Background and Aims: Statins are the first-line medication to treating hypercholesterolemia. Several studies have investigated the impact of statins on the risk of hepatocellular carcinoma (HCC). However, the extent to which statins may prevent HCC remains uncertain. Therefore, we performed a meta-analysis of relevant studies to quantify the magnitude of the association between statins use and the risk of HCC. Methods: A systematic literature search of PubMed, EMBASE, Google Scholar, Web of Science, and Scopus was performed for studies published between January 1, 1990, and September 1, 2019, with no restriction of language. Two reviewers independently evaluated the literature and included observational and experimental studies that reported the association between statin use and HCC risk. The random-effect model was used to calculate the overall risk ratio (RR) with a 95% confidence interval (CI), and the heterogeneity among the studies was assessed using the Q statistic and I2 statistic. The Newcastle Ottawa Scale (NOS) was also used to evaluate the quality of the included studies. Results: A total of 24 studies with 59,073 HCC patients was identified. Statin use was associated with a reduced risk of HCC development  compared with nonusers. Moreover, the rate of HCC reduction was also significant among patients with diabetes , liver cirrhosis , and antiviral therapy  compared with nonusers. Conclusion: This study serves as additional evidence supporting the beneficial inhibitory effect of statins on HCC incidence. The subgroup analyses of this study also highlight that statins are significantly associated with a reduced risk of HCC and may help to direct future prevention efforts. Additional large clinical studies are needed to determine whether statins are associated with a lower risk of HCC. Hepatocellular carcinoma (HCC) is a growing public health issue worldwide and the most common primary malignancy of the liver . HCC hasRho-dependent kinase [TNF)-mediated interleukin (IL6) production [Akt [Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are commonly used as standard therapy for the management and prevention of cardiovascular disease and stroke by reducing blood cholesterol level . A meta-t kinase , tumor noduction , Akt [21ion [Akt  , compared to nonusers . In the secondary analysis, the relationship between statin use and HCC development in patients with DM (Diabetes Mellitus), liver diseases, or antiviral therapy was considered. In patients with DM, statin use was significantly associated with a reduced risk of HCC  compared to that of nonusers. In patients without DM, statin use also showed a significant risk reduction of HCC  . In patiThe study design, region, dose, and different types of statins were considered in the subgroup analysis . The ovep for trend <0.0001). An analysis of different types of statins showed protective effects, particularly for fluvastatin , lovastatin , rosuvastatin , simvastatin , and atorvastatin . However, cerivastatin and pravastatin showed protective effects  but were statistically insignificant  compared with nonusers (RR 0.55 (95% CI: 0.46–0.65) and RR 0.47 (95% CI: 0.36–0.61) for ≤365 cDDD and >365 cDDD, respectively; nificant .To detect publication bias, the pooled analysis or subgroup analyses were not sufficient. Therefore, we used the Egger test and the Begg test to identify publication bias. However, visual inspection of the funnel plot revealed no publication bias, later confirmed by the Begg adjusted rank correlation test .I2 = 84.39%). We also analyzed the beneficial effect of statins on HCC risk reduction in patients with high-risk factors  . In the GTPase down, which decreases the translocation of Ras and Rho and their functions, decreasing cell proliferation and migration [HSC activation is suppressed by statins, through the paracrine effect of hepatocytes. Statins can also downregulate profibrogenic gene expressions  and protein expression of αSMA in HSCs; thus, it reduces liver fibrosis [IL-6, IL-1β, TNF, and reactive oxygen species (ROS) [IL-6 and TNF-α expression and by significantly attenuating metalloproteinases activity and production of ROS [Myc [miRNA-145 [There are several convincing biological explanations that statin use can reduce the risk of HCC. Statins indeed have several pleiotropic effects to reduce the risk of HCC, including antioxidative, anti-inