Limited information is available on carcinogenicity of asbestos on non-respiratory organs. We aimed at conducted an updated systematic review and meta-analysis of cohort studies on occupational exposure to asbestos and risk of kidney cancer. We searched through three databases, PubMed, Embase and Scopus for article published after 2000, and after eliminating duplicates and non-relevant studies, we identified 13 studies. We combined their results with those of 31 non-overlapping studies included in a previous review up to 2000. We conducted a meta-analysis based on random-effects models. The pooled relative risk of kidney cancer for asbestos exposure was 0.94 , with no differences according to type of asbestos fiber, geographic region, period of exposure, or estimated quality of the study. Our results showed a lack of association between occupational asbestos exposure and risk of kidney cancer.The online version contains supplementary material available at 10.1007/s10654-021-00769-x. In 1973 the International Agency for Research on Cancer (IARC) declared asbestos in all its commercial forms as established human carcinogen [However, worldwide asbestos exposure has not yet stopped. The Global Burden of Disease (GBD) project estimates that 125 million people are exposed to asbestos globally each year .Asbestos-induced carcinogenesis is a complex event resulting from different factors including physicochemical characteristics of the fibers , time and dose of exposure and, finally, host genetic determinants .Occupational and non-occupational asbestos exposures play a well-known role in determining of asbestosis, pulmonary function decline, lung cancer and mesothelioma –7; in adAlthough asbestos damages primarily the airways , some studies suggested a correlation between asbestos occupational exposure and kidney cancer .Kidney cancer is the 14th most common cancer worldwide and ninth most common cancer in Europe. The incidence varies globally, with the highest rates in more developed regions such as North America and Europe and the lowest rates in Asia and Africa .Apart from genetic factors and family history of kidney cancer, established risk factors such as smoking, obesity and hypertension are still prevalent. In addition to such lifestyle factors, environmental agents  independently screened papers the titles and abstracts of the articles and selected those matching the inclusion and exclusion criteria. After that, the same two authors read full texts of papers that were considered potentially eligible and selected those that reported relevant results. In case of disagreements, consensus was reached.We also searched for additional articles through the lists of recent reviews and metanalyses and those of the articles retained for the meta-analysis.Inclusion criteria of studies for the meta-analysis were (1) Design: cohort and nested case–control study; (2) Asbestos exposure: workers with exclusive or predominant occupational exposure to asbestos (3) Outcome: incidence or mortality due to kidney cancer (C64-ICD10).Exclusion criteria consisted in (1) Design: community-based studies, cross-sectional and case–control studies (2) type of exposure to asbestos: we excluded studies of workers who might have occasional, low-level exposure to asbestos, as well as exposure to other known carcinogens, such as seamen, bitumen workers, and mechanics.In Fig. For each mortality study we extracted the standardized mortality ratio (SMR) of kidney cancer and its 95% confidence interval (CI); when these measures were not directly available from publications, we calculated them. Similarly, we abstracted or calculated (if not specified in the text) the standardized incidence ratio (SIR) corresponding CI for cancer incidence studies. Incidence studies obtained data from cancer registries, while mortality studies were based on information from death certificates.In addition, we extracted data about (1) type of industry or occupation of employment ; (2) asbestos type, classified as pure chrysotile (Ch), predominantly chrysotile (PCh), amphiboles (Am), and mixed or unspecified (Mix); (3) geographic region, categorized as Europe, North America, and others; (4) source of diagnosis: cancer registry, death certificate; (5) composition of the cohort by sex: female when cohort was formed up to 80% by women, male when there were up to 80% of men, and mixed in case of both male and women comprised less than 80% of the entire cohort; (6) years of employment; (7) proportion of cohort members lost to follow-up; (8) period of first exposure: we distinguished cohorts first exposed to asbestos before 1945, from 1946 to 1960 and after 1961; (9) duration of exposure and time since first exposure (latency).We also performed quality assessment (QA) according to NIH score for quality assessment tool for Observational Cohort and Cross-Sectional Studies. We modified predefined criteria basing on our object of study ; we retaWe conducted random-effects . meta-anTo evaluated results stability, we performed sensitivity analyses by quality score and repeated the meta-analysis after excluding one study at a time. Furthermore, we considered the funnel plot and performed the Egger’s regression asymmetry test to assess publication bias .metan, metabias, and metafunnel.Analyses were performed by STATA16 program , using sIn total, 927 publications were identified from search conducted among three databases from 2001 to 2020. We found out 243 results from PubMed (MEDLINE), 491 from Scopus and 193 from Embase, of which 414 were removed because they were duplicates.We screened the titles and abstracts of 513 articles and rejected 382 of them because not relevant .p = 0.3; I2 = 11%). The summary RR of results on cancer incidence was 0.98 (95% CI 0.79–1.22) with no evidence of heterogeneity between studies ; that of results on mortality 1.15 .Figure Table We performed quality assessment by NIH score for studies included in our analysis published after 2000. Only two studies were considered good quality because of good exposure assessment , low proportion of lost to follow up and analysis adjusted for others risk factors of kidney cancer. Eight studies were of moderate quality, only few of them included a satisfactory description of sample size justification or prior measurement of the outcome.Some authors considered also others circumstances of asbestos exposure. Kjaerheim et al. (2005) studied the effect of exposure to asbestos in drinking water; the SIR for kidney cancer was 1.4 (95% CI 0.6–2.7). Van den Borre et al. (2015) distinguished between manual workers and non-manual workers exposed to asbestos, and found no differences between the two groups, with SMR equal to 1.88 (95% CI 0.23–6.80) and 3.24 (95% CI 0.08–18.06), respectively.Only two studies reported data about latency or duration of exposure , 34.As shown in Fig. Kidney cancer is the 14th common cancer in the world and, while 50% of kidney cancer are not attributable to known risk factors for that malignancy , only feOur results show a lack of association between occupational asbestos exposure and kidney cancer; indeed, pooled analysis shows relative risk 1.1 (95% CI 1.0–1.3). This result was confirmed in subgroup analyses stratified by type of asbestos fibers, country, sex or period of first exposure. These results are also consistent with those of a previous meta-analysis of studies published up to 2000 .Our study suffers from several limitations. The most important problem is that seven studies we selected after systematic review of literature showed no cases of kidney cancers among cohorts exposed to asbestos, and were excluded from the meta-analysis, that was based on log-transformed measures of associations. In order to assess the magnitude of the bias away from the null, we performed also a meta-analysis without logarithm transformation both including and excluding studies with no observed cases or deaths, and the results were not materially changed by the exclusion of these latter studies.Our analysis included a small number of studies based on cancer incidence, and results of studies on cancer mortality might be affected by determinants of survival, such as access to effective treatment. Furthermore, many studies evidenced low accuracy of COD, especially among elderly people who more frequently have a multiple comorbidity before death (62).The incidence of kidney cancer is often underestimated as it is a tumor that is diagnosed late, sometimes when metastases are already present in other sites and it is not always assumed that it is possible to trace the primary tumor .Furthermore, only three studies , 54, 63 In addition only two papers (mentioned before) reported data about latency and duration of exposure, for that reason we decided to not perform a dose–response meta-analysis.Finally, exposure assessment remains an issue in occupation cohort studies based on job titles or industries of employment, without direct exposure measurements. Such approach does not distinguish between circumstances at different levels of exposure, leading to possible underestimate of the effects.We decided to review the data about risk for kidney cancer among workers exposed to asbestos due to well-known role of asbestos fibers in determining carcinogenic process in other organs and some supporting biological data. Boor et al. showed an increase of renal fibrosis and production of inflammatory mediators locally in rats exposed to amiosite fibers . and thaMore evidence of capacity for asbestos fibers to reach kidney has been provided by necropsy studies of humans; moreover, asbestos fibers have been founded in human urine .A strength of our study is the large number of cohort studies included in the meta-analysis. Furthermore, the limited heterogeneity between study results, the consistency of results across different subgroups of studies, and the lack of evidence of publication bias support the main conclusion of our meta-analysis.In conclusion our updated meta-analysis provided additional evidence to the hypothesis of a lack of association between occupational exposure to asbestos and risk of kidney cancer.Supplementary file1 (DOCX 18 KB)Below is the link to the electronic supplementary material.


ERAP1) gene polymorphisms with psoriasis. Five databases of PubMed, China National Knowledge Infrastructure (CNKI), Embase, Web of Science, and Cochrane Library were searched for potential studies until 25 December 2019. Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed with PRISMA. A total of 9 case-control studies including 4858 psoriasis cases and 10,542 healthy controls were included. Three loci of ERAP1 gene polymorphisms  were evaluated in this meta-analysis. There was no significant association between rs26653 polymorphism and risk of psoriasis . However, there was a significant association between rs30187 polymorphisms and psoriasis susceptibility  and a significant association between rs27524 polymorphisms and psoriasis susceptibility . For there were insufficient data of rs27044, rs151823, rs2248374, and rs2910686, we only conducted a systematic review for them. The rs30187 (C/T) and rs27524 (G/A) polymorphisms of ERAP1 are associated with increased risk of psoriasis. However, no significant association is observed between rs26653 (G/C) polymorphism and risk of psoriasis.This study is to investigate the relationship of endoplasmic reticulum aminopeptidase 1 ( Psoriasis is a common chronic inflammatory disorder –3. PsoriERAP1), which belongs to the M1 family of aminopeptidases, plays a central role as a “molecular ruler,” proteolyzing of N-terminal of the antigenic peptides before their loading onto HLA-I molecules for antigen presentation in the endoplasmic reticulum  OR ERAP1 OR Adipocyte-derived leucine aminopeptidase, human OR Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator, human OR endoplasmic-reticulum aminopeptidase-1, human).The online databases of PubMed, China National Knowledge Infrastructure (CNKI), Embase, Web of Science, and Cochrane Library were searched for eligible studies until 25 December 2019. Medical Subject Headings (MeSH) together with free terms were as keywords for literature searching. The following searching strategies for PubMed were employed: (polymorphism OR single nucleotide polymorphism OR variation OR gene) AND (psoriasis OR “Psoriasis” ) AND ; studies with psoriasis diagnosed according to clinical diagnosis criteria; studies on the relationship between The methodological quality of each eligible study was evaluated by two investigators, respectively, in compliance with Newcastle-Ottawa Scale (NOS). NOS contains three aspects: selection (four items), comparability (two items), and the outcomes of case-control studies (three items). Each included study was scored as 0-9 points according to these items. A higher score indicated a better quality. Studies with scores ≥ 5 points were considered to have a high quality for further analysis. When disagreements occurred between the two investigators, a third reviewer was consulted to make the final decision.ERAP1 polymorphisms, Hardy-Weinberg equilibrium (HWE) results.The following information was extracted from each study by two independent investigators: first author, year of publication, ethnicity of study population, numbers of cases and controls, and the allele frequencies of the ERAP1 gene polymorphisms and psoriasis was calculated by merging ORs with 95% CIs . The Q-statistical test and I2 test were employed to evaluate the heterogeneity among all included studies [P < 0.1 or I2 > 50%), or the fixed-effects model was used when it was out of heterogeneity (P > 0.1 or I2 < 50%) [This meta-analysis was performed with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) . The all studies . The ran2 < 50%) , 21. A lThe detailed process of the literature screening is shown in General characterizations of all included studies are demonstrated in ERAP1 polymorphisms.Due to the limited number of studies on other loci, we only meta-analyzed three loci of rs26653 (G/C), rs30187 (C/T), and rs27524 (G/A) of P < 0.00001, I2 = 87%). Therefore, the random-effects model was used. The results indicated that no significant association was observed between rs26653 polymorphism and risk of psoriasis , and therefore, the fixed-effects model was used. The results suggested that there was a significant association between rs30187 polymorphisms and psoriasis susceptibility  polymorphism and psoriasis susceptibility was on the basis of five studies , 23, 24,P < 0.00001, Analysis of the association of rs27524 polymorphism and psoriasis susceptibility was also based on five studies , 25, 28,ERAP1 gene and psoriasis susceptibility. In Wiśniewski et al.'s study [Since there were only a few studies that reported detailed information on rs27044, rs151823, rs2248374, and rs2910686, we only performed a narrative description for these loci. Three studies reported rs27044 polymorphisms in the 's study , rs27044's study   class I ligands in the endoplasmatic reticulum by trimming the peptides to a required length for presentation [ERAP1 is also involved in the indirect presentation of cytoplasmic MHC-II ligands [ERAP1 will upregulate the antigen-presenting properties and deregulate the immunological effect produced by MHC-I molecules in the host defense against pathogens [ERAP1 also participates in the process of oncogenesis [ERAP1 on angiotensin II modulates angiogenesis and therefore leads to the occurrence of endometrial carcinoma [ERAP1 regulates the immune defense against tumorigenesis by affecting the balance of activating and inhibitory signals through MHC-I proteins [ERAP1 also has other biological functions, such as regulating blood pressure and angiogenesis [ptidases  and contptidases . ERAP1 pentation , 46. Apa ligands , 48. Theathogens –51. ERAPogenesis . The effarcinoma . ERAP1 rproteins . ERAP1 aogenesis , 43.Several limitations of the present meta-analysis should not be overlooked. First, the study number and the sample size of included studies were relatively small, which might provide a limited conclusion. Second, the heterogeneity between studies was relatively considerable, and thus, the conclusion of this meta-analysis should be quoted with caution. Third, only studies on Caucasian and Asian populations were included. Whether the conclusions are consistent with those on other populations needs further investigation. Fourth, due to the limited number of included studies, meta-regression analysis was not performed. Last, we only searched English and Chinese databases to perform this work. Potentially relevant articles published in other languages may be ignored.ERAP1 polymorphism of rs30187 (C/T) and rs27524 (G/A) was associated with an increased risk of psoriasis. However, no significant association between rs26653 (G/C) polymorphism and psoriasis risk was observed. The results of this study may provide a more comprehensive evaluation of the relationship between ERAP1 polymorphism and psoriasis susceptibility.In summary,


However, the results remain controversial. Therefore, this study aimed to explore the role of MBOAT7-TMC4 rs641738 in the risk of hepatocellular carcinoma (HCC) and persistent hepatitis B virus (HBV) infection.A hot genetic variant, rs641738 within the We first conducted a case-control study that included 779 HCC cases and 1412 cancer-free controls. Controls consisted of 678 persistent HBV carriers and 734 spontaneously recovered subjects. The gene variant rs641738 was genotyped using the MassARRAY platform. The results were analyzed in five genetic models using multivariate logistic regression analyses. Next, we performed a systematic review and meta-analysis to further explore the role of this variant in HCC risk.MBOAT7-TMC4 rs641738 and HCC risk in most genetic models . Although a marginally significant association was observed in TT vs. CC (P = 0.037) and the recessive models (P = 0.044). The meta-analysis of 2135 HCC cases and 4388 controls supported that this variant was not related to HCC risk, even in the TT vs. CC and recessive models. We also determined that this variant did not influence persistent HBV infection.The results suggested no association between MBOAT7-TMC4 rs641738 is not associated with the risk of HCC or persistent HBV infection. This study provides some clues to identify the “truth” of potential disease-related genetic factors in the post-genome era.Our work highlights that  Hepatocellular carcinoma (HCC) is a common rapidly progressing cancer, with high mortality worldwide, especially in China . As the membrane-bound O-acyltransferase domain containing 7(MBOAT7) gene, rs641738, C>T, increased the risk of alcohol-related cirrhosis (transmembrane channel-like 4 (TMC4) gene, which is not abundantly expressed in the human liver  have identified hundreds of genes and loci associated with HCC risk. How to identify the “truth” of these genetic factors is becoming an urgent issue in the post-genome era. In 2015, a GWAS study reported that a genetic variant near the fibrosis –11.MBOAT7-TMC4 rs641738 on HCC risk in a Chinese population. We then performed a systematic review and meta-analysis to further explore the role of this variant and validate our results.Here, we first conducted a case-control study including 779 HCC cases and 1,412 cancer-free controls, aiming to explore the effects of This case-control study included 779 HCC cases and 1,412 cancer-free controls. The cases were pathologically confirmed and enrolled between January 2014 and June 2016 at Tongji Hospital of Huazhong University of Science and Technology (HUST), central China. The controls are consisted of 678 persistent HBV carriers and 734 spontaneously recovered subjects, who were recruited from a health screening in the same hospital during the same period as the cases were included. Persistent HBV carriers were people who were positive for both of the hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb), but negative for antibody against hepatitis C virus (anti-HCV). Spontaneously recovered subjects were people who were negative for both of HBsAg and anti-HCV, but positive for both of HBcAb and hepatitis B surface antibody (HBsAb). All subjects were unrelated Han Chinese from Wuhan and the surrounding regions. Cases and controls were frequency-matched for sex and age (± 5 years). At recruitment, a 2-ml peripheral blood sample and a written informed consent were collected from each subject, and demographic information  were also obtained by questionnaire. The definitions of smoking and drinking status have been detailed previously . BrieflyEnzyme-linked immunosorbent assay (ELISA) was used to detect serum HBsAg, HBsAb, HBcAb, and anti-HCV . There were three positive controls, two negative controls, and one blank control in each reaction plate. About 5% of the samples were randomly chosen for repetition, and results were 100% concordant.MBOAT7-TMC4 rs641738 was genotyped using the Sequenom MassARRAY iPLEX Platform . All assays were conducted using a 384-well plate with positive and negative controls for each plate, without information on the disease status of the samples. We randomly selected 5% of the samples as duplicate sets and got a 100% concordance rate. The average call rate of this variant was 99.7%. A polar plot of rs641738 is shown in Genomic DNA was extracted from leucocyte pellets of 2-ml peripheral blood by the coagulated blood DNA mini-extraction kit . 