Background: The findings of associations between prenatal air pollution exposure and hypospadias risk in offspring are inconsistent. No systematic review or meta-analysis has yet summarized the present knowledge on the aforementioned topic.Methods: Relevant manuscripts were identified by searching PubMed and Web of Science databases through January 31, 2020. Summary odds ratios (ORs) with 95% confidence intervals (CIs) in meta-analyses were estimated based on a random effects model. Publication bias was evaluated by funnel plots, Begg’s test, and Egger’s test.2.5 exposure in the first trimester was related to increased risk of hypospadias .Results: The search identified 3,032 relevant studies. Sixteen studies cumulatively involving 21,701 hypospadias cases and 1,465,364 participants were included. All of these studies were classified as having a low risk of bias. We classified pollutants as nitrogen oxides, particulate matter (PM), ozone, and other exposures. The exposure window to pollutants varied from three months before conception to seven days after delivery. In the meta-analyses, only PM2.5 exposure on hypospadias risk. Improvements in the areas of study design, exposure assessment, and specific exposure window are needed to advance this field.Conclusion: We found evidence for an effect of PM Increasdiseases , and cardiseases . Notablydiseases –8. Amongdiseases , 10. Prediseases –14.2.5 and heavy metal hazardous air pollutants increased hypospadias risk [2, PM10, PM2.5, and heavy metal hazardous air pollutants (HMHAPs) in early pregnancy [Hypospadias, which occurs between 8 to 16 weeks of gestation , is one ias risk , 17–21. regnancy –22. The regnancy –14, mainThe detailed process of study selection is illustrated in The key characteristics of the included studies are reported in The risk of bias of included studies was evaluated according to OHAT criteria. Overall, low risk was assessed for most of the studies in this systematic review, especially for the selection bias, confounding bias, and performance bias . It was Due to the lack of basic information provided for the control group, two studies , 25 wereIn general, we observed consistent results across the risk assessments for bias in different studies. The analogy in study design explains the consistency of the bias rating risks allocated across the studies. Our literature search revealed 16 studies considered of sufficient quality to prove the conclusions of our systematic review.X [2 [2 exposure [X, NO2, and NO exposures in the 3 months post conception were mainly positively associated with hypospadias though there was no statistical significance. Furthermore, Huang et al. [X as well as NO2 exposure and hypospadias risk during the 3 months before pregnancy and other months after pregnancy. No statistically significant results were found. However, Salavati et al. [X and NO2 during the periconceptional period.Three, five, and one studies were carried out to investigate the relationship between prenatal NOX , 17, 20,X [2 , 31, andX [2  exposureexposure , 31, twoexposure . In genei et al.  found a 10 [2.5 [2.5–10 [10 and PM2.5 exposure during 3 months after pregnancy, three, three, and one studies reported an insignificant positive association [2.5–10 exposure and hypospadias risk.A total of 10 studies (three cohort and seven case–control studies) investigated the connection between PM exposure and hypospadias risk in seven countries, including the USA, Spain, Italy, the Netherlands, Britain, China, and Israel. Seven, eight, and two studies focused on prenatal exposure to PM10 , 29, 31,10 [2.5 , 28, 31, [2.5–10 , respectociation , 18, 20,ociation –29, and ociation . Of noteociation  and Huan3 increments in PM2.5 by the first trimester period [2.5 during the first trimester was associated with higher odds of hypospadias  with moderate heterogeneity   . Visual = 0.039)  and the 3 exposure and hypospadias risk [3 exposure with the risk of hypospadias [3 during the first trimester were not significantly associated with hypospadias risk   . In addi3 exposure and hypospadias risk in the first month after conception. Of note, Huang et al. [3 and hypospadias risk, but no statistically significant result was found.However, Huang et al.  observedg et al.  also focg et al. , 27 inve2, CO, landfill sites, garbage wastes, hormonally active hazardous air pollutants, and HMHAPs in seven countries, including Belgium, Denmark, France, Italy, Britain, the USA, and Israel. Six studies focused on the exposure window in the prenatal period [Seven case control studies and two cohort studies were included , 30, 31.l period –26, 30 al period , 27, 31.l period  observedl period  found a 2.5 exposure during the first trimester was related to statistically significant increases in the risk of hypospadias, but no statistically significant increase in the risk of hypospadias in relation to continuous O3 exposure during the first trimester. In the present study, we did not perform further meta-analyses to assess hypospadias with other air pollutants or exposure windows because of the small number of studies presented.As the first systematic review summarizing the association between prenatal exposure to air pollution and hypospadias risk, our study added depth and clarity to the current evidence exploring the aforementioned topic. Meta-analysis suggested that continuous PMA few established biological processes that occur in the first trimester are related to the development of the urogenital system. Any interference happening in the pivotal window of internal and external urogenital development could become a cause of hypospadias . RecentlOur systematic review had several strengths. Compared to the limited sample size of individual studies, the present review comprehensively included all published observational studies (n = 16), which had relatively large sample sizes. The OHAT risk of bias rating tool was applied to systematically identify underlying risk of bias associated with multiple fields of studies included, while the NOS was used to assess the quality of the studies. Of note, the risk of bias in the included studies was low.10. Moreover, large well-designed cohort analyses are warranted in the future to explore whether there is a crucial association between air pollution and hypospadias risk.Although we conducted a meta-analysis of some exposures, several challenges should be taken into consideration. First, published studies included in this meta-analysis were too few to carry out a comprehensive analysis. Although studies were each of reasonable quality, high heterogeneity was generated by the different study designs, geographical locations, exposure windows and assessments, and cofounding adjustments. This may have affected the accuracy of the quantifiable findings in the meta-analysis. For instance, Vinceti et al.  reportedSecond, we could not exclude potential biases due to the misclassification of exposure and outcome. Using a fixed monitor to specify individual-level exposure within a specific radius around the monitor, including land-use regression models, has been widely accepted . HoweverThird, the criteria for considering eligible studies for systematic review should be based on a more rigorous PECOS structure. For example, as for exposure, the women in the first trimester of pregnancy were combined as a whole for the meta-analysis because of the small number of articles included. It is well-known that embryonic growth and development occurs in the first trimester of pregnancy, which is the critical time when most teratogenic exposures result in birth defects, including hypospadias. Of note, if the high concentration of certain pollutants or their metabolites accumulate for a long time in the pre-pregnancy period, it may cause a more obvious risk of congenital abnormalities . InteresFourth, besides the variations in method of measurement and exposure window, the strategies of analyses and forms of results reporting have been different among these studies. Based on the distribution of exposure in each study, air pollution was divided into dichotomy, trisection, and quartering. However, because of the different populations and exposure levels of each study, these aforementioned categories of exposure made it surely complicated to explain and compare the results. Dose-response analysis using a continuous exposure assessment model may provide more informative and nonbiased results, and more accurately reflect the association between ambient air pollution and birth defects than categorical variables, with higher levels of evidence.Finally, the importance of subgroup data should be recognized and, if possible, future studies should include subgroup analyses of the most relevant socio-demographic and clinical characteristics. Because all individual studies were observational in nature and multivariable analyses were carried out in the primary studies, the chance of residual confounding bias from unscanned variables cannot be excluded. More subgroup analyses stratified by these important potential confounders should be performed in future studies.3 increments in PM2.5 in the first trimester increased the risk of hypospadias. However, we could not determine the relationship between other ambient air pollutants and hypospadias risk. Further studies that focus on other exposures , as well as a more accurate assessment of exposures, better case ascertainments, and adjustments for a large number of potentially confounding effects, are needed to provide more evidence toward this topic.In summary, the present meta-analysis indicated that 10 μg/mThis systematic review and meta-analysis were based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines  and the We implemented a compositive search in PubMed and Web of Science databases to determine all potentially correlative articles from inception through January 31, 2020. The following critical keywords were applied in the literature search: (air pollution) OR (traffic pollution) OR (outdoor