that develops outside the uterine cavity . In addiTo the best of our knowledge, there has been no systematic effort to summarize and critically appraise this body of existing evidence. Therefore, we conducted the first umbrella review of the evidence arising from existing systematic reviews and meta-analyses of observational studies to provide an overview of the breadth, strength, and validity of the reported associations between a diverse array of risk factors and the risk of endometriosis. We summarize the risk factors that have been associated with endometriosis in previous meta-analyses, assess the quality of the methodology used, evaluate the evidence for diverse bias, and determine which of the associations are supported through convincing epidemiological evidence.We followed a standardized method and reported our findings in accordance with the recommendations put forward by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses  and MetaClinicalTrial.gov databases from inception to June 30, 2020, to identify systematic reviews or meta-analyses of observational studies that were performed to examine the associations of environmental (non-genetic) factors and biomarkers with the risk of endometriosis with no restrictions. We used the following search strategy: (endometriosis) and   focused on the risk factors for endometriosis. We systematically searched the PubMed, EMBASE, Web of Science, and Publications were initially screened on the basis of the title and by reading the abstract. The full texts of potentially eligible publications were then scrutinized by the two independent investigators (YZ and N-YM). Any disagreement was solved through a discussion. We considered the publications that were meta-analyses of epidemiological studies  that were conducted to investigate any environmental exposure (non-genetic) and the risk of endometriosis. If an article described a separate meta-analysis of more than one environmental risk factor, we included each of these factors separately. Furthermore, if there was more than one meta-analysis on the same association, we kept the one with the largest number of primary studies included. If meta-analyses on the same association included the same number of primary studies, we kept one with the largest amount of prospective data.The publications that investigated pure genetic markers of endometriosis were excluded because they did not fall into the remit of this study. Trials were not available for our specific research question. We excluded the systematic reviews that did not feature quantitative analysis, meta-analyses based on individual data without a systematic review, or the articles that included animal trials or laboratory studies. We also excluded the systematic reviews or meta-analyses that lacked study-specific data .For each eligible meta-analysis, we extracted the first author's name, journal name, publication year, the number of studies included, study population , environmental risk factors, type of effect metric in meta-analyses, and level of comparison. Also, we extracted information from each primary study used in meta-analyses, including the first author, publication year, study design , the number of cases and controls (for case-control studies), total participants or person-years (for cohort studies), risk estimates, and 95% CIs. We extracted the most fully adjusted risk estimates  and 95% CIs. We also extracted information related to dose-response relationships from all meta-analyses. In practice, the measures of effect yield similar estimates because endometriosis is a rare occurrence. Two independent investigators (YZ and N-YM) extracted the data from eligible publications. In the case of discrepancies, the final decision was made through a discussion.p, using both fixed- and random-effects models  for each of the included meta-analyses. If the SE was <0.10, then the 95% CI would be <0.20 . Egger's regression asymmetry test was also used to determine small-study effects. The value of  effects .t distribution  number of nominally significant findings was significantly different from the expected (E) number of statistically significant studies. To do this, we performed a chi-squared test to compare the difference between O and E . The effribution . Excess if O > E . StatistTwo independent investigators (YZ and N-YM) assessed the methodological quality for each included systematic review and meta-analysis using the A Measurement Tool to Assess systematic Reviews (AMSTAR) 2 checklist –22. Thisp < 0.05) into convincing, highly suggestive, suggestive, weak evidence, or non-significant associations , if the 95% PIs excluded the null hypothesis if the I2 statistic for heterogeneity was <50% if there was no evidence of small-study effects (p > 0.10), and if excess significance bias (p > 0.10) was indicated.Using the methodology described earlier and according to the grading scheme applied in previously published studies, we classified the associations that presented nominally statistically significant summary results , reproductive factors (n = 3), early life factors (n = 4), and a range of other risk factors, including vitamin D levels (n = 1), body mass index (BMI) (n = 3), an exposure to EDCs (n = 5), phthalate metabolites (n = 5), and race/ethnicity (n = 3).As reported in p < 0.05, the summary effect sizes were significant for 25 (62.5%) and 17 (42.5%) association estimates in fixed- and random-effects models, respectively. At a more conservative threshold of p < 10−6, 7 (17.5%) and 1 (2.5%) associations were statistically significant in fixed- and random-effects models, respectively. The magnitude of the observed summary random effect estimates was in the range from 0.17 and 4.49, and 62.5% of the observed estimates were between 0.70 and 1.30 .At a threshold of and 1.30 . In a meI2 ≥ 50% and I2 ≤ 75%), and 11 (27.5%) showed very large heterogeneity (I2 > 75%) . About 12 meta-analyses (30.0%) exhibited large heterogeneity (2 > 75%) . We furtin utero).Evidence for significant small-study effects was observed in 11 