Previous epidemiological studies have investigated the association of fish and marine n-3 polyunsaturated fatty acids (n-3 PUFA) consumption with cardiovascular disease (CVD) mortality risk. However, the results were inconsistent. The purpose of this meta-analysis is to quantitatively evaluate the association between marine n-3 PUFA, fish and CVD mortality risk with prospective cohort studies. A systematic search was performed on PubMed, Web of Science, Embase and MEDLINE databases from the establishment of the database to May 2021. A total of 25 cohort studies were included with 2,027,512 participants and 103,734 CVD deaths. The results indicated that the fish consumption was inversely associated with the CVD mortality risk . The higher marine n-3 PUFA intake was associated with the reduced risk of CVD mortality . Dose-response analysis suggested that the risk of CVD mortality was decreased by 4% with an increase of 20 g of fish intake  or 80 milligrams of marine n-3 PUFA intake  per day. The current work provides evidence that the intake of fish and marine n-3 PUFA are inversely associated with the risk of CVD mortality. Cardiovascular diseases (CVD) are a group of disorders of the heart and blood vessels, including coronary heart disease, cerebrovascular disease, rheumatic heart disease and other conditions. The global CVD mortality increased 12.5% from 2005 to 2015. 17.9 million people died of CVD in 2015 ,4. Fish Marine n-3 polyunsaturated fatty acids (n-3 PUFA)—including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA)—mainly exist in fatty fish. A high consumption of n-3 PUFA from fatty fish led to an increase in high-density lipoprotein and a decrease in inflammation factors ,8. BesidPrevious epidemiological studies have investigated the association of fish consumption with CVD mortality risk ,11. A reSystematic search was performed on PubMed, Web of Science, Embase and MEDLINE from the establishment to May 2021. The search was limited to English literature, and the search keywords were “fish”, “seafood”, “fish products”, “fish oil”, “EPA”, “eicosapentaenoic acid”, “DHA”, “docosahexaenoic acid”, “DPA”, “docosapentaenoic acid”, “n-3 polyunsaturated fatty acid”, “ω-3 polyunsaturated fatty acid”, “n-3 PUFA”, “ω-3 PUFA”, “cardiovascular diseases”, “CVD”, “cardiovascular”, “cohort”, “follow-up”, “prospective” and “longitudinal”.Two project members (L.J. and B.Z.) independently screened all titles and abstracts of the retrieved studies. Disagreements regarding the inclusion of the studies and the interpretation of the data were resolved by discussion among investigators. The studies were included in this meta-analysis if they met the following criteria: (1) study design: prospective cohort studies; (2) exposure: fish and marine n-3 PUFA; (3) source of n-3 PUFA: marine-derived n-3 PUFA ; and (4) outcomes: total CVD mortality which was reported as multivariate-adjusted relative risk (RR) and 95% confidence intervals (CI). The studies were excluded with the following criteria: (1) irrelevant; (2) not human studies; (3) not cohort studies; (4) not English studies.The following information was extracted from each eligible study: first author’s surname; the year of publication; country; age; follow-up duration; the number of CVD deaths, sample size; gender; exposure levels; multivariate-adjusted RR with 95% CI for the highest versus the lowest category of fish or marine n-3 PUFA intake; adjusted covariates. Consumption of fish and marine n-3 PUFA was collected with adjusted RR (95% CI) to conduct dose-response analyses. Newcastle–Ottawa Quality Assessment Scale (NOS) was adopted to evaluate the quality of each included study . The NOSThe quality evaluation was performed independently by two project members (L.J. and B.Z.). The NOS quality score system assessed 3 items: population selection, comparability of the groups and outcome assessment. Any discrepancies in grading the quality were addressed by group discussion.p < 0.05 was considered as statistically significant. The summary estimation was conducted through the comparison of the highest and the lowest category. Heterogeneity was assessed using the I2 statistic. In the case of heterogeneity for I2 > 50%, a random-effect model was adopted to pool the results. Otherwise, a fixed effect model was chosen.All statistical analyses were performed using Stata (Version 15.1). RRs with 95% CI for all the exposure categories were extracted for the analysis. The main effect was RRs with 95% CI. A two-tailed p < 0.1 was considered statistically significant).Sensitivity analysis was implemented by deleting one study at a time. Subgroup analyses and meta-regression were performed to identify the possible sources of heterogeneity. In the subgroup analyses, the included studies were stratified by location , follow-up duration (<9 and ≥9 years), etc. In meta-regression, gender, country, dropout rate, follow-up duration, CVD history, adjustment for diabetes and adjustment for smoking were used as the covariates. Potential publication bias was accessed using funnel plots and Egger’s test   . Sensiti= 70.0%) . Subgrou= 70.0%) . No publp non-linearity < 0.001). The adjusted RR reached a steady value when fish consumption increased beyond 40 g/d. In the linear dose-response analysis, the summary RR (95% CI) for a 20 g/d increment was 0.96 (0.94–0.99) for CVD mortality risk (p trend = 0.002).2 = 37.8%) . Linear dose-response analysis suggested that an increase of 80 milligrams of n-3 PUFA per day was associated with a 4% lower risk of CVD mortality .Ten eligible studies with 1,337,660 participants and 76,537 CVD deaths explored the association of marine n-3 PUFA intake with CVD mortality risk ,37,38,39= 37.8%) . Sensiti= 37.8%)  35]. Th. Th2 = 3= 37.8%) . No publTo our knowledge, the current work is the first meta-analysis of prospective observational studies for associating marine n-3 PUFA intake and CVD mortality risk. This study showed a significant inverse association between fish, marine n-3 PUFA intake and CVD mortality risk. Nonlinear dose-response relationship found that an increase of 20 g of fish intake or 80 milligrams of marine n-3 PUFA intake per day was associated with a 4% reduction in risk of CVD mortality.In accordance with the previous study, the fish consumption was inversely associated with the CVD mortality risk in the current meta-analysis . BechthoIn most studies where fish exits as an exposure variable, the observed benefits could often be attributed to the presence of fatty acids ,56. The In this meta-analysis, we also found a negative association between the marine n-3 PUFA intake and the CVD mortality risk. In previous studies, the results were not consistent . A randoThe dose–response analysis showed that the risk of CVD mortality decreased with the increase of fish consumption from zero to 40 g/d. The adjusted RR reached a steady value when fish consumption increased beyond 40 g/d. Therefore, we believe that 40 g/d is the ideal dose for preventing CVD mortality. This is basically consistent with the average fish intake of the population of Europe and America ,30. HoweThis study has several strengths. First, compared with the previous meta-analysis , this stThe limitations should be acknowledged. First, several deep-sea fishes may be contaminated, while only one article reported whether fishes had pollutants or not . Second,This meta-analysis indicated that the fish and marine n-3 PUFA intake were inversely associated with reduced risk of CVD mortality. This finding has important public health implications in terms of the prevention of CVD mortality. Since the biomarkers of fish and n-3 PUFA within an individual are important for food absorption, further research needs to be performed in biomarkers.