pollution) OR (outdoor air pollution) OR (particulate matter) OR (nitrogen dioxide) OR (sulfur dioxide) OR (sulphur dioxide) OR (ozone) OR (carbon monoxide)) AND ((hypospadias) OR (hypospadia) OR (isolated hypospadias) OR (birth defects) OR  OR ). In addition, the bibliography of all included articles and related reviews and meta-analyses were further reviewed to determine whether there are other eligible articles. Searches were limited to English language articles. There is no geographical restriction.Two independent authors (ZX and SZ) deleted duplicates, filtered titles and abstracts for relevance, and determined records as included, excluded, or inconclusive. In case of uncertainty, the two authors obtained the full-text to determine eligibility. Any difference was settled through discussion and negotiation.Eligible studies were determined on the basis of the following PECOS  criteria: i) population: our study drew participants from pregnant women and their newborns; ii) exposure: the primary exposure of interest was air pollution on pregnant women; iii) comparison/comparator: the concentration of air pollutants to which the pregnant women were exposed; iv) outcome: the primary outcome of interest was the risk of hypospadias in offspring; the outcomes of other birth defects were not included; and v) study type. We targeted observational study designs ; studies without original data (review articles) were not included.Data extraction was carried out by SZ and confirmed independently by another author (ZX). The following data were from eligible studies: first author’s family name, publication year, study location, time period, study design, sample size, exposure characteristic , and main findings of the results.Two authors (ZX and SZ) independently assessed the quality of the observational studies using the Newcastle-Ottawa Scale (NOS) . The scaThe Office of Health Assessment and Translation (OHAT) risk of bias rating tool  was empl3 increase in PM2.5 and per 5 ppb increase in ozone (O3). The summary odds ratios (ORs) in the meta-analyses were estimated based on a random effects model, following the method of DerSimonian and Laird [2 statistic. The cutoff points ≤ 25%, ≤50%, ≤75%, and >75% were used to indicate no, small, moderate, and significant heterogeneities, respectively [If at lowest three studies mentioned the same air pollutant and exposure window of pregnancy available, then the impact estimates were combined in the meta-analyses. We figured summary risk estimates for congenital hypospadias per unit increase of persistent pollutant concentration. If multiple and single pollutant models were reported simultaneously, the single pollutant model analysis was chosen. In addition, if studies demonstrated effect estimate for more than one pregnancy exposure window, we extracted the results during the first trimester of gestation. To compare and contrast among different studies, units were harmonized to per 10 μg/mnd Laird . Heterogectively . Furtherectively , 54. STASupplementary Table 1Supplementary Table 2Supplementary Table 3


Antidepressant drugs are mainly used to treat depression clinically. ABCB1 affects the P-glycoprotein activity and changes the amount of drugs in the blood tissue barrier that can be squeezed back into the blood, thus affecting the efficacy of antidepressants. In this present study, Meta-analysis was performed to further investigate the influences of ABCB1 gene polymorphism on antidepressant response.Relevant literatures were searched from the PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc, and Wan Fang databases up to May 2021 without any language restrictions. STATA 16.0 software was applied for this meta-analysis. Odds ratio (OR) and its corresponding 95% confidence interval (CI) were calculated.The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.This meta-analysis will summarize the effects of ABCB1 gene polymorphism on antidepressant response. Meanwhile, 12% to 15% of patients cannot tolerate the adverse reactions of the drug and discontinued treatment.,7 Many studies have identified that genetic variations may partially explain individual differences in response to antidepressants.At present, a wide variety of drugs and methods can be adopted to treat depression. However, in clinical practices, it has been discovered that even with standard doses of antidepressants for 6 to 8 weeks, 35% to 45% of patients do not fully recover to their pre-onset state.–11 Many antidepressants act as substrates for P-glycoprotein. ABCB1 gene is located on human chromosome 7. On the other hand, as an important component of the blood-brain barrier and gastrointestinal barrier, its encoded 1280 amino acid transporter P-glycoprotein can limit drug infiltration and accumulation in the brain, and regulate the effectiveness and toxicity of drugs.–15 Therefore, ABCB1 gene polymorphism may affect the function of P-glycoprotein, thus changing the concentration of substrate drugs in the brain, with various degrees of impacts on the clinical efficacy of anti-depression drugs. According to the existing research results, ABCB1 gene polymorphism has a certain correlation with the efficacy of antidepressants.A large number of studies have revealed that P-glycoprotein is involved in the transmembrane transport of many antidepressants.,17–20 To date, no meta-analysis has been carried out on the relationship between ABCB1 gene polymorphism and antidepressant response. Therefore, we conducted a meta-analysis to elucidate the association between ABCB1 gene polymorphism and antidepressant efficacy.It is of great significance to improve the response rate of antidepressants from the perspective of genetics. At present, the relationship between ABCB1 gene polymorphism and the efficacy of antidepressants is still controversial.22.1The protocol of this review was registered in OSF (OSF registration number: DOI 10.17605/OSF.IO/R28W7). It was reported to follow the statement guidelines of preferred reporting items for systematic reviews and meta-analyses protocol.2.2(1)Published studies on the effects of ABCB1 gene polymorphisms on the efficacy of antidepressants;(2)The study participants were depressed patients;(3)The relationship between ABCB1 gene polymorphism and antidepressants can be obtained from original literatures;(4)The antidepressants all patients took were the substrates of P-glycoprotein.2.3The exclusion criteria included case reports, meta-analysis, review articles, and studies without detailed genotype data.2.4Relevant studies in PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc, and Wan Fang databases were searched by May 2021. The search strategy was based on the following key words: “antidepressant”; “response”; “ABCB1”; “genetic polymorphisms”; and others. The search strategy for PubMed is displayed in Table 2.52.5.1The flowchart is demonstrated in Fig. 2.5.2Data extraction was carried out for all literatures that were included in the final analysis. The extracted contents include first author, year of publication, ethnicity of the case studied, year, age, number of people, scale used in the study, type of antidepressant used by patients, number of days of treatment, ABCB1 sites studied, and so on.2.5.3 If the Newcastle-Ottawa Scale score of the literature is ≥6, it can be considered as high quality.We investigated the quality of each study based on the 9-point Newcastle-Ottawa Scale.2.5.4If there exists insufficient or missing data in the literature, we would only analyze the currently available data and discuss its potential value.2.5.5Q statistic and quantified by I2 value. If P > .1or I2 <50%, the fixed effect model was used for analysis; if P < .1 or I2 > 50%, it indicated the existence of large heterogeneity, and the random effects model analysis should be used. All analyses were carried out with STATA 16.0 .The combined odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the effects of ABCB1 polymorphism on antidepressant efficacy. Five genotypic models were adopted to detect the relationship between SNPs and response rate: allele model (T vs C), heterozygote model (TC vs CC), homozygote model (TT vs CC), dominant model (TT + TC vs CC), and recessive model (TT vs TC + CC). Heterogeneity was tested by 2.5.6We performed subgroup analyses by ethnicity, type of drug, and duration of treatment.2.5.7The eligible study was sequentially removed to perform the sensitivity analysis.2.5.8,25If no <10 studies are included, funnel charts are used to assess publication bias.2.5.9The content of this article does not involve moral approval or ethical review and would be presented in print or at relevant conferences.3 Its main function include the prevention of drugs and foreign substances from entering body tissues, such as antidepressants, anti-tumor drugs, glucocorticoids, and amyloid proteins.–29 Due to the exogenous effects of P-glycoprotein on exogenous substances and drugs, ABCB1 gene polymorphism and different P-glycoprotein expression may lead to different populations or individuals with different susceptibility to some diseases. Previous reports on the relationship between ABCB1 gene mutation and antidepressant efficacy are inconsistent. Through meta-analysis, this study further explored the relationship between ABCB1 gene polymorphism and the efficacy of antidepressants, so as to provide an etiological basis for individualized treatment in patients suffering from depression.Being known as multidrug resistance gene, ABCB1 gene is located at 7q21 and encodes p-glycoprotein.Conceptualization: Rixia Zhu, Xiaoying Zheng.Data curation: Rixia Zhu, Zejuan Fu.Formal analysis: Zejuan Fu, Xiaomei Chen.Funding acquisition: Rixia Zhu.Investigation: Zejuan Fu.Methodology: Mingxia Wang.Project administration: Rixia Zhu.Resources: Xiaomei Chen.Software: Xiaomei Chen.Supervision: Rixia Zhu.Validation: Mingxia Wang, Xiaoying Zheng.Visualization: Mingxia Wang.Writing – original draft: Rixia Zhu, Xiaoying Zheng.Writing – review & editing: Rixia Zhu, Xiaoying Zheng.