meta-analyses, and evidence for statistically significant excess significance bias was noted for the one risk factors (diethylstilbestrol n = 4) of the published articles, and critically low for 66.7% (n = 8)  . The mosp for random effects <10−3. Furthermore, 15 associations  and longer than or equal to 29 days (LEQ29)], pre-term birth, low birth weight, diethylstilbestrol in utero, feeding pattern, vitamin D levels, BMI, polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), phthalate esters (PAEs), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and race/ethnicity [white vs. black or Asian]) presented weak evidence with the value of p for random effects <0.05. Finally, 23 associations did not present even a nominally statistically significant result.By applying the predefined methodological criteria, we further investigated whether the nominally significant associations between environmental risk factors and endometriosis were supported by convincing evidence, highly suggestive evidence, suggestive evidence, weak evidence, or no association . OverallThis umbrella review involves previous meta-analyses of observational studies and provides a comprehensive overview and critical assessment of the environmental risk factors associated with endometriosis. About 40 risk factors were investigated for their association with endometriosis, including lifestyle, reproductive factors, early life factors, race/ethnicity, and other risk factors. However, among these factors, only the two factors  presented suggestive evidence to indicate a strong, significant, and positive association with endometriosis. Several other putative risk factors  presented weak evidence for their association with endometriosis.Four of the included meta-analyses investigated the relationship between alcohol intake and the risk of endometriosis . HoweverEndocrine disruptor chemicals are exogenous chemical entities or mixtures of compounds, which exert their toxicity by interfering with the normal hormonal homeostatic mechanisms that promote the growth and development of tissues . Our resAdditional potential risk factors showed weak evidence for endometriosis, including moderate/regular alcohol intake, the length of the menstrual cycle, early life factors  vitamin D levels, BMI, certain types of EDCs , MEHHP, and race/ethnicity factors. This might be due to the fact that these meta-analyses had large or very large levels of heterogeneity and small-study effect/excess significant bias. We also found that breastfeeding was positively associated with the risk of endometriosis although this may be affected by a certain amount of bias . A previWith regard to race/ethnicity, the results related to the risk of endometriosis have been inconsistent thus far. For example, a meta-analysis conducted by Bougie indicated that the risk of endometriosis is higher in Asian women and lower in black women ; this waTo the best of our knowledge, this is the first systematic and comprehensive assessment of the potential association between environmental factors and the risk of endometriosis using a robust analysis and by evaluating biases and methodological limitations. The classification of evidence was based on extensive statistical analysis and a large number of previous meta-analyses and aims to assess the strength and validity of the published evidence. The criteria chosen to classify each meta-analysis by evidence level  is a transparent and systematic means of assessing the strength of evidence in the literature. In addition, we used AMSTAR-2 to assess the methodological quality of the mate-analyses included; this strategy had helped to identify the most common reasons for reduced quality and will help to improve the quality of future articles in this field.Nevertheless, there are some possible limitations and caveats associated with this study. First, the present analysis relies upon the articles cited by the original authors and the results that have already been published in systematic reviews and meta-analyses. Although some studies may have been missed in the initial searches, this is unlikely to have affected our results, as repeat meta-analysis resulted in similar results. Second, the statistical tests we used to explore the existence of bias can only provide clues for the presence of potential bias, these tests cannot prove the existence of bias or its exact source. However, our estimates may be conservative because a negative result for bias does not rule out its potential existence. Third, we did not assess the quality of the preliminary studies for individual components as this was beyond the scope of this umbrella review; rather, the initial systematic review and meta-analysis were responsible for this aspect. However, we classified epidemiological evidence on the basis of well-recognized and pre-specified criteria. Fourth, some of the included meta-analyses exhibited large or very large levels of heterogeneity, along with signs of small-study effects or excess significance. In cases of particularly extensive heterogeneity, it is possible that Egger's test may lead to false signals with small-study effects , 54. HetIn conclusion, the intake of any alcohol and exposure to EDCs may represent potential risk factors for endometriosis; these associations were linked through suggestive epidemiological evidence. However, further research is still needed. Such research should incorporate data from a larger number of studies and investigate the specific sources of heterogeneity so that we can better understand the relationship between these factors and the risk of endometriosis.maningyehead@163.com.The data that support the findings of this study are available from the corresponding author upon reasonable request. Requests to access these datasets should be directed to N-YM: conceived and designed the study. YZ: literature search, data curation, formal analysis, and writing the original draft. All authors: writing, reviewing, and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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