Abnormalities of cortical thickness (CTh) in patients with their first episode psychosis (FEP) have been frequently reported, but findings are inconsistent.To define the most consistent CTh changes in patients with FEP by meta-analysis of published whole-brain studies.The meta-analysis used seed-based d mapping (SDM) software to obtain the most prominent regional CTh changes in FEP, and meta-regression analyses to explore the effects of demographics and clinical characteristics. The meta-analysis results were verified in an independent sample of 142 FEP patients and 142 age- and sex-matched healthy controls (HCs), using both a vertex-wise and a region of interest analysis, with multiple comparisons correction.The meta-analysis identified lower CTh in the right middle temporal cortex (MTC) extending to superior temporal cortex (STC), insula, and anterior cingulate cortex (ACC) in FEP compared with HCs. No significant correlations were identified between CTh alterations and demographic or clinical variables. These results were replicated in the independent dataset analysis.This study identifies a robust pattern of cortical abnormalities in FEP and extends understanding of gray matter abnormalities and pathological mechanisms in FEP. However, reported results are inconsistent: compared with healthy controls (HCs), lower CTh has been reported in the superior  software. We used a mask specifically designed for whole-brain CTh, which minimizes the effect of subcortical gray matter  AND . In addition, we manually checked the references of these studies to identify further studies for inclusion. Studies meeting the following criteria were included: (i) studies published in English in a peer-reviewed journal; (ii) studies that recruited individuals who met the diagnostic criteria of FEP and healthy controls based on the cross-diagnostic approach  that scores potential risk of bias for case-control studies in terms of six aspects of study quality (Keramatian www.sdmproject.com) software .First, we performed a pooled meta-analysis with all included studies. Then subgroup meta-analyses of studies using 3.0 T and 1.5 T MRI scanners were performed to investigate the possible effects of field strength. SDM  by discarding one dataset at a time to determine whether the results remained significant. We estimated the statistical (between-studies) heterogeneity of individual clusters using q statistics  and tested for heterogeneity of findings with a permutation approach. The possibility of publication bias for regions showing altered CTh was examined using Egger tests.Replicability was assessed by jackknife sensitivity analysis. The main statistical analysis was repeated et al., Meta-regression analyses were conducted to examine the effects of age, illness duration , gender , and medication status (percentage of medicated participants) on CTh. Meta-regression analysis of age at onset and symptom severity was not possible, being reported in fewer than nine studies  (Kay http://surfer.nmr.mgh.harvard.edu) using the following steps: (i) head motion correction, (ii) skull stripping, (iii) transformation to the Talairach space, (iv) segmentation of gray/white matter, (v) surface inflation and registration to a spherical atlas, (vi) CTh calculation as the shortest distance between the gray–white interface and the pial interface  tests, Shapiro–Wilk (SW) tests, and visual assessment of the histogram were comprehensively used to analyze the normality of clinical variables . Correlations between CTh and age, GAF, and PANSS scores were separately examined for each vertex in the FEP group. Statistical significance of correlations was set at P < 0.05 after correction for multiple comparisons using the criteria of false discovery rate (FDR).In the independent sample, whole-brain vertex-wise analysis assessed the group differences of CTh using a general linear model (GLM) based on QDEC  in FreeSurfer. Monte Carlo simulation controlled for multiple comparisons . Finally, correlations  .Results were also confirmed using an ROI method. First, we created ROI masks based on the meta-analysis results . Next, wet al., et al., et al., et al. separated 52 FEP patients into two medication-type datasets: first-generation antipsychotics (FGA) and second-generation antipsychotics (SGA) included here as two datasets  and gender  between FEP patients and HCs. The clinical characteristics of included datasets are listed in Table The meta-analysis incorporated 10 studies, with a total sample of 624 patients with FEP , mean age 24.2 years), and 505 healthy controls , mean age 24.5 years). Three of the 10 studies recruited two subgroups depending on the medication type  extending to superior temporal cortex (STC), insula, and anterior cingulate cortex (ACC) Table .P = 0.662), insula (P = 0.188), and ACC (P = 0.243).In whole-brain jackknife sensitivity analysis, lower CTh in the right MTC, insula, and ACC was highly replicable, being statistically significant in all but one combination . No statFor the eight datasets that used a 1.5 T scanner, FEP patients showed lower CTh in the right MTC extending to STC, insula, ACC, and inferior frontal cortex, and higher CTh in the left precentral cortex than HCs . For theMeta-regression analysis revealed no statistically significant correlation between CTh and age, gender, illness duration, or medication status .The studied FEP patients and HCs did not significantly differ in age or gender. Table et al., et al., et al., We used a coordinate based meta-analysis approach to define the most robust cortical thickness alterations in patients with FEP, and to assess the effects of clinical and demographic factors. We found three regions within the default mode network and salience network that showed lower CTh : the right middle temporal cortex extending to superior temporal cortex, insula, and anterior cingulate cortex. Previous meta-analyses have reported lower gray matter volume in the STC, insula, and ACC in FEP, which may be part of its neural substrate . The results of subgroup analyses should be regarded with caution: the minimum number of studies recommended for subgroup analyses in SDM software is 10  connecting the cingulate cortex and temporal areas  and SN (i.e. insula and ACC), which was replicated in an independent sample of patients and control participants. We suggest that these reflect the neuropathologic basis of deficits of salience processing, and cognitive and emotional integration, which are important in FEP. Future studies with medication-naïve FEP participants will help verify our conclusions. Longitudinal studies will provide crucial information in understanding the clinical progress of CTh alterations from high psychosis risk to chronic status.kkab015_Supplemental_FilesClick here for additional data file.


The association between miRNA-499 rs3746444 and a variety of autoimmune diseases has been reported. However, these results were contradictory and just focused on one or two autoimmune diseases. The present study aims to examine the possible association between rs3746444 polymorphism and the risk of autoimmune diseases.The studies that evaluated the association between miRNA-499 gene polymorphism and autoimmune diseases were retrieved. Five different genetic models were used to evaluate the association. The random-effects model was used to pool the effect sizes. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the associations. Stratification analyses were performed by ethnicity and type of autoimmune diseases. False-positive report probability (FPRP) was performed for determining noteworthy associations.Seventeen articles (twenty studies) involving 4,376 cases and 4,991 controls were identified and included in our meta-analysis. The pooled ORs of all eligible case-control studies indicated a significant association between miRNA-499 gene polymorphism and autoimmune diseases: . Stratified analysis indicated a significant association across both Caucasian  and Asian  populations. There was also a significant association in Behcet’s disease, rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis populations.Our meta-analysis suggested that the miRNA-499 rs3746444 polymorphism was associated with an elevated risk of autoimmune diseases in the overall analysis as well as Caucasian and Asian populations. MicroRNAs (miRNAs) are small non-coding RNAs of 19 to 25 nucleotides, and their function is to regulate the expression of their target gene , 4.MiRNAs are present in many biological fluids and can regulate a broad range of physiologic and pathologic processes . VariantAn association between miRNA-499 rs3746444 and a variety of autoimmune diseases including rheumatoid arthritis , systemiThe present study aimed to examine the possible association between rs3746444 polymorphism and the risk of autoimmune diseases.Case-control studies included in this study met these criteria: i evaluated the association between miRNA-499 gene polymorphism and autoimmune diseases; ii available and sufficient data including the distribution of genotype frequency in case and control groups. The study exclusion criteria were: i review papers, editorials, comments; ii studies without controls; iii not provided enough information to calculate the odds ratios (ORs) and 95% confidence interval; iv Hardy-Weinberg Equilibrium (HWE) <0.05 in the control group.PubMed, Embase, Scopus, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure databases were searched with the full electronic search strategy as follows: (“microRNA-499” OR “miRNA-499” OR “rs3746444” OR “Pre-miR-499”) AND  AND . The last search was performed on December 15, 2021. We also searched for additional pertinent studies through the references of all identified publications. There was no language restriction in the literature search.Two authors independently extracted the following data from the selected studies: first author; year of publication; country; ethnicity; sample size; genotype frequencies; type of autoimmune diseases; Genotyping methods; Hardy–Weinberg equilibrium(HWE) for controls. Study quality was assessed according to the Newcastle-Ottawa quality-assessment scale. Quality scores ranged from 0 to 9. The work of extraction of data was operated by 2 independent researchers (Kong and Ma). Any disagreement was discussed and resolved with a third author (Xu).The main meta-analysis compared the presence of miRNA-499 gene polymorphism among patients with autoimmune diseases as cases versus healthy subjects as controls. We assessed HWE via Chi-square test in the control populations. The association between miRNA-499 gene polymorphism and autoimmune diseases was estimated by odds ratios (ORs) and 95% confidence intervals (CIs). The strength of the association was determined based on five different genetic models: allelic model (T vs. C), heterozygote model (TC vs. CC), homozygote model (TT vs. CC), dominant model (TT vs. TC+CC), recessive model (TT+TC vs. CC). Because the random-effects model (DerSimonian and Laird method) can incorporate a heterogeneity parameter and enable the modeling of differences between studies, we used it to pool the effect sizes in our analysis , 20. A POur search initially yielded a total of 244 potential articles . After tAmong these studies, eight studies were carried out in the Asian population , 36, 37.A sensitivity analysis was applied to assess the influence of each study on the pooled ORs. When the association between any systemic autoimmune disease and miRNA-499 gene polymorphism was analyzed in model T vs. C, the exclusion of each study showed a significant association. The res9, 3, 3, and 2 of the included studies analyzed miRNA-499 gene polymorphism in patients with RA, SLE, UC, and BD, respectively. Based on the type of autoimmune diseases, subgroup analysis was performed to assess the relationship between miRNA-499 gene polymorphism and RA, SLE, UC, and BD. In RA studies, there was a significant association in some genetic models . In SLE studies, the result show that there has been a marked association in dominant model. In UC studies, two contrast genetic models (T vs. C and TT vs. CC) showed statistically significant association with random effect model . In BD studies, four contrast genetic models  showed statistically significant association with random effect model.To further minimize random errors to confirm the positive association between miRNA-499 rs3746444 and a variety of autoimmune diseases, we performed an FPRP analysis. The results are shown in Tables Autoimmune diseases include a wide range of human diseases, which are characterized by loss of immune tolerance to autoantigens, and the presence of autoreactive immune cells and/or autoantibodies against healthy cells and normal tissues . The etiThe miRNA-499 gene is located on chromosome 20, which regulates the expression of its target genes including IL-2, IL-6, IL-17RB, IL-21, IL-23a, and so on –46. IL-1Numerous case-control studies suggest that the miRNA-499 rs3746444 polymorphism is related to a variety of autoimmune diseases –14, and Ultimately, Seventeen articles (twenty studies) with 4,376 cases and 4,991 controls were included in our analysis. Our results suggested that the C allele of miRNA-499 rs3746444 T/C variant was associated with an elevated risk of autoimmune diseases under the allelic model. In addition, by subgroup analysis, we found that T allele in the Asian population and TT genotype in the Caucasian population were protective factors for predisposition to autoimmune diseases, respectively under allelic model (T vs. C) and dominant model (TT vs. TC+CC). Subgroup analysis by disease types showed the T allele and TT genotype behave as protective factors for predisposition to RA, SLE, and UC populations under some genetic models. Conversely, both case-control studies on BD showed that the T allele of miRNA-499 rs3746444 T/C was linked to an increased risk of BD.There are some previous genome-wide association studies (GWAS) relevant to Behcet’s Disease , rheumatThere are several limitations in our meta-analysis. First, there were only three studies on ulcerative colitis (UC) and two studies on Behcet’s disease (BD). Only one study each was related to autoimmune thyroid diseases, ankylosing spondylitis (AS), and Graves’ disease (GD). Because of the limited number of studies and types of autoimmune diseases, the results we have obtained so far still need to be updated in the future. Second, there were different geographic areas and genetic backgrounds in the included studies. The environmental factors might influence the pooled results. Moreover, we could not analyze the gene-environment interactions to investigate the association between rs3746444 polymorphism and autoimmune disease risk.Despite the limitations, there are some strengths in our meta-analysis. Seventeen articles (twenty studies) were included in our article. The number of studies was significantly greater than that in other meta-analyses published before. This could increase the statistical power in the overall analysis. Seven studies were related to RA in our analysis. There was sufficient data to fully confirm the association of RA and rs3746444 polymorphism.In conclusion, this meta-analysis suggested that the miRNA-499 rs3746444 polymorphism was associated with an elevated risk of autoimmune diseases in the overall analysis as well as Caucasian and Asian populations. Moreover, significant associations were also found in stratified analysis in Behcet’s disease, rheumatoid arthritis, systemic lupus erythematosus, and ulcerative colitis populations.S1 File(XLS)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S1 Checklist(DOCX)Click here for additional data file.


Methamphetamine use in men who have sex with men population is significantly higher than that in the general population. Meth use can cause high-risk sexual behaviors, such as having sex with a variety of sexual partners. The aim of this study was to determine the association between meth use and the number of sexual partners in MSM.Searching international databases (PubMed (Medline), Scopus, Web of Sciences, Embase (Elsevier), PsycInfo (Ovid), Cochrane CENTRAL (Ovid)) until March 2021 was performed in this meta-analysis using appropriate keywords terms to identify related articles. After retrieving articles in these databases, screening was performed based on the title, abstract and full text of the articles, and the final related studies were selected and evaluated using the Newcastle Ottawa scale checklist.The sample size consisted 18,455 people in this study, including four cohort studies with a sample size of 15,026 MSM and four case–control studies with a sample size of 3429 MSM. The results of meta-analysis showed that meth use increased the number of sexual partners in MSM . The results of subgroup analyze based on the number of sexual partners showed that in MSM taking meth, the risks of having one to three, four to five, and six or more than six sexual partners were respectively 2.82, 2.98 and 5.89 times higher than those in MSM who did not take meth.The results showed that meth uses in MSM increased the number of their sexual partners. Due to the fact that increasing the number of sexual partners and high-risk sexual behaviors increase the risk of contracting sexually transmitted diseases such as HIV, it is necessary to adopt control programs to prevent meth use by this group, or to implement programs of reduction in the risk of STIs for this group. Methamphetamine (meth) is currently a global public health concern and is estimated to have been used by 14 to 53 million people worldwide in 2015 . These sThis systematic review and meta-analysis was based on preferential reporting items for systematic review and meta-analysis (PRISMA) according to the following 5 steps of search terms and search strategy, screening and selection, data extraction, risk of bias, and meta-analysis .In the present study, a comprehensive search of articles was conducted in the international databases of PubMed (Medline), Scopus, Web of Sciences, Embase (Elsevier), PsycInfo (Ovid), Cochrane Central (Ovid) from January 1990 to March 2021. The main keywords for searching in the present meta-analysis were meth, multiple sex partners, and MSM. Synonyms of these keywords were extracted from Mesh and Emtree to formulate search and search strategy in different databases. After searching in the mentioned databases, manual search was performed by checking the references of selected related articles.At the end of the search strategy, and checking for duplicates of articles, the studies were entered into EndNote software (version 8) for screening based on titles, abstracts and full texts, respectively. All screening cases were performed according to the study inclusion criteria. It should be noted that the strategy of searching and screening articles was independently done by the two authors (SM and YM) and the disputes were resolved by a third expert (GM).Preliminary studies in which the study population was MSM, meth use was considered as exposure, and the number of sexual partners was considered as the outcome, were included in the present meta-analysis. Also, in terms of the study type, only cohort or case–control studies were considered because the aim of this meta-analysis was to determine the association between meth use and the number of sexual partners of MSM. In addition, the indicators of measuring the desired association for meta-analysis were the odds ratio (OR), risk ratio (RR), and hazard ratio (HR) in selected studies.In the present meta-analysis, the letter to the editor, review studies, meta-analyses, case reports or case series with non-MSM populations, clinical or interventional trials, studies with measurement indicators other than OR, RR, or HR were excluded from analysis.The data from each eligible study were extracted by the two independent researchers (SM and YM) and recorded in Excel while differences were discussed in the presence of a third expert (GM) to reach an agreement. Each OR, HR or RR was reported and the corresponding 95% confidence interval (CI) was extracted from each study for determining the association between meth use and the number of sexual partners of MSM. In addition to the effect size (ES), information such as name of the first author, year of publication, country, profile of the participant population, age range or mean age, gender, number of participants and cases, time period of follow-up for prospective studies, and number of sexual partners was extracted. If a study reported its findings based on the number of sexual partners, that study was separately listed several times based on the different categories of sexual partners in the data extraction table.Quality of studies available in the current meta-analysis was evaluated using the Newcastle Ottawa Scale (NOS) . Based oAll analyzes were performed using STATA software, version 16 . First, After searching international databases and screening articles by title, abstract and full text, 10 studies related to the topic and aim of the meta-analysis remained. After a more detailed review of the article full text, 4 more studies were removed because in their methods, a combination of drug use, different from the aim of this study, which was meth use, was examined as exposure. Finally, after performing a manual search, two articles done by Hoenigl and Prestage were added to the number of final studies , 29. At n = 2643) and Brown et al. [n = 75), respectively. Among prospective studies, the highest and lowest sample sizes were related to the studies of Hoenigl et al. [n = 8905) and Prestage et al. [n = 764), respectively. The quality assessment scores of the articles ranged from 7 to 9 based on the NOS checklist. In this research, five studies received a score of seven, and two studies received a score of eight and one study received a score of nine l et al.   . Also, meth use increased the risk of having 6 or more sexual partners by 5.89 times , respectively   while for studies with a sample size equal to or more than 1000 people, this effect was equal to 4.44   while it increased this risk by 5.38 times in the age group of participants over 33 years   and Oceania (1.3%). The form of used amphetamines considerably varies from region to region. In North America, medicines containing stimulants are mostly used for non-medical purposes. Crystalline meth is used in East and Southeast Asia and Oceania , and amphetamine is used in Western and Central Europe and the Middle East. Since 2010, the use of amphetamines has relatively been stable in most Western and Central European countries. But in North America, there are signs of increased meth use while meth use, especially crystalline meth, has been reported in East and Southeast Asia . RegardiThe results of the present meta-analysis showed that meth use in MSM increased the number of sexual partners and provided evidence to strengthen this association. Due to the association between increasing the number of sexual partners, high-risk sexual behaviors and the incidence of STIs such as HIV, HBV and HCV, it is necessary to adopt control programs to prevent the use, and reduce the risk of STIs in this group, especially among meth users. Implementing programs of harm reduction for MSM meth users, including provision of syringes, use of methadone, and provision of condoms, is very effective in controlling high-risk sexual behaviors and reducing the incidence of STIs in meth users.


P < 0.001), 95% confidence interval (95% CI), − 1.82 to − 0.68; the risk ratio (RR) of the incidence of PSD was 0.52 , which was significantly lower in the escitalopram groups; Escitalopram is safe for stroke patients; there was improvement of the motor function. However, in sensitivity analyses, the conclusions of the motor function and the incidence of drowsiness were altered. The study suggests that escitalopram has a potentially effective role compared with control groups and demonstrates escitalopram is safe. However, the results of the motor function and the incidence of drowsiness should be considered carefully and remain to be discussed in the future.Depression is very common after stroke, causing multiple sequelae. We aimed to explore the efficacy of escitalopram for poststroke depression (PSD). PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, Clinical trials. gov, Wan fang Data (Chinese), VIP (Chinese) and CNKI (Chinese) were retrieved from inception to May 2021. We recruited Randomized Controlled Trials (RCTs) which met the inclusion criteria in our study. The depression rating scores, the incidence of PSD, adverse events as well as functional outcomes were analyzed. 11 studies and 1374 participants were recruited in our work. The results were depicted: the reduction of depression rating scores was significant in the escitalopram groups and the standard mean difference (SMD) was − 1.25 ( Additionally, an epidemiology meta-analysis revealed 31% of patients developed depression during 5 years following stroke2. Frustratingly, poststroke depression (PSD) could impair the cognitive level and activities of daily living (ADL), cause negative sequelae on the recovery of patients, and increase the burden of caregivers3.Approximately 79,5000 people suffer a new or recurrent stroke each year5. Stroke survivors with the homozygous short variation allele genotype of the serotonin transporter-linked polymorphic region (5-HTTLPR) have a higher risk of PSD6. Both stroke and depression are associated with increased inflammation7. Antidepressants can lower the levels of pro-inflammatory cytokines8. These new promising methods show that, in terms of the physical consequences of stroke, these drugs can reduce bad mood9. Escitalopram is a selective serotonin reuptake inhibitor (SSRI) with few drug interactions, and is thus suitable for stroke patients who are prescribed multiple medications10. In recent years, SSRI escitalopram has been proved to be effective for the treatment and prevention of PSD, but there are still controversy12.So far, the etiological mechanisms of PSD have not been revealed clearly. Psychological, social, and biological factors contributed to PSD together11. Moreover, it also shows that there are no significant differences on cognitive function compared with problem-solving therapy (PST) and placebo. However, a study of escitalopram by Kim et al.12 shows that the occurrence of moderate or severe depressive symptoms and adverse events are not statistically significant except diarrhea, ADL improvement, cognitive function, motor