N = 337,129). The allele score-based MR was obtained by regressing the allele scores to CAD risks. Second, summary-level MR was performed with the CARDIoGRAMplusC4D data for CAD . Higher genetically predicted eicosapentaenoic acid and dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD both in the allele-score-based and summary-level MR analyses. Higher allele scores for linoleic acid level were significantly associated with lower CAD risks, and in the summary-level MR, the causal estimates by the pleiotropy-robust MR methods also indicated that higher linoleic acid levels cause a lower risk of CAD. Arachidonic acid showed significant causal estimates for a higher risk of CAD. This study supports the causal effects of certain n-3 and n-6 PUFA types on the risk of CAD.We aimed to investigate the causal effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) on the risk of coronary artery disease (CAD) through Mendelian randomization (MR) analysis. This MR study utilized a genetic instrument developed from previous genome-wide association studies for various serum n-3 and n-6 PUFA levels. First, we calculated the allele scores for genetic predisposition of PUFAs in individuals of European ancestry in the UK Biobank data ( Coronary artery disease (CAD) is a comorbidity that critically affects patient prognosis and is associated with a substantial socioeconomic burden globally . A majorAs metabolic disorders are common predisposing factors for CAD , maintaiMendelian randomization (MR) is a useful tool for investigating causal effects from modifiable exposure to complex diseases . In MR, In this study, we aimed to investigate the causal effects of serum n-3 and n-6 PUFA levels on the risk of CAD by MR analysis testing the association between genetic predisposition for each PUFA type and the risk of CAD or myocardial infarction (MI). We performed both allele-score-based MR by individual-level data and MR based on summary-level data in different cohorts to replicate the findings. We hypothesized that certain n-3 or n-6 PUFAs would have causal effects on the risk of CAD.This study was an MR analysis including genetically explained exposures and outcomes from observational cohorts independent of the population where the genetic instrument was developed . The study first utilized the UK Biobank data, which is the largest cohort to date with deep genotyping and collection of various clinicodemographic information . The UK P < 5 × 10−8) single nucleotide polymorphisms (SNPs) that were not in linkage disequilibrium (R2 < 0.1) with the PUFAs identified by the GWAS. The genetic instruments were repetitively utilized in the literature, including MR analysis, to study the causal effects of PUFA levels on various diseases and were identified to be on genes that are relevant to lipid metabolism [The study utilized two well-known genome-wide association meta-analysis results for the serum levels of specific types of n-3 and n-6 PUFAs of individuals of European ancestry ,21. The tabolism ,23,24. WThe MR investigation requires three assumptions to be met to demonstrate causal effects . First, The UK Biobank is a prospective population-based cohort of >500,000 individuals aged 40–69 years from 2006 to 2010 in the United Kingdom. The details of the database have been published before ,25,26. FIn the allele-score-based MR, we assessed the risk of MI in the UK Biobank data, which was algorithmically defined by the UK Biobank and included death from MI and ST-segment elevated MI or non-ST-segment MI events based on hospital admission records and death registries. We included events through 29 February 2016, as complete hospital inpatient data were available until that date in all three regions of the nation: England, Scotland, and Wales, in the current data.p-values < 0.05 were considered significant.We calculated allele scores for the exposures by multiplying the gene dosage matrix with the effect sizes of the genetic instrument by using PLINK 2.0  . The assAdditional summary level-based MR was performed with the summary statistics provided by the CARDIoGRAMplusC4D study including participants mainly of European ancestry . We testThe baseline characteristics of the UK Biobank participants of white British ancestry utilized for the genetic analysis are presented in The causal estimates by the allele score-based MR are presented in When the analysis was replicated with the CARDIoGRAMplusC4D data, the genetic predisposition for higher serum eicosapentaenoic acid levels was significantly associated with a lower risk of CAD, but not with the risk of MI . For docThis study, including MR investigation, identified that serum levels of certain n-3 or n-6 PUFAs causally affect the risk of CAD or MI. Higher genetically predicted eicosapentaenoic acid was significantly associated with a lower risk of MI in the UK Biobank data and of CAD in the CARDIoGRAMplusC4D data. Dihomo-gamma-linolenic acid levels were significantly associated with a lower risk of CAD or MI. Linoleic acid was also considered to be protective against CAD or MI in our results. Arachidonic acid was the n-6 PUFA that showed significant causal estimates for a higher risk of CAD or MI. Higher docosapentaenoic acid and adrenic acid may also be causative for CAD development, but the causal estimates were inconsistent or marginal in our investigations.The clinical significance of n-3 and n-6 PUFAs has been debated. Several observational findings and meta-analyses reported the possible benefits of n-3 or n-6 PUFAs on the risk of cardiovascular disease ,8. In adWe performed this study to investigate the causal effects of various PUFA types on the risk of CAD or MI by implementing MR analysis. MR has a particular strength in that the method can reveal causal estimates from a modifiable exposure to complex diseases . The appAmong the most abundant n-3 PUFAs, our MR findings indicated that higher serum eicosapentaenoic acid may causally decrease the risk of CAD, while the results for docosapentaenoic acid were inconsistent. Primarily in liver, a partial conversion of n-3 PUFAs occurs by elongation and desaturation enzymes, converting α-linoleic acid to eicosapentaenoic acid, to docosapentaenoic acid, and to docosahexaenoic acid. A meta-analysis of 13 trials suggested that supplementation of marine n-3 PUFAs lowers the risk of CAD . A previSome of the MR analysis results need additional explanation. First, the statistical power of an MR investigation generally increases by utilizing a large number of genetic variants to explain the exposure of interest . HoweverThere are several limitations and unanswered questions in this study. First, as stated above, although this study suggested the causal effects of certain serum PUFA levels on CAD development, whether an effective intervention of modifying serum PUFA levels can actually be helpful for primary prevention of CAD should be answered by a future clinical trial. Second, additional experimental study is warranted to reveal the mechanism of different effects of certain serum PUFA levels on CAD risks. Third, as MR is weak for detecting nonlinear effects and as quantitative interpretation of our results is limited, the extent to which a serum PUFA level is beneficial or harmful cannot be answered by this study. Last, the study was mainly based on individuals of European ancestry due to data availability, so our results cannot be generalized to other ethnic populations. Future development of large-scale genetic data including various ethnic populations would be helpful to expand the diversity of ethnic populations which can be investigated by an MR analysis.In conclusion, this study supports the causal effect of certain n-3 and n-6 PUFAs on the risk of CAD or MI. Additional clinical trials targeting specific n-3 or n-6 PUFAs are warranted to reveal possible beneficial dietary interventions for the primary prevention of CAD and to determine the target population.


Background: Studies have identified that MIF -173 G>C gene polymorphism is associated with idiopathic nephrotic syndrome (INS) susceptibility and steroid resistance, but the results remain inconclusive.Methods: We searched PubMed, Embase, and Web of Science for relevant studies published before 31 March 2021. Pooled data were reported as odds ratio (OR) with 95% confidence interval (CI). Noteworthiness of significant OR was estimated by the false positive report probability (FPRP) test. Trial sequential analysis (TSA) was used to control type I and type II errors.Results: We selected seven case-control studies that included 1,026 INS children (362 were steroid-resistant NS and 564 were steroid-sensitive NS) and 870 controls. The results showed that MIF -173 G>C polymorphism was significantly associated with INS susceptibility in allelic, heterozygous and dominant genetic models , and FPRP test and TSA indicated that the associations were true in heterozygous and dominant models. The pooled results also revealed that MIF -173 G>C polymorphism was significantly associated with steroid resistance in allelic, homozygous and recessive models , but FPRP test indicated that all these associations were not noteworthy. Furthermore, TSA revealed that the non-significant associations between MIF -173 G>C polymorphism and steroid resistance in heterozygous and dominant models were potential false negative.Conclusions: This meta-analysis could draw a firm conclusion that MIF -173 G>C polymorphism was significantly associated with increased INS risk in heterozygous and dominant genetic models. MIF -173 G>C polymorphism was not likely to affect steroid responsiveness, but more studies were needed to confirm. Childhood idiopathic nephrotic syndrome (INS) is characterized by severe proteinuria, hypoalbuminemia, and generalized edema. It is one of the most common glomerular diseases with an incidence of 1·15-16·9 per 100,000 children , 3.5−8 microsatellite repeat (rs5844572) and the -173 G>C (rs755622), are associated with disease susceptibility or clinical severity  is a pleiotropic cytokine that contributes to the pathogenesis of many immune-inflammatory and autoimmune diseases and can also regulate glucocorticoid-mediated immunosuppression , 5. Two peat rs584572 and G>C rs75522, are aIn this meta-analysis, exposure is G to C transition at position -173 of MIF gene, and outcomes are INS and steroid resistance.Two independent researchers (DJY and HJZ) comprehensively searched PubMed, Embase and Web of Science to identify eligible studies regarding the association between MIF -173 G>C polymorphism and INS published up to 31 March 2021. The search strategy was (“macrophage migration inhibitory factor” or MIF) and (polymorphism or mutation or variant or genotype) and “nephrotic syndrome.” In addition, references from relevant articles and reviews were also searched for additional worthy studies. The search was restricted to English language papers. Discrepancies were resolved by a third researcher (MJJ) or consensus-based discussion.The following inclusion criteria were used to select the eligible studies: (1) case-control studies investigated the association between MIF -173 G>C polymorphism and childhood INS (onset age <18 years); (2) studies have enough data to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The exclusion criteria were: (1) study included secondary cause of NS; (2) case reports, meeting abstract, reviews, repeated literature; (3) detailed genotype data were not available. Furthermore, for the meta-analysis of MIF -173 G>C polymorphism and steroid resistance, studies that did not classify INS patients into SSNS and SRNS were excluded.https://ihg.gsf.de/cgi-bin/hw/hwa1.pl). We used the Newcastle-Ottawa scale (NOS)  test. For each study, HWE was calculated using a web-based statistical tool (le (NOS)  to assesZ-test, and P < 0.05 was considered significant. Heterogeneity among the studies was checked using the Q-test and I2 test, with I2 > 50% indicating high heterogeneity. The fixed-effect model was selected to calculate pooled ORs when I2 < 50% or PQ > 0.1 (P < 0.05 was considered significant publication bias).We used Stata 14.0  to perform data analysis. Pooled ORs and 95% CIs were used to assess the association of MIF -173 G>C polymorphism with INS susceptibility and steroid responsiveness. The pooled ORs were computed for the allelic (C vs. G), homozygous (CC vs. GG), heterozygous (GC vs. GG), dominant (CC + GC vs. GG) and recessive (CC vs. GC + GG) genetic models. The statistical significance of the pooled ORs was determined with the PQ > 0.1 . Otherwiwww.ctu.dk/tsa).We performed false-positive report probability (FPRP) tests for all the significant pooled ORs. FPRP values were calculated at the prior probability of 0.001 to detect ORs of 1.5 by using the Excel spreadsheet offered by Wacholder et al. . An FPRPP < 0.05)  . The maiP = 0.042), heterozygous , and dominant model   . These s< 0.001) . Therefo< 0.001) . Further< 0.001) . Sensiti< 0.001) . There w< 0.001) .P = 0.044; CC vs. GG: OR = 4.789, 95% CI: 2.109-10.877, P < 0.001; CC vs. GC + GG: OR = 4.188, 95% CI: 1.831-9.578, P = 0.001) (P > 0.05)  . However= 0.001) . TSA was= 0.001) . The cum= 0.001) . However= 0.001) . Egger's > 0.05) .In this first meta-analysis aimed to investigate the associations between MIF -173 G>C polymorphism and INS susceptibility and steroid responsiveness, we performed the FPRP test and TSA to evaluate the results from the traditional pooled analysis method. Our results showed that MIF -173 G>C polymorphism was significantly associated with increased INS risk under both heterozygous and dominant models and the currently available evidence was sufficient to draw this conclusion. For MIF -173 G>C polymorphism and steroid responsiveness, no truly significant association was identified, and the currently available evidence was not enough to confirm the negative results.MIF is a pleiotropic protein that acts as a potent upstream regulator of the immune system . Due to via affecting NF-κB/IκB signaling or triggering the mitogen-activated protein kinase (MAPK) signaling , the Sun Yat-sen University Basic Scientific Research Young Teacher Training Project (Grant no. 19ykpy65 to YX), and the Science and Technology Planning Project of Guangzhou, China (Grant No. 202103000001 to XJ).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: The etiology of congenital heart disease (CHD) has been extensively studied in the past decades. Therefore, it is critical to clarify clear hierarchies of evidence between types of environmental factors and CHD.Methods: Electronic searches in PubMed, Embase, Web of Science, Cochrane database were conducted from inception to April 20, 2020 for meta-analyses investigating the aforementioned topic.Results: Overall, 41 studies including a total of 165 meta-analyses of different environmental factors and CHD were examined, covering a wide range of risk factors. The summary random effects estimates were significant at P < 0.05 in 63 meta-analyses (38%), and 15 associations (9%) were significant at P < 10−6. Of these meta-analyses, eventually one risk factor  had significant summary associations at P < 10−6, included more than 1,000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I2 < 50%), small-study effects , or excess significance (P > 0.10). Eight associations (5%)  had results that were significant at P < 10−6, included more than 1,000 cases, and had 95% prediction intervals excluding the null value (highly suggestive).Conclusion: This umbrella review shows that many environmental factors have substantial evidence in relation to the risk of developing CHD. More and better-designed studies are needed to establish robust evidence between environmental factors and CHD.Systematic Review Registration: [PROSPERO], identifier [CRD42020193381]. Congenital heart disease (CHD) is defined as a gross structural abnormality of the heart or great vessels , and is Numerous meta-analyses and systematic reviews of environmental risk factors associated with CHD have been published. However, to the best of our knowledge, there has been no effort to summarize the evidence from these meta-analyses and systematic reviews, as well as their associated limitations, and thus contribute to better understanding of environmental risk factors for CHD. Therefore, in order to provide an overview of the range and validity of the reported associations of diverse environmental risk factors with CHD in infants, we performed the first umbrella review and summarized the environmental risk factors in previously published meta-analyses and systematic reviews. We assessed the quality and strength of the evidence, evaluated whether there are biases in this evidence and how they manifested, and identified which could be the most robust associations between environmental risk factors and CHD in infants without potential biases.The report of this umbrella review followed the recommendations of the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guideline  and the We conducted computerized literature searches of databases including PubMed, Embase, Web of Science, and the Cochrane database from inception to April 20, 2020 to identify systematic reviews and meta-analyses of epidemiological studies investigating the association between environmental (non-genetic) factors and risk of CHD. The search key words and Medical Subject Heading (MeSH) terms are provided in Articles were eligible if the authors had performed a systematic search to identify pertinent studies. We included only systematic reviews and meta-analyses of epidemiological studies in humans. We excluded meta-analyses that investigated the association between genetic markers and CHD risk. We also excluded meta-analyses that did not present study specific data . Additionally, studies that examined CHD as a risk factor for other medical conditions or diseases were also excluded. If an article presented separate meta-analyses on more than one eligible exposure factor, these were assessed separately. We did not apply any language restrictions in the selection of eligible studies. When more than one meta-analysis on the same scientific question was eligible, the meta-analysis with the largest number of studies was selected for further analysis, but we conducted sensitivity analyses to assess the concordance of the summary associations  in these duplicate meta-analyses .From each eligible meta-analysis, data extraction was done independently by two investigators [T-NZ and Y-SL], and in case of discrepancies, the final decision was that of a third investigator [Q-JW]. We retrieved the first author, year of publication, journal, study design, exposure factors and duration, outcomes, and number of studies. For dose-response meta-analyses, we also retrieved drug dosage exposure factors. If a quantitative synthesis was conducted, we also extracted the study-specific risk estimates  together with the corresponding CIs and the number of cases and controls in each study for each risk factor.The authors [T-NZ and Y-SL] independently assessed the methodological quality of qualified systematic reviews and meta-analyses using AMSTAR 2 (A Measurement Tool to Assess systematic Reviews) . DiscrepEstimation of the summary effct—for each unique meta-analysis, we estimated the summary effect and 95% CIs using both fixed and random effects models .I2 statistics. When I2 exceeds 50 or 75%, heterogeneity is considered large or very large, respectively  , 16. A PP < 0.05) is larger than their expected (E) number  was set as the plausible effect size  number of studies with nominally significant results  number . Two-taiect size . The excP < 10−6, >1,000 cases, P < 0.05 of the largest study in the meta-analysis, I2 < 50%, no evidence of small-study effects, no evidence of excess significance bias, the 95% PI excludes the null value for strong evidence; P < 10−6, >1,000 cases, P < 0.05 of the largest study in the meta-analysis for highly suggestive evidence; P < 10−3, >1,000 cases for suggestive evidence; and P < 0.05 for weak evidence. Non-significant associations were those with P > 0.05. All analyses were performed using STATA 12.0.The associations were categorized into strong, highly suggestive, suggestive, or weak according to the following criteria : P < 10−n = 23), study specific data missing (n = 44), not English publications (n = 5), and meeting abstract (n = 1). The reference list of these excluded studies is shown in Overall, 23,874 studies were searched, and 41 studies including a total of 165 meta-analyses were eligible . The chaThe included meta-analyses summarized 1,088 individual study estimates. There were three to 55 study estimates combined per meta-analysis, with a median of five studies. The included studies covered 137 associations between different kinds of environmental factors and CHD, over 1.4 million cases and 128 million subjects in total. The median number of cases and total population in each meta-analysis was 2,167 and 589,785, respectively. A total of 101 meta-analyses had at least 1,000 CHD cases.n = 16) (n = 13) (n = 13) (n = 10) (n = 4) (n = 2) (n = 4) (n = 6) (n = 3) (in-vitro fertilization (n = 5) (n = 5) (n = 2)  of the 165 meta-analyses studied associations between maternal body mass index (BMI)  and CHD risk –22. Twenn = 16) , materna(n = 13) –45, pate(n = 13) , 47, mat(n = 10) –50, mate (n = 4) , 52, mat (n = 2) , 54, mon (n = 4) , materna (n = 6) , materna (n = 3) , assiste (n = 5) , materna (n = 5) , and mat (n = 2) .We performed methodological quality assessments of 41 included studies using the AMSTAR 2 questionnaire, which is a revised instrument based on AMSTAR retaining 10 of the original domains and 16 items in total . AMSTAR P < 10−6  indicated that different kinds of environmental factors were related to CHD, including two protective factors  and other 61 risk factors.The meta-analyses of the 137 associations were re-performed using a fixed-effects and random-effects model. The magnitude of the observed summary random effect estimates ranged from 0.57 to 12.5; 72% of the estimates lay between 1.00 and 2.00 . There wP < 10−6 ; Table 1I2 ≥ 50%) and 20 (12%) meta-analyses had very high heterogeneity (I2 > 75%). The meta-analyses with very high heterogeneity examined exposure to a selective serotonin reuptake inhibitor (throughout pregnancy), folate supplement, air pollutants , and SO2 as a risk factor for TOF), maternal alcohol consumption, secondhand smoking, underweight (for outflow tract defects), maternal fever (for left obstructive defects), parity number, paternal age, paternal smoking and alcohol consumption. The 95% PI was also calculated to further assess inter-study heterogeneity. Only the 95% PIs of 14 (8%) meta-analyses excluded the null value (Twenty-four (15%) meta-analyses had high heterogeneity  meta-analyses by use of the Egger's test with a more conservative effect in the largest studies. Except for those 16 meta-analyses, there was no evidence for the presence of small-study effects for the other 149 meta-analyses according to Egger's test and comparison between the random effects summary estimate and the point estimate of the largest study .P < 0.1 and O > E. As a result, we reported there were 29 meta-analyses in which the excess significance test was positive.We detected excess significance using the following criteria: P < 0.05) according to a random-effects calculation  had nominally significant summary associations  were supported by highly suggestive evidence , 51, 56,Finally, we also conducted several sensitivity analyses noting the same associations that would satisfy the same criteria but with fewer individual studies. We noticed that the grading of the evidence for CHD with maternal obesity (highly suggestive evidence), SSRI exposure in the first trimester (suggestive evidence), maternal overweight (weak evidence), and maternal smoking (weak evidence) was not changed. There were no meta-analyses with fewer individual studies that got a higher grading of evidence compared with the meta-analyses that included more individual studies.P < 10−6, low heterogeneity (I2 < 50%), not suggestive of a small-study effect and excess significant bias, and 95% PIs excluding the null value. In addition, we also reported eight associations  that were supported by evidence with highly suggestive epidemiological credibility. Among these studies with convincing and highly suggestive evidence, the summary effect sizes were relatively large for maternal exposure to lithium (RR > 2).In this umbrella review, we provide an overview and appraisal of environmental risk factors that have been associated with CHD risk and its related subtypes. Overall, our umbrella review examined 63 risk factors that could influence the development of CHD in infants. Notably, one (severe obesity)  of theseA possible association between different kinds of environmental factors and the development of CHD has long been speculated, aiming for better prevention and reduced morbidity of CHD from maternal and paternal factors. In our study, 63 of 165 (38%) meta-analyses reported significant results, suggesting their potential role in the process of developing CHD. However, among these nominally significant results, we noticed that 17 (27%) associations had high (or very high) heterogeneity, and 32 (51%) associations had a small-study effect and/or excess significance bias. The applied Egger test may give a spurious signal of small-study effects when there is genuinely high between-study heterogeneity . HeterogAs for CHD, we noticed that maternal severe obesity was a risk factor , which was supported by convincing evidence. Similarly, when we analyzed the association between obesity/moderate obesity and CHD, we also found that obesity and moderate obesity could also become risk factors for CHD, which were supported by highly suggestive evidence. Additionally, obesity could become the risk factor for some specific subtypes of CHD. For example, obesity had a tendency to increase the incidence