In studies with a sample size of ≤ 400 participants and a mean age over 45, SBP and DBP were found to be substantially reduced. Overall, this umbrella meta-analysis indicates that n-3 PUFAs supplementation might play a role in improving DBP and SBP.Several meta-analyses have revealed that n-3 PUFAs can lower blood pressure, but the findings are conflicting. In this regard, the present umbrella meta-analysis aimed was performed to clarify whether n-3 PUFAs have effects on blood pressure. PubMed, Scopus, Embase, Web of Science, and Google Scholar were used as international databases from inception to May 2022. To examine the effects of n-3 PUFA supplementation on blood pressure, a random-effects model was applied. The leave-one-out method was performed for the sensitivity analysis. The pooled estimate of 10 meta-analyses with 20 effect sizes revealed significant reductions in both systolic (ES = −1.19 mmHg; 95% CI: −1.76, −0.62,  Hypertension is among the most common health conditions worldwide affecting over 1 billion people and accounting for 9.4 million deaths annually . ResearcOmega-3 polyunsaturated fatty acids (PUFAs) mainly consist of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA) . Diets dThe current umbrella of meta-analysis was performed based on the PRISMA. We registered our study protocol in PROSPERO (CRD42022311888).AND “hypertension” (Mesh) OR “hypertension” (tiab) OR “HTN” (tiab) OR “blood pressure” (tiab) OR “BP” (tiab) OR “hypertens” (tiab) AND “systematic review” (Publication Type) OR “meta-analysis” (tiab)]. Additionally, we enhanced sensitivity of the search strategy by using the wildcard term “*”. To ensure no publications were missing, reference lists of relevant studies were manually screened. In this umbrella of meta-analysis, English-language articles were eligible.Searches were conducted in PubMed, Scopus, Embase, Web of Science, and Google Scholar databases to find relevant studies published inception to May 2022 The following search strategy using MeSH terms and keywords was applied; [“omega-3 fatty acid” (Mesh) OR “omega-3 fatty acid” (tiab) OR “fish oil” (tiab) OR “omega-3 polyunsaturated fatty acids” (tiab) OR “EPA” (Mesh) OR “DHA” (Mesh) OR “DHA” (tiab) OR “EPA” (tiab) In vivo, in vitro, and ex vivo studies, observational studies, quasi-experimental studies, case reports, and controlled clinical trials were excluded.A PICO analysis was conducted to summarize the results of the current umbrella meta-analysis. The PICO criteria were: population/patients (P: adults over 18 years’ old who received omega-3 PUFAs); intervention (I: omega-3 PUFAs therapy); comparison (C: control or placebo group); outcomes (O: BP including SBP and DBP). Our study included meta-analyses that assessed the effects of n-3 PUFA supplementation on BP (SBP and DBP) along with their effect sizes (ES) and corresponding confidence intervals (CI). In terms of their methodology, two independent reviewers (VM and MV) performed AMSTAR2  questionnaires to evaluate the quality of meta-analyses . The queBased on eligibility criteria, articles were screened by two independent reviewers (MV and VM). After reviewing based on their titles and abstracts, irrelevant studies were removed. Then, by evaluating the full text of the relevant articles, eligible studies for the umbrella of meta-analysis were identified. Finally, any disagreement was resolved by discussion and consulting with other researchers (PD). The first author’s name, the publication year, the sample size, the study location, supplementation dosages, and duration, as well as the ESs and CIs for SBP and DBP, are extracted from the selected meta-analyses.Q test and I2 statistics were used to determine heterogeneity. When I2-value > 50% or the Q-test had p < 0.1, we considered between-study heterogeneity significant. The random-effects model was chosen when there was significant between-study heterogeneity. By performing subgroup analysis based on predefined variables including sample size, duration of intervention, health condition, the dose of supplementation, and mean age, potential sources of heterogeneity were detected. Sensitivity analysis was conducted to investigate the impact of one single study omission on the pooled effect size. Tests Egger’s and Begg’s were used to assessing a small-study effect. The publication bias was assessed by visual inspection of the funnel plots, and if any publication bias was detected, then a trim and fill test was carried out subsequently. In order to run the meta-analysis, we used STATA . In this study, p < 0.05 was considered statistically significant.ESs and CIs were applied to estimate overall effect sizes. Cochran’s A total of 210 articles were found after searching the electronic databases. 173 articles were carefully screened with titles and abstracts, after removing 37 duplicate articles, of which 21 articles were selected for full-text evaluation. Finally, 10 meta-analyses were included in the current umbrella meta-analysis. Results of the quality assessment of the qualified studies using the AMSTAR2 questionnaire are presented in p < 0.001), with high heterogeneity between-studies . N-3 PUFA supplementation > 4,500 mg/day to hypertension subjects > 45 years of age and a sample size of ≤ 400 significantly reduced DBP  . Subgroup analysis showed that EPA supplementation  in intervention duration of > 15-weeks, a mean age > 45 years, and a sample size of ≤ 400 participants contributes to a more pronounced influence in decreasing SBP  . There wsing SBP .Sensitivity analysis indicated that the effect of n-3 PUFAs supplementation on DBP and SBP levels was not significant .p = < 0.001 and 0.626, respectively), and SBP . In addition, publication bias was detected through a visual assessment of the funnel plots , stroke, renal disease, and mortality , 34. In Our results are consistent with three other meta-analyses , 30, 35.N-3 PUFAs may exert its hypotensive effects by several mechanisms. N-3 PUFAs may control the caveolae composition resulting in increased nitric oxide synthase . In partThe main strength of this review was that this umbrella meta-analysis provided a comprehensive summary of the literature and its results and given the potential effect on the management and treatment of hypertension, this is a useful attempt. We revealed that there is sufficient evidence for n-3 PUFAs to elicit helpful effects on blood pressure. In the sensitivity analysis, no changes in the results were observed excluding each meta-analysis; this supports the robustness of our results. However, current study has several limitations. The analyses involved subjects with several health statuses such as T2DM, dyslipidemia, kidney transplant recipients, NAFLD, and metabolic syndrome. While this allowed more meta-analyses and subjects to be included for analysis, this could affect generalizability. However, we done random effects model in our analyses as well as explored for heterogeneity, the current findings are limited by possible residual confounding such as different background diets of participants. Finally, the proportion of n-6 PUFAs: n-3 PUFAs may play an important role in decreasing the risk factors of CVDs –54. HoweIn summary, this umbrella meta-analysis of 10 meta-analyses revealed that, compared with control, n-3 PUFAs intake was related to meaningfully greater degree of SBP, and DBP decrease, and this effect was more obvious in hypertensive subjects. Consequently, supplementation with n-3 PUFAs may be a useful adjuvant therapy in hypertensive patients.The original contributions presented in this study are included in the article/VM and PD designed research. ZK and MV conducted a systematic search. BN and ZK screened articles. ZK and VM extracted data and drew tables. VM and MV analyzed and interpreted the data. MV, VM, and ZK wrote the manuscript. PD had primary responsibility for the final content. All authors read and approved the final manuscript.


Patients with gastric intestinal metaplasia (IM) are at increased risk of gastric cancer (GC). The endoscopic grading of gastric intestinal metaplasia (EGGIM) with high-definition endoscopes has shown the potential to facilitate GC risk stratification. However, a comprehensive review and meta-analysis of published articles are lacking. We conducted a meta-analysis to access the value of EGGIM in the assessment of histological IM.Studies were selected from PubMed, Medline, Embase, and Cochrane . We extracted relevant data to calculate the accuracy of EGGIM compared with the operative link of gastric intestinal metaplasia (OLGIM) and to calculate pooled odds ratio (OR) with a 95% confidence interval (CI) assessing GC risk with different grading.Four diagnostic studies and three case-control clinical trials were included in the analysis, which included 665 patients and 738 patients, respectively. Compared with OLGIM III/IV, EGGIM(5-10) had a pooled sensitivity and specificity of 0.92(95%CI 0.86-0.96) and 0.90(95%CI 0.88-0.93), and the area under the curve(AUC) was 0.9702. In assessing early GC, the pooled OR of patients with EGGIM(5-10) was 7.46(95%CI 3.41-16.31) compared with that of EGGIM(0-4).EGGIM is highly consistent with OLGIM, and patients with EGGIM(5-10) are at a higher risk for early GC. Some heterogeneity in the current research suggests that we need to carry out more strict control of confounding factors.https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=248691], (Prospero registration number: 248691)[ Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide and the fourth most common cause of cancer-related death . More thOperative Link on Gastric Intestinal Metaplasia (OLGIM) is a grading standard to risk stratify IM, which involves five biopsy specimens: two from the antrum two from the corpus, and one from the angle of the stomach. Patients with OLGIM stage III-IV are at an increased risk of early gastric neoplasia  and may develop early gastric neoplasia within two years , there aIn recent years, image-enhanced endoscopy (IEE), including narrow-band imaging (NBI), linked color imaging (LCI), and blue laser imaging (BLI), has improved the performance of endoscopy . IEE canIn this study, we conducted a systematic review and meta-analysis to explore the value of the EGGIM system in the assessment of histological IM and the risk classification of early gastric cancer.We performed a systematic search for diagnostic studies and case-control studies that evaluate the diagnostic accuracy of the EGGIM system using the OLGIM system or GC incidence as a gold standard. The protocol for this study has previously been registered with PROSPERO (registration no. 248691). The protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  guidelinFour scientific databases  were searched by two researchers (WL and QXL) independently from their inception through Oct 14, 2021. Eligible articles published after this date were added manually. The last elicitation date was Jun 25, 2022. The references of identified articles were also checked to retrieve potential missed articles. The detailed search strategy is shown in The inclusion criteria were as follows: 1) Diagnostic studies whose primary or secondary outcome was the evaluation of the accuracy of EGGIM using OLGIM as a gold standard, or case-control studies using EGGIM to stratify GC risk. 2) True positive (TP), true negative (TN), false positive (FP), false negative (FN), or the number of GC events were included in the paper. 3) The papers were published in English. We excluded study types, including letters, reviews, expert opinions, study protocols, animal studies, preclinical trials, and studies with fewer than 10 cases.Two reviewers (YY and DSJ) read the included articles and extracted data independently. The following variables were collected: the first author, publication year, country, study period, sample size, gender, the experience of endoscopists, endoscopic technology, and details of the measurement data. All collected data were double-checked by a third reviewer (FSS). Two reviewers(FSS and WL) scored the included diagnostic studies independently for risk of basis according to Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2)  and scor2 statistics. A fixed-effects model was used when heterogeneity was absent (I2 <50% or p > 0.1) and a random-effects model was used if heterogeneity existed (50% <I2 <80% or p < 0.05). When heterogeneity was substantial (I2 >80% or p < 0.01), a descriptive analysis was used, and subgroup analyses implement for different image-enhanced technology when the necessary data were available. All P-values were two-tailed, and P values < 0.05 were deemed to be statistically significant.Meta-DiSc 1.4 and RevMan 5.4.1  were used to analyze the data. Heterogeneity was assessed with Cochrane’s Q test and Higgins’s IWe identified a total of 435 studies. Four diagnostic studies with 665 patients , 16, 17 The assessment of the risk of bias and applicability concerns for the four diagnostic studies are presented in According to the NOS assessment, three case-control studies , 18, 19 Compared with OLGIM III/IV, EGGIM(5-10) obtained a pooled sensitivity and specificity of 0.92(95%CI 0.86-0.96) and 0.90(95%CI 0.88-0.93), and the area under the curve(AUC) was 0.9702 Figure 2P=0.0034, 2 =I78.1%), between the studies, which means there are differences in the diagnosis of true negatives between studies. Rui Castro et al.  (A high EGGIM score (5-10) has a significantly higher risk for GC compared with a low EGGIM score (0-4), with an odds ratio of 7.46  Figure 3The OLGIM system based on histological examination to assess GC risk has been reported in the Kyoto global consensus . HoweverOur meta-analysis evaluated the effectiveness of EGGIM as a GC risk stratification tool. EGGIM was compared with the gold standard- the pathology-based OLGIM system. We found that EGGIM was in high concordance with OLGIM with an AUC of 0.9702, and patients with EGGIM (5-10 points) had a 7.46-fold higher risk of developing early GC than those with EGGIM (0-4 points). The EGGIM system as a tool for endoscopic GC risk stratification may be helpful for daily clinical practice.Meta-analysis of the EGGIM system compared with OLGIM shows heterogeneity in specificity between different studies. The results suggest that there are differences in the number of false-positive cases in the various studies. The EGGIM system overestimated the GC risk for some patients with OLGIM stages 0-II. On the other hand, the EGGIM system has a high sensitivity with no apparent heterogeneity, indicating that EGGIM can identify high-risk patients well. Therefore, EGGIM can identify the high-risk population with an acceptable rate of false positives, which can serve as the first step in risk stratification. An endoscopic-guided biopsy will improve the efficiency of GC screening and reduce the need for pathological examinations.P=0.007)  . Kimura-P=0.315). The Kyoto classification risk scoring system based on white light endoscopy may result in a lower diagnostic power than IEE. Meanwhile, it incorporates multiple endoscopic features that may fail to provide new risk predictors. Further studies are recommended to explore the clinical utility of these endoscopic features. We hope these endoscopic and pathological risk assessment tools would be complementary to each other and optimally applied in practice.The Kyoto classification risk scoring system, which adds observations of intestinal metaplasia, Fhypertrophic fold enlargement, and nodularity to the Kimura-Takemoto system, is also widely used to assess GC risk , 30. TheThere are some limitations of this meta-analysis. First, the number of included studies was small, with only 4 diagnostic studies and 3 case-control studies. Second, the specificity of EGGIM compared to OLGIM is heterogeneous, and there is a heterogeneity of EGGIM in predicting GC risk. Due to insufficient literature, subgroup analysis could not be performed for the operating physicians, the endoscopic techniques, etc. The EGGIM stage in one of the included case-control studies  was baseIn summary, our meta-analysis is the first one to synthesize multiple studies to assess the effectiveness of EGGIM. The results showed that EGGIM was a reliable tool for gastric cancer risk stratification. Even though EGGIM carries a false-positive rate, it can still be complementary to pathological biopsy in risk stratification. In addition, with the development of endoscopic technology, endoscopic diagnosis of GC precancerous mucosa has shown great potential, and a unified diagnostic standard may be helpful to promote its application in daily practice. Finally, further prospective studies on endoscopic GC risk stratification systems such as EGGIM are needed to clarify their clinical utility.The original contributions presented in the study are included in the article/SF: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Supervision. YF: Investigation, Writing. SD: Validation, Visualization. LW: Investigation, Data curation. XQ: Investigation, Data curation. XL: Investigation, Data curation. GS: Supervision, Project administration,. YY: Supervision, Project administration, Data curation. WW: Conceptualization, Methodology, Supervision, Project administration, Funding acquisition. All authors contributed to the article and approved the submitted version.National Traditional Chinese Medicine Inheritance and Innovation Team Project (No. ZYYCXTD-C-202210). Scientific and technological innovation project of China Academy of Chinese Medical Science (No. CI2021A01008 and CI2021A01820). Science Research Program for TCM Industry (No. 201507001-09).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.


Objective: To explore the association between vitamin A (vit A) status and risk of asthma.Methods: PubMed, Web of Science, Embase and the Cochrane Library were electronically searched to identify related studies that reported the association between vit A status and asthma. All databases were searched from inception to November 2022. Two reviewers independently screened literature, extracted data, and assessed risk bias of included studies. Meta-analysis was performed on R software Version 4.1.2 and STATA Version 12.0.Results: A total of 19 observational studies were included. A pooled analysis showed that the serum vit A concentrations in patients with asthma was lower than that in healthy controls (standard mean difference (SMD)= −2.479, 95% confidence interval (CI): −3.719, −.239, 95% prediction interval (PI): −7.510, 2.552), and relatively higher vit A intake in pregnancy was associated with an increased risk of asthma at age 7 years (risk ratio (RR)= 1.181, 95% CI: 1.048, 1.331). No significant correlation was observed between serum vit A levels or vit A intake and the risk of asthma.Conclusion: Our meta-analysis confirms that serum vit A levels are lower in patients with asthma than in healthy controls. Relatively higher vit A intake during pregnancy is associated with an increased risk of asthma at age 7 years. There is no significant correlation between vit A intake and asthma risk in children, nor between serum vit A levels and asthma risk. The effect of vit A may depend on age or developmental stage, diet and genetics. Therefore, further studies are needed to explore the association of vit A and asthma.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/CRD42022358930, identifier CRD42022358930 Asthma is a respiratory disease characterized by recurrent airway obstruction, airway hyperresponsiveness and chronic airway inflammation . The preAntioxidants can counteract the damaging effects of oxidative stress and play a crucial role in maintaining respiratory health . VitaminConsequently, there is an urgent need for evidence-based information obtained from systematic synthesis of studies on the association between vit A and asthma risk for the primary prevention of asthma onset. The aim of this systematic review was to synthetize the available scientific evidence on the association of vit A and asthma risk, thus supporting or preventing the use of vit A.This study doesn’t require ethical approval and informed consent because it is a systematic review and meta-analysis of previously published literature and doesn’t address ethics or patient privacy. Our study was analyzed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . The stuTwo reviewers independently performed a comprehensive literature search in four electronic databases, including PubMed, Web of Science, Embase and the Cochrane Library. All databases were searched from inception to November 2022. The following MeSH terms and keywords were searched  AND . References within the identified articles were manually examined to identify other potentially eligible studies. The details of the search strategy were provided in The following criteria were predefined for inclusion of a study: 1) the original observational or interventional study reported the relationship between vit A and asthma risk; ii) the study provided the serum vit A or vit A intake levels, relative risks (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs); iii) cases were diagnosed with asthma (informed by clinician). The exclusion criteria were as follows: i) the cases weren’t only asthma patients, but also patients with wheezing, atopic dermatitis, allergic rhinoconjunctivitis or other allergic disease, resulting in the inability to independently obtain the association of vit A and asthma; ii) studies with insufficient data; iii) reviews or meta-analyses, conference abstract, and study protocols.Screening of studies, selection, exclusion, and data extraction were performed by two reviewers independently. Any disagreements were discussed and reached a consensus. We extracted the following information from case-control and cohort studies: first author, publication year, study location and design, participants, age, vitamin measurements, statistical methods and outcomes of interest.Case-control and cohort studies were assessed using the Newcastle-Ottawa scale (NOS)  consisti2 and Tau2 statistic and 95% prediction interval (PI) . Data of dichotomous outcomes were pooled using the risk ratio (RR) or odds ratio (OR) and presented as the 95% confidence interval (CI). Continuous outcomes were pooled using the standard mean difference (SMD) and 95%CI. Heterogeneity was assessed statistically by using the Cochran’s Q test, Ival (PI) . When p selected . The preselected . Sensitiwww.ctu.dk/tsa). In the present trial sequential analysis, we estimated the RIS and built O’ Brien-Fleming α-spending boundaries by using type I error of 5% and type II error of 20%, which were two-side values. If the cumulative Z-curve crossed the trial sequential monitoring boundary or RIS boundary, no further trials were considered to be needed and firm evidence was obtained.We performed a trial sequential analysis (TSA) to assess if the available evidence is up to the required information size (RIS) for robust conclusion . For conThe initial search identified 1986 relevant studies. After 344 duplicate studies were excluded, 1,642 articles remained. Then 1,584 articles were excluded after screening the titles and abstracts according to the eligibility criteria and 58 potential articles were reviewed for full text. After reading the full text, 39 articles didn’t meet the inclusion criteria: nine studies were review articles; 20 articles provided insufficient data; 10 articles reported wheezing or other allergic disease. Finally, 19 eligible studies were included in the present meta-analysis  Hijazi .16 case-control studies and three cohort studies were included in our meta-analysis. Studies were performed in Asia, Europe and America, respectively. The participants were asthmatic patients or non-asthmatics, including children, adolescents and adults. We extracted the outcomes of serum vit A and vit A intake levels in the asthma and healthy group. As the studies of Bai and Bishopp showed, the study population was respectively divided into Severe, Moderate, Mild, Control groups  and Seve2 = 99.5%, Tau2 = 4.6975)   . The metau2 = 0) .2 = 72.8%, Tau2 = 0.0222)    . Two cohau2 = 0) . However= .0157) .2 = 99.4%, Tau2 = 15.9572). Similar results were observed in subgroups of children, children and adolescents or high-quality studies. However, patients with asthma had higher serum vit A levels than healthy controls in European populations  or adults   . No sign 0.1893) .In trial sequential analysis of the comparison of serum vit A levels between asthma and control groups, we estimated a required sample size of 13,863, and the cumulative Z-curve significantly crossed the conventional monitoring boundary and trial sequential monitoring boundary, but didn’t cross the RIS boundary, further suggesting that the pooled result is less likely to be a random finding owing to a lack of power or multiple testing if bias could be ignored .p = 0.451, Egger’s test: p = 0.452). The funnel plot was shown in Given the limited number of studies included in the pooled analysis, we performed publication bias test and sensitivity analysis for the pooled result which included 12 studies. Begg’s test and Egger’s test were conducted to evaluate the publication bias and the results revealed that no significant publication bias existed among our studies (Begg’s test: Asthma is characterized by chronic airway inflammation and many features