function and neurological defects.It demonstrates that escitalopram is safe in a randomized controlled trial (RCT) for prevention of PSD, and decreases effectively the incidence of PSD, as well as improving ADL and social function14 enrolled RCTs of escitalopram have been found, to our knowledge, which both only included a study of Robinson et al.11. Recently, new RCTs of escitalopram are pouring out23, which were conducted in different circumstances, and the integration effects of these studies was vague.Two SSRI systematic reviewsTherefore, we aimed at conducting a systematic review and meta-analysis of RCTs about escitalopram arm compared with the placebo/the blank control arm, evaluating the depression rating scores, the occurrence of depression along with depressive symptoms, the frequency of adverse events and other significant clinical outcomes.8 databases were searched , Medline via PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, Clinical Trials.gov, CNKI (Chinese), Wan fang (Chinese), and VIP database (Chinese), from inception to May 2021. In addition, we scrutinized references of relevant papers and also contacted with authors to get the detailed data if necessary.Inclusion criteria: ① RCTs were enrolled for participants with a clinical diagnosis of stroke; ② The experimental group was treated with escitalopram at any dose, by any mode of delivery and the control arm was included a placebo or the blank control; ③ The primary outcomes: depression rating scores, in which the Hamilton Depression Scale (HAMD) was preferred, the incidence of PSD, and adverse events including gastrointestinal side effects, sexual side events, cardiovascular adverse effects, and other adverse events. The secondary outcomes: neurological deficit scores, ADL, cognitive impairments, and motor function. For functional outcomes, we gave preference to the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index (BI), Fugl—Meyer motor scale (FM), Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA).Exclusion criteria: ① The type of study was a non-randomized controlled study; ② The subjects were not stroke patients or no clear diagnostic criteria; ③ The experimental group was not treated with escitalopram, or the control arm was not included a placebo or the blank control, or drugs and therapies with mixed effects; ④ Outcome indicators were not required in this study; ⑤ Intervention methods were not expressed clearly and could not be verified by the authors.Two team members exacted data of each literature independently. A third investigator was discussed with if necessary.Study quality was independently assessed by two reviewers based on the Cochrane Collaboration’s risk of bias tool including randomization, allocation concealment, blinding, incomplete outcome data, and selective reporting. An opinion was sought from a third reviewer if the first two reviewers could not reach an agreement.P < 0.05 was used as a cutoff for statistical significance. Statistical heterogeneity of trials was evaluated by I224. We used a random-effect model to calculate the pooled estimates if we observed I2 > 50% or P < 0.10, and on the contrary, we used a fixed-effect model.Pooled analyses were carried out at any follow-up point by RevMan 5.3 software . Risk ratio (RR) with 95% confidence interval (CI) was described by categorical data. Standardized mean difference (SMD) with 95% CI was used for continuous outcomes. Subgroup analyses were conducted based on different rating scales, depression or not at recruitment and follow-up duration (< 3 months vs 3 ~ 6 months vs > 6 months).P < 0.10 was considered as statistically asymmetry25.In sensitivity analyses, the trails with high heterogeneity were excluded. Publication bias was assessed by a funnel plot and Egger statistical test that was carried out by Stata 12.0 and Our study was conducted according to the PRISMA 2020 guidelines. We analyzed the data about previous studies which were published early in our research, so ethical approval and patient consent were not necessary and therefore not provided.23. Most of the papers excluded the participants with severe comprehension deficits, aphasia, and unstable medical conditions.We searched 5 English databases  and 3 Chinese databases  from inception to May 2021. After removing duplicates, there existed 285 records and 51 full texts were obtained. Finally, 11 articles were recruited  among participants allocated escitalopram compared with control. But there was moderate heterogeneity among participants who were with depression  or not depression  at recruitment and with no heterogeneity between subgroups . It was reported that the antidepressant efficiency was obvious statistical significance (P < 0.05) in escitalopram group (88.9%) compared with the control (64.7%) in one trail, but we could not obtain the detailed scores23.Figure 2 = 91%) and the group of 3 ~ 6 months , however, there were no advantage of escitalopram in the subgroups, follow-up duration ≥ 6 months, but only one trial was included. Significant heterogeneity was among subgroups .Figure 2 = 72%; Fig. The incidence of PSD was higher in control compared with escitalopram and with moderate heterogeneity  among trials. There was also no statistical significance for other gastrointestinal side events: the dry mouth  among trials. Only 2 trails reported the chest pain, and the RR was 1.35  in escitalopram group compared with the control, including the incidence of the paraesthesia, tremor, pruritus and peripheral oedema, however, they were only reported in one trail12.The escitalopram was safe for the other adverse events, except for the drowsiness , regarding different scales NFI (Neurologic Function Impairment)  vs NIHSS  vs MESSS . It was reported that the recovery rate of neurological function was obvious statistical significance (P < 0.05) in escitalopram group (86.1%) compared with the control (58.8%) in one trail, but we could not obtain the detailed scores23.The SMD was − 0.97 .The SMD was 0.56 , between different motor function scales FM  vs Hemispheric Stroke Scale .There was a better effect in the escitalopram versus the control  and the drowsiness . Moreover, the I2 was decreased from 94 to 79% in the pooled analysis of the ADL. The inverted funnel plot of visual examination depression score  was not affected by publication bias.The quality of studies enrolled was shown in Fig. The systematic review and meta-analysis give an up-to-date and detailed description of the efficacy of escitalopram for PSD, in which 11 papers and 1374 participants were enrolled. Excitingly, participants allocated to the escitalopram were more improved than the control, including depression rating scores, the incidence of PSD and motor function, but the participants enrolled in the escitalopram group did not experience more improved in aspect of the ADL, neurological function and cognitive function. Furthermore, the participants in the escitalopram groups did not suffer more adverse events compared with the control groups in our research, except for the drowsiness. However, in sensitivity analyses, the conclusions of motor function and the drowsiness were not stable, which should be considered carefully.26 and is different from two previous meta-analyses27, due to different types of antidepressants enrolled in that researches, especially tricyclic antidepressants included in Xu et al.27. It is negative for the functional indexes we analyzed except for the motor function. In the sensitivity analyses, only the result of motor function is altered. The conclusions of functional indexes are not consistent with previous meta-analyses28, which maybe only ≤ 4 papers are enrolled in each functional index and the validity should be interpreted cautiously and proved in the future.Our research reveals escitalopram reduces effectively the depression rating scores and the incidence of PSD, which demonstrates the escitalopram is effective in the treatment and prevention of PSD. Escitalopram is safe for stroke patients in our meta-analysis. The pooled results show the participants treated with escitalopram are well tolerated for adverse events, including the gastrointestinal, cardiovascular, sexual and other adverse events but the drowsiness which only 2 trails were enrolled, however, the escitalopram groups did not experience more drowsiness in the sensitivity analyses, which is consistent with our previous meta-analysis29. So in the sensitivity analyses, the I2 was decreased from 94 to 79% in the pooled analysis of the ADL. Secondly, different rating scales were used in the studies included, and one study shows the occurrence of PSD is different by different depression scales (HAM-D17 vs. HAM-D6)30, which proved different scales could lead to different outcomes and conclusions. It is testified in the subgroup analyses of neurological function  was obviously longer than other trails enrolled. Fourthly, after removing the trail12, heterogeneity  decreased significantly in the pooled analysis of cognitive function, which maybe the weight of the trail was too large and the studies enrolled were too few.One of the potential weaknesses was the high heterogeneity among trials in our research, except for the incidence of PSD and adverse events. The possible reasons were analyzed. Firstly, it may be small samples of most trials we enrolled and low quality of some trails, which may lead to high risk of bias and overestimationThe main problems of the serious cognitive impairment, aphasia, and the severe stroke about the participants were excluded in the studies recruited, therefore we could not know whether those patients could be treated with escitalopram, which was also a limitation of our research. Another limitation was that the studies enrolled were too few in some pooled analyses and related original studies should be conducted to clarify and testify the results.The strengths also existed in our study. An extensive search was conducted, including online papers, references and unpublished trials, as well as a fairly wide range of important clinical results. Additionally, sufficient sensitivity analyses and enough subgroup analyses were performed to ensure the reliability and robustness of the results. In the future, it should be necessary to develop more detailed and rigorous basic experiments on mechanisms and clinical trials to make a better choice for clinicians and patients.Taken together, our findings prompt escitalopram is safe and effective for PSD. However, the pooled analyses of the motor function and the incidence of drowsiness should be explained cautiously. Moreover, limitations and inspirations are provided for further researches in our study. Therefore, more multicenter, larger sample, more rigorous and more result indexes designed RCTs are needed to evaluate the protective role of escitalopram on PSD.Supplementary Information.