rate of ASD  and outflow tract defects , which were also supported by highly suggestive evidence. What's more, the associations between obesity (including moderate obesity and severe obesity) and several subtypes of CHD  also passed our evaluation as risk factors with evidence of suggestive or weak epidemiological credibility. All aforementioned associations highly suggested obesity as a risk factor in the process of developing CHD, and several potential mechanisms could explain the associations. Increased fat mass, and in particular increased visceral fat mass, is associated with insulin resistance, hyperinsulinemia, lipo- and glucotoxicity, subclinical inflammation, endothelial dysfunction, and oxidative stress , 63. TheConsidering the number of studies reporting the association between maternal drugs intake and CHDs, our analyses confirmed the associations. We found that several studies concentrated on the association between maternal exposure to anti-depressive drugs  and CHD. We re-performed the different meta-analyses mainly according to the types of anti-depressive drugs as well as the maternal exposure period. Notably, we failed to get any significant association between total SSRI and CHD risk when the maternal exposure period was throughout pregnancy. However, when we focused on the first trimester of pregnancy, we noticed that maternal exposure to total SSRI could increase the risk of CHD (supported by suggestive evidence). This might be because the first trimester of pregnancy is the most critical period for heart development. Additionally, our studies also confirmed that maternal exposure to several specific SSRIs (paroxetine and fluoxetine) could lead to the development of CHD. Considering the high prescription rate of SSRIs in pregnant women with depression and that SSRIs could cross the placenta, especially since previous research has shown that serotonin and serotonin transporters have a significant role in heart development , the safn = 15,647) (n = 333) (Quantitative synthesis showed that lithium exposure at any time during pregnancy was associated with a significantly increased risk of CHD (supported by highly suggestive evidence). Notably, we also performed sensitivity analysis to explore the association between lithium exposure and CHD using the study performed by Munk-Olsen et al. but failed to draw any significant results. This discrepancy could be due to the inclusion of a larger sample size in the study performed by Fornaro et al.   than than = 333) . Expandin = 41,747). An improved understanding of the association between alcohol consumption and CHD may have important public health implications, and could help guide future health education on alcohol-related health risks during pregnancy. In addition, we observed a positive association between maternal smoking during pregnancy and the risk of CHD. The potential mechanism regarding maternal smoking leading to CHD is that in utero exposure to nicotine could induce fetal hypoxia and elevate fetal blood pressure  and smoking (weak evidence) during pregnancy have also received attention as risk factors for CHD. Recently, the health problems caused by alcohol consumption have become of global public health concern. Although the different individual study results on this association are often inconsistent, we re-evaluated this association and reported maternal alcohol consumption could be a risk factor for CHD through analyses including 55 studies, which contained a large number of cases  . ConsideBesides the maternal factors, we also reported that paternal factors could influence embryo development and lead to CHD. For example, our study suggested that paternal age, paternal smoking, and even paternal alcohol consumption had impacts on CHD in infants (supported by suggestive and weak evidence). As for paternal age, the mechanism behind such an association is suggested to be that advanced paternal age was previously found to be associated with increased DNA mutations and chromosomal aberrations in sperm . GeneticThis umbrella review is the first and the most comprehensive systematic review of meta-analyses on environmental factors and CHD risk. Umbrella reviews have the advantage of building on existing meta-analyses, as opposed to performing new meta-analyses from scratch which would require far more resources with unclear advantages. The robustness and the validity of a total of 63 associations were strictly rated based on the assessment results of a series of statistical analyses. Notably, our umbrella review provided a comprehensive understanding between environmental factors and CHD risk in infants.Several additional limitations should be considered in the interpretation of our findings. First, some of the caveats pertaining to the interpretation of tests for statistical bias and the potential effect of inflation even in the largest studies, are applicable to all umbrella reviews of risk factors, as previously discussed , 61. SecOur umbrella review provides evidence for 63 associations between environmental factors and CHD in infants. Notably, one (severe obesity) of these risk factors for CHD was supported by evidence with convincing epidemiological credibility, eight risk factors for CHD were supported by highly suggestive evidence, and other risk factors for CHD were supported by suggestive or weak evidence. Data from more studies and an investigation of the sources of heterogeneity are needed to examine the associations between other environmental factors and CHD risk in infants. Although the mechanisms of these risk factors are not well-understood, our study provides evidence for researchers and policy makers, and thus generates public health implications for CHD prevention.The original contributions presented in the study are included in the article/T-NZ, Q-JW, and Y-HZ conceived the study and contributed to the design. T-NZ, Y-SL, and J-LL conducted the literature search, literature screening, and extracted the data. Q-JW and HS performed the statistical analysis. T-NZ and Q-JW wrote the first draft of the paper. Y-HZ is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria were omitted. All authors interpreted the data, read the manuscript, and approved the final version.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.


Background and Objective: Parkinson’s disease (PD) is a progressive neurological disorder characterized by an accumulation of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra. The treatment options currently available are only partly effective and fail to restore the lost dopaminergic neurons or slow the progression. β2-adrenoceptors (β2AR) are widely expressed in various human tissues and organs, regulate many important metabolic functions, and are targeted for treatment of various diseases. Studies have reported a link between chronic use of the β2AR antagonist propranolol and an increased risk of PD, and chronic use of β2AR agonists has been associated with a decreased risk of PD. We conducted a meta-analysis on the association between both β2AR agonist level and β2AR antagonist level and the risk of PD. Materials and Methods: A comprehensive electronic search was conducted on the databases of PubMed, ScienceDirect, ProQuest, Cochrane Library, and ClinicalKey from the start of each database until 30 June 2021. The objective was to identify prospective cohort and case–control studies that have reported on the association between β-adrenoceptor agonist level, antagonist level, and PD risk. Results: A meta-analysis of the data extracted from eight studies revealed that β2AR agonist use was associated with reduced PD risk . Compared with the control group, β2AR antagonist use was associated with an increased risk of PD . Propranolol, a type of β2AR antagonist, was related to an increased risk of PD . Conclusions: In this meta-analysis, β2AR agonists were associated with a decreased risk of PD, and β2AR antagonists were related with an increased risk of PD. However, further studies with larger sample sizes and an evaluation of the long-term effects of varying dosages of medications are needed. Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after dementia. However, PD is associated with more rapid progression towards disability and death . PD is aα-synuclein is a protein closely related to the occurrence of PD. When the protein is misfolded in nerve cells, Lewy bodies are formed, and excess accumulation can cause nerve cell damage ,10. The This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines  18]. . 18]. The literature was searched on PubMed, ScienceDirect, ProQuest, Cochrane Library, and ClinicalKey from the start of each database until 30 June 2021 using the following keywords: (Beta adrenoreceptor) and (Parkinson’s disease), (Beta Blocker) and (Parkinson’s disease), (β2-adrenoreceptor antagonist) and (Parkinson’s disease), and (β2-adrenoreceptor agonist) and (Parkinson’s disease). The search strategy included handsearching the reference lists of eligible studies and of recent reviews for additional records. Two independent reviewers screened potential studies by title and abstract to remove duplicate and obviously irrelevant studies. Two authors independently extracted data from the studies after verifying these studies’ eligibility for meta-analysis. The variables extracted from the studies were author names, year of publication, study sample size, sample age, gender, use of medications, follow-up duration, outcomes, and study quality evaluation. The outcome assessed in the meta-analysis was the risk ratio of PD in patients with exposure to β2AR agonist or antagonist. Studies were excluded if they were animal studies or studies not related to the treatment effect of PD.Q test and the I2 statistic. The threshold for statistical significance was set at an alpha level of 0.05 (two-tailed). Due to the presumed heterogeneity of the included studies, the data were analyzed using random-effects meta-analysis models on Comprehensive Meta-Analysis software version 3 . We calculated risk ratios (RRs) with a 95% confidence interval for outcomes. Publication bias was examined by visually inspecting funnel plots with the Egger’s regression test. The heterogeneity of the included studies was measured using a Following the initial database search and screening, 56 full-text articles were assessed for eligibility. We ultimately included eight articles in this meta-analysis. p = 0.043). Among these six studies, significant heterogeneity was noted . The funnel plot of the included studies, for indicating publication bias, exhibited symmetry (p = 0.40). A subgroup analysis for different types of β2AR agonist indicated that formoterol , salbutamol , salmeterol , and terbutaline  were related with a reduction in PD risk (As indicated in symmetry b. The Eg PD risk c. p < 0.005) . The funnel plot analysis for publication bias showed symmetry among the included studies (p = 0.35). Propranolol, a type of β2AR antagonist, was often used to treat heart problems, help with anxiety, and prevent migraines. It was related with an increase in PD risk   a. Among  studies b. Statis< 0.005) c.In this meta-analysis, we found that β2AR agonists were related with a reduction in the risk of developing PD. For individual medications, formoterol, salbutamol, salmeterol, and terbutaline were associated with reduced risk of PD. By contrast, the use of β2AR antagonists, including propranolol, was related with an increased risk of PD.The misfolding and aggregation of alpha synuclein protein, encoded by the SNCA gene, is an important cause of neuronal death in PD . The oveThe association between exposure to β2AR agents and risk of PD may vary according to the presence of comorbidities. In a French nested case–control study, β2AR agonist exposure was associated with a reduced risk of PD only in the population without diabetes. Conversely, increased risk of PD was found in patients with diabetes who were exposed to a β2AR agonist . SeveralA recent large case–control study was performed to a evaluate 31 potential modifiable protective factors or risk factors of PD, including lifestyle and environmental factors, and drugs and comorbid conditions . The stuThis meta-analysis found that propranolol increased the risk of PD. However, the mechanism between exposure to β2AR blockers and risk of PD was unclear. The development of PD with propranolol use is considered a very rare adverse drug reaction at five-year follow-up  ,19. NeveOur study has several limitations. First, PD is a neurological disorder with a complex pathogenesis implicating both environmental and genetic factors. For example, previous studies have reported that pesticide exposure and well water drinking increased the relative risk of PD ,28. ThesThe present meta-analysis shows evidence that β2AR agents are related to the risk of PD. However, future big data approaches or clinical trials with varying dosages and treatment durations will help us better assess PD risk and protective factors.