2 test was applied to assess the Hardy-Weinberg equilibrium (HWE) in controls. Differences between cases and controls were examined by independent t-test, analysis of variance (ANOVA), or Pearson’s χ2 test according to the category of variables. The risk of HCC or persistent HBV infection was estimated by odds ratio (OR) and 95% confidence interval (CI), using a multivariate logistic regression analysis after adjusting for age, sex, smoking, and drinking status. Statistical significance was defined as a two-tailed P value < 0.05. All the analyses above were performed using IBM SPSS Statistics . We calculated the statistical power of this study using Power V3.0  .MBOAT7,” “TMC4,” “rs641738,” and “hepatocellular carcinoma.” References from the identified publications were also reviewed to obtain potentially potential relevant studies.A comprehensive literature search was conducted through PubMed, Embase, and Web of Science databases up to December 2020 without any restrictions. The search items included “MBOAT7-TMC4 rs641738 and HCC risk; (2) providing ORs and 95%CIs, or allele frequency and/or genotypes of this variant; and (3) the number of cases was more than 30. A study was excluded if it met one of the following criteria: (1) review, meta-analysis, comment, or conference abstract; (2) insufficient data to estimate OR and 95%CI; (3) a deviation from HWE in controls; and (4) studies with overlapping data. If a study contained overlapping data with another, we retained the study with a larger sample size.The inclusion criteria were as follows: (1) a case-control or cohort study to evaluate the association between Data were extracted from each included study as follows: first author, publication year, country, ethnicity, sex, age, sample size, genotype distribution, genotyping method, adjustment, and HWE information. Two authors independently assessed the studies as described above. Disagreements were resolved through discussion. The quality of each included study was evaluated through the Newcastle-Ottawa scale (NOS) . For casMBOAT7-TMC4 rs641738 and HCC risk. Multivariate-adjusted ORs and 95%CIs were preferentially extracted if available. Otherwise, the unadjusted ORs and 95%CIs were calculated instead. Between-study heterogeneity was examined using the Q test and 2I statistic. If P < 0.10 or 2I > 50%, significant heterogeneity was considered, and a random-effects model was applied. Otherwise, the fixed-effects model was used. To evaluate the quality, we performed a sensitivity analysis and publication test (We used ORs and 95%CIs to estimate the association between ion test . SensitiP = 0.551), age (P = 0.240), smoking (P = 0.071), and drinking status (P = 0.091). Genotypes of MBOAT7-TMC4 rs641738 in all groups did not deviate from HWE .A total of 779 HCC cases, 678 persistent HBV carriers and 734 spontaneously recovered subjects were included in this study. Demographic characteristics are summarized in vs.) all controls, we found that after adjusting for sex, age, smoking, and drinking status, MBOAT7-TMC4 rs641738 did not confer any increased risk of HCC in the dominant, additive, or allelic models . Although this variant seemed to be a risk factor for HCC in the two models, the results were marginally significant . Similar results were also observed in a subsequent comparison of HCC vs. persistent HBV carriers. When we set spontaneously recovered subjects as controls, we observed that MBOAT7-TMC4 rs641738 was not associated with HCC risk . To explore whether this variant influenced the risk of persistent HBV infection, we conducted a further comparison between persistent HBV carriers and spontaneously recovered subjects. The results suggested that this variant was also unrelated to persistent infection or the clearance of HBV .We performed four comparisons under the five genetic models, and the results are shown in P = 0.031). In the UK NAFLD cohort, the number of HCC cases was too small (n = 20) to meet our inclusion criteria (n > 30). Therefore, we excluded this study from our meta-analysis. In addition, the study of Kawaguchi (2018) provided data on NAFLD type 4 and NASH-HCC rather than HCC data, therefore, we could not extract sufficient data to estimate the association between rs641738 and HCC risk and excluded this study  included two cohorts, the Italian non-alcoholic fatty liver disease (NAFLD) cohort and the UK NAFLD cohort . In the is study . The rem17 includis study –23. Finais study  and thisis study Figure 1MBOAT7-TMC4 rs641738 was not associated with HCC risk , which was stable suggested by the sensitivity analysis . Considering that marginally significant results were observed in our study, we performed meta-analyses using other common genetic models. As shown in MBOAT7-TMC4 rs641738 and HCC risk. All pooled results were stable  and recessive model (P = 0.044), all other genetic models demonstrated non-significant results. We also performed a systematic review and meta-analysis to explore the role of MBOAT7-TMC4 rs641738 in HCC susceptibility. A total of 2135 HCC cases and 4388 controls were included in the meta-analysis. The results consistently suggested that MBOAT7-TMC4 rs641738 was not associated with HCC risk, even in both the TT vs. CC and recessive models. In addition, our study revealed that this variant was also not related to persistent HBV infection in any of the genetic models. To the best of our knowledge, it is the first study to investigate the association between MBOAT7-TMC4 rs641738 and the risk of HCC and persistent HBV infection in Asians.We conducted a case-control study including 799 HCC cases and 1412 controls to investigate the effect of MBOAT7-TMC4 rs641738 with HCC risk, but did not find a significant result  for the publication of any potentially identifiable images or data included in this article.Conceptualization: NS. Methodology and data curation: PW and YL. Formal analysis: LL and RZ. Writing—original draft preparation: PW. Writing—review and editing: NS and RZ. All authors contributed to the article and approved the submitted version.This work was supported by National Natural Science Foundation of China (NSFC-81601839 to NS and NSFC-81602407 to LL).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.


P = 0.003; heterogeneity, 2I = 89.3%; P< 0.001). In line with this finding, the combined effect derived from five included studies of HCV also supported a significant positive association between chronic HBV infection and GC development . In conclusion, both chronic HBV and HCV infections were related to a high risk of GC. The plausible mechanisms underlying such association might be correlated to HBV/HCV infection-induced persistent inflammation, immune dysfunction, and cirrhosis.Mounting studies demonstrated both chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection might be associated not only with an increased risk of hepatocellular carcinoma but also extrahepatic malignancies, i.e., gastric cancer (GC). However, a quantitative result addressing the association between HBV/HCV infection and GC development is scarce. A systematic search to identify the eligible studies was performed in four databases, including MEDLINE, EMBASE, Cochrane Library, and the PsychINFO. The relationship between HBV/HCV infection and the risk of GC was quantified by calculating the hazard ratio (HR) with a 95% confidence interval (CI). More methodologies of this study were available in the PROSPERO (ID: CRD42021243719). Thirteen included studies involving 7,027,546 individuals  were enrolled in the pooled analyses. Two articles provided the clinical data of both HBV and HCV infections. The proportion of high methodological quality studies was 76.9% (10/13). Synthetic results from 10 eligible studies of HBV showed that HBV infection was associated with a significantly higher risk of GC when compared with the healthy controls without HBV infection , identifier (CRD42021243719).PROSPERO ( Helicobacter pylori infection is believed to be the leading cause of noncardia GC   remains one of the most frequent and lethal malignancies worldwide and is responsible for over 1,000,000 new cases in 2020 and an estimated 769,000 deaths globally . This paardia GC . Known rvs. 3.3%, P= 0.025). In line with Kocoglu et al.’s findings, a study conducted in Iran demonstrated that HBV DNA was detected in 3.17% of GC individuals (2/63), but no HBV DNA was identified in normal individuals  (vs HCV uninfected cohorts: 51/37725 (0.14%) vs 16/30180 (0.05%), P<0.05] .In addition to hepatocellular carcinoma, both chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection have gradually been recognized to associate with the development and progression of multiple extrahepatic malignancies, including colorectal cancer , lung ca%, 0/21) . As for  P<0.05] . Besides P<0.05] . Althoug P<0.05]  also indP>0.05) (P= 0.12)  . Similarvia a quantitative and pooled analysis, which might better facilitate the clinical understanding with this issue.At present, the underlying connection between chronic HBV/HCV infection and the risk of GC is still controversial among different clinical studies. A number of more recent studies have been struggled to address this association continually , whereashttp://www.crd.york.ac.uk/PROSPERO).The present systematic review and pooled analysis were performed in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The PRISMA checklist with detail was listed in We have systematically searched four databases, including MEDLINE (PubMed), EMBASE (OVID), the Cochrane Library, and the PsychINFO, to filter the potential studies prior to March 1, 2021. Only studies representing the English language and human participants were included. The searching strategy employed for screening the relevant studies in PubMed databases was:  OR (Chronic Hepatitis B)) OR ) OR (Chronic Hepatitis B Virus Infection)) OR (HBV)) OR ) OR (HCV)) AND (“stomach neoplasms”[Mesh]) OR ) OR (stomach neoplasm)) OR ) OR (gastric neoplasms)) OR (gastric neoplasm)) OR ) OR ) OR (cancer of stomach)) OR (stomach cancers)) OR (gastric cancer)) OR ) OR ) OR (gastric cancers)) OR (stomach cancer)) OR ) OR ) OR (cancer of the stomach)) OR ). Moreover, we also reviewed the reference list to identify additional studies by a manual inspection.Patients with chronic HBV/HCV infection and GC were according to the International Classification of Diseases (ICD) using the corresponding codes and the standard of the World Health Organization (WHO). The presence/positivity of HBsAg was the most primary serum marker for identifying the cases of HBV infection. Patients with chronic HCV infection were diagnosed by anti-HCV seropositivity for 6 months or liver histology. The diagnosis of GC was confirmed by histopathological examination.Any studies reporting the incidence of GC in chronic HBV/HCV infected patients compared with a non-chronic hepatitis group were considered eligible. Besides, those studies reporting with the association between HBV/HCV infection and risk of GC by calculating with a hazard ratio (HR), odds ratios (OR), or relative risk (RR) with the 95% confidence intervals (CI) were additionally included. Moreover, studies providing sufficient data to generate the effect sizes were also included. The inclusion criteria for this systematic review and pooled analysis were in accordance with the standard of Patient, Intervention, Comparison, Outcome, and Study design (PICOS). The scientific question guiding this cumulative analysis was: Is there a positive relationship between chronic HBV/HCV infection and risk of GC? The components for the PICOS evidence were as follows: chronic HBV/HCV-infected individuals (P); diagnosis of GC or stomach cancer (I); compared with the general healthy population (C); the incidence of GC or the HR of GC (O); study designs (S).in-vitro experiments; (IV) those studies reporting the study sample are co-infected with HBV and HCV because the present study is designed for investigating whether HBV or HCV is an independent risk factor for GC development; (V) cross-sectional studies are excluded in this meta-analysis because this kind of studies could not show the direction of causality between chronic hepatitis virus infection and the risk of gastric cancer, as it lacks the information about the temporality of associations. Based on the inclusion and exclusion criteria, the process of study selection was conducted by two authors independently. Any ambiguities were resolved by the corresponding author.The exclusion criteria in this pooled analysis were as follows: (I) review articles, reader or editorial comments for the published studies, and case reports; (II) duplicated data or previous publications for same samples and the same scientific questions; (III) animal or Study characteristics in every single study were extracted by two authors independently. According to a data collection form, the following information was extracted, including the first authors’ names, publication year, study area, study design, age of the participants, GC cases in the HBV/HCV group and the control group, adjusted HR with 95% CI, and variable adjustment in each included study.The methodological quality of the cohort studies and case-control studies was evaluated by the Newcastle–Ottawa Scale (NOS), in which low quality, moderate quality, and high quality were based on the scores of 0–3, 4–6, and 7–9, respectively.P values < 0.05. I2 statistics and the Cochrane Q statistic were used for the heterogeneity test. I2 > 50% was regarded as substantial heterogeneity, whereas the P-value of the Q test < 0.10 was considered to be statistically significant. On account of a high likelihood of between-study variance for differences in a designed study and the demographic characteristics, a random-effects model rather than a fixed-effects model was used in the current study. Subgroup analyses on different important factors were performed to better illustrate the association between HBV/HCV infection and risk of GC and further explore the origin of heterogeneity. Additionally, sensitivity analyses were applied to identify the potential origin of the between-study heterogeneity. The funnel plot, Begg’s rank-correlation test, and Egger’s regression asymmetry test were used to evaluate the publication bias.The pooled analysis was conducted by using STATA version 13.0 software for Windows . The overall HR with 95% CI synthesized by all the included studies was used to quantitatively evaluate the strength of the relationship between HBV/HCV infection and the risk of GC. Statistical significance was assumed at a two-tailed The selection process for screening the eligible articles is shown in The publication years of the 13 eligible studies ranged from 2014 to 2020. The mean age of the participants ranged from 42.6 ± 12.6 to 71.9 ± 14.59 years. For the study geographical area, 10 studies were conducted in Asia, 2 studies in the United States, and 1 study in Europe. The study design of the eligible studies included cohort and case-control studies. The sample size among these included ranged from 1,160 to 5,332,903, involving a total of 7,027,546 individuals. Among the 13 included studies, two studies   providinBased on the NOS, three included studies , 19, 24 P=0.003) by using a random-effects model. Statistical heterogeneity was identified during this meta-analysis .As shown in In the present study, we have conducted subgroup analyses to detect the source of heterogeneity in the relationship between HBV infection and the risk of GC. Notably, the disease duration of HBV infection, antiviral therapy, gender, and mean age among different studies might be the confounding factors. However, only limited included studies have provided detail information on the above factors, so we could not perform a subgroup analysis on these confounding factors.P <0.001), and no significant heterogeneity was identified . However, such association was not found in the seven case-control studies , and the substantial heterogeneity was detected . When focused on the geographical area, this subgroup analysis revealed that the positive association between HBV infection and the risk of GC was existed either in the Europe/US or the Asian countries . Furthermore, we have found that such association is stronger in the Asian countries  than the Europe/US   .Based on the above results, the stratified analysis revealed that patients with HCV infection exhibited an increased odds of GC as compared to those with HBV infection  to 1.49  after excluding any of the studies. Besides, similar heterogeneity was observed after each exclusion, the I2 ranged from 67.4% to 90.1% . The abovementioned results indicated that no single study dominated the pooled HR and heterogeneity in those studies reporting HBV.In this study, sensitivity analysis from both of the studies of HBV and HCV was conducted to assess the influence of individual study on the newly generated overall HR. As listed in P= 0.006) to 2.103 . Intriguingly, the substantial heterogeneity disappeared after omitting the study conducted by Hong et al.’s study , suggesting that this study was the origin of the substantial heterogeneity of the combined effect . Similar to this finding, the funnel plots from five eligible studies reporting HCV infection cases also demonstrated that no significant publication bias existed in the combined HR  (As displayed in o 11.61) Figure 8P = 0.003). This result was consistent with two previous meta-analyses related to this topic, which also supported a significant positive relationship between HBV infection and GC development (P = 0.001). In the present study, sensitivity analyses showed that the quantification of the risk for GC in patients with either HBV or HCV remained prominently higher in all of the included studies , indicating that our findings were robust. In this study, all the HRs were adjusted for the common confounders, including the known risk factors for GC  and some other factors, such as age, sex, geographical region, occupation, and comorbidities. Based on the abovementioned evidence, a significant positive relationship between HBV/HCV infection and GC development was verified. Also, HBV/HCV infection might be an independent risk factor for the tumorigenesis of GC.Mounting studies have confirmed a significant positive association between virus infection and the development of various malignancies, i.e., Epstein-Barr (EB) virus in nasopharyngeal carcinoma , human pelopment , 33. Up In the subgroup analysis of the study design, studies with cohort design have verified the positive association between HBV infection and the high prevalence of GC but such association was eliminated in those studies with a case-control design. According to the epidemiologic investigation, a cohort is defined as studies that sample participants on the basis of exposure and assess the outcome during follow-up. In a cohort study, patients are sampled on the basis of exposure and are followed up over time, and the occurrence of outcomes is assessed. Case-control studies, the common analytical epidemiological studies, are the only practical approach for identifying risk factors for some diseases. Case-control studies lack temporality because they are retrospective designs. Therefore, the methodological quality and the level of evidence are higher in cohort studies as compared with case-control studies. Given this inconsistent outcome, further well-signed cohort studies are still warranted to validate the evidence of HBV infection predisposing to the development of GC. In the subgroup analysis of different research areas, pooled results from studies conducted in the Asian countries had a higher prevalence of GC when compared with the Europe/US. This phenomenon may be attributable to the prevalence and the disease severity of HBV infection, which are higher in Asian countries than those in Europe and the United States. However, few studies have been conducted to investigate the prevalence of GC in HBV infection patients in both Asian and European countries. Therefore, the etiology underlying this observation is still unknown.The pathophysiological mechanisms of HBV/HCV-associated GC development remain elusive. The underlying mechanisms that existed in the association between HBV/HCV infection and the development of GC might be correlated with multiple etiologies, including chronic inflammation, systemic impairment of immune function, liver cirrhosis, and the direct effects of HBV/HCV proteins on oncogenesis and/or on tumor suppression genes , 35.HBV is one of the most common hepatotropic viruses, which replicate in the hepatocytes. Viral oncogenic hepatitis B virus X proteins (HBX) have been confirmed to play a key role in the development of multiple cancers. Intriguingly, however, some investigators also found that HBX was significantly higher in GC cells than in healthy parts of the specimens . In addivia the integration of their genomes into the host’s chromosomes or immune system inhibition , Science and Technology Planning Project of Taizhou City, Zhejiang Province (ID: 1902ky37 and 20ywb40), the Scientific Research Project of Taizhou University (ID: 2017PY047), and the High-level Hospital Construction Research Project of Maoming People’s Hospital.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.