Cardiovascular disease (CVD) is a leading cause of mortality globally and is strongly influenced by dietary risk factors. The aim was to assess the association between egg consumption and risk of CVD risk/mortality, including coronary heart disease (CHD), stroke, and heart failure.MEDLINE, Embase, and Web of Science databases were searched through April 2020 for prospective studies. Two independent reviewers screened and extracted the data through standardized methods. Size effects were calculated as summary relative risks (SRRs) in a dose–response fashion through random-effects meta-analyses.Thirty-nine studies including nearly 2 million individuals and 85,053 CHD, 25,103 stroke, 7536 heart failure, and 147,124 CVD cases were included. The summary analysis including 17 datasets from 14 studies conducted on CVD  showed that intake of up to six eggs per week is inversely associated with CVD events, when compared to no consumption ; a decreased risk of CVD incidence was observed for consumption of up to one egg per day [SRR = 0.94 ]. The summary analysis for CHD incidence/mortality including 24 datasets from 16 studies showed a decreased risk up to two eggs per week . No associations were retrieved with risk of stroke. The summary analysis for heart failure risk including six datasets from four studies showed that intake of one egg per day was associated with increased risk raising for higher intakes compared to no consumption . After considering GRADE criteria for strength of the evidence, it was rated low for all outcomes but stroke, for which it was moderate (yet referring to no risk).There is no conclusive evidence on the role of egg in CVD risk, despite the fact that higher quality studies are warranted to obtain stronger evidence for a possible protection of CVD associated with moderate weekly egg consumption compared to no intake; equally, future studies may strengthen the evidence for increased heart failure risk associated with high regular egg consumption.The online version of this article (10.1007/s00394-020-02345-7) contains supplementary material, which is available to authorized users. Cardiovascular disease (CVD) represents the leading cause of mortality globally, responsible for a total of about 18 million deaths in 2017, while increasing from 12.3 million in 1990 . Eggs, ahttps://www.ncbi.nlm.nih.gov/pubmed/), EMBASE (https://www.embase.com/), Web of Science (www.webofknowledge.com) databases of studies published up to April 2020 was performed with the following search strategy: “[(egg OR eggs) AND ] AND ”. Studies were selected if they met the following inclusion criteria: (i) they were conducted on general population of human adults ; (ii) had a prospective design; (iii) evaluated associations between egg intake and risk of CVD , cardiovascular-related outcomes , and heart failure; (iv) assessed and reported hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% CI for ≥ 3 exposure categories (egg consumption) or provided HRs for increased intake of egg (as a continuous variable); and (v) provided a defined amount of egg consumption per category of exposure . Reference lists of studies of interest were also examined for any additional study not previously identified. If more than one study was conducted on the same cohort, only the dataset including the larger number of individuals, the longest follow-up, or the most comprehensive data  was included on a case by case situation, depending on the analysis performed (see below). We did not exclude studies based on language or publication date. All references were evaluated by two independent reviewers  with a third reviewer (A.M.) available in case of disagreement.The design, analysis, and reporting of this study followed the meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (ESM Table 1). A systematic search on PubMed (Data were abstracted by the two independent reviewers from each identified study using a standardized extraction form. The following information was collected: (i) first author name; (ii) year of publication; (iii) study cohort name and country; (iv) number, sex, and age (mean or range) of participants; (v) follow-up period; (vi) endpoints and cases; (vii) distributions of cases and person-years, HRs and 95% CIs for all categories of exposure; (viii) covariates used in adjustments.Risk of bias was assessed using the Cochrane Risk of bias in Non-randomized Studies of Interventions (ROBINS-I) tool previously used in comprehensive meta-analyses with similar outcomes , 11. TheOutcomes evaluated in the analyses included total CVD, CHD, and stroke (including sub-types hemorrhagic and ischemic stroke) incidence and mortality. Also risk of heart failure incidence was assessed.P value by testing that the two regression coefficients were simultaneously equal to zero. We then calculated a P value for non-linearity by testing that the coefficient of the second spline was equal to zero. A subgroup analysis was conducted for those studies providing risk measures by diabetic status. A number of sensitivity analyses were conducted to test stability of results, including (i) exclusion of one study at the time, (ii) exclusion of studies that did not report number of cases and person-years for each category of exposure, and (iii) stratifying studies by variables of interest . To facilitate interpretation of the results and easy application for dietary advices for the general population, the analyses were provided in depth for arbitrarily defined doses, such as “habitual” (daily) egg consumption corresponding to one egg per day, and “moderate” (weekly) egg consumption corresponding to four eggs per week. Publication bias was assessed with Egger’s regression test. Statistical heterogeneity between studies was assessed using the χ2 test  and quantified through the multivariate generalization of the I2 statistic. All analyses were performed with R software version 3.0.3, dosresmeta and mvmeta packages .When egg consumption was reported by ranges of intake, the midpoint of the range was used. When the highest category was open-ended, we assumed the width of the category to be the same as the adjacent category. When the lowest category was open-ended, we set the lower boundary to zero. Two-stage random-effects dose–response meta-analysis was performed to examine linear and non-linear relationship between egg consumption and CVD outcomes. In the first stage the method reported by Greenland and Orsini  was used to calculate study-specific coefficients on the basis of results across categories of egg consumption taking into account the correlation within each set of retrieved HRs ,13. Non-I2 ≥ 50% and Phet < 0.10), indirectness , imprecision [95% CIs were wide or crossed a minimally important difference of 5% (SRR 0.95–1.05) for all CVD outcomes] and publication bias  with no evidence of publication bias (PEgger = 0.772). The analysis restricted to CVD mortality showed wide confidence intervals while a decreased risk of CVD incidence was observed for consumption of up to 1 egg per day . Distinction between studies on CHD incidence or mortality showed that the associated reduced risk was referring to the former, yet with evidence of heterogeneity , The summary analysis for stroke including 22 datasets from 16 studies showed no related risks associated with any dose of egg consumption compared to no consumption, with lower SRRs for stroke mortality, though with large CIs (Table I2 = 37%) and no publication bias (PEgger = 0.630).The summary analysis for heart failure risk including six datasets from four studies showed that intake of one egg per day was associated with increased risk raising for higher intakes compared to no consumption , with no evidence of heterogeneity . Also in the sensitivity analyses excluding studies with no complete data on number of individuals and cases risk estimates associated to egg consumption were unchanged for CVD and heart failure, while no associations with CHD and stroke were detected (ESM Table 3); moreover, both ischemic and hemorrhagic stroke risk was reduced with up to one egg per day compared to no consumption (ESM Table I2 = 63%)] compared to no consumption.The subgroup analysis including results on cohort restricted to diabetic individuals showed that the direction of the risk associated with egg consumption was substantially inverted for all outcomes Table ; among aI2 = 0%) , SRR = 0.89 , and 0.84 , respectively] with no evidence of heterogeneity between studies was observed Table . When co%) Table . No sign%) Table .Several stratified analyses have been performed to test the stability of results taking into consideration the geographical localization of the cohorts as well as the level of adjustment models and the quality of the studies included. The analyses have been considered for a moderate consumption (four eggs per week) and a habitual consumption (one egg per day). Concerning the intake of 4 eggs/week, the decreased risk of CVD was confirmed when restricting the analyses to the majority of better quality studies, such as those adjusting for BMI, other dietary factors, longer follow-up, larger sample size, including heart failure in the definition of CVD, and scoring moderate risk of bias , agent associated with increased atherosclerosis in the coronary vasculature [There is a biological rationale to explain how moderate egg consumption might be associated to decreased risk of CVD. Eggs have been historically considered a controversial food for nutritional experts and health agencies due to its content in cholesterol. However, researchers argue that the focus of common dietary guidelines on specific nutrients  do not take into account that health effects varies depending on the specific food source . Furtherculature . Double culature . Phosphoculature . Egg yolculature .Despite the evidence reported, nearly all analyses showed substantial heterogeneity of results between studies, leading to a weakening of the evidence. We hypothesize that the certain inconsistency of the results may depend on the variability of response to dietary cholesterol between individuals and the overall dietary and lifestyle framework within populations and individuals. Despite the majority of population experience moderate to no difference in blood cholesterol following the intake of dietary cholesterol , about a third of individuals suffer of an abnormal rise in circulating LDL cholesterol (thus described as “hyper responders”) as a result of an increase fractional absorption and/or endogenous cholesterol synthesis in response to dietary cholesterol intake . An abnoThe results of this meta-analysis on heart failure seems to provide indication of potential increased risk for habitual consumption (one egg per day) despite this evidence was affected by some limitations, including the role of sex: while sex seems to act as confounding factor for CVD, the observed variation in the direction for risk heart failure (increased in men and decreased in women) may lead to consider sex as an effect modifier. The reasons for such finding is not clear. The role of cholesterol abnormalities and risk or worsening of heart failure is unknown; data on worsening heart failure and lipid moieties are now beginning to emerge but conclusions are far to be made . The facAnother concern regard the different risk estimates observed in diabetic individuals showing an increased risk of CVD associated with consumption of one egg per day, notably in the different direction than for the general population. The increased risk of developing CVD among individuals with type 2 diabetes may be mainly attributed to the impaired cholesterol absorption and synthesis. Studies on type 2 diabetic patients with uncontrolled hyperglycemia showed higher cholesterol synthesis and plasma lipid concentrations , includiThe findings reported in this study should be considered in light of some limitations. First, some analyses showed substantial heterogeneity: several reasons for such discrepancy of results across studies have been aforementioned, but no firm explanation can be drafted at this moment due to lack of data. Second, we stratified the analyses testing the role of controlling for potential confounding factors known to be related to cardiovascular outcomes in the original studies and revealed the importance of conducting higher quality studies to observe a decreased risk of CVD associated with moderate egg consumption; however, we cannot rule out the possibility that residual or unmeasured confounding may persist. Third, time-related variables, including potential reverse causation , period of evaluation , or duration of egg intake have been not investigated. Finally, the GRADE system may not be the best suit for assessing evidence in nutritional epidemiology, as by definition it tends to underestimate the strength of the evidence due to the observational nature of the studies. However, it helps to have a clearer idea of which can be the strengths and weaknesses of the studies evaluated  and a guide for future investigations.Given the inconsistency of current findings on egg consumption and risk of CVD, future studies should improve the characterization of the population investigated, aiming to identify and remove genetic bias, such as the determinants of normal/hyper-response to dietary cholesterol. However, current evidence is not sufficient to address egg consumption as unhealthy nor to generalize potential detrimental effects to the whole population. While waiting for better designed and more complete studies overcoming the aforementioned limitations and lack of information on genetic profile, there may be no need to discourage egg consumption at the population level.Supplementary file1 (DOCX 38 kb)Below is the link to the electronic supplementary material.