of asthma are caused by the release of pro-inflammatory mediators induced by oxidants . OxidatiVit A is primarily stored in the liver, which closely regulates the circulating retinol levels, and serum retinol levels do not decline until the liver is almost depleted . Serum vin utero milieu can decrease the risk of asthma in children (Few human studies, to our knowledge, have assessed the risk of child asthma in relation to pregnancy intake of vit A. Many aspects of maternal-fetal transfer of retinoic acid and carotenoid, their metabolism in developing tissues, and the control of homeostasis in the case of excessive maternal dietary vit A intake are still poorly known . Throughchildren . Our anachildren . We specSubgroup analysis revealed that in Asian populations, the serum vit A concentration in patients with asthma was lower than that in healthy controls, while an opposite result was obtained in European populations. The disparity of results for different ethnicity might be explained by genetic variance, culture and dietary habits, socioeconomic status, healthcare system, and so forth . A recenOur study has several limitations. First, any dietary assessment method is subject to measurement error. The use of both dietary recall instrument and food frequency questionnaires to estimate dietary vit A intake provided relatively imprecise quantitative estimates. Second, assessing the dietary habits of vit A in young children seems difficult, because they often eat little food and are unable to adequately report their vit intake. In practice, parents are unlikely to always be good surrogate reporters for their children’s diet. Third, studies in humans are limited by potential toxic effects and the lack of viable biomarkers to assess appropriate or subtoxic status. Thus, no randomized controlled study was included in present study to evaluate the effect of vit A supplementation on asthma. In addition, more relevant cohort studies are needed to be included in our pooled analysis to further enhance the stability of the result.In conclusion, our meta-analysis confirms that serum vit A levels are lower in patients with asthma than in healthy controls, particularly in Asian and non-adult subpopulations. Relatively higher vit A intake during pregnancy is associated with an increased risk of asthma at age 7 years. There is no significant correlation between vit A intake and asthma risk in children, nor between serum vit A levels and asthma risk. Our analysis also suggests that the interaction of vit A and asthma may depend on age, ethnicity, or other factors, or be obscured in heterogeneous populations. Therefore, more studies are needed to further explore the association of vit A and asthma.


Benzene is a known carcinogen for adult leukemia. Exposure to benzene through parental occupation and the use of household products has been associated with childhood leukemia (CL). Ambient benzene has also been associated with CL and central nervous system (CNS) tumors. We aimed to investigate whether the higher ambient levels of benzene in proximity of petrol stations are associated with a greater risk of childhood cancers, leukemia, and CNS tumors.2, distance to highways, level of urbanization, and presence of a cantonal cancer registry. In addition, we ran a meta-analysis pooling current results for CL with those of previous studies.We identified children diagnosed with cancer at age 0–15 years during 1985–2015 from the Swiss Childhood Cancer Registry and selected 10 age and sex-matched controls per case from national censuses. We calculated the distance from children’s home to the nearest petrol station using precise geocodes. We estimated odds ratios using conditional logistic regression adjusting for ambient levels of NOWe identified 6129 cases, of which 1880 were leukemias and 1290 CNS tumors. 24 cases lived within 50 m from a petrol station. The adjusted odds ratio of a cancer diagnosis for children thus exposed compared to unexposed children (> 500 m) was 1.29 (0.84–1.98) for all cancers combined, 1.08 (0.46–2.51) for leukemia, and 1.30 (0.51–3.35) for CNS tumors. During 2000–2015, when exposure assessment was more precise, the adjusted odds ratio for any cancer diagnosis was 1.77 (1.05–2.98). The summary relative risk estimate for CL in the meta-analysis including four studies was 2.01 (1.25–3.22).Our study provides weak support for an increased risk of childhood cancers among children living close to petrol stations. A meta-analysis including our study suggests an increased risk for CL.The online version contains supplementary material available at 10.1007/s00420-021-01767-y. Little is known about potential environmental risk factors of cancers in childhood. The most common cancers affecting children in most world regions are leukemias and tumors of the central nervous system (CNS)  SAEFL . BenzeneThree case–control studies investigated the risk of childhood leukemia associated with residential proximity to petrol stations  are at greater risk of developing childhood cancer. We separately investigated all diagnostic groups combined, leukemia, and CNS tumors using exposure at birth and at diagnosis. We also considered possible differences in associations by sub-periods accounting for the decline in background levels of benzene over the 1985–2015 study period.http://map.geo.admin.ch). We obtained precise geocodes to within 50 m for approximately 93% of the available cases . The SCCR is a nationwide cancer registry with an estimated completeness of over 90% since 1985 and about 95% since the mid-1990s , leukemia (ICCC3 main group I.), and CNS tumors (III.). We selected these outcomes a priori based on previous studies and the number of cases in the SCCR available for analysis (minimum threshold 1000 cases). For leukemia, we conducted a separate analysis for cases diagnosed under 5 years of age.We obtained individual data on the Swiss resident population, including place of residence, from the Swiss national censuses  through the Swiss National Cohort. We randomly sampled ten controls per case matched by age, sex, and census corresponding to year of diagnosis of the index cases. For cases diagnosed between census years, we sampled controls probabilistically from either the previous or following census, attributing more weight to the census closest to the index cases’ year of diagnosis. For example, if a case was diagnosed in 1993, we sampled controls with probability 0.7 and 0.3 from the 1990 and 2000 census, respectively. We followed the same approach to select controls for analysis at time of birth, but only sampled children aged < 1 year old at time of census. We selected ten controls per case to approach statistical power Taylor .We extracted exact geocodes of all petrol stations registered in the Swiss Business Censuses, which have been conducted by the Swiss Federal Office of Statistics in 1995, 1998, 2001, 2005, 2008, and annually since 2011. We calculated the minimum (Euclidean) distance of the cases’ and controls’ residence to the nearest petrol station recorded in the latest business census preceding the index cases’ diagnosis, except for the years 1985–1994, for which we used the 1995 Swiss Business Census for lack of an earlier census. We only considered the locations of petrol stations, excluding automotive repair garages or service stations. We calculated distance to petrol stations based on the locations recorded in a single business census year for each case and its matched controls, even for cases diagnosed between population census years, for whom we sampled controls randomly from both the preceding and the following census.2 (µg/m3) as estimated by the national dispersion model PolluMap in 1990, 2000, and 2010 for a nationwide grid of cells of 200 × 200 m  outdoor air concentration level of NOWe used conditional logistic regression conditioning on matched case–control sets to estimate odds ratios (ORs) and 95% confidence intervals for the following categories of distance to petrol stations: ≤ 50, > 50–100, > 100–250, > 250–500, > 500 m (reference category). No cases nor controls were lost to the analyses due to missing data except for missing geocodes. We report ORs unadjusted and adjusted for the potential confounders considered. We carried out separate analyses by restricting the study period to the more recent periods 1995–2015 and 2000–2015, respectively. The rationale for these analyses was: first, to reduce the risk of exposure misclassification due to the lack of contemporary data on the locations of petrol stations before 1995; and, second, to allow for potentially altered exposure-outcome relationships after the enforcement of tighter clean air regulations, in particular limiting the benzene content of petrol to 1% volume in the year 2000.In an additional meta-analysis, we pooled our results with those of the three previous studies included by Steinmaus and Smith  to estimWe used the R language for statistical computing version 3.6.0 for all analyses, including GIS calculations to determine levels of exposure . Distances from cases’ home to the closest petrol station ranged from 0 m (i.e. children living in a building with a built-in petrol station) to 28.4 km. 24 cancer cases lived in close proximity to a petrol station (≤ 50 m) at diagnosis, six of which were diagnosed with leukemia and five with CNS tumors (Table The unadjusted odds ratio of a cancer diagnosis for children living in close proximity to a petrol station compared to unexposed children (> 500 m) was 1.35  for all cancers combined, 1.10 (0.47–2.56) for leukemia, 0.91 (0.28–2.99) for leukemia in children under 5 years of age, and 1.47 (0.57–3.75) for CNS tumors (Table I2 = 21%). However, given the small number of included studies, the 95% confidence interval of the heterogeneity statistic was large (0–95%).The summary relative risk estimate from the random-effects model of our meta-analysis including the results of the three previous studies and our own analysis on the risk of childhood leukemia was 2.01 (1.25–3.22). All four original studies reported positive associations with odds ratios ranging from 1.08 to 4.00  among children living in close proximity of a petrol station when assessing exposure at diagnosis. The observed association was stronger during the last two decades compared to the full study period (1985–2015), and strongest during 2000–2015, a sub-period, during which ambient exposure levels were substantially lower. The observed association appeared to be stronger for CNS tumors; there was little indication of an association for leukemia nor for leukemia in children under 5 years of age. However, a meta-analysis pooling our results with those from three previous studies found evidence of an increased risk of childhood leukemia. In the analysis of residence at birth, we found little indication of an association between proximity to petrol stations and childhood cancer for the entire study period. However, we did observe some indication of an increase in cancer risk during the later sub-periods.Previous studies investigating cancer risks associated with residential proximity to petrol stations focused exclusively on childhood leukemia. Using a fixed effects model, a first meta-analysis of three previous studies, which included two French studies  and of the locations of petrol stations, minimizing the risk of misclassification bias. Among the 24 exposed cases in our full analysis at diagnosis, the margin of error of the geocodes of the residential address was less than 100 m in 22 instances; it was less than 50 m for all 17 exposed cases included in the analysis for the 2000–2015 sub-period. Similarly, the geocodes were accurate to < 100 m for 13 out of the 16 cases exposed at birth and accurate to < 50 m for all 11 exposed cases included in the analysis for the 2000–2015 sub-period. A Greek study suggested that benzene concentration in outdoor air reverts to background levels already at 50 m from a petrol station  and the third most important diagnostic group after leukemias and CNS tumors in absolute numbers. This finding concurs with a Californian study that also observed a higher incidence of neuroblastomas among the offspring of women exposed to higher ambient levels of benzene around their homes during pregnancy  of petrol stations. The number of exposed cases included in our study was small and does not allow any conclusions for specific diagnostic groups. However, a meta-analysis combining results of the present and three previous studies suggests that living near a petrol station is associated with an increased risk of childhood leukemia.Supplementary file1 (DOCX 61 KB)Below is the link to the electronic supplementary material.