Background: The association between plant-based diets and cardiovascular disease (CVD) remains poorly characterized. Given that diet represents an important and a modifiable risk factor, this study aimed to assess (1) the relationships between the impact of adherence to plant-based diets on cardiovascular mortality, incident CVD, and stroke; (2) if associations differed by adherence to healthful and less healthful plant-based diets.Methods and Findings: MEDLINE and EMBASE databases were searched up to May 2021. Studies assessing CVD outcomes with relation to plant-based dietary patterns or according to plant-based dietary indices (PDI) were included. A meta-analysis of hazard ratios (HR) was conducted using DerSimonian and Laird random effects model. Thirteen studies involving 410,085 participants were included. Greater adherence to an overall plant-based dietary pattern was significantly associated with a lower risk of cardiovascular mortality  and a lower risk of CVD incidence . Among the studies that used PDI, unhealthful plant-based diets were associated with increased risk of cardiovascular mortality , but not CVD incidence. Conversely, healthful plant-based diets were associated with decreased CVD incidence , but not mortality. Vegetarians also had significantly lower CVD incidence , but similar CVD mortality or stroke risk when compared to the meat-eaters.Conclusion: To date, this comprehensive study examines the effects of a plant-based diet on major clinical endpoints using more holistic PDIs. These findings highlight the favorable role of healthful plant-based foods in reducing cardiovascular mortality and CVD. Cardiovascular disease (CVD) is the leading cause of death, accounting for 32% of all global deaths in 2019  with adherence to the Preferred Reporting Items for Systematic Review and Meta-Analyses 2020 for its synthesis . Two elea priori indices such as healthy eating index, alternate Mediterranean diet score, and dietary approaches to stop hypertension; and (3) studies which did not provide outcomes of interests in the hazard ratio (HR).Two authors (JXQ and GL) independently performed the title abstract sieve and full-text review based on the predefined inclusion criteria. Any discrepancies were resolved by consensus or in consultation with a third independent author (NWSC). Only original articles in the English language were included, excluding conference abstracts, reviews, commentaries, and editorials. The primary exposure of interest was adherence to plant-based dietary patterns, defined as higher consumption of plant-based foods and lower consumption or exclusion of animal-based foods. In line with this definition, vegetarian or vegan dietary patterns were also classified under plant-based dietary patterns. Thus, the inclusion criteria were prospective cohort studies involving vegan or vegetarian participants or studies that assessed the plant-based diet of the subjects using various PDIs such as healthful PDI (hPDI) and unhealthful PDI (uPDI) with reported outcomes on cardiovascular mortality, cardiovascular disease, or stroke events. The exclusion criteria included (1) studies that focused on single food groups such as vegetables, beans, nuts, or specific cruciferous vegetables that did not reflect a major part of the diet; (2) studies that used Relevant data from included articles were extracted by a pair of independent authors (JXQ and GL) into a structured proforma. The primary outcomes of interest were cardiovascular mortality, CVD, and stroke. Cardiovascular mortality was defined in accordance to the International Classification of Diseases (ICD), 9th or 10th edition , 27, wheI2 statistic and the Cochran Q test, where a p-value of ≤ 0.10 was considered significant for heterogeneity  using the meta package. A conventional pairwise meta-analysis was conducted in hazard ratio using the DerSimonian and Laird random effects model to assess the association of plant-based diets with cardiovascular health outcomes . The risogeneity , 31. An ectively . The ranectively . Howeverogeneity , 34.To explore potential sources of heterogeneity, the analysis was stratified according to definitions of plant-based diets i.e., vegetarian diet vs. plant-based dietary scores. In studies that classified adherence to plant-based dietary patterns using overall PDI, subgroup comparison was conducted for hPDI vs. uPDI to analyze the effects of quality of plant-based foods on cardiovascular health. Publication bias was assessed by visual inspection of the respective funnel plots . For quaA systematic search of the literature yielded a total of 605 references before 103 duplicates were removed, following which 386 articles were excluded after the title abstract sieve. In addition, nine studies were retrieved for full text review after screening the references of included articles and other meta-analyses , 37–41. 2. The majority of the studies administered food frequency questionnaires to assess the dietary intake of participants (n = 10) (n = 3)  , 47, 48.p = 0.0193, I2 = 88.5%, N = 124,501) and lower risk of CVD incidence , respectively. However, there was a non-significant decrease in the risks of total stroke with greater adherence to an overall plant-based diet . However, there was no evidence of publication bias from the funnel plots in the The pooled analysis of seven studies involving 1,24,501 and 3,23,854 subjects demonstrated that a greater adherence to an overall plant-based dietary pattern was significantly associated with decreased risk of cardiovascular mortality  that assessed plant-based diets using overall PDI, there was a non-significant decrease in cardiovascular mortality between subjects with the greatest adherence to a plant-based diet in the highest quintile compared with the least adherent subjects in the lowest quintile . Similarly, among studies using hPDI to calculate diet scores, cardiovascular mortality was found to be comparable between those in the highest and lowest quintile . In contrast, studies that utilized uPDI showed a significantly increased risk of cardiovascular mortality for subjects who adhered most closely to an unhealthful diet as compared with the least adherent subjects . There was a significant difference between hPDI and uPDI (p = 0.05)  . Heterogp = 0.0054, I2 = 34.2%, N = 211,585). For studies using hPDI to calculate diet scores, subjects who were the most adherent to a healthful plant-based diet also had a decreased risk of CVD compared with those who were the least adherent . However, analysis of studies utilizing uPDI showed no significant association between CVD and adherence of participants to an unhealthful plant-based diet . There was no significant subgroup difference between studies utilizing hPDI compared with uPDI . There was low, moderate, and high heterogeneity with I2 of 34.2, 57.5, and 95.5% in overall PDI, hPDI, and uPDI analysis, respectively.Pooled analysis of seven studies using overall PDI showed that subjects with the greatest adherence to a plant-based diet had significantly lower risks of CVD compared with those who were the least adherent . However, vegetarians were found to have significantly reduced risks of CVD compared with regular meat eaters . There was low heterogeneity for both cardiovascular mortality and CVD analysis with I2 of 0.00 and 22.2%, respectively. Further analysis showed a non-significant decreased risk of total stroke , hemorrhagic stroke  and ischemic stroke  between vegetarians and regular meat eaters. There were high levels of heterogeneity with I2 of 87.3, 84.8, and 81.9% for total stroke, hemorrhagic stroke, and ischemic stroke, respectively.Participants following a vegetarian diet had a non-significant decrease in cardiovascular mortality compared with regular meat eaters , with a lower intake of saturated fat and energy density . ConsequOur results on an overall plant-based diet and lowered risk of CVD are broadly consistent with prior studies which found a lowered incidence of coronary or ischemic heart disease among vegetarians compared to non-vegetarians , 22. HowCurrent guidelines by the Academy of Nutrition and Dietetics , the AmeHitherto, plant-based diets have not been examined in randomized controlled trials of hard cardiovascular endpoints, possibly limited by the long induction periods of CVD with respect to its dietary etiology. This study, therefore, presents high quality evidence for major clinical endpoints such as cardiovascular mortality, CVD, and stroke by pooling a robust sample size of 410,085 participants in HR which remains the gold standard for time-dependent survival analysis. Most included studies were adjusted for important confounders including age, BMI, smoking, and alcohol history. In addition, dietary intake was largely assessed via the validated food frequency questionnaire which has been shown to have high reproducibility (2, a measure of heterogeneity, was significantly large in this analysis albeit attributable to the large sample size. It is well recognized that large sample sizes often inflate heterogeneity estimates (2 > 90% (cibility . Howeverstimates , 34, as (2 > 90% . Most in(2 > 90% , more evThis study provides important evidence to suggest a possible protective role of plant-based dietary patterns against cardiovascular mortality and CVD among the general population. Importantly, not all plant foods are equally beneficial, but unhealthful refined carbohydrates, added sugars, and oils should be avoided. In future studies, it may be worth exploring the potential of healthful plant-based diets as secondary prevention among patients with preexisting CVD and the dose-response association between the level of plant food intake and cardiovascular benefits.The original contributions presented in the study are included in the article/JQ, GL, WL, CN, WS, JT, XP, and YC contributed to the acquisition of data, analysis and interpretation of data, and drafting of the article. JQ, GL, WL, and CN aided in formal analysis, methodology, and validation. MM, SC, NN, MC, RF, NC, and PL aided in revising the article critically for important intellectual content. All the authors read and gave final approval of the version to be submitted. The manuscript, including related data, figures and tables has not been previously published, and that the manuscript is not under consideration elsewhere.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.