This study aimed to identify independent risk factors for first occurrence of stroke in Chinese individuals based on prospective cohort studies. Forty prospective cohort studies assessing 1,984,552 individuals were selected for the final meta-analysis. The identified risk factors for stroke in the Chinese population included old age , hypertension , cardiovascular disease history , chronic kidney disease , diabetes mellitus , metabolic syndrome , hyperglycemia , obesity , smoking , prolonged sleep time , higher levels of triglyceride , C-reactive protein . High fruit-rich diet  was associated with a lower risk of stroke. The spectrum and power of risk factors varied among different cohort inclusion years. These findings provide a comprehensive tool for the primary prevention of stroke in Chinese individuals. Stroke is considered the second most common cause of death and disability-adjusted life years (DALYs) among adults aged 50 years or over, according to the Global Burden of Disease Study 2019 –5. Via rIn the current study, we performed a meta-analysis of prospective cohort studies in Chinese individuals to identify potential risk factors for first occurrence of stroke. Stratified analyses based on types of stroke were also carried out in this study.This comprehensive quantitative meta-analysis was carried out and reported, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement . StudiesThe initial study selection by reviewing titles and abstracts was conducted by two authors independently, followed by the full-text evaluation based on group discussion involving 3 authors independently. Any disagreement among the authors was settled by the corresponding author after reviewing the original articles. Studies satisfying the following inclusion criteria were included in the meta-analysis: (1) prospective cohort design; (2) assessed risk factors including demographic features, pre-existing diseases, lifestyles, and biochemical exposures reported in ≥ 3 studies; (3) reported original data or adjusted effect estimates  with 95% confidence interval (CI); (4) inclusion of healthy Chinese individuals aged ≥18.0 years without stroke history.Data extraction and quality assessment were carried out by 2 authors. Any disagreement among the authors was settled by an additional author reviewing the original articles. The extracted data were entered in a standardized data collection form. The collected items included name of the first author or the whole study group, publication year, sample size, mean participant age, number of men/women, follow-up duration, reported outcomes, adjusted factors, and effect estimates of the risk of stroke. The Newcastle-Ottawa Scale (NOS), a comprehensive tool and partially validated method for assessing the quality of observational studies , was useI2 index and Q statistic; significant heterogeneity was considered with a P-value for Q statistic <0.10  was employed for data analysis.The profile of risk factors for first occurrence of stroke in Chinese individuals was examined as binary data. Given the low incidence of stroke, the OR could be regarded as equal to the RR. Moreover, the HR was considered to be approximately equal to RR because the included studies were designed as prospective cohort trials. Then, the pooled RR was calculated by a random-effects model for each parameter . Heterogic <0.10 . Sensitiic <0.10 . Regressubgroups . Publicaubgroups . The P-vThe initial electronic search yielded 21,109 articles, and 14,461 were excluded owing to duplicate titles. The remaining 6,648 articles were reviewed by titles and abstracts, and 6,147 were further excluded due to topic irrelevance. A total of 501 studies were retrieved for full-text evaluation, and 40 cohorts reported in 89 studies assessing 1,984,552 individuals were selected for final quantitative meta-analysis. A further manual search throughout the reference lists of included studies yielded no more eligible studies. Details concerning literature search and the study selection process are shown in The pooled results for stroke risk factor profiles are summarized in P < 0.001) was associated with increased risk of stroke, whereas no sex difference was found regarding the risk of stroke . Pre-existing hypertension , cardiovascular disease (CVD) history , chronic kidney disease (CKD) , diabetes mellitus (DM) , metabolic syndrome , hyperglycemia  and obesity  were associated with increased risk of stroke. Unhealthy lifestyles, including smoking  and prolonged sleep time (>7.5 h) , increased the risk of stroke. Meanwhile, alcohol intake, short sleep time (<6.5 h), and sleep behavior disorder were not associated with the risk of stroke. Besides, higher fruit-rich diet intake led to a reduced risk of stroke . In addition, higher levels of triglycerides (TG)  and C-reactive protein (CRP)  were associated with increased risk of stroke, whereas TC, LDL, HDL, hypertriglyceridemia, and uric acid were not associated with the risk of stroke in the Chinese population. Significant heterogeneity was observed for sex , hypertension , CVD history , CKD , DM , obesity , smoking , alcohol intake , prolonged sleep time (>7.5 h) , short sleep time (<6.5 h) , sleep behavior disorder , fruit-rich diet , TG , LDL , HDL , hypertriglyceridemia , and uric acid . No other significant heterogeneity across the included studies was observed. The associations of hypertension, obesity, and smoking with the risk of stroke in Chinese individuals were reported in ≥ 10 cohorts, and sensitivity analysis suggested that the pooled conclusions were robust irrespective of excluded studies , hypertension, DM, obesity, smoking, and elevated TG and HDL with the risk of stroke . In poolP = 0.020) and obesity (P = 0.046) in HS decreased with increasing inclusion years. However, no association was observed between cohort inclusion years and the effects of alcohol, CKD, DM, sex, hyperglycemia, hypertension, metabolic syndrome, obesity, and smoking on the risk of all types of stroke. Furthermore, the associations of CKD, hypertension, obesity, and smoking with the risk of IS were not affected by cohort inclusion years. Finally, cohort inclusion years did not affect the association between smoking and the risk of HS.Next, the potential role of cohort inclusion years in pooled effect estimates was investigated for factors reported in ≥5 cohorts . The resPEgger = 0.468; PBegg = 0.113). Although the Begg's test indicated no significant publication bias for obesity (P = 0.944) and smoking (P = 0.150), the Egger's test suggested potential significant publication bias for obesity (P = 0.007) and smoking (P = 0.051). After adjustment by the trim and fill method, the pooled conclusions were not significantly changed ; and the biochemical parameters of high TG and CRP levels were all associated with increased risk of stroke in Chinese individuals. Only high fruit-rich diet intake could decrease the risk of stroke. Subgroup analysis suggested the RRs of hypertension and sleep behavior disorder were high in HS, while that of obesity was high in IS. The protective effect of fruit-rich diet was stronger in HS compared with IS. It was also found that the cumulative RRs of hypertension and obesity in HS decreased with increasing inclusion years.A previous meta-analysis by Wang et al. including only 15 cohorts and 178 case-control studies found hypertension, DM, CVD history, family history of stroke, hyperlipidemia, overweight, and smoking were correlated with high risk of stroke, while PA could reduce the risk of stroke , 16–32. Stratified analyses suggested risk factors for HS and IS differed. Cohort inclusion years could affect the impacts of these risk factors. Several issues should be highlighted based on these findings. (1) As shown above, hypertension was the main risk factor for HS and exerted more effects on HS than on IS. We also found the risk of hypertension decreased for HS while remaining unchanged for IS, and the accumulative RR for hypertension decreased with increasing inclusion years. This may be explained by the current status of hypertension control in China. Hypertension control rates are increasing, coinciding with a rising hypertension prevalence across the nation. According to six national epidemiological investigations, the awareness (26.3 vs. 51.6%), treatment (12.1 vs. 45.8%), and control (2.8% vs. 16.8%) rates for hypertension increased from 1991 to 2015, while hypertension prevalence increased from 5.1% (in 1959) to 7.7% (in 1980), 13.6% (in 1991), 18.8% (in 2002), 25.2% (in 2012), and 27.9% (in 2015) . We can There has been an increasing interest in novel nontraditional risk factors, some of which are considered to be specifically important in the Chinese population but are not included here due to the limited number of studies taken in. Taking air pollution as an example, the relation between exposure to fine particles and stroke has been reported previously . It was The strengths of this comprehensive, quantitative meta-analysis should be highlighted: (1) this study was based on prospective cohort trials, and selection and recall biases could eliminate the concerns of retrospective observational studies; (2) the analysis was based on a large sample size, and the present conclusions were robust than that of any individual study; (3) comprehensive risk factor profiles for the incidence of stroke were provided; and (4) the analysis was stratified by stroke type and cohort inclusion years, which helped explore the potential differences between IS and HS and avoid selection bias.However, several limitations of this meta-analysis should be acknowledged: (1) the adjusted models were different among the included studies, which might play an important role in the progression of stroke; (2) for certain identified factors, only small numbers of included studies were available, and as a result, the statistical power might not be enough to detect potential associations; (3) this study was based on published articles, and publication bias was therefore inevitable; and (4) the current analysis was based on study-level findings, and individual data were not available, which prevented a more detailed analysis.We provided a comprehensive updated set of risk factors for stroke in Chinese individuals, which would inspire the design of interventional studies and support future development in guideline or policy for stroke prevention.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.WX was the study guarantor and designed the review protocol. FS developed the search strategy. WY and FS selected the studies and extracted the data. WX and WY analyzed the data and drafted the manuscript. BW, ML, BS, XH, and FS revised the manuscript for important intellectual content. All authors approved the final version of the manuscript. All authors had access to all the data in the study and take responsibility for the integrity of these data and the accuracy of data analysis.The funder had the following involvement: data collection. The funder was not involved in the study design, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.FS was employed by Amgen. This study received funding from Amgen. The funder was involved with data collection. The remaining 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. The reviewer W-JT declared a shared affiliation, with no collaboration, with several of the authors WY and WX to the handling editor at the time of the review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The association between environmental and socioeconomic risk factors and the occurrence of hepatocellular carcinoma (HCC) are still inconclusive. A meta-analysis was conducted to address this issue.We systematically searched the databases including PubMed, Web of Science, and Google Scholar and collected the related risk factors of HCC before March 6, 2020. Statistical analysis was performed on the odds ratio (OR) value and 95% CI of the correlation between environmental and socioeconomic factors and HCC. Begg's rank correlation test, Egger's linear regression test, and the funnel plot were employed for identification of the publication bias.P < 0.05) and OR values and 95% CIs were 1.37 , 2.42 (1.10–5.31), 1.90 (0.87–4.17), 5.36 (0.72–40.14), 1.48 , 1.74 (1.00–3.03), 1.49 (1.06–2.08), 1.52 (1.07–2.18), 1.43 , 1.46 , 2.58 (1.67–3.97), and 1.52 (0.95–2.42), respectively. We found 6–9, 9–12, and ≥12 years of education that statistically reduced the risk of the occurrence of HCC (P < 0.05) and OR values and 95% CIs were 0.70 , 0.52 , and 0.37 , respectively. No significant associations (P > 0.05) were observed between race (Hispanic and Asian), passive smoking, marital status, place of birth, place of residence, and HCC. In stratified analysis, exposure of pesticide was statistically significant (P < 0.05), while race of black was on the contrary.Out of 42 studies, a total of 57,892 participants were included. Environmental and socioeconomic risk factors including ever educated (illiteracy); race ; medium and low incomes; occupations (farmer and labor); passive smoking; place of residence ; blood aflatoxin B1 (AFB1) adduct level; exposure of pesticide, etc., were statistically increased with the occurrence of HCC (Environmental and socioeconomic risk factors have great impacts on the incidence rate of HCC. Improving national education and income levels can significantly reduce the risk of HCC.https://www.crd.york.ac.uk/prospero/, identifier: CRD42020151710. Hepatocellular carcinoma (HCC) has become a growing global concern in the recent years. According to the Global Cancer Statistics 2020 by the International Agency for Research on Cancer, there are approximately 905,677 new cases of liver cancer and 830,180 deaths worldwide , about 3The prevention of HCC is imminent and it is necessary to control the etiology that affects the incidence, especially the