It is unclear whether uterine carcinosarcoma (UCS) is more aggressive than endometrial serous carcinoma (SC) and clear cell carcinoma (CCC).To compare the prognosis of UCS to that of endometrial SC and CCC, through a systematic review and meta‐analysis.vs SC and/or CCC. HRs for death with 95% confidence interval were extracted and pooled by using a random‐effect model. A significant P‐value <0.05 was adopted.Four electronic databases were searched from January 2000 to October 2020. All studies assessing hazard ratio (HR) for death in UCS P = 0.008) and at early stage . Similar results were found for UCS vs SC  and UCS vs CCC .Six studies with 11 029 patients  were included. UCS showed a significantly worse prognosis than SC/CCC both overall (HR = 1.51; Compared to SC and CCC, UCS has a significantly worse prognosis, with a 1.5–1.6‐fold increased risk of death. This might justify a more aggressive treatment for UCS compared to SC and CCC. Further studies are necessary to define the prognostic impact of different molecular subgroups. Uterine carcinosarcoma shows worse prognosis than serous and clear cell carcinoma; this could impact patient management. UDC‐DDC was not considered because there are too few studies assessing its prognosis in comparison to other histotypes. Our aim was to determine if a more aggressive management is justified in UCS.22.1The several stages of the systematic review and meta‐analysis  were defined before the beginning of the study, based on methods of previous studies.2.2Four electronic databases  were searched from January 2000 to October 2020 by using the following combination of text words: (uterine OR endometr*) AND  AND (serous OR clear cell). The data search was conducted in November 2020. All studies reporting hazard ratios (HR) for overall survival in UCS vs other high‐grade endometrial carcinoma were included. Exclusion criteria were: overlapping patient data, different endometrial carcinoma histotypes lumped together in the analysis, reviews. Reference list of eligible studies were also searched.2.3Data were extracted from primary studies according to the “PICOS”,2.4The risk of bias within studies was assessed by using the QUADAS‐22.5I2), as previously described.HRs with 95% CI were pooled by using a random effect model, based on the assumption that results may vary based on factors such as geographical setting. Results were reported graphically on forest plots with 95% confidence interval (CI). Statistical heterogeneity among studies was quantified by using Higgins’ inconsistency index I2, as pre33.1Six studies with 11029 patients  were included.3.2For the “patient selection” and the “reference standard” domains all studies were considered at low risk of bias since they exhaustively reported inclusion criteria and period of recruitment and performed multivariate Cox regression survival analysis.For the “index test” domain, two studies reported that histological slides were reviewed and were considered at low risk,For the “flow and timing” domain two studies were considered at unclear risk since they did not report the follow‐up duration,The results of the risk of bias assessment are reported in Figure 3.3Based on the available data from the primary studies, we consulted to define the following analyses: UCS vs SC/CCC (any stage); UCS vs SC/CCC (early‐stage only); UCS vs SC; UCS vs CCC.P = 0.008); statistical heterogeneity among studies was low (I2 = 29.09%)  Figure .P < 0.001), with null statistical heterogeneity among studies (I2 = 0%)  Figure .P < 0.001), with low heterogeneity (I2 = 20.05), and CCC , with null heterogeneity (I2 = 0%)  Figure .The funnel plot showed no significant risk of publication bias Figure .4This study showed that UCS has a significantly increased hazard of death (1.5–1.6 fold) compared to both SC and CCC, independently of FIGO stage.Histopathological features, such as histotype, grade and lymphovascular space invasion (LVSI), are of paramount importance in the prognostic stratification of endometrial carcinoma. In fact, the current ESGO/ESTRO/ESP system identifies five risk categories to drive the patient management: low risk, intermediate risk, high‐intermediate risk, high risk, advanced/metastatic. In such system, UCS is lumped together non‐endometrioid carcinomas; this means that UCS is considered at intermediate risk when limited to the endometrium, at high‐risk in the case of FIGO stage I‐II and III‐IVA with no residual disease, and advanced/metastatic in the case of FIGO stage III‐IVA with residual disease or IVB.In recent years, The Cancer Genome Atlas (TCGA) and subsequent studies showed that endometrial carcinoma can be subdivided into four molecular prognostic subgroups, i.e. POLE‐mutated , microsatellite‐instability/mismatch‐repair deficient , copy‐number‐low/no specific molecular profile  and copy‐number‐high/p53‐abnormal .Despite showing an outstanding prognostic value, the TCGA might be affected by further relevant histopathological factors such as tumor budding or microcystic, elongated and fragmented (MELF) invasion patternWe found that UCS showed a significantly worse prognosis than SC and CCC. Considering all patients independently of FIGO stage, UCS showed a 1.51‐fold increased hazard of death compared to SC/CCC. We also performed a subgroup analysis to compare the hazard of death in UCS to that of SC and CCC separately; we found very similar results (HR = 1.534 for SC and 1.600 for CCC). On the one hand, these results support that SC and CCC have a similar prognosis and thus should be included in the same risk category; consistently, our previous study showed that CCCs of the CNL/NSMP and CNH/p53abn groups  might be considered. Further studies in this field are warranted to assess the prognosis and the optimal management of these histotypes stratified according to the molecular signature.The authors report no conflict of interest.AT and AR: conception, protocol, data extraction, risk of bias assessment, data analysis, manuscript preparation, results interpretation, disagreement resolutions. DR, MM: protocol, study selection, manuscript preparation, results interpretation, disagreement resolutions. VDV and UV: protocol, electronic search, manuscript preparation, disagreement resolutions. RS: protocol, manuscript revision, results interpretation, disagreement resolutions, supervision. FZ and LI: conception, protocol, manuscript revision, results interpretation, disagreement resolutions, supervision.


ABCG1, CPT1A, and SREBF1 genes on serum TG levels were selected. The National Institutes of Health (NIH) checklist was used to assess the quality of included articles. Among 2790 articles, ten studies were included in the quantitative analysis and fourteen studies were included in the systematic review. DNA methylation of ABCG1 gene had significant positive association with TG levels . There was significant inverse association between DNA methylation of CPT1A gene and serum TG levels . DNA methylation of SREBF1 gene was positively and significantly associated with serum TG levels . DNA methylation of ABCG1 and SREBF1 genes has positive association with serum TG level, whereas this association is opposite for CPT1A gene. The role of epigenetic factors should be considered in some populations with high prevalence of hypertriglyceridemia.Epigenetic modifications might be associated with serum triglycerides (TG) levels. This study aims to systematically review the studies on the relationship between the methylation of specific cytosine-phosphate-guanine (CpG) sites and serum TG levels. This systematic review and meta-analysis study was conducted according to the PRISMA 2020  statement. A systematic literature search was conducted in Medline database (PubMed), Scopus, and Cochrane library up to end of 2020. All observational studies  were included. Studies that assessed the effect of DNA methylation of different CpG sites of  Elevated level of serum triglycerides (TG) is one of the major components of the metabolic syndrome. It is associated with adverse health effects including cardiovascular disease (CVD), obesity, and insulin resistance –3. Some Epigenetic processes are natural and require for functions of various organisms. However, their improper occurrence will have detrimental impacts on health and behavioral. Epigenetic changes are DNA changes without any effect on DNA sequences but impact on gene expression and activity ,10. SeveABCG1, CPT1A and SREBF1 have been assessed more than others. The contradictory findings of various studies show the importance of providing a holistic overview. Therefore, this systematic review and meta-analysis aims to provide a summary of the literature that have evaluated the relationship between methylation of different CpGs of ABCG1, CPT1A, SREBF1 genes and serum TG levels.Several studies have assessed the relationship between DNA methylation at different loci of different genes with serum TG levels, and had inconsistent findings. Some results did not show significant association between DNA methylation and TG levels ,13, wherThe current systematic review and meta-analysis study was conducted according to the PRISMA 2020  statement . The proTwo reviewers (SMT and MHB) independently reviewed and screened the appropriate published papers based on title, abstract, and full text. In addition, the reference lists of related review articles were checked to find undetected relevant studies. Any discrepancy related to eligible records was resolved by the third reviewer (RK).Only English-language articles and human studies were included. We included studies that extracted DNA from blood samples and measured DNA methylation. All observational studies  on individuals over 18 years of age that assessed the effect of epigenetic changes on serum TG levels were included without restriction of gender, race, ethnicity, and year of publication.Those papers with the following criteria were excluded: duplicate publications and studies that assessed the effect of hypertriglyceridemia on epigenetic changes.ABCG1, CPT1A, and SREBF1 were greater than others. So, we selected them for the meta-analysis. Data extraction was conducted by two reviewers (SMT and MHB) independently and was checked by the third reviewer (RK). The following information was extracted from eligible studies: first author, publication year, study design, sample size, age, body mass index (BMI), the gene(s) and loci and type of tissue sample.The number of studies on some genes including In order to evaluate the risk of bias of 14 included studies in the systematic review, two reviewers  independently assessed the quality of the articles by National Institutes of Health (NIH) Quality Assessment Tool . All inc2 index. The pooled results were calculated by the random-effects model.The β-coefficient values of selected studies were applied for pooled analysis. The potential heterogeneity across studies was evaluated using the Cochran's Q-test and was expressed using the ISubgroup analyses based on CpG sites were performed to seek the sources of heterogeneity. In addition, meta-regression was used for assessing the mean age, mean BMI, sample size and the year of publication of studies as the possible source of heterogeneity. The sensitivity analyses were performed by excluding one study at a time to gauge the robustness of our results. Publication bias was evaluated by Funnel plot and Egger's test. The possible publication bias was adjusted using the trim and fill method. Statistical