Flaxseed is widely used as a functional food for its rich sources of linolenic acid, lignans and dietary fibers in the world. This systematic review and dose–response meta-analysis on randomized controlled trials (RCTs) is first to evaluate effects of different flaxseed products  on lipid profiles, inflammatory and anthropometric parameters in patients with dyslipidemia related diseases.Literature search was performed in PubMed, Embase, Cochrane Central, Scopus, and Web of Science from the inception dates to January, 2020. Weighted mean differences with the 95% confidence interval (CI) were pooled using fix or random-effects models.P = 0.005), LDL-C , TG , apolipoprotein B , TC/HDL-C  and weight ; Lignans supplementation significantly reduced TC , LDL-C  and TC/HDL-C . Although flaxseed oil supplementation had no such lowering-effect on lipid, meta-analysis revealed its lowering-effect on IL-6  and hs-CRP . Subgroup analysis revealed that whole flaxseed decreased TC, LDL-C and TG levels irrespective of country and the intervention time prescribed, but was more pronounced when the dose of whole flaxseed was ≤ 30 g/day , rather not a dose > 30 g/day. Moreover, a linear relationship between dose of whole flaxseed and absolute changes in C-reactive protein (P = 0.036) and a nonlinear relationship between with IL-6 (P < 0.001) were detected.Thirty-one RCTs involving 1,698 participants were included. The present meta-analysis revealed that flaxseed consumption had an overall beneficial effect on serum TC, LDL-C, TG, apo B and IL-6 in patients with dyslipidemia related diseases, but not on apo A, HDL-C, hs-CRP, CRP and anthropometric indices. However, different flaxseed products showed obviously different effects. Whole flaxseed supplementation significantly reduced TC (− 11.85 mg/dl, 95% CI − 20.12 to − 3.57, Flaxseed intervention suggested the positive effects on lipid profiles, inflammatory cytokines and anthropometric indices in patients with dyslipidemia related diseases. Of these, whole flaxseed and lignans play an important role in reducing blood lipid, while flaxseed oil mainly plays in anti-inflammatory. Lipid- and weight-lowering was significant when whole flaxseed was consumed at doses < 30 mg/d, for lipid status with mixed dyslipidemia and patients with BMI > 25.The online version contains supplementary material available at 10.1186/s12986-021-00619-3. Linum usitatissimum L.) is widely used as a functional food in the world, because it is a rich source of linolenic acid, lignans (secoisolariciresinol diglucoside [SDG]), and soluble and both insoluble dietary fibers, which are related to cholesterol control  were extracted. If a study had some comparisons by different intervention time, different product-types or doses of intervention, we regarded these comparisons as multiple studies. There are three studies –21 with Assessment of study quality was independently performed by two reviewers (Y.F.L. and D.F.X.) using the Cochrane Collaboration tool for assessing risk of bias in RCTs . The Coc2) and inflammatory cytokines (net change in pg/mL or mg/L) between the subjects assigned to consume flaxseed or its derivatives and those assigned to the control regimens. Standard deviations (SDs) of the mean difference were calculated using correlation coefficient methods referenced in the Cochrane Handbook by the following formula: SD = square root [(SD baseline)2 + (SD end)2 − (2R × SD baseline × SD end)]  , assuminSD end)] . If stan2 index were used to assess the heterogeneity among the included studies. Substantial heterogeneity was indicated as P < 0.05 in the χ2 test and an I2 > 50%. The fixed-effect models and random-effects models were used to calculate the WMD and 95% confidence interval (CI) for each variable according to the level of heterogeneity. If significant heterogeneity was present, then a random-effect model was used.The meta-analysis was performed by using STATA SE . Q test and IMeta-regression was implemented to examine characteristics of the studies that were hypothesized to influence the observed treatment effects. It was performed to assess the association between the overall estimate of effect sizes with potential moderator variables, including type of flaxseed, BMI categories, lipid status, study country, intervention time and study design .2, 25- < 30 kg/m2, and ≥ 30 kg/m2) and lipid status . Sensitivity analyses were completed to detect the robustness of the statistical results and analyze possible sources of heterogeneity by excluding studies on a one-by-one basis, followed by the exclusion of those with a high risk of bias. Egger’s test was conducted to quantitatively explore the possible publication bias (significant level = 0.05). All tests were two-tailed and P < 0.05 indicated statistical significance.Further subgroup analyses were performed to explore impacts of certain characteristics: type of flaxseed , country (Asian or Westerner), interventional time (≤ 10 weeks or > 10 weeks), dose of flaxseed products , BMI categories ; 511 articles were excluded during an initial review (with title and abstract). We retrieved the full text for the remaining 126 articles based on PICOS criteria, of which 32 were retrieved for a complete evaluation. Finally, 31 citations met the inclusion after excluding one  with incTable Milled flaxseed  compared to control groups, in which TC concentrations were decreased more significantly in studies using whole flaxseed and lignan supplementation , rather not using flaxseed oil . Meta-regression was conducted to explore the heterogeneity, and found that the heterogeneity could be explained by type of flaxseed products (P = 0.01)  suggested publication bias in the meta-analysis.Egger’s linear regression , in which whole flaxseed and lignan supplementation had significant lowering-effect on LDL-C concentrations, rather than flaxseed oil intervention  . But subgroup analysis on whole flaxseed and lignan supplementation respectively showed mild net change on TC/HDL-C ration with significant difference   and HDL-C (I2 = 92.0%). Meta-regression was conducted to explore the heterogeneity, and found that the heterogeneity of LDL-C related studies could be explained by factors that were lipid status (P = 0.013) and type of flaxseed products (P = 0.001), the heterogeneity of HDL-C related studies could be explained by intervention time (P = 0.036) , rather than HDL-C concentrations .Egger’s linear regression revealed a potential publication bias in the meta-analysis of flaxseed’s effects on plasma LDL-C concentrations . Whole flaxseed supplementation had a significant effect on reducing TG concentration  compared to control group according to the meta-analysis for different type of flaxseed products . Meta-regression was conducted to explore the heterogeneity, and found that the heterogeneity of TG related studies could be explained by lipid status (P = 0.044) and country factor (P = 0.041)  suggested no publication bias in the meta-analysis.Egger’s linear regression . Thereinto, whole flaxseed supplementation has significant effects on apolipoproteins , but flaxseed oil intervention had no such effect . , no matter whole flaxseed intervention or flaxseed oil .Egger’s linear regression suggested no publication bias in the meta-analysis of flaxseed supplementation on Apo A, Apo B and Apo B/Apo A  in flaxseed supplementation compared to control group. Subgroup analysis revealed no effectiveness of whole flaxseed supplementation on IL-6 ; but revealed a significant effect of flaxseed oil on IL-6   in the meta-regression  suggested no publication bias in the meta-analysis.Egger’s linear regression  and hs-CRP  .Seven comparisons included 284 participants from 6 studies reported the results for hs-CRP, and 11 comparisons included 443 participants from 9 studies reported CRP. Meta-analysis revealed no significant effect of supplementation with flaxseed-containing products on CRP  in the meta-regression of flaxseed intervention on CRP, but no factor could explain the heterogeneity in the meta-regression of flaxseed intervention on hs-CRP .Egger’s linear regression suggested no publication bias in the meta-analysis  in 202 participants in 6 comparisons (from 5 studies)  Fig. d.There is moderate level of heterogeneity among the studies. The heterogeneity among the studies could not be explained by presupposed factors in the meta-regression  suggested no publication bias in the meta-analysis.Egger’s linear regression   compared with the control group, while flaxseed oil supplementation did not (P = 0.991).The results for weight were reported in 12 comparisons from 11 studies including 706 participants. The pooled result from these studies showed no significant effect of supplementation with flaxseed-containing products on weight change , no matter whole flaxseed or flaxseed oil.Seventeen comparisons included 949 participants from 16 studies reported the results for net change on BMI value . The high level of heterogeneity among the studies was explained by lipid status (P = 0.001) and study country (P = 0.047) in the meta-regression .Egger’s linear regression suggested no publication bias in the meta-analysis of flaxseed supplementation on weight and BMI value   compared to control group.Eleven comparisons from 10 studies reported the results for WC, which involved 621 participants. The pooled analysis suggested that there was no significant net change in WC following supplementation with flaxseed-containing products  .Four comparisons included 200 participants from 3 studies reported the results for net change for WHR. Meta-analysis revealed no net change on WHR following supplementation with flaxseed-containing products . The moderate level of heterogeneity among the studies was explained by study country (P = 0.047) in the meta-regression  suggested no publication bias in the meta-analysis of flaxseed supplementation on weight and BMI value.Egger’s linear regression  , anthropometric indices , and other inflammatory cytokines  . It indicated a linear relationship between dose and absolute changes in CRP   . It indicated a nonlinear relationship between dose and absolute changes in IL-6  had obviously different effects. Meta-analysis revealed a significant reduction on TC, LDL-C, TG, apo B, TC/HDL-C and weight loss in patients allocated to whole flaxseed; flaxseed lignan had a significant lowering effect on TC, LDL-C and TC/HDL-C; however, flaxseed oil showed a significant reduction on IL-6 and hs-CRP.Our present results on TC, LDL-C and TG in patients with dyslipidemia related diseases were consistent with a meta-analysis  that stuSubgroups analysis after stratifying pooled results according different type of flaxseed intervention  on inflammatory cytokines, did not reach consistent conclusions , 80, 81. P = 0.027; I2 = 0.0%) compared to control group. Although we did not find its significant reduction