The occurrence of postoperative reintubation (POR) in patients after general anesthesia (GA) is often synonymous with a poor prognosis in patients. This is the first review analyzing scientific literature to identify risk factors of POR after general anesthesia. The purpose of this study was to collect currently published studies to determine the most common and consistent risk factors associated with POR after GA.We have retrieved all relevant research published before April 2021 from PubMed, Embase, Web of Science, and the Cochrane Library electronic databases. These studies were selected according to the inclusion and exclusion criteria. The Z test determined the combined odds ratio (OR) of risk factors. We used OR and its corresponding 95% confidence interval (CI) to identify significant differences in risk factors. The quality of the study was evaluated with the NOS scale, and meta-analysis was carried out with Cochrane Collaboration's Revman 5.0 software.A total of 10 studies were included, with a total of 7,789 recipients of POR. We identified 7 risk factors related to POR after GA: ASA ≥ 3 (OR = 3.58), COPD (OR = 2.09), thoracic surgery (OR = 17.09), airway surgery (OR = 9.93), head-and-neck surgery (OR = 3.49), sepsis (OR = 3.50), DVT (OR = 4.94).Our meta-analysis showed that ASA ≥ 3, COPD, thoracic surgery, airway surgery, head-and-neck surgery, sepsis and DVT were associated with POR after GA.https://www.crd.york.ac.uk/prospero/display_record.php?, Identifier: CRD42021252466. Postoperative reintubation (POR) refers to intubation after extubation failure following general anesthesia . IndicatThe causes of POR can be divided into respiratory causes and non-respiratory causes. The former include hypoxia, respiratory muscle weakness, muscle relaxant residue, airway obstruction, phrenic nerve injury, to name a few, while the latter include accidental catheter prolapse, hemodynamic imbalance, unexpected change of operation, to name a few –7. Many To that end, we are first to review and perform a meta-analysis of the risk factors associated with POR in patients after GA.This meta-analysis was registered on Prospero with the registration number of CRD42021252466 and performed according to the PRISMA statement and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines , 9.We conducted a meta-analysis of all English language articles using the Cochrane Library, PubMed, Embase and Web of Science databases. The search included all relevant reports before January 2022, the date of the initial search is January 8, 2022. Additional records were identified by contacting authors and searching reference lists from the literature. This study followed the PICO statement , and theThe inclusion criteria were as follows: (1) Types of studies: observational studies including cohort, case-control and cross-sectional studies; (2) Types of participants: patients who have undergone POR after GA; (3) Types of comparison: comparisons of risk factors for POR after GA.The following types of records were excluded: (1) records with incomplete data; (2) nonoriginal studies ; (3) records rated 4 and below by the NOS. Two reviewers independently assessed the eligibility of all studies. A consensus was reached through discussion in cases of disagreements.We used standardized data collection tables to extract the following information: author name, year of publication, country, study design, study period, number of patients in cases and controls, risk factors, odds ratio (OR), and study quality.The quality of the studies was evaluated according to the Newcastle-Ottawa Scale (NOS) . NOS conTwo reviewers (LJW and TLP) independently conducted the data extraction and study quality assessment. Disagreements were resolved through discussion.Z test was used to determine the significance of the difference. χ2 test and I2 statistics were used to evaluate the heterogeneity in the analysis. A value of I2 of 0–25% represents insignificant heterogeneity, 26–50% low heterogeneity, 51–75% moderate heterogeneity and 76–100% high heterogeneity (I2 > 50% or P < 0.05). Otherwise, the fixed-effect model was adopted. A sensitivity analysis was carried out by excluding individual study sequentially and compare the pooled results by using a fixed effect model and a random effect model. When there is no significant difference in the P-value of the corresponding combination effect, the result can be considered robust. Harbord's test of Stata Version 15.0  was used to check publication bias. P > 0.1 indicates no publication bias in this study  software was used for statistical analysis of the data. We would conduct a meta-analysis if a risk factor was reported by at least two studies using multivariate regression analysis. The pooled odds ratio (OR) was calculated to evaluate the risk factors of bivariate variables of POR after GA. ogeneity . The ranis study . The comAccording to our search strategy and other sources, a total of 1,529 potentially relevant studies were identified. Among them, 850 were excluded due to duplication, 604 were excluded after screening the title and abstract, and 65 were excluded after full-text review because they did not meet the criteria. Finally, a total of 10 studies and 5,15,940 patients were included in this meta-analysis. , 13–19 TThe included studies were published between 2010 and 2021. Five studies were conducted in the United States, four in China and one in Thailand. The sample sizes included in the study ranged from 180 to 3,16,640. All identified studies followed an observational design: nine were case-control studies, while one was a retrospective cohort study. 2 statistics were used to evaluate the degree of statistical heterogeneity. The following 7 risk factors for POR were significantly different: ASA≥ , COPD , thoracic surgery , airway surgery , head-and-neck surgery , sepsis . DVT . The percentage of cases attributable to exposure factors in the population was estimated using PARP. This meta-analysis calculated the PARP of risk factors of binary variables as shown in In the analysis of COPD, we carried out a sensitivity analysis by excluding each study one by one to explore whether a study significantly impacts the results or whether it has a significant contribution to heterogeneity . OverallP = 0.403). However, we detected publication bias in ASA ≥ 3, COPD and Head-and-Neck Surgery .There was little evidence of publication bias regarding airway surgery, as indicated by Harbord's test  dominated the results as it included 80% of studied cases,which have played a big part in our conclusions. Finally, the summarized results were based on 10 or fewer studies since relatively few studies investigated the risk factors associated with POR after GA. Therefore, it is necessary to conduct more carefully designed studies on the potential risk factors of POR in patients after GA.In conclusion, this meta-analysis identified some risk factors for POR in patients after GA and provided a reference for the prevention of POR. However, more strictly designed prospective cohort studies are needed to substantiate our findings and further identify effective measures to control POR.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.ZX made substantial contributions to conception and design of the study. JL and SW conducted the search. YD and LY screened articles. JL and LT conducted the data extraction and study quality assessment. ZX analyzed the data and wrote the manuscript. ZY and LT revised the manuscript. All the authors approved the final version of the manuscript.This research was supported by Science and Technology Department of Jiangxi Province, Grant/Award Numbers: 20192BBGL70016 and 20181BBG78028. The funder were not involved in study design, data collection, analysis and interpretation, report writing, and publication. All researchers are completely independent of the funders.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.


Head and Neck Cancer (HNC) survivors are at increased risk of developing a second primary cancer (SPC). Along with the environmental risk factors, genetic factors have been associated with a potential increased susceptibility to SPC development. We aim to identify the Single Nucleotide Polymorphisms (SNPs) that contribute to SPC development among HNC survivors through a systematic review and meta-analysis.2 statistics. Quality of the included studies was assessed using the Q-Genie tool.We searched PubMed, Scopus and ISI Web of Science for eligible studies published in English until January 31st, 2020. We included studies reporting primary data that evaluated the association between SNPs and SPC risk in HNC patients. Data were pooled in a random-effect meta-analyses, when at least two studies on the same SNP evaluated the same genotype model. Heterogeneity was assessed using the χ2-based Q-statistics and the ITwenty-one studies, of moderate to good quality, were included in the systematic review. Fifty-one genes were reported across the included studies to have significant associations with an increased SPC risk. Overall, 81 out of 122 investigated SNPs were significantly associated with the SPC risk. Seven studies were included in the meta-analysis, which showed five SNPs associated with an increased risk of SPC: p21C70T, CT + TT ; FASLG -844C > T, CT + TT , P21 C98A, CA + AA ; FAS -670A > G  and GST-M1, Null genotype .The identified SNPs in our systematic review and meta-analysis might serve as potential markers for identification of patients at high risk of developing SPC after primary HNC.CRD42019135612.The online version contains supplementary material available at 10.1186/s12885-021-08335-0. Head and neck cancer (HNC) is a group of cancers that occur in oral cavity, pharynx and larynx, it is the sixth most common cancer, with approximately 650.000 new cases and 300.000 deaths annually . AlthougThis systematic review was conducted and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocol (PRISMA-P) checklist  Additio. The proStudies were considered eligible for inclusion if they evaluated the association between SNPs and SPC risk in HNC patients, and if they provided the effect measures with the corresponding 95% confidence interval (CI). Studies reporting primary data were included. There were no restrictions on primary HNC stage or treatment status. According to Warren and Gates criteria, a SPC is defined as a second cancer that developed after a primary cancer, that is of non-squamous cell origin, or which has developed in a different location other than the primary cancer. If the second cancer is of squamous cell origin and has developed in the same region as the primary cancer, it is only coded as an SPC if more than 60 months had passed since the primary cancer diagnosis . Therefo(((Head and Neck) OR pharynx OR pharyngeal OR oropharynx OR oropharyngeal OR hypopharynx OR hypopharyngeal OR nasopharynx OR nasopharyngeal OR larynx OR laryngeal OR  OR (upper aerodigestive tract) OR UADT) AND ) AND ((second primary) OR SPC) AND ) OR gene OR microRNA OR SNP OR (single nucleotide polymorphisms) OR polymorphism* OR biomarker*).Two researchers  systematically searched PubMed, Scopus and ISI Web of Science online databases for eligible studies published in English from inception until January 31st, 2020. The following search query was used in PubMed: Other two databases were searched using the appropriately modified PubMed search query (details are available upon request).Subsequently, the reference lists of the included studies were manually searched for additional relevant publications. In the second step, aiming to understand whether GWASs identified any genetic loci associated with the risk of SPC in HNC patients, we also explored the following GWAS databases: GWAS Central National Human Genome Research Institute  , The datIdentified studies from all databases were uploaded to Mendeley Reference Manager and duplicate articles were removed. Two independent researchers  performed the first screening based on titles and abstracts. In the second stage of screening, studies with full texts available were carefully reviewed. Studies that met the eligibility criteria were selected for inclusion. The PRISMA flow chart was created, reporting all the steps of search strategy and study selection: total number of studies retrieved, number of excluded studies during title/abstract screening, and number of studies excluded during full-text assessments, along with reasons of exclusion. Disagreements were resolved through discussion with the third researcher [RP] until the consensus was reached.From each of the included studies, two researchers  independently extracted the following data: first author, year of publication, study design and setting, study size, patients' ethnicity, primary HNC site, follow-up period, number of patients with SPC, SPC site(s), genes, chromosomes, SNPs, measure of association and corresponding genetic model. Researchers double-checked the extracted data and few subsequent discrepancies were resolved through discussion and in consultation with another researcher [RP].Two researchers  independently assessed quality of the included studies using the Q-Genie tool, which was specifically designed for the evaluation of genetic association studies . This toI2 statistics [I2 value was < 25%. P-values of less than 0.05 were considered statistically significant. To assess the presence of publication bias (where appropriate), we conducted Egger’s asymmetry test (level of significance p < 0.05) for the SNPs with at least three pooled studies [The main findings were reported in a tabular synthesis, separately for each SNP, and the qualitative synthesis reported possible associations of each SNP with the SPC risk. Meta-analysis was performed considering different study designs, and the SNPs studied reported in each study. When at least two studies on the same SNP were available and evaluated the same genotype model, the data were pooled in a random-effect meta-analyses . Effect atistics . The het studies . StatistThe initial search of PubMed, ISI Web of Science and Scopus databases identified a total number of 3053 articles. After removing the duplicates, 2635 articles were screened by title and abstract. One hundred forty-seven full-text articles were evaluated, of which twenty-one articles met the inclusion criteria. No additional studies were included after checking the reference lists of the included articles. The entire process of the literature search and study selection is reported in details in the PRISMA Flowchart in Fig. Characteristics of the twenty-one included studies –43 are rp53, GST, p73, p21, ERCC5, MDM4, MMP21, GSTM5, BCCIP, TNKS1BP1, RAD54L, CAD9, CDK8, FAS, JAK2, P27, SLC31A1, DNMT3B, MDM2, P14ARF, MMP3, RXRA, TSC1, CDC25C, FASL, FLT3, CASP3, KRAS, RGS5, BCL2L2, GPX1, MKI67, MNAT1, RNASEN, IGF1R, PDGFB, TNFRSF10B, CDK6, AXIN, XPO5, CAT, GLI2, CFTR, RGS11, GSTM4, IL1R1, NR1I2, NHEJ1, SMC1B, SSTR2, RNF2) were reported to have significant associations with the SPC risk. Overall, the most investigated genes were GST gene family (five studies), p53 (four studies), p73 (three studies), and by 2 studies each of the following genes p21, FAS and FASL, and XPD (ERCC2). A total of 122 different SNPs were explored, of which 81 SNPs were significantly associated with the SPC risk, in particular with an increased risk. Data for the investigated SNPs are reported separately, according to the study design. The SNPs investigated in cohort studies are reported in Table GST gene family polymorphisms explored were GST-M1, GST-T1 and GST-P1. GST- M1 null genotype was associated with an increased risk for any SPC  and for tobacco-related SPCs , whereas the GST-T1 null genotype demonstrated statistically non-significant protective effects for the SPC development . Patients with both GST non null genotypes were 0.52 times less likely (95% CI: 0.28–0.96) to develop a SPC compared to participants who had the GST-M1 null and GST-T1 non null genotypes. Patients with the GSTP1 gene Ile105Val polymorphism had a 1.7-fold elevated risk for developing SPC compared to patients with the wild-type genotype . The combined risk of GSTP1 gene 105 and GSTP1 114 polymorphisms, increased SPC risk, suggesting that two polymorphisms may have a joint effect on the risk of SPC development [Fifty-one genes  genotypes, and patients with the combined polymorphisms p53 codon 72 and p73 G4C14-to-A4T14 [The genotype  and patigenotype  had an ito-A4T14 , had a sp21 gene C98A and C70T polymorphisms genotypes were distributed significantly different between patients who developed SPC and those who did not. Patients with p21 98 CA/AA and p21 70 CT/TT variant genotypes had a significantly increased SPC risk [p21 98 A or p21 70 T) had a 2-fold increased SPC risk compared with patients with the combined p21 98 CC and p21 70 CC wild-type genotypes [The SPC risk , 43. Theenotypes , 43.FAS gene polymorphism showed that the SPC risk differed according to the index HNC site. Patients with index OPC and FASL 844 CT/TT genotype had significantly increased SPC risk  while index non-OPC patients with FAS670 AG/GG and FasL844 CT/TT genotypes had significantly increased risk of SPC . Patients carrying more FAS/FASL variants had significantly increased risk of SPC among index non-OPC patients [FAS -670 AA and the FASLG -844 CC genotypes was also reported by Lei D et al. [The patients . OverallD et al. , which fXPD gene Lys751Gln polymorphism carriers had a non-significant reduced SPC risk [XPD gene Lys751Gln polymorphism with other six SNPs of the core genes in the nucleotide excision repair (NER), in a dominant model there was a trend for increased SPC risk with increasing number of risk genotypes [The SPC risk , 39. TheResults of the quality assessment of the included studies are reported in Additional file p21 C70T, CT + TT genotype; FASLG -844C > T, CT + TT genotype; P21 C98A, CA + AA genotype; FAS gene -670A > G; GST-M1, Null genotype; GST-T1, Null genotype; and XPD Lys 751 Gln, Gln/Gln genotype.Seven cohort studies, that reported the same genotype of the same SNP in at least two studies, were included in the meta-analysis. The included SNPs and their genotypes were All the studies included in the meta-analysis adjusted the estimates for age, sex, smoking and alcohol , 40, 43.I2 = 0.0%); FASLG -844C > T, CT + TT genotype ; P21 C98A, CA + AA genotype variant ; FAS -670A > G  and GST-M1, Null genotype variant . A non-significant decreased SPC risk was associated with GST-T1, Null genotype variant ; and XPD Lys751Gln, Gln/Gln genotype variant . In each of the pooled analysis there was no heterogeneity between studies. The Egger test demonstrated no statistical evidence of publication bias for funnel plot FASLG -844C > T (p = 0.363) and FAS -670A > G (p = 0.24).The associations between SNPs and SPC risk, stratified by SNP, are shown in the Forest plot in Fig. I2 = 25.1%). For tobacco-related SPC, the risk was decreased in GST-T1 Null carriers . and increased in GST-M1 Null carriers , although the associations did not reach the level of significance  were significantly associated with an increased SPC risk in our meta-analysis. Genes of these five SNPs are involved in different pathways of carcinogenesis, such as apoptosis process or cell cycle regulation, DNA repair mechanism and carcinogen detoxification processes [This systematic review on genetic associations of SPC development after primary HNC included twenty-one studies and reported fifty-one genes with a significantly increased SPC risk. These genes were involved in different carcinogenesis pathways, including detoxification, DNA repair, apoptosis or cell cycle regulation, developmental pathway and cell adhesion. A total of 122 SNPs were investigated, of which eighty-one SNPs were significantly associated with an increased risk of SPC among HNC patients. Five SNPs  Checklist.Additional file 2. Quality assessment of the twenty-one studies included in the systematic review using Q-Genie Tool.Additional file 3. Stratified analyses according to Second Primary Cancer site, for each SNP genotype.


The prognostic value of the systemic immune-inflammation index (SII) in patients with pancreatic cancer is conflicting according to previous investigations. Therefore, we performed a meta-analysis to explore the association between SII and pancreatic cancer prognosis. Electronic databases were searched for studies exploring the association of SII with prognostic outcomes in pancreatic cancer. The endpoints were overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and clinicopathological parameters. The prognostic value of SII was estimated by hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (CI). Nine studies containing 11 cohorts with 2,365 subjects in total were included in this meta-analysis. Elevated SII was associated with poor OS , RFS/PFS/DFS , and CSS  in patients with pancreatic cancer. Additionally, there was no significant association between SII and other parameters in pancreatic cancer such as sex, tumor location, lymph node metastasis, tumor-node-metastasis stage, vascular invasion, and grade. This meta-analysis suggested that elevated SII was a significant prognostic marker for short-term and long-term survival outcomes in patients with pancreatic cancer. Pancreatic cancer is a highly aggressive malignant tumor and the seventh leading cause of cancer-related deaths worldwide , 2. In 2Various studies have shown that systemic inflammation plays an important role in cancer progression . SystemiThe initial literature search identified 64 studies, out of which, 23 studies were selected after eliminating the duplicate records. Following the examination of titles and abstracts, 11 studies were excluded, and the entire text of the remaining 12 studies was examined. Subsequently, six studies were excluded for the following reasons: two studies did not provide survival outcomes, two studies did not identify the cut-off value of SII, one study did not provide usable data for analysis, and one study was a meeting abstract. Following an updated literature search, three additional studies –18 were At the end of the selection process, nine studies –18 were I2 = 76.4%, P < 0.001). The pooled results were as follows: HR=1.50, 95% CI =1.15–1.96, p=0.002  independently performed the literature search, and any disagreements were resolved by consensus. The selection criteria were established based on previous meta-analyses of the SII , 32, 33.Two investigators (Y.S. and M.C.) independently extracted data from the included studies, and discrepancies were resolved by discussion with a third investigator (X.G.). The following information was extracted: name of the first author, year of publication, country, sample size, age, histological type, tumor stage, treatment, study period, cut-off value of SII, cut-off determination method, study design, follow-up, survival endpoints, survival analysis, and the HRs and 95% CIs of survival outcomes. The quality of the included studies was evaluated using the NOS , which e2 statistics. In the presence of significant heterogeneity (I2 > 50% and/or P < 0.10), REM was used to combine the HRs and 95% CIs. Otherwise, a fixed-effects model (FEM) was adopted. Subgroup analysis was conducted to explore the sources of heterogeneity. The association between SII and clinicopathological factors was evaluated using odds ratios and 95% CIs. Publication bias was estimated using the Begg’s test and Egger’s test. Statistical significance was set at p < 0.05. All the statistical analyses were performed using Stata version 12.0 .The HRs and 95% CIs were used to evaluate the prognostic role of the SII for OS, RFS/PFS/DFS, and CSS in pancreatic cancer. The heterogeneity among studies was assessed using the Cochran’s Q test and ISupplementary Table 1