analyses were conducted using the STATA 12.0 software . P < 0.05 was considered as significance level.The flow diagram for the process of study selection is shown in Fourteen eligible studies were included in the systematic review. ABCG1 gene , CPT1A gene  and SREBF1 gene  were assessed. Methylation at seven CpG sites in ABCG1, five CpG sites in CPT1A and three CpG sites in SREBF1 genes showed significant association with TG.All the selected studies were conducted among individuals over 18 years of age, and their designs were cohort, cross-sectional and pooled analysis of cohorts. The sample tissue for all of them was blood cells. There was a wide difference in sample size. It varied from 37 to 4,261. Some studies conducted more than one assessment including discovery set, replication set and a pooled analysis of both. Methylation of CpG site in ABCG1 gene had significant positive association with serum TG levels  using random effect model. There was significant heterogeneity (P < 0.001), with I2 values of 95%. Therefore, the subgroup analysis, meta-regression and sensitivity analysis were used to explore the potential sources of heterogeneity , cg27243685  and others CpG sites   was positively and significantly associated with serum TG levels. Only one paper had the relevant effect size for each of the following sites, cg07397296, cg01881899, cg02370100, ABCG1-CPG3. So we considered these sites as one group. The heterogeneity was significant for each three groups of CpGs . It explained 92.65% of the heterogeneity. Mean BMI, sample size and the publication year of studies did not lead to heterogeneity  as the main source of the heterogeneity . Furthermore, with excluding the study with unadjusted effect size (2 = 95.1%).Results of sensitivity analysis showed that the pooled effect size (β) and heterogeneity did not influence after excluding studies one by one. After excluding the study of Guay and cols. , which wect size , the pooFunnel plot showed asymmetry. The P-value for Egger's test was < 0.0001, which revealed obvious publication bias among studies. Therefore, trim and fill analysis was performed and the pooled effect size was obtained ; number of trimmed studies: 10).CPT1A gene had significant inverse association with serum TG levels  using the random effects model. The heterogeneity was significant . 2 = 95.3%), cg17058475  and other CpG sites  . Two studies had the relevant effect size for cg09737197, and one study had the relevant effect size for cg01082498, so we considered these sites as one group. The heterogeneity was significant for each three groups of CpGs (p < 0.001). The results of meta-regression analysis showed that mean age, mean BMI, sample size and the year of publication had no significant effect on the association between DNA methylation of CPT1A gene and serum TG levels (p > 0.05)  .Results of sensitivity analysis showed that the pooled effect size (β) was not influenced after excluding studies one by one. Funnel plot was asymmetry. The P-value for Egger's test was < 0.001, thus there was obvious publication bias among these studies. Trim and fill analysis were applied, but no studies were filled. It showed that the publication bias had a non-significant effect on the results.SREBF1 gene was positively and significantly associated with serum TG levels . The heterogeneity was significant . The subgroup analysis based on CpG sites showed that pooled estimates for CpGs of cg11024682  and also for other group   were positive and significant (SREBF1 gene on serum TG levels (p > 0.05). Results of sensitivity analysis showed that the pooled effect size (β) was not influenced after dropping studies one by one. Funnel plot was asymmetry. The P-value for Egger's test was 0.001. Therefore, there was publication bias among these studies. So, trim and fill analysis was performed and the pooled effect size obtained ; number of trimmed studies: 6).The findings of meta-analysis on 5 studies showed that DNA methylation of nificant . One stuABCG1, CPT1A, SREBF1 and serum TG levels. Higher methylation of ABCG1 and SREBF1 genes, and lower methylation of CPT1A gene were significantly associated with higher serum TG levels. These findings can explain the reason of the large variations in the prevalence of hypertriglyceridemia in different populations.The present meta-analysis investigated the association between DNA methylation of different CpG sites of ABCG1 gene is located on chromosome 21 and encodes ATP-binding cassette sub-family G member-1 protein and controls macrophage lipoprotein lipase (LPL) activity. LPL controls the level of circulating blood lipids such as TG. Therefore, circulating TG could be affected by the level of ABCG1 expression  and carnitine palmitoytransferase-2 (CPT2) transfer long-chain fatty acids into mitochondria. CPT2 exists in all tissues. However, CPT1 is expressed mostly in three specific tissues including liver (CPT1A), muscle (CPT1B) and brain (CPT1C)  ,28. CPT1d kidney . The lev00574958 –25,30,3100574958 ,24,30,3100574958 ,16,24,30eridemia ,16. DNA CPT1A methylation but not vice versa  gene is located on chromosome 17 and encodes sterol regulatory element binding proteins (SREBPs)  . SREBP-1proteins ,33. Acco11024682 ,15,23–2511024682  has signeridemia ,23. The 11024682 . MicroRNtty acid ,35.ABCG1, CPT1A, and SREBF1 genes was associated with some cardio-metabolic risk factors including total cholesterol and insulin levels, as well as anthropometric indices of general and abdominal obesity. Therefore, study on these genes can be important in prevention of non-communicable diseases (Recent studies demonstrated that the methylation of diseases ,15,23.According to the current findings, DNA methylation affects gene expression and new therapeutic pathways could be appeared for management of hypertriglyceridemia. Some medications including fenofibrate might affect serum TG levels through altering DNA methylation . HoweverThe present study has some limitations. First, the selection bias was unavoidable. Second, heterogeneity existed in our meta-analysis, and it could not be solved by applying any statistical method, differences in the genetic methods, age, BMI, or race of participants in various studies might be the reasons of this heterogeneity. The main strength of our study is its novelty; to the best of our knowledge, no previous systematic reviews and meta-analysis have specifically evaluated the relationship between methylation of different CpGs of some genes and serum TG levels. Meta-regression analysis was used to find potential variables as the main source of the heterogeneity.ABCG1 and SREBF1 genes have positive association with serum TG levels, whereas this association is inverse for methylation of CPT1A gene. DNA methylation on cg06500161 and cg27243685 at ABCG1 gene, cg00574958 and cg17058475 at CPT1A gene and cg11024682 at SREBF1 gene are correlated with serum TG levels more than other CpGs. Although there are several studies that assessed the effect of DNA methylation on serum TG levels, but limited experience exists on the impact of serum TG levels on DNA methylation. Further studies with long follow up periods are needed to assess the causal effect of DNA methylation on serum TG levels and vice versa.In conclusion, the results of the present meta-analysis show that methylation of The role of epigenetic factors should be considered as one of underlying factors for the considerable variations in the prevalence of hypertriglyceridemia among different populations.


However, smokers had a higher incidence of total complications (p = 0.01), surgical complications (p < 0.01), pneumonia (p < 0.01), and revision surgery (p = 0.01). No significant difference in the risk of blood transfusion (p = 0.42), deep vein thrombosis (p = 0.31), pulmonary embolism (p = 0.34), urinary tract infection (p = 0.46), or mortality (p = 0.39) was found between smokers and non-smokers. In conclusion, the study indicated that tobacco has two diametrically opposite effects on TKA patients: (1) Tobacco increases the incidence of surgical complications, pneumonia and revision after TKA; (2) It decreases the overall risk of being a candidate for TKA.Osteoarthritis and rheumatoid arthritis are the most ubiquitous joint disorders which cause tremendous loss of life quality and impose an economic burden on society. At present, the treatment options for these two diseases comprise non-operative and surgical treatments, among those total knee arthroplasty (TKA). Various studies have recognized smoking as a significant risk factor for post-operative complications. Therefore, the purpose of this study was to examine the impact of smoking on the incidence and post-operative complications after a TKA by a systematic review and meta-analysis. The research was performed using PUBMED, Cochrane Library and EMBASE, extracting data from thirteen suitable studies and incorporating 2,109,482 patients. Cohort studies evaluating the impact of smoking on TKA with sufficient data were included for the study, and cohort studies without a proper control group and complete data were excluded from the analysis. A fixed-effects or random-effects model was used to measure the pooled risk ratio or hazard ratio with 95% confidence interval (CI). Compared to non-smokers, smokers had a significantly lower incidence of TKA ( Osteoarthritis (OA), which affects an estimated 240 million individuals globally with 8.6/1000 new cases per year . Some paHence, it is worthwhile to re-conduct a comprehensive meta-analysis to assess the overall effect of smoking on TKA in OA and RA patients, including the risk before surgery and to re-analyze the impact of smoking on complications after surgery. Due to investigate the real impact of smoking on TKA, we systematically reviewed all the relevant research and performed this meta-analysis from cohort studies.https://www.crd.york.ac.uk/PROSPERO, Identifier: CRD42021235436) , we screened retrieved 1353 studies for review. There were 420 duplicates removed using an approach to ensure accuracy and prevent accidental loss of records. One hundred twenty-one articles on animal research, letters, meta-analyses, reviews, and comments were subsequently removed. The remaining 814 articles were screened by the title and abstract. Seven hundred sixty-three articles were excluded because they did not involve TKA or smoking, and 21 articles were excluded because they were not cohort studies. Out of 32 papers reviewed in detail, 17 were excluded due to no proper control group or proper outcomes  , we sThese 13 studies, representing a total of 2 109 482 patients, came from Switzerland (n = 1), America (n = 4), Germany (n = 1), Spain (n = 2), UK (n = 2), Australia (n = 1), Norway (n = 1), and Singapore (n = 1). Six articles studied whether smoking affected the risk of TKA in patients diagnosed with OA or RA, and nine articles studied the effect of smoking on complications after TKA. The year of publication were from 2012 to 2020, the duration of follow-up ranged from 2 to 26 years, and the mean ages of the patients were between 45 and 74 years old. Eight studies utilized data from prospectively gathered cohorts and other seven studies were retrospective. The NOS score of all the studies was 6.54 ± 1.00, and all 13 studies had adequate quality for meta-analysis. All detailed study characteristics are summarized in 2 > 50%), a random-effects model was employed in the meta-analysis. All the studies indicated that smoking can significantly reduce the