on BMI value (P = 0.719), however, subgroup result suggested its significant net change in participants with dyslipidemia . These results suggest that flaxseed has a beneficial effect on anthropometric indices. Whole flaxseed rather than flaxseed-oil seems effective in weight and BMI reduction which is attributed to the fact that the flaxseed can control the energy intake and increase satiety by containing 28% fibers [Our meta-analysis found whole flaxseed consumption had a significant reduction on net change for weight  the most of SDs of the net change were estimated using correlation coefficient methods referenced in the Cochrane Handbook, rather than were exact value; (2) many characteristics that vary within studies could not remove to be factors of between-study heterogeneity, such as difference of the different background of the patients included, the varying control groups, or the uneven quality of the studies; (3) some relevant studies might be missing from our pooling because neither grey literature databases were used for identifying studies, nor non-English studies were considered; (4) influences of the other covariates could not be fully determined because of the lack of information of the quality of products and the amount of specific bioactive components in flaxseed and their bioavailability. Further studies are needed with large sample sizes, adequate durations, and solid study designs to investigate the effectiveness of flaxseed supplementation.All in all, flaxseed intervention suggested the positive effects on lipid profiles, inflammatory cytokines and anthropometric indices in patients with dyslipidemia related diseases. Of these, whole flaxseed and lignans play an important role in reducing blood lipid, while flaxseed oil mainly plays in anti-inflammatory. Lipid- and weight-lowering was significant when whole flaxseed was consumed at doses < 30 mg/d, for lipid status with mixed dyslipidemia and patients with BMI > 25. Additionally, a linear association between whole flaxseed consumption and absolute changes in C-reactive protein and a nonlinear relationship between with IL-6 was observed.Additional file 1. Subgroup analysis of flaxseed supplementation on lipid profiles, inflammatory cytokines and anthropometric indices in patients with dyslipidemia related diseases.Additional file 2. The flow diagram of systematic review and meta-analysis.Additional file 3. Meta-regression investigating the associations between flaxseed-derived product intakes and lipid profiles, inflammatory factors and anthropometric indices.Additional file 4. Subgroup analysis on the effects of flaxseed powder and flaxseed oil on lipid profiles, inflammatory cytokines and anthropometric indices in patients with dyslipidemia related diseases.Additional file 5. Meta-regression on linear relationship between dose and absolute changes in lipid profiles, inflammatory cytokines and anthropometric indices.Additional file 6. Curvilinear regression on nonlinear relationship between dose of whole flaxseed powder and absolute changes inlipid profiles, inflammatory cytokines and anthropometric indices.


Background: Long non-coding RNA associated with poor prognosis of hepatocellular carcinoma (AWPPH) is dysregulated in a variety of human cancers. However, the prognostic value of AWPPH in various cancers remains unclear.Methods: Comprehensive literature search was performed in PubMed, Web of Science, CNKI and Wangfang databases, and eligible studies were obtained according to the inclusion and exclusion criteria. The pooled hazard ratios (HRs) and odds ratios (ORs) were applied to assess the clinical value of AWPPH expression for overall survival (OS) and clinicopathological features.P<0.001). Subgroup analysis revealed that tumor type and sample size affect the predictive value of AWPPH on OS, whereas cut-off value and HR estimation method have no impact on it. In addition, the pooled data also showed that AWPPH was positively linked to advanced TNM stage , bigger tumor size , macro-vascular invasion  and lymph node metastasis . Moreover, the results of the trim and fill analysis confirmed the reliability of our finding.Results: A total of 19 articles including 1699 cancer patients were included in the study. The pooled results demonstrated that evaluated AWPPH expression was positively related to a poorer overall survival of patients with cancers (HR = 1.79, 95%CI: 1.44–2.14, Conclusions: Up-regulation of AWPPH was associated with advanced TNM stage, bigger tumor size, worse lymph node metastasis, macro-vascular invasion and shorter overall survival, suggesting that AWPPH may serve as a biomarker for prognosis and clinicopathological characteristics in human cancers among the Chinese population. Cancer is a major public health problem worldwide, and it has been the leading cause of death in China since 2010 , which mLncRNA is a typical kind of non-coding RNA without meaningful open reading frame, which also possesses many significant functions and plays important roles in tumorigenesis and tumor progression. Most lncRNA transcripts involved in the epigenetic, transcriptional, and posttranscriptional regulation of cancer cells . FurtherAWPPH, also well-known as AK001796, MIR4435-2HG, LINC00978 and other names, was localized at 2q13 and found to be dysregulated in many human cancers. Growing evidence showed that AWPPH was associated with tumorigenesis and prognostic outcome . HoweverThis meta-analysis was performed in accordance with the PRISMA 2009 guidelines (Supplementary S1) . We perfEligible studies should meet the following inclusion criteria : (1) Studies evaluated the association between AWPPH and cancer patient samples; (2) Available prognosis outcomes or clinicopathologic features data; (3) sufficient information to obtain hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (95% CI). The following articles were excluded from the study: (1) reviews, letters or case reports; (2) non-human studies; (3) duplicated publication; (4) studies with insufficient data for HR/OR/95%CI extraction.Eligible articles were reviewed by two reviewers (Li and Rui) independently according to the inclusion and exclusion criteria. Disagreement was resolved during a consensus with a third reviewer (Chen). The essential information was screened and extracted from each eligible study, including the name of first author, year of publication, origin country, cancer type, sample size, detection method of AWPPH, HR and corresponding 95%CI for OS, as well as clinicopathological features. The HRs with 95%CIs were obtained directly from studies which performed the multivariate analysis, and the Kaplan–Meier curves were used for the extraction of the survival information if the 95% CIs and HRs have not been directly reported from the researches according to the method described in the previous publication . The NewI2 test as well as the chi-based Q-test, to determine heterogeneity between several studies. Heterogeneity was considered as statistically significant with I2 < 50%. The fixed-effect model was used if heterogeneity exists (I2 > 50% and P<0.05), otherwise, the random-effect model was applied. Publication bias was assessed using Begg’s funnel plot and Egger’s regression test. The sensitivity analysis was used to check the stability of the combined results and to determine the source of any heterogeneity. The P-value <0.05 was considered to be statistically significant.The present meta-analysis was performed with STATA SE 15.0 (Stata Corporation). HR and corresponding 95%CI for OS were applied to determine the pooled effect for clinical outcomes, and the odds ratio (OR) with 95%CI were used to evaluate the correlation between LncRNA AWPPH and clinicopathological parameters. Statistical heterogeneity was assessed using the n=3), colorectal adenocarcinoma , ovarian carcinoma , triple-negative breast cancer , non-small cell lung cancer , osteosarcoma (n=1), cervical cancer , oral squamous cell carcinom , clear cell renal cell carcinoma , GC (n=1), prostate carcinoma , breast cancer , esophageal squamous cell carcinoma . Clinical outcomes were recorded including 19 studies for overall survival (OS), 3 for recurrence-free survival (RFS), 1 for progression-free survival (PFS), and 1 for disease-free survival (DFS). HRs with corresponding 95% CIs were obtained from the original data in 4 studies, and calculated from Kaplan–Meier curves for the rest 15 studies. In addition, for the quality assessment, the Newcastle–Ottawa Scale (NOS) score of individual cohort studies was ranged from 6 to 8, which indicated that the methodological quality of included studies was medium or high. The clinicopathological features of the included studies were summarized in As shown in P<0.001) with non-significant heterogeneity . Furthermore, subgroup analysis across several different variables, including cancer type, sample size, HR estimation method, and cut-off value, were further performed to explore the association between HRs and OS. The results showed that cancer type and sample size influence the prognostic value of AWPPH on OS  .The correlation between AWPPH expression and clinicopathological characteristics were examined with OR analysis in 15 studies with 1332 cancer patients . About 1P<0.001) B. The reP=0.001, D. In addt = 0.06, P=0.953). Sensitivity analyses were performed to evaluate whether individual study influenced pooled HRs by excluding one study by turns. The results showed that the pooled HR was not significantly changed after removing each study, suggested that the results were stable  or sponge for miRNAs to regulate the initiation, development, and chemoresistance of cancer. For example, in gastric cancer, Bu et al. demonstrated that AWPPH promotes cell proliferation and tumorigenesis by regulating miR-497/NTRK3 axis . Recentl. . In NSCL. . Further. , miR-802. , miR-206. , miR-122.  and miR-. .Nevertheless, several limitations to this meta-analysis should be taken into account. First, all included studies were performed in the population from China, which may limit the applicability of our results for other ethnic population. Second, the cut-off values were lack of uniform standard in different types of cancer, which may result in some heterogeneity and affect the results of the study. Third, some of the HRs were calculated based on data extracted from the survival curves, which may not be very accurate and result in a calculation bias.To conclude, this meta-analysis revealed that AWPPH expression level served as a prognostic indicator in multiple cancers in the Chinese population. Higher expression of AWPPH was significantly associated with poorer overall survival in patients with cancers and correlated with advanced TNM stage, higher risk of LNM and MVI, and bigger tumor size. Ultimately, more high-quality studies were required to certify clinical utility of AWPPH in cancers.