Biliary tract cancers (BTCs) are rare but highly fatal. Although the etiology of BTC is poorly understood, gallstones are proposed to be a major risk factor. We conducted a systematic review and meta-analysis to examine the associations between gallstone characteristics and BTC risk.We searched the MEDLINE, Embase, and Cochrane Central databases and systematically reviewed cohort and case-control studies published before April 9, 2018. All the included studies reported appropriate risk estimates and confidence intervals (CIs) for associations between the presence, size, number, or duration of gallstones and the risk of BTC, including gallbladder cancer (GBC), extrahepatic bile duct cancer (EBDC), and ampulla of Vater cancer (AOVC). Summary odds ratios (ORs) and their 95% CIs were calculated using a random-effects model in the meta-analysis. Subgroup analyses were conducted to inspect sources of potential heterogeneity, and the Egger test was performed to assess publication bias.2=91.2%), GBC , EBDC , and AOVC . Gallstone size  was significantly associated with the risk of GBC.Seven cohort studies and 23 case-control studies in Asian, European, and American populations were included. The presence of gallstones was associated with an increased risk of BTC (OR, 4.38; 95% CI, 3.23 to 5.93; IGallstone characteristics, such as presence, size, and number, are associated with an increased risk of BTC. However, significantly high heterogeneity in the meta-analyses is a limitation of this study.  Biliary tract cancer (BTC) is relatively uncommon in most parts of the world , but is Gallstones, concretions formed in the biliary tract, have been suggested as an important risk factor for BTC . The carWe conducted a systematic review and meta-analysis of published cohort and case-control studies on associations between gallstone characteristics and the risk of BTC. This study aimed to update the latest studies through a systematic review and to provide a better description of the association of gallstones with the risk of BTC, encompassing its known subtypes GBC, EBDC, and AOVC , while iThe study protocol followed the PRISMA  guidelines.The first and second reviewers (DH and HJ) searched the PubMed, Embase and Cochrane Library databases for epidemiological studies with the following keywords:  AND . Medical subject headings (MeSH) terms were used for the PubMed search, and Emtree explode terms were used for the Embase search when available. The last search was conducted on Aug 9, 2018. The language was restricted to English in PubMed and Embase, but not in the Cochrane Library database. In terms of publication status, our search was confined only to published human studies. Papers published before April 9, 2018, were reviewed. Duplicates were excluded, and additional papers obtained by manually searching the references of the selected articles were included.The inclusion criteria for eligible studies were as follows: (1) cohort or case-control studies on the association between gallstones and the risk of BTC ; (2) gallstones  as the exposure of interest; (3) studies in which the primary outcome was the occurrence of BTC ; and (4) studies that reported risk estimates  and their 95% confidence intervals (CIs). Studies were excluded if any of the following criteria were met: (1) non-human studies; (2) non-observational studies or observational studies without an analytical epidemiologic approach; (3) irrelevant exposure or outcome variables (hepatolithiasis or intrahepatic cholangiocarcinoma); (4) duplication or unobtainable abstract/full-text; (5) the absence of a risk estimate that was either reported or could be calculated by the given information.The first and third reviewers (DH and WK) (under the supervision of AS) independently screened the titles and abstracts of studies that met the inclusion criteria. The full texts were reviewed by 2 independent reviewers (DH and HJ) and the supervisor (AS).The 2 independent reviewers (DH and HJ) extracted data using a standardized extraction form. When discrepancies arose, a fourth investigator (NS) made the final decision for study eligibility and data extraction. The relevant data included the last name of the first author, publication year, study country, study design (cohort or case-control study), study period, sex, sample size (number of cohorts and incident cases for cohort studies or number of cases and controls for case-control studies), exposure variables , measurement of exposure (with or without imaging studies), outcome variables , duration of follow-up for cohort studies, adjustment variables in the statistical analysis, and risk estimates, such as OR, RR, and HR with corresponding 95% CIs.Quality assessment data were extracted using the Newcastle-Ottawa scale (NOS), which contains 9 items, with 8 items receiving 1 point and 1 item accounting for 2 points, leading to a maximum of 10 points . A qualiIn this study, the summary risk estimates and their corresponding 95% CIs were calculated using a random-effects model . Selecte2 statistic and the chi-square-based Q tests. I2 values of 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively [Statistical heterogeneity across studies was appraised using the Iectively . For theectively  were conectively  with theectively , and p-vInformed consent was waved due to the study design .The characteristics of the 7 cohort studies ,22-27 anA total of 26 studies presented associations between the presence of gallstones and the risk of BTC . Among t2=90.5%; p<0.001) and cohort studies . The pooled risk estimate was also statistically significant , with high heterogeneity across the studies .We identified 7 cohort studies and 19 case-control studies that presented associations between the presence of gallstones and the risk of BTC. When we examined the results stratified by the study design, a statistically significant positive association was shown in both case-control studies  than in males, larger in Asia  than outside of Asia, larger in studies conducted before 2000  than in studies conducted around and after 2000, larger in studies with imaging studies  than in studies without imaging studies, and larger in low-quality studies  than in high-quality studies. The meta-analysis indicated that the association became weaker after adjusting for age, sex, and comorbidities. A stronger association than the original result was observed after adjusting for geographic areas, lifestyle factors, and education. However, there were no significant differences between the magnitudes of association under any stratifications.In subgroup meta-analyses, all results showed statistical significance, regardless of sex, geographic area, study period, measurement of exposure, study quality, and adjustment for confounders, as shown in 2=35.8%; p=0.132) among the subgroups including more than 2 studies.The heterogeneity varied substantially as the stratification method changed, and subgroup analysis with the studies that reported the outcomes of only the male patients exhibited the lowest level of heterogeneity  and cohort studies . The pooled risk estimate including case-control and cohort studies was also statistically significant , with high heterogeneity across the studies .Among the 20 studies on associations between gallstones and the risk of GBC, 16 studies presented associations between the presence of gallstones and the risk of GBC, as shown in 2=86.2%; p<0.001) versus non-Asian areas , measurement of exposure with imaging studies  versus without imaging studies , and adjustment for education  versus the original summary risk estimates .Meta-analyses were stratified by diverse subgroups, as presented in 2=35.2%; p=0.201)  [2=63.8%; p=0.096) [With regard to gallstone characteristics, we found that the risk of GBC was associated with gallstone size  ,30,31,402=95.0%; p<0.001) than the studies on CCA (or BDC)  without statistical significance.A total of 17 studies presented associations between the presence of gallstones and the risk of EBDC in its broadest sense , as shown in 2=96.0%; p<0.001) and cohort studies . The pooled risk estimate was also statistically significant , with high heterogeneity across the studies .In the comprehensive meta-analysis of EBDC, when we analyzed the results according to the study design, a statistically significant positive association was shown in both case-control studies . In the subgroup analyses, the magnitudes of association were significantly higher in Asian studies  than in non-Asian studies  and in studies that measured gallstones by an imaging modality  than the studies that did not   .The sensitivity analyses for the relationships between the presence of gallstones and the risk of BTC are given as Our systematic review and meta-analysis provided the most comprehensive evidence to date on the associations between gallstones and the risk of BTC, including GBC, EBDC, and AOVC. This study showed that the risks of GBC, EBDC, and AOVC increased with gallstone presence, and statistically significant associations were observed both in 7 cohort studies and in 19 case-control studies. In terms of gallstone size and number, the meta-analyses revealed that only size (> 1 vs. < 1 cm) was significantly associated with the risk of GBC. Sensitivity analyses of studies restricted according to the study quality or adjustments, as well as sequentially excluding studies one by one, supported the stability of the results.Based on the meta-analysis results for the BTC subsites, specifically GBC and AOVC, a common trend of significantly stronger summary effect sizes on the association between the presence of gallstones and the risk of cancer was present in Asian studies and studies that measured gallstones with various imaging modalities  than among their counterpart groups -4. This The previous reports that were reviewed altogether indicated that having gallstones was associated with an increased risk of BTC ,36,48 anWith respect to the high heterogeneity of the included studies in our meta-analyses, no single factor among the study design, sex, geographic area, study period, measurement of exposure, study quality, and adjustments of confounders dramatically reduced the heterogeneity in subgroup analyses. A notable finding is that a cohort study design, male sex, and measurement of gallstones with imaging studies slightly alleviated the heterogeneity in the main analysis . SimilarThe biological mechanisms linking gallstones to the risk of BTC are not well known. One hypothesis suggests that gallstones dropped down from the upstream biliary tract might result in chronic inflammation of the bile duct epithelium as an underlying condition for tumor development. That is, gallstones could lead to EBDC by causing inflammation of the bile duct wall . In addiThere are several limitations to this systematic review and meta-analysis. First, we tried to capture the association between gallstones and the risk of BTC, thereby inevitably excluding some other studies -56 that Despite these limitations, our study has several strengths. To the best of our knowledge, this study is the first systematic review and meta-analysis of the associations between gallstone characteristics and the risk of BTC. Unlike a previous systematic review , we repoWe found statistically significant associations between gallstones and an increased risk of BTC through systematic reviews and meta-analyses. We verified that the presence of gallstones is a critical risk factor for BTC as well as for GBC, EBDC, and AOVC. Our study provides a better description of the association between gallstones and the risk of BTC.