incidence of TKA . To decline the high heterogeneity, subgroup analysis was performed according to different outcome indicators. Three studies that used HR had low heterogeneity (I2 = 0%), and meta-analysis of them indicated that smoking can decline the incidence of TKA . However, two studies using the number of surgical cases indicated that there was no statistical difference between smoking and incidence of TKA . Sensitivity analysis was also conducted, yielding similar results  or OA (n = 4). There were two indicators to report the outcome: three studies used HR to report the outcome ,15,38, a results . Meanwhi2 = 60%), a random-effects model was used for the meta-analysis. The results showed that smoking can increase total complications after TKA . The results revealed that smoking can increase surgical complications after TKA , a fixed-effects model was used for the meta-analysis. The results of the analysis revealed that deep wound infection  and superficial wound infection  were more present in the smoking group than in the non-smoking group . The result indicated that smoking increased the risk of pneumonia after TKA . Sensitivity analysis was also conducted, which produced similar results , a random-effects model was used for the meta-analysis. We found that there were no statistical differences between the two groups in terms of the blood transfusion  and the result would be different (p < 0.01).In three studies involving a total of 1,811,012 patients, blood transfusion after TKA was compared. Since the heterogeneity between the studies was significant (I2 > 50%). The results indicated that there were no statistical differences between the two groups concerning deep vein thrombosis , and the result would be changed (p < 0.01).Three of the included studies compared deep vein thrombosis after TKA in the smoking and non-smoking groups with a total of 1,858,448 patients. A random-effects model was employed in the meta-analysis owing to significant heterogeneity (I2 > 50%), a random-effects model was used for the meta-analysis. The results showed that there was no statistical difference between the two groups in terms of the pulmonary embolism  and the result would be statistically significant (p < 0.01).Three studies, including a total of 1,858,448 patients, reported the number of patients who experienced pulmonary embolism after TKA. Since the heterogeneity was significant (I2 > 50%), we used a random-effects model to analyze. Meta-analysis of the included studies suggested that no significant difference in the risk of implant dislocation was found between smokers and non-smokers , and the result would be altered (p < 0.01).Urinary tract infection was mentioned in four studies, including a total of 1,858,448 patients. Due to the high heterogeneity (I2 = 37%); hence, the fixed-effects model was employed in the meta-analysis. The results indicated a significantly increased risk of revision in the smokers after TKA , a random-effects model was employed. Meta-analysis results indicated that there were no statistical differences between the two groups in mortality , and the outcome would be altered (p < 0.01).The mortality after TKA was reported in four studies with a total of 1,867,999 patients. Because of the strong heterogeneity of these experiments  is generally lower in smokers, and the second is that nicotine has a protective effect on chondrocytes. Obesity is a recognized risk factor for knee OA , as wellt for OA . Nicotint for OA . In bothPost-operative complications are a problem that will never be eliminated entirely. All surgeons want to reduce the incidence of post-operative complications, but some are inevitable. In terms of the impact of smoking on TKA post-operative complications, the results of this study are similar to those of previous studies , indicatIn vivo experiment, a custom-made chamber with airflow for rats to inhale cigarette smoke continuously, was established by Chang et al., and it was found that cigarette smoke inhibited early angiogenesis using a femoral osteotomy model, analyzed by radiograph and micro-CT imaging and various biomechanical and biological tests [Further subdividing the total complications, we found that surgical complications mainly caused them. Smokers are more likely to develop deep wound infection, superficial wound infection and wound dehiscence after surgery in comparison to non-smokers by 1.07-fold, 1.08-fold, and 2.83-fold, respectively. Sensitivity analysis confirmed the stability of the positive association between smoking and the risk of surgical complications. al tests . Other eal tests , suppresal tests  and incrRegarding internal medicine complications, pneumonia was the only statistically significant complication, which means smoking has little effect on post-operative internal medical complications except for pneumonia. Nevertheless, all the internal medicine complications had a high heterogeneity, and their results were unstable using sensitivity analysis. The reason may be that the number of literatures included in the study was too small, and the difference in sample size between studies was too large. For example, Sean et al.  includedRevision is another indicator that surgeons are very concerned about after surgery. Common reasons for post-operative revision include instability, implant loosening, arthrofibrosis, and deep infections . AnalyziSmoking cessation is another hot spot that orthopedists focus on. In this study, seven included studies distinguished the former smokers and current smokers, four of them focused on the incidence of TKA ,14,37,38Although these data revealed a very interesting impact of smoking on TKA, our conclusion must be treated with caution and considered in the presence of possible limitations. Firstly, the meta-analysis included just cohort studies, and observational studies can only provide details about correlations, but not the causality. Secondly, the number of included studies was insufficient, especially in medical complications and mortality indicators. This lead up to the excessive heterogeneity of the two indicators, and the results were unstable. Moreover, the definitions of smoking status were diverse and ambiguous. Most studies judged patients’ smoking status only based on their memories; therefore, the amount of smoking cannot be quantified. This would cause the subjective deviation of the patients, which may affect the results.Meanwhile, despite the fact that these studies attempted to match smokers’ and non-smokers’ other conditions, we cannot rule out the possibility that smoking patients have more surgical contraindications, resulting in lower surgery rates. Patients’ symptoms or radiological changes are better ways to evaluate the progress on knee disease, but the current researches have different opinions. Felson et al. insist that smoking modestly protects against the development of knee OA by assessing weight-bearing knee radiographs ,56. WildIn conclusion, this study suggests that tobacco use can enhance the incidence of complications after TKA for both OA and RA patients, especially when it comes to surgical complications and pneumonia, but decreases the risk of TKA implantation in the population. Although smoking reduces the risk of TKA, we would not recommend smoking to prevent the occurrence or progression of OA or RA. However, smoking cessation should be encouraged, as it cannot affect the existing protective effect of tobacco on the knee joint, and can reduce post-operative complications. The deeper meaning is also that chemoprophylaxis drugs based on nicotine analogs should be further studied with the aim of producing medicine that can delay severe knee OA or RA. The possibility of patient selection due to comorbidity attributed to smoking must be ruled out in further studies.


VDR) polymorphisms and polycystic ovary syndrome (PCOS) are inconclusive.The results of case-control studies on the association between vitamin D receptor gene  with a 95% confidence interval were determined.PubMed, Scopus, Science Citation Index, and Google Scholar databases were searched to retrieve related reports released up to the end of 2020. To evaluate the association strength of the VDR BsmI polymorphism did not show association with PCOS susceptibility.In total, 1,119 subjects (560 PCOS cases and 559 controls) from 7 studies were included which met the inclusion criteria. A statistically significant association between the TaqI polymorphism and PCOS susceptibility was found in the Eastern Mediterranean Regional Office population (T vs. t: OR = 0.715; TT vs. tt: OR = 0.435, p VDR ApaI in the dominant model, VDR FokI in the recessive model, and VDR TaqI polymorphisms in all genetic models are associated with vulnerability to PCOS. However, further studies with a larger sample size are required.Our meta-analysis revealed that the  Polycystic ovary syndrome (PCOS) is one of the most common syndromes in reproductive-age people, distinguished by clinical characteristics such as prolonged anovulation, menstrual dysfunction, and polycystic ovaries . According to the National Institutes of Health 1990 criteria and the Rotterdam 2003 criteria, the combined prevalence of PCOS is Interactions between genetic and environmental factors are believed to play a significant role in the incidence and progression of PCOS . Insulin resistance and hyperinsulinemia are recurrent metabolic disturbances in PCOS. Research demonstrates that levels of vitamin D could be related to hormonal and metabolic conditions (11). Vitamin D is converted to 1, 25-dihydroxycholecalciferol in the kidneys and liver . Lines of evidence suggest a significant relationship of vitamin D levels with the pathogenesis, signs, and symptoms of PCOS (14). A recent meta-analysis identified more considerable variation in serum 25-hydroxyvitamin D, total cholesterol, serum insulin, low-density lipoprotein cholesterol, and triglycerides in women with PCOS than in healthy subjects (15).VDR), a ligand-dependent transcription factor belonging to the steroid/thyroid hormone receptor superfamily, is responsible for vitamin D's effect. VDR is commonly found in many tissues of the female reproductive system and regulates the biological effects of vitamin D . As is illustrated in figure 1, VDR and unoccupied retinoid X receptor form a heterodimer transcription unit which regulates the transcription through binding to the vitamin D response element in the promoter region of target genes . About 3% of the human genome, including genes essential to glucose metabolism, are regulated by VDR (13).The vitamin D receptor (VDR gene is located on chromosome 12q13.11 and contains 14 exons that provide instruction for a 427-amino-acid protein (20). The VDR gene contain 4 mostly reported single nucleotide polymorphisms (SNPs) including FokI (rs10735810) in exon 2, ApaI (rs7975232) in intron 8, TaqI (rs731236) in exon 9, and BsmI (rs1544410)in intron 8(21). The previous meta-analyses have reported the association of VDR gene polymorphisms with PCOS risk . However, these analyses must be updated and performed on specific populations. It has been shown that the VDR polymorphisms may correspond to PCOS susceptibility in the Eastern Mediterranean Regional Office (EMRO) population, even though results are as yet uncertain and conflicting owing to the small sample size and limited statistical power (23-33). Appropriate and accurate data from developing countries in the EMRO are lacking; the majority of published data