risk factors of liver cancer. There are three main categories of factors  affectinInclusion criteria: All the case–control studies associated with environmental factors and HCC were included in this study. Studies should report odds ratios (ORs) with corresponding 95% CIs or provide enough data to calculate. Exclusion criteria: (1) control population with additional liver diseases; (2) publications such as review, editorial, commentary, qualitative studies, and so on; (3) studies in language other than English; and (4) studies by using the same data. The protocol for this analysis was registered with the PROSPERO (CRD42020151710).The meta-analysis was carried out according to the criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . An elecStudy retrieval and data extraction were carried out in document management software by two researchers independently. Title, abstract, and full text of the studies were reviewed by using the selection criteria. A third researcher committed to resolve the difference through discussion. After screening, the data were extracted to evaluate the quality of the included studies and conduct for data analysis. The extracted information includes the following terms: author, publication year, research year, country, study design, number of the case and control groups, source of the control group, relative factors, OR, 95% CI, etc.Study quality was evaluated mainly through the Newcastle–Ottawa scale (NOS)  to reducP-value for each result. Heterogeneity test for the included studies was checked by the I2 test with values of 25, 50, and 75% representing low, moderate, and high degrees, respectively  was used to analyze the outcome of OR, 95% CI, and the two-sided ectively . When I2According to the PRISMA statement, there are four steps in total and the inclusion studies are strictly handled. The selection process and the results of the literature search are given in The quality of the studies was evaluated through the NOS scale and the articles with a score >5 were included. The NOS scale was divided into three parts including selection, comparability, and exposure. Finally, 26 articles were defined as high-quality documents scored ≥8 and 12 articles scored ≥6. Additionally, 4 articles scored ≤ 5 were excluded . The detP < 0.05).In this meta-analysis, a total of 42 case–control studies with 57,892 participants were included. There were not any statistical significances in these factors such as race, place of birth , urinary AFB1 albumin level , and infection of schistosome .I2-values of urinary AFB1 albumin level, place of birth, and infection of schistosome are <50%, which could be analyzed by using a fixed-effects model. It suggested that urinary AFB1 albumin level  and infection of schistosome  were statistically significant , race (95.2–98.7%), income (87.4–95.8%), occupation (80.6–71.3%), passive smoking (96.8%), marital status (93.5%), blood AFB1 adduct level (77.6%), and exposure of pesticide (81.1%) were much greater than other factors ; source of control population ; study quality ; and sample size [number of the case group (≥500) vs. the control group (<500)]. The significant factors are shown in We incorporated sample size, study design, study quality, and source of control population into regression equation for a comprehensive analysis of the sources of study heterogeneity. Factors that included <10 studies were not tested. The data showed that the source of control population was the heterogeneity source of the factor occupation (farmer). More details are shown in P > 0.05). More details are shown in Through sensitivity analysis, we could qualitatively define whether the results of those factors were reliable by comparing the outcomes consistency of a random- and a fixed-effects model. It exhibited that the results of the factors such as education, income, occupation, place of residence, place of birth, blood AFB1 adduct level, urinary AFB1 albumin level, and infection of schistosome are much stable . Begg's This systematic meta-analysis was based on 42 case–control studies with 57,892 participants in 11 countries. Thus, it provides the up-to-date epidemiological evidences that clarifying the association and makes full use of the risk factors related to its incidence rate, reduce the risk of HCC, and provide a scientific basis for prevention and treatment. According to the Global Cancer Statistics 2020, except for the chronic infection with hepatitis B and C virus, the main risk factors for HCC are AF-contaminated foods, heavy alcohol intake, excess body weight, type 2 diabetes, smoking, etc., . In factHere, there are two aspects for education. One is that whether the population were educated with a total of 11 studies included. The pooled data showed that compared with the educated population, OR value of the uneducated population was 1.37 (95% CI: 1.00–1.89), which suggested that education was found a protective factor for HCC in this study. The other is involved in the years of education with a total of 17 studies included. When the population with primary education or below as a control group, it demonstrated that, with the increasing of the education time, OR values were gradually decreased, which would reduce the occurrence and development of HCC, suggesting that years of education could also be considered as a protective factor for the incidence of HCC.In China, the rural population still accounts for a considerable proportion of Chinese population. Due to urban-rural disparity of educational conditions and educational level , relativI2-value of 80.6%. The second was labor, with an OR value of 1.52 (95% CI: 1.07–2.18) and I2-value of 71.3%. All the above results presented statistical significance (P < 0.05) and revealed that they were two of the risk factors of HCC. However, the heterogeneities of the two factors in this study were high. Thus, some following analyses were taken in order to figure out the source of heterogeneity. Sensitivity analysis indicated that the results remained coincidence after comparing with the consistency of outcomes of the two effect models, which mean that the results were more reliable. In the stratified analysis and regression analysis, the results showed that the source of the control population was a synergistic heterogeneity source of the occupation factor. Occupation in this study represented the farmer population and labors with hard work and poor economic conditions, which may be the lead cause of HCC. All the participants were divided into three levels by their incomes and we chose the highest level as the control group. OR values of the medium- and low-income groups were 1.48 (95% CI: 1.11–1.96) and 1.74 (95% CI: 1.00–3.03).When talking about occupation, it could be divided into two aspects. The first was farmer, with an OR value of 1.49 (95% CI: 1.06–2.08) and The stratified result based on frequency matching of the low-income group was 3.34 (95% CI: 1.72–4.95), showing a high correlation with the occurrence and development of HCC and occupation was highly correlated with income. Most of the farmers and labors belong to the low- and medium-income groups in China and the two results were corresponding to each other. As we know, China, as the largest developing country, is still a large agricultural country. Although China is in the status of rapid development, the disparity of many aspects, especially conditions of economy, medical care, and resources between rural and urban areas, still exists . By acceI2-value was 81.1%. The sensitivity analysis reported that the result was unstable. After stratified by the source of the control group, the heterogeneity of the result in the hospital control was low, with an OR value of 1.58 (95% CI: 1.01–2.15), indicating that exposure of pesticide is considered as a risk factor for developing HCC, as it is one of the most important reasons for the high incidence rate of HCC in agricultural workers in rural areas. Several points should be reminded in order to prevent liver cancer caused by exposure of pesticide in rural areas. First, government should provide favorable conditions for propaganda, education, and supervision to society for use of highly toxic pesticides, minimize pesticide exposure, and without keeping at home. Second, the use of new-type pesticides with lower toxicity should be encouraged. Finally, it is recommended to follow strict instructions or guidelines for ensuring good health protection against pesticides.Pesticides, chemicals employed to manage and treat pests, have been linked to human cancers. Pesticides are widely used or abused in agriculture and horticulture and human exposure primarily occurs via diet. Five studies were incorporated in the analysis of this group. OR value of exposure of pesticide was 1.52 (95% CI: 0.95–2.42) and Schistosoma mansoni, Schistosoma haematobium, or Schistosoma japonicum (S. japonicum). Only S. japonicum is found in China and Oncomelania is the only intermediate host of it. As schistosomiasis is a parasitic disease mainly caused by eggs, it enters the portal vein of human liver and gallbladder system. It mainly destroys the intestinal mucosa of the human body, produces secretions, metabolites, and mechanical stimulation, and causes damage to the liver. We have included two studies in our research. Considering it as a risk factor for HCC, OR value was 3.17 (95% CI: 1.92–5.23). The vulnerable groups at most risk are fishermen and farmers. Control measures are to eliminate Oncomelania and to strengthen the management of manure and water.In terms of impact, schistosomiasis is the second only to malaria as the most devastating parasitic disease. People are found to be infected when the skin is in contact with contaminated freshwater by schistosome. Most human infections are caused by Aflatoxin is a naturally toxic substance with many derivatives , among wI2-value was 0.0%. The result was stable, suggesting that it was significantly associated with the occurrence and development of HCC. Residence place in rural region had an OR value of 1.05  and the I2-value of 61.3%. Although the degree of heterogeneity was relatively high, the sensitivity analysis showed that it was reliable. Therefore, it also suggested that there was no significant correlation between the occurrence and development of HCC. However, there are still many rural areas all over the world including China. Many factors such as food storage methods, eating habit, drinking water, exposure of the pesticide, and working for a long time may also lead to the occurrence of HCC. From the above results, we found being a farmer or a labor was a risk factor for HCC (P < 0.05). As far as we know, studies included for synthesis might be too limited to reflect the real situation. More samples and further studies are still required in the future.In terms of place of birth and residence, our emphasis is mainly on rural regions. However, the number of the included studies were two and three, respectively. Here, we make a concise analysis. OR value of birth place in rural region was 1.46  and the P > 0.05). Hence, there are no obvious correlations between these three factors and the occurrence and development of HCC.In these factors, analysis for racial divisions were included as White (as the control), Black , Hispanic , and Asian , the marital status , and the passive smoking . For these abovementioned factors, the sensitivity analysis results remained unstable. All the races by stratified analysis indicate no statistical significance ; race ; medium and low incomes; occupations (farmer and labor); passive smoking; place of residence ; blood AFB1 adduct level; exposure of pesticide, etc. were statistically increased with the occurrence and development of HCC. Moreover, our findings suggested that it is critically pivotal to improve effective policies and programs for national education level, the increasing of public and physician awareness, the acceleration of urbanization process in the high-risk populations and areas especially in rural areas, and elimination and reduction of the differences between urban and rural areas including medical and educational resources and levels, healthcare services, economic income, employment, etc. All of these are effective means for prevention and control of HCC.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/FZ, DT, and NL were involved in the administrative support, conception and design of the manuscript, data interpretation, reviewed, and revised the manuscript. WL was involved in the conception and design of the manuscript, collection and assembly of the data, data analysis, and drafted the initial manuscript. ZL, RZ, and LD were involved in the collection and assembly of data and drafted the initial manuscript. WX, WC, and RZ were involved in the conception and design of the manuscript, reviewed, and revised the manuscript. YC and YT were involved in the conception, design of the manuscript, and data interpretation. ZL and LL were involved in critically reviewed the manuscript for important intellectual content. All the authors contributed to the article and approved the submitted version of the manuscript.The authors gratefully acknowledge the financial support by the National Natural Science Foundation of China (No. 81872584), the National 863 Young Scientist Program (No. 2015AA020940), the Natural Science Foundation of Guangdong Province (No. 2016A030313138), Key Projects of Guangzhou Science and Technology Program (No. 201704020056), the Natural Science Foundation of Shenzhen (No. JCYJ20210324093211030), the Medical Scientific Research Foundation of Guangdong Province (No. A2020490), Military Logistics Research Project (No. CKJ20J031), and Interdisciplinary Research for First-class Discipline Construction Project of Henan University (No. 2019YLXKJC04).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.