The association of the Mediterranean diet (MD) with mortality among people with a history of cardiovascular disease (CVD) has not been systematically examined. Hereby, our objective was to investigate the association of MD with all-cause and cardiovascular mortality in people with a history of CVD. We searched five electronic databases including Embase, PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials to screen eligible studies published before 31 August 2020. A random-effect model was used to examine the association of a 2-unit increment in MD score with the risk of all-cause and cardiovascular mortality. We conducted sensitivity and subgroup analyses and examined potential publication bias by Egger’s and Begg’s tests. Seven cohort studies (eight datasets) with a total of 37,879 participants who had a history of CVD were eligible for the main analysis. The pooled hazard ratios were 0.85  for all-cause mortality and 0.91  for cardiovascular mortality for each 2-unit increment in a score of adherence to MD. Subgroup analyses for all-cause mortality showed that the association appeared relatively stronger in Mediterranean areas (HR = 0.76 [0.69–0.83]) than non-Mediterranean areas (HR = 0.95 [0.93–0.98]) and in studies with a shorter duration (HR = 0.75 [0.66–0.84] for <7 years vs. HR = 0.94 [0.91–0.98] for ≥7 years). No evidence of publication bias was observed. The present meta-analysis of prospective cohort studies provided evidence that adherence to MD improved survival in people with a history of CVD. Researches on comprehensive dietary patterns provide better insight rather than a single food for understanding the association of diet with risk of chronic diseases . The MedA second prevention trial showed that MD was effective in preventing cardiovascular death in people with myocardial infarction . During https://www.crd.york.ac.uk/PROSPERO (Registration No: CRD42020201529). Two authors (C.T. and J.-Y.D.) independently conducted study search, study selection, data extraction, and statistical analysis. The following databases were examined and searched for potentially eligible studies that were published before 31 August 2020: Embase, PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials. The keywords of exposure, outcome, and study design were used for literature search (detailed in www.opengrey.eu) was also searched.The present study was conducted and presented as stated in MOOSE guidelines . The stuEligible studies for meta-analysis were those that strictly complied with the following criteria: (1) adherence to traditional or modified MD was analyzed as exposure; (2) the outcome of interest included all-cause or cardiovascular mortality ; (3) a prospective cohort design in which risk estimates with 95% confidence interval (CI) was reported for people with CVD. Any disagreements involved in study selection and inclusion were determined through a consensus meeting.We extracted characteristics and results from each study by a standard form. Detailed information consisted of the last name of the first author, publication year, characteristics of the population under study , number of cases and participants, follow-up duration, dietary assessment, death assessment, risk estimates for mortality (95% CI), as well as confounders in the fully adjusted model.The Newcastle–Ottawa scale was utilized to assess the quality of each included study in terms of participant selection, covariate adjustment, and outcome assessment.I2 [I2 ≤ 25% indicated low heterogeneity, I2 = 26–74% indicated moderate heterogeneity, and I2 ≥ 75% indicated high heterogeneity. We further performed subgroup analysis according to sex, study duration, and study location. Sensitivity analysis was conducted by excluding one study in sequence and then pooling the risk estimates of remaining studies in each turn. Begg’s and Egger’s tests were utilized to examine publication bias. All statistical analyses were conducted in Stata, version 15, and p value < 0.05 was regarded as statistically significant.In each selected study, the reported relative risks or odds ratios were thought to be equal to hazard ratios (HRs). The risk estimate of mortality for a 2-unit increment of MD score was the main estimate effect of interest in the present study. Values of 0 or 1 were assigned to each indicated component of MD. Individuals who consumed above the sex-specific median value of indicated food components were assigned a value of 1. Summing up these values resulted in a summary score, and a higher score represented a higher degree of adherence to MD. Two studies ,19 that I2 . I2 ≤ 25The process of study search and study selection is shown in Characteristics of the selected individual studies are presented in I2 = 88.9%; P-heterogeneity < 0.001). For risk of mortality from CVD, the pooled HR was 0.91 for each 2-unit increment of MD score . In an additional analysis that combined the HRs for men and women in the study by Lopez-Garcia et al. [The HRs of each cohort study and the pooled risk estimate are shown in a et al.  and thenp values > 0.10).As shown in the sensitivity analysis, the pooled HR ranged from 0.83 to 0.91 for all-cause mortality and from 0.82 to 0.95 for cardiovascular mortality respectively. No single study was found to have a substantial effect on the overall pooled risk estimates. The results of subgroup analyses of adherence to the MD and risk of all-cause mortality are presented in In the present meta-analysis of seven prospective cohort studies, a greater degree of adherence to MD had an association with a reduced risk of mortality from all-cause death among populations with CVD. The association appeared evident in Mediterranean areas than that in non-Mediterranean areas. In addition, each 2-unit increment of MD score was associated with a borderline significantly decreased risk of mortality from CVD.MD is characterized by higher intakes of fruit, vegetables, whole grains, soy, nuts, fish, and olive oil. The potential mechanism for the inverse association of MD with all-cause mortality among patients with CVD might be attributed to these food groups that have beneficial effects on blood pressure, lipid and glucose metabolism, endothelial function, thrombosis, and inflammation, contributing to improved cardiovascular endpoints ,26. FurtIn the primary prevention of CVD, the significance of MD has been well studied. A previous meta-analysis conducted among general populations free of CVD has shown a 10% (95% CI: 9–11%) reduction in risk of all-cause mortality for a 2-unit increment of MD score . The preOur subgroup analyses revealed that the association of MD with all-cause mortality among people with a medical history of CVD was relatively stronger in Mediterranean areas (pooled HR = 0.76) than that in non-Mediterranean areas (pooled HR = 0.95). This finding was in accordance with the results from the previous meta-analysis conducted among the general population (pooled HR = 0.82 in Mediterranean populations vs. 0.92 in non-Mediterranean populations) . One posIn the present study, we observed an inverse, significant association of adherence to MD with mortality from all-cause death, whereas for cardiovascular mortality the association was of borderline significance. The absence of significance for cardiovascular mortality may be due to a limited number of studies and hence weak statistical power for the analysis. Further studies on cardiovascular mortality are therefore needed to verify the role of adherence to MD in secondary prevention of CVD.As far as we know, the present study is the first meta-analysis to examine the association of adherence to MD with all-cause mortality and cardiovascular mortality in people with CVD. However, several limitations should be noted. First, the quantity of included studies for meta-analysis was relatively limited. Although many prospective cohort studies have examined the association of adherence to MD with risk of mortality, only a few of them concerned populations who were diagnosed with or have a medical history of CVD. Second, despite careful control of covariates in individual cohort studies, residual confounding remained a potential interpretation for the observed results. For instance, the time from the onset of cardiovascular events and treatment for the diseases were not extensively considered in individual cohort studies. Third, relatively high heterogeneity was observed in the main analysis. Differences in population characteristics, food composition, food preparation, and evaluation on the degree of adherence to MD were likely to contribute to the observed heterogeneity. Nevertheless, we were able to detect the source of heterogeneity by the subgroup analysis, which suggested that the study region may be a possible source of inconsistency across studies. Finally, publication bias challenges the validity of any meta-analysis. Nevertheless, no evidence of such bias was observed in our study.In conclusion, the present meta-analysis of prospective cohort studies provided evidence that adherence to MD may improve survival in people with a history of CVD. Because of the observational nature of included studies, the findings needed to be verified in randomized controlled trials.


The purpose of this meta-analysis is to assess whether there is an association between headache disorders and all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD).P > 0.1 and I2 ≤ 50%, a fixed-effects model was adopted. If I2 > 50% (which indicated great heterogeneity), a random-effects model was adopted. The funnel plot and Egger's test were used to evaluate publication bias.PubMed, Cochrane Library, Embase, and Web of Science were searched for cohort studies published from database inception to October 8, 2021, using medical subject headings (MeSH) and keywords. All statistical analyses were performed using Stata statistical software version 14.0. If I2 = 81.6%, P < 0.001). The history of any headache was associated with an increased risk of AD  and VaD . In the subgroup analysis, females with a history of headache have a slightly higher risk of dementia than males  and the risk of dementia in the retrospective cohort was slightly higher than in the prospective cohort .This meta-analysis included 12 cohort studies covering 465,358 individuals, which were published between 2001 and 2020. The pooling analysis shows that a history of any headache disorder is associated with an increased risk of all-cause dementia (OR = 1.35; 95% CI: 1.21–1.50; Our meta-analysis shows that any headache disorder increases the risk of all-cause dementia, AD, or VaD. These findings provide evidence that headache should be recognized as an independent risk factor for dementia, AD, or VaD. Dementia is a neurological disorder characterized by cognitive, behavioral, social, and emotional deterioration. It is a major public health problem in the world and has a high incidence rate  are associated with a high incidence rate, low quality of life, low productivity, and high economic costs. A global disease burden study listed headache as the second largest cause of disability in the world. Among people aged 15–49, the incidence of migraine is the third highest   and keywords. The search terms included dementia, AD, VaD, headache, head pain, migraine, and cohort studies. The full search strategy of PubMed is included in The trials were included on the basis of the following eligibility criteria: (1) cohort studies or nested case-control studies based on cohort trials; (2) investigations of the association of headache disorders with the risk of incident all-cause dementia, AD, or VaD. In this meta-analysis, “any headache” was defined as “patients who suffered from any type of primary headache in the past.” All-cause dementia was chosen as the primary outcome, AD, and VaD as the secondary outcomes.Trials were excluded if they did not provide an odds ratio (OR) estimate with corresponding 95% confidence interval (CI). If more than one study reported data from the same cohort, we included the study with the longest follow-up or the largest number of participants. Furthermore, the following articles were also excluded: conference abstracts, study protocols, duplicate publications, and studies with no outcomes of interest.Study selection was performed by two reviewers (HLQ and ZCY) who independently screened the literature based on the eligibility and exclusion criteria. Duplicate and irrelevant articles were first excluded according to their titles and abstracts. Thereafter, the full texts of the potentially eligible articles were downloaded and read to identify all eligible studies. Any disagreements were resolved by the third reviewer (SDY), who acted as an arbiter.Data extraction was performed independently by the two above-mentioned reviewers (HLQ and ZCY) who consulted the guidelines on data extraction for systematic reviews and meta-analysis  was used to assess the quality of cohort studies , a random-effects model was adopted. The sensitivity analysis was performed by excluding one study each time and rerunning to verify the robustness of the overall effects. The funnel plot was visually inspected to confirm publication bias, and Egger's regression test was used to statistically assess publication bias. We conducted a subgroup analysis based on gender and research type. All statistical analyses were performed using Stata statistical software version 14.0 .The adjusted OR and 95% CI from each trial were used to assess the association between headache disorders and risk of dementia, AD, or VaD. The χThe systematic search of cohort studies published before October 8, 2021, identified 1,176 results. After title and abstract screening, 20 articles were considered potentially relevant. Twelve studies , but the risk is lower than that of non-migraine headache patients  likewise indicated no publication bias in our meta-analysis.A visual inspection of the funnel plot showed no evidence of a significant publication bias in the outcome of any headache disorders and risk of all-cause dementia . Egger'sThis meta-analysis included 12 cohort studies covering 465,358 individuals, which provided a comprehensive evaluation on the association between headache and dementia. We found a significant increase in the risk of all-cause dementia, AD, or VaD among individuals with headache, with an overall 1.35-fold, 1.49-fold, or 1.72-fold increase in risk, respectively, compared with non-headache controls. This indicates that headache might be an independent risk factor for dementia.A previous review investigated the relationship between headache and dementia  can be found in the article/XS and HC conceived the study. HQ and ZY collected the data and drafted the manuscript. SY revised the manuscript and language. HQ conducted the subgroup analysis. All authors have read and approved the manuscript.This study was supported by the Doctoral Research Start-Up Fund Project of Liaoning (No. 2019-BS-234) and the Young and Middle-Aged Scientific and Technological Innovation Talents Support Program of Shenyang (No. RC210374).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.