from these areas are outdated, heterogeneous, and suffering from limited sample sizes (34).The VDR gene polymorphisms with susceptibility to PCOS in the EMRO population.Consequently, the present study aimed to conduct an updated systematic review and meta-analysis to more reliably examine the association of The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to conduct the present meta-analysis (35). An online search was carried out in PubMed, Scopus, SCI, and Google Scholar to retrieve related reports up to the end of 2020. The search strategy was based on terms and keywords including: `polycystic ovary syndrome OR PCOS', `vitamin D receptor OR VDR', and `polymorphisms OR variants'. Manual searches in the references cited within retrieved articles were also performed to select the relevant publications. Other prospective studies not included in the database were manually sought in the references of the obtained papers.VDR gene with PCOS, investigations on the accessibility of genotype distributions in cases and controls for calculating odds ratios (ORs) and their 95% confidence intervals (CI), as well as studies on PCOS diagnosis using Rotterdam and National Institute of Child Health and Human Development criteria. Case reports, publications without full text, reviews, editorial comments, repeat publications, those with unavailability of the genotypic data, reports on the association of other polymorphisms in the VDR gene with PCOS, and the current meta-analysis did not include research that used an animal model. In the case of multiple publications reported by the same team, the most recent or largest sample sizes were chosen.The inclusion criteria for this meta-analysis required that the articles be written in English, and included case-control studies, research on the association of ApaI, BsmI, FokI, and TaqI polymorphisms in the The eligible studies were selected according to the following criteria by 2 independent authors (A.Az and A.SH), and any disagreements were decided by a third reviewer. The first author of each study, publication year, country of origin, the sample size of cases and controls, and data of the frequency genotype of distribution were recorded.The study was performed under the approval of the Ethical Committee of Kurdistan University Medical Sciences, Sanandaj, Iran (Code: IR.MUK.REC.1398.216).VDR gene variants and PCOS risk was determined. Allelic, recessive, and dominant genetic models were used in all analyses. A Chi-square test based on Q statistics was used to evaluate the inter-study heterogeneity, wherein the fixed model was applied when the p-value was Using crude ORs and their 95% CI, the statistical power of the relationship between VDR gene or PCOS were excluded from the extracted records, which consisted of 152 papers. Then, we excluded 3 studies because there was inadequate evidence to quantify ORs and 95% CIs, or it was not a case-control design. Finally, this meta-analysis contained 7 articles conducted on the association of ApaI, BsmI, FokI, and TaqI polymorphisms in the VDR gene with risk of PCOS in the EMRO population.The studies used in this meta-analysis were selected using the preferred reporting items for systematic reviews, and meta-analyses flow diagram, as seen in figure 2. To begin, we searched the abovementioned databases and found a total of 1,516 reports. The 1,354 duplicates and ineligible records were removed before screening, and reviews, irrelevant reports, and studies not considering the VDR gene ApaI rs7975232 . No significant relationships of the VDR ApaI polymorphism with susceptibility to PCOS were observed in the other models . The heterogeneity test found that no substantial heterogeneity occurred in any of the included reports, and the fixed effects model results of the Mantel-Haenszel method were added to the analysis. There was no significant correlation between the VDR BsmI variant and PCOS susceptibility in the included EMRO population . A significant association of decreased risk was observed in the recessive genetic model  . In the allelic (F vs. f), homozygote (FF vs. ff), and dominant (FF vs. Ff+ff) genetic models, the pooled analysis found no significant association between this locus and PCOS risk , and evaluated their association with PCOS risk in the EMRO population. The meta-analysis included a total of 7 articles based on 560 PCOS patients and 559 controls, which showed that the VDR TaqIpolymorphism in all comparisons consisting of allelic, homozygote, dominant, or recessive genetic models was associated with PCOS susceptibility. Furthermore, the VDR ApaI variant in the dominant model and VDR FokIpolymorphism in the recessive model were found to be significantly related to the risk of PCOS. However, the BsmI polymorphism was not significantly correlated with PCOS susceptibility in the included population.In this meta-analysis, we presented the evidence on 4 VDR, as seen in figure 1. VDR gene variations have been linked to serum levels of insulin in women with PCOS in previous investigations (38). Serum 25-hydroxyvitamin D ([25 [[OH]] D) has been demonstrated to have a negative influence on VDR-mediated insulin resistance via regulating the expression of target genes (30). The VDR gene, which is involved in the insulin signaling system, could be a candidate risk factor for PCOS (39).Complex gene-gene and gene-environment interactions have been identified as major risk factors for the development of PCOS. PCOS is often associated with several complications, including hyperandrogenism, oligoanovulation, insulin tolerance, and metabolic anomalies. According to various reports, vitamin D deficiency has been linked to several metabolic risks in women with PCOS . The active form of vitamin D exerts its effect by binding to VDR gene, but they do not affect the VDR protein. ApaI, BsmI, and TaqI variants have also been shown to be in deep linkage disequilibrium (40). Even though these SNPs may not affect structural or protein expression, they can impact VDR transcript stability by adding changes in miRNA binding sites or other regulatory factors and gene expression while they are in linkage disequilibrium with different variants in the VDR gene's 3-untranslated region (41). Nevertheless, VDR mRNA produced by the t allele is more stable in peripheral blood mononuclear cells with the Tt TaqI haplotype than those with the T allele (42). Consequently, these VDR gene polymorphisms could be involved in the development of PCOS; nevertheless, since these polymorphisms are mostly nonfunctional, linkage imbalances with another undisclosed functional variant of the VDR gene seem to be the most plausible reason for the observed association.The polymorphisms ApaI, BsmI (intron 8), and TaqI (exon 9) are adjacent to the 3'-untranslated portion of the VDR BsmI variant and PCOS risk. The association of the TaqI variant with PCOS has been assessed in several studies.In allele comparisons, the pooled results of the current meta-analysis revealed a substantial connection between the TaqI polymorphism and PCOS susceptibility. Our findings revealed a 0.715-, 0.435- and 0.696-fold lower risk for PCOS in the allelic, homozygote, and dominant models, respectively. Accordingly, the recessive genetic model of the TaqI variant (tt vs. TT+Tt) showed a 1.791-fold higher risk for PCOS. We compared minor alleles vs. major alleles in all analysis models. Our data indicated that the minor allele of the TaqI polymorphism  provides a protective genetic background against PCOS and the major allele  is a predisposing factor. Furthermore, the present meta-analysis showed that the ApaI variant is significantly associated with PCOS in the dominant genetic model by increasing the disease risk by 1.466-fold. This highlights the predisposing effect of the minor allele of the ApaI polymorphism. Lack of association for the other genetic models could be due to the quality and power of the included studies and their low sample sizes. Besides, we did not find any significant protective/predisposing association between the VDR TaqISNP was significantly associated with PCOS risk. However, a correlation of VDR ApaI and BsmI with susceptibility to PCOS was not found in any of the included studies (43). In contrast to our findings, a meta-analysis published in 2019 found a link between ApaI and BsmI, and PCOS vulnerability in the Asian population. However, VDR TaqI did not show a connection (22). In a similar study, a group of researchers discovered an essential link between ApaI and PCOS vulnerability but no link between TaqI and risk of PCOS (14). However, they found only a small increase in PCOS risk associated with the BsmI A/G polymorphism in Asians based on ethnic diversity. Overall, this study's results are aligned with some studies  and are in contrast to others (44-46), and might shed some light on how to proceed henceforth in determining the etiology of PCOS. The fact that the meta-analysis contained different studies, with different sample sizes and different statistical abilities may explain the contradictory findings.Consistent with our results, a meta-analysis disclosed that the T allele of the VDR variants is FokI, which is located on exon 2 and results in a protein of different sizes. While this SNP has not been shown to interact with ligand binding, heterodimer formation with retinoid X receptor, or DNA binding, most studies have indicated that the shorter type of the protein (424 aa) is somewhat more active than the longer form (427 aa). However, it tends to be a gene- and cell-type-specific phenomenon, indicating that specific genes and cell types could be more susceptible to the polymorphism's effect than others . According to some research, this polymorphism controls mRNA expression and may lead to different diseases (48). Although our study found that VDR FokI in the recessive genetic model (ff vs. FF+Ff) can influence PCOS, the other genetic models did not reveal significant protective/susceptible effects. Similar to our findings, 2 other meta-analyses also showed that VDR FokI (rs2228570) did not reveal a relationship with PCOS susceptibility . The association of the FokI polymorphism with PCOS susceptibility has been examined in several case-control studies with varied results . These inconsistencies may be due to different sample sizes, included reports and levels of statistical power.Another of the Despite the usefulness of the present meta-analysis , we are aware of several limitations that should be addressed in interpreting our results. These are: the potential language bias from the exclusive focus on English-language publications; the fact that most of the studies were conducted in Iranian populations and the comparatively small number of studies examining the other EMRO populations; the lack of consideration for other factors potentially impacting PCOS susceptibility ; and the relatively small sample size.VDR ApaI in the dominant model, VDR FokI in the recessive model, and VDR TaqI polymorphisms in all genetic models are associated with PCOS susceptibility in the EMRO population. The BsmI variant did not reveal a relationship with PCOS susceptibility. However, these observations may not extend to other ethnic groups. Further analysis with a larger sample size and consideration of other confounding variables are needed before a firm conclusion can be drawn.In summary, the current meta-analysis provided statistical evidence that The authors declare that there is no conflict of interest.