Published researches have suggested some associations between PPAR‐γ and ischemic stroke (IS) development. This meta‐analysis was conducted to evaluate the association between PPAR‐γ gene polymorphisms and IS risk.A systematic search was conducted in PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and WanFang databases. The pooled association of odd ratios (ORs) and its 95% confidence interval (CI) was calculated to assess the IS risk of PPAR‐γ rs1801282 C/G and rs3856806 C/T polymorphisms. Furthermore, the heterogeneity test, cumulative analyses, sensitivity analyses, and publication bias were conducted.p = .03, I2 = 0%; GG vs. CC+CG: OR = 2.15, 95%CI = 1.07–4.32, p = .03, I2 = 0%). The similar results were also found in the subgroup analysis. In addition, no significant association was observed between rs3856806 C/T polymorphism and IS risk.Sixteen publications with 3786 cases and 5343 controls were identified. Overall findings indicated that rs1801282 C/G polymorphism may be associated with an increased risk for IS  are one of the most common diseases resulting in disabilities and death among adults. Our meta‐analysis indicated that the individuals with G mutation of rs1801282 C/G polymorphism would face an increased risk of IS. But there was no significant association between rs3856806 C/T polymorphism and IS risk. More than 13.7 million new stroke cases and 5.5 million deaths, in addition to 116.4 million disability‐adjusted life years, were recorded worldwide in 2016 alone  belongs to the nuclear receptor superfamily, which mainly mediates ligand‐dependent transcriptional activation and repression. PPAR‐γ plays a key role in the regulation of adipocyte differentiation, lipid metabolism, and insulin sensitivity in vivo, with PPAR‐γ2 exhibiting a higher activity in adipocytes than other types. Accumulating evidence indicates that PPAR‐γ participates in the regulation of adipocyte differentiation, lipid metabolism, and the concentration of lipids and cholesterol. Dyslipidemia is a well‐established risk factor for cardiovascular diseases, which triggers the development of atherosclerosis and increases the risk of IS risk. PPAR‐γ also plays an important role in regulating inflammatory processes, participates in vascular endothelial cell repair, and inhibits thrombosis formation  loci in the PPAR‐γ gene, and have been extensively studied in different ethnic groups and found to be associated with the risk of several metabolic diseases, including diabetes and its complications. This mutation may change the transcriptional activity and subsequently alter the protein synthesis of PPAR‐γ  statement. All collected data were extracted from published studies, and no ethical issue was involved :2.2The criteria for inclusion of identified studies for the purpose of this meta‐analysis were as follows: (1) case–control studies on the association between PPAR‐γ rs1801282 C/G, rs3856806 C/T polymorphisms, and IS risk; (2) studies supplying sufficient information on the genotypes in both case and control groups with respect to evaluate the odd ratios (ORs) and 95% confidence intervals (CIs); (3) studies published either in English or Chinese; (4) the polymorphism locus was calculated with at least three studies; and the largest or latest data with more adequate information were collected when duplicate publications or overlapping data were presented. The exclusion criteria were as follows: (1) review articles, case reports, and animal experiments; (2) biological fundamental research; (3) studies without sufficient data; and (4) duplicate or overlapping data on the same theme.2.3Two authors (Cheng and Zhou) independently reviewed the included studies and extracted the relevant information: the first author’ name, year of publication, study country, ethnicity difference, control design, genotyping method, sample sizes of the cases and controls, frequency of the genotype distribution in the cases and control groups, the degree of Hardy–Weinberg equilibrium (HWE) in the control group, minor allele frequency, and Newcastle–Ottawa scale (NOS) evaluation. The NOS was adopted to evaluate the quality of the included studies. The scores ranged from 0 (worst) to 11 (best) . Statistical significance was set at p <.05.The ORs and 95% CIs were calculated to examine the statistical power between PPAR‐γ polymorphisms and IS risk using five genetic models: allelic model , codominant models: heterozygous model  and homozygous model , dominant model , and recessive model . Heterogeneity among the included studies was examined using Cochran's 33.1n = 2], other polymorphism loci [n = 3], reviews [n = 3], irrelevant studies [n = 16], and biology studies [n = 38])  Figure . Of thes) Figure  and, sev) Figure . In addi3.2p = .03, I2 = 0%; GG vs. CC+CG: OR = 2.15, 95%CI = 1.07–4.32, p = .03, I2 = 0%)   and among those studies with more than 500 individuals    .Cumulative analyses and sensitivity analyses were conducted, and the results indicated a consisted trend without any fluctuation. In addition, no publication bias was observed with symmetrical funnel plots in all five genetic models, which was further verified with the Egger's test , stroke is one of the leading causes of mortality and disability worldwide and is responsible for approximately 6.1million deaths in 2019 , and tumor necrosis factor‐α, which are known to decrease the level of inflammation in many IS models, have been shown to attenuate proinflammatory mediators during IS development. In contrast, murine stroke models with PPAR‐γ knocked out also present a stronger proinflammatory response with a higher risk of secondary intracerebral hemorrhage . Tong et al. (p < .001). However, most studies have suggested that there is no significant correlation between this mutation and IS risk  and IS risk. Some advantages exist in this study that help to improve the stability and credibility of the results: (1) a comprehensive and scientific retrieval strategy was used to collect complete information; (2) the current study included a large sample size with all published studies to date; (3) rigorous and accurate methods, including the NOS evaluation, HWE test, cumulative/sensitivity analyses, and publication bias were used one at a time; and (4) subgroup analyses in two polymorphism loci were conducted to explore potential associations. Inevitably, there are certain limitations that need to be addressed: (1) only two polymorphism loci were examined in this study separately, and the interaction mechanism between loci and heterozygous/homozygous state was not involved; (2) we incorporated studies that mainly originated from Asian and European countries, and the number of collected studies or participants from each study was insufficient, which may lead to uncertainty and variations in results; (3) This study was based on unadjusted data, and other environmental exposure factors, such as serum triglyceride, blood pressure, and body mass index were not involved, which limits our understanding of the underlying mechanisms; and (4) some moderate heterogeneity was observed in genetic models among two polymorphism loci, which might affect the reliability and accuracy of the results.5In summary, this meta‐analysis suggests that the PPAR‐γ rs1801282 C/G polymorphism may be associated with IS risk in Asians. More studies with larger sample sizes in different ethnic backgrounds are needed to either refute or verify the current conclusions in the future.The authors declare no conflict of interest.Fan Cheng, Xiao‐Min Si, and Lan Zhou conceived the study. Fan Cheng and Xiao‐Min Si searched the databases and extracted the data. Xiao‐Min Si and Gong‐Li Yang analyzed the data. Fan Cheng, Xiao‐Min Si, and Gong‐Li Yang wrote the draft of the paper. Lan Zhou reviewed the proof. All of the authors approved the final manuscript.https://publons.com/publon/10.1002/brb3.2434The peer review history for this article is available at