P < 0.001). In the subgroup analysis by ethnicity, STAT4 rs7574865 T allele was shown to be risk factor in SLE in Asian, European, and American origins. Our results do support STAT4 rs7574865 polymorphism as a susceptibility factor for SLE in populations of different ethnic and that its prevalence is ethnicity dependent.Previous studies have reported that STAT4 rs7574865 conferred the susceptibility to systemic lupus erythematosus (SLE). In this study, a meta-analysis (including 32 comparative studies of 11384 patients and 17609 controls) was conducted to investigate the role of STAT4 polymorphism in SLE in a comprehensive way. We found that the Asian population had the highest prevalence of the T allele than any other study population at 32.2% and that STAT4 rs7574865 polymorphism was associated with SLE in the overall population (OR = 1.579, 95%CI = 1.497-1.665,  Systemic lupus erythematosus (SLE) is classified as an inflammatory autoimmune disease characterized by production of autoantibodies to nuclear antigens and immune complex formation , leadingGenome-wide association studies have identified signal transducer and activator of transcription4 (STAT4) as a novel susceptibility gene associated with SLE . STAT4 cAs the investigation varied greatly among studies, the association between STAT4 rs7574865 polymorphism and SLE risk has reported mixed results , which mWe conducted a comprehensive literature search for available articles in which STAT4 polymorphism were analyzed in SLE patients, using the databases of PubMed, Web of Science, CNKI , and Wanfang. The relevant articles were retrieved by keyword combinations as follows: “STAT4,” “Signal transducer and activator of transcription 4,” “rs7574865,” “polymorphism,” and “systemic lupus erythematosus.” The references in the obtained studies were also examined to identify additional studies not included by the electronic databases, with no language or country restrictions.The inclusion criteria were listed as following: case-control studies, original data (independence among studies), and enough data to calculate an odds ratio (OR) with 95% confidence interval (CI). We excluded the following: studies in which the number of risk alleles could not be ascertained or contained overlapping data. These studies were assessed by two investigators independently. In case of any disagreement, it could be resolved by consultation with a third author.We extracted the following information from each article: first author, year of publication, demographics, ethnicity, the numbers of cases and controls, and allele frequency of the STAT4 rs7574865 polymorphism.Z-test, and P < 0.5 was considered statistically significant. In addition, Cochran, s Q statistics was used to assess within-study and between-study variation and heterogeneities. This heterogeneity test assesses the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity was quantified using I2. In our meta-analysis, P < 0.10 for the Q-test and I2 more than 50% was considered that significant heterogenicity among studies could not be ignored. Data were combined using both the fixed effects model (the inverse variance-weighted method) and the random effects model (DerSimonian and Laird method) [We performed meta-analyses to estimate the association between STAT4 rs7574865 polymorphisms and SLE risk by odds ratios (ORs) and its 95% confidence interval (CI). The significance of the pooled ORs was determined by the  method) , 28. We Subgroup analyses were performed by ethnicity, to examine the potential sources of heterogeneity observed in the meta-analyses. Because of the limitations of funnel plotting, publication bias was evaluated using the Egger linear regression test , which mAs shown in P < 0.001) in all participants. The heterogeneity among studies was moderately obvious . Thus, we performed stratified analysis by ethnicity, indicating that the association between risk factor T allele carriers and SLE was significant in Asians, Europeans, and Americans, with no obvious difference. The pooled ORs for the T allele of STAT4 rs7574865 were 1.706  for populations of American, 1.518  for Asian, 1.674  for Europeans. The results of subgroup analysis revealed that between-study heterogeneity was moderately obvious in European  and American , but no such heterogeneity was found in Asian . . .P value > 0.05). . .Sensitivity analysis was conducted to evaluate the influence of a single study on pooled OR by the “trim and fill” method. Corresponding pooled OR was not substantially changed when any individual study was deleted, which confirmed the stability of our overall result. The estimated number of missing studies is 5, and the adjusted pooled OR estimated is 1.514 (95%CI = 1.462-1.567), which showed still significantly increased risk for SLE .Systemic lupus erythematosus is a highly heterogeneous autoimmune disease, with influence of complex genetic. Studies in multiple ethnic populations have reported up to 100 risk loci of importance in SLE, although the mechanisms underlying these associations are still elusive –33.Previous studies suggest that several single-nucleotide polymorphisms (SNPs) in LD in the third intron of STAT4, tagged by rs7574865, were initially demonstrated as SLE risk variants . The minIn our comprehensive meta-analysis, we identified 21 relevant studies including 11384 SLE cases and 17609 healthy controls. The results do support a trend of association between STAT4 rs7574865 polymorphism and SLE risk in overall. When stratified by ethnicity for STAT4 rs7574865 polymorphism, positive correlations were observed in Asian, European, or American origin. Regarding STAT4 rs7574865 polymorphism in overall samples, we observed that the average frequency of T allele was 39.4% in patients with SLE compared with 29.5% in controls. The prevalence of the rs7574865 T allele was found to vary among ethnic populations.Nevertheless, several limitations presented in this meta-analysis should be considered. First of all, the association between the STAT4rs7574865 polymorphism and disease severity and/or clinical features could not be performed limitation of amount of available data. Secondly, our ethnicity-associated results are applicable only to Asian, European, and American patients, as the data obtained from these ethnic groups. In addition, the heterogeneity has been presented obviously in European and American population, in subgroup analysis. Due to population demographics and lower SLE risk predisposition, or publication bias, fewer relevant studies were obtained in European and American, which may have distorted the heterogeneity, even have affected the final result, despite performing the “trim and fill” method and Egger regression test. Last but not least, STAT4 polymorphism may interact with other potential confounding risk factors.In summary, our results stressed the importance of STAT4rs7574865 polymorphisms in increasing the risk of SLE in multiple ethnic groups and that the prevalence of the STAT4rs7574865 T allele may depend on ethnicity, which may improve our understanding of SLE pathogenesis. However, additional research with well-designed and large sample sizes is needed to be carried out about European, American, and other ethnicities in the future.


Gestational diabetes mellitus (GDM) and preeclampsia (PE) are common complications during pregnancy. Studies indicated that abnormal bile acid metabolism is related to its pathogenesis. Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease, which classic symptoms include generalized pruritus that commonly and biochemical evidence of elevated bile acids. Our study aimed to explore the correlation between the ICP presence and risk of GDM, PE incident in pregnant women.A meta-analysis, which included 10 eligible studies including 17,688 ICP cases and 1,386,771 controls, was performed to assess the correlation of ICP with preeclampsia (PE) and gestational diabetes mellitus (GDM). There were 7 studies investigating the relationship between ICP and PE, and 9 studies that evaluated the relationship between ICP and GDM. All eligible studies were screened from Pubmed, Web of Science and EBSCO databases.The results of this meta-analysis indicate that ICP significantly increase the risk for both PE  and GDM . In the sensitivity analysis of GDM, excluding the largest heterogeneity study cannot change the result .This meta-analysis shows that ICP is closely associated with ICP increased risk of PE and GDM) during pregnancy. Both preeclampsia (PE) and gestational diabetes mellitus (GDM) are common metabolic disorders during pregnancy, associated with neonatal and maternal mortality, increased hypertension and type 2 DM after pregnancy Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific condition identified by different degrees of pruritus, abnormal transaminases and elevated serum total BAs, affecting approximately 0.4~4% of pregnancies based on different regions Reviewed studies were screened from PubMed, Web of Science and EBSCO database published from 1 January 2000 to 1 January 2018, with the following medical subject headings (MeSH): intrahepatic cholestasis of pregnancy, obstetric cholestasis; preeclampsia, eclampsia, pregnancy-induced hypertension, gestational hypertension; gestational diabetes mellitus, gestational diabetes; clinical trial, case-control and cohort study The included studies followed the following standards: 1) the clinical manifestation  and the laboratory examination  are necessary for the case/exposure definition; 2) absence of ICP is the primary condition for the control or no-exposure definition; 3) clear definition of the outcomes: PE and GDM; 4) clear and separate data for the outcomes: PE and GDM. Studies were excluded if they lacked a clear definition for the case/exposure, control/no-exposure, outcomes, and clear and independent data of outcomes The Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of included studies. Two researchers participated in the evaluation of studies quality. Scores 2 statistic. P < 0.05 and I2 > 50% indicate significant heterogeneity. Sensitivity analyses were used to assess metaanalysis results' stability by removing included studies one by one. Begg's and Egger's tests were used for quantificational evaluation of publication bias. Funnel plots were used with In ORs and selnORs to visualize publication bias. Revman 5.3.3  was used to calculate the pooled OR and evaluate the sensitivity, and STATA 16.0  was used to assess publication bias.Data were extracted from the number of GDM or PE in ICP and no-ICP to represent the outcome of ICP. In addition, the first author's name, publication year, country, and the numbers of cases/exposure and controls/no-exposure, as defined in inclusion and exclusion criteria, were also included. The metaanalysis was performed by Revman 5.3.3  and STATA 16.0 . Association of PE or GDM with ICP was estimated using crude odds ratios (OR) with 95% confidence intervals (95% CI), and P < 0.05 was considered to be statistical significance. All crude ORs were pooled through a random-effects model for generating conservative conclusions. Heterogeneity test was performed by a Chi-square-based Q test and IA total of 10 articles 2heterogeneity = 35%, p heterogeneity = 0.16)  A. Each t2heterogeneity = 81%, p heterogeneity < 0.001). Although sensitivity analysis cannot reverse this conclusion, we still focused on the source of heterogeneity. By ruling out Shan's study, we observed that heterogeneity is completely eliminated, and the conclusion (pooled OR: 2.86 (95%CI: 2.59~3.16), I2heterogeneity = 0%, p heterogeneity = 0.56) (There are 9 studies  = 0.56) C is consFunnel plots of two results from this meta-analysis are symmetrical B. Begg'sIn this meta-analysis, which included 10 eligible studies including 17,688 ICP cases and 1,386,771 controls, we found that ICP can increase the risk of metabolic disorders  during pregnancy.ICP is transient and generally follows a benign course in gravidas but may adversely affect the prognosis of the fetus. The primary adverse fetal outcomes that have been reported include PTB, MSAF, fetal distress, RDS, and asphyxia S1PRs, including S1PR1-5, are a family of G protein-coupled receptors with sphingosine 1 phosphate (S1P) as their primary ligand The pathogenesis and pathophysiology of GDM include increased estrogen, progesterone, hormones, adipokines and cortisol during pregnancy. Insulin resistance plays a vital role in the development of GDM In the present study, we found that the primary source of heterogeneity was derived from the Shan et al. study Since ICP is a late pregnancy disease, often diagnosed at the 30th week of gestation, we do not know the sequence of metabolic disorders and ICP in included studies. So the increased risk in this metaanalysis refers to the risk of prevalence rather than the incident risk.In summary, we find that ICP also increases the risk of metabolic disorders  through this meta-analysis. This study provides evidence-based medical evidence for the increasing risk of PE and GDM in ICP, provides new insight into the role of abnormal bile acid metabolism in promoting metabolic disorders, and provides a new idea for the prevention of gestational diabetes mellitus and preeclampsia clinicians.GDM, Gestational diabetes mellitus;
PE, Preeclampsia;
ICP, Intrahepatic cholestasis of pregnancy;
Bas, bile acid;
FXR, Farnesoid X receptor;
TGR5, Takeda G-proteinreceptor 5(TGR5);
OR, odds ratio;
S1PR2, Sphingosine-1-phosphate receptor 2.The authors thank those who collected data or performed the measurement.This research did not receive any specific grant or funding from any commercial or nonprofit organization or public agency.Formal institutional review board approval was not required as this manuscript only addresses data extracted from already published studies.All the authors declare that they have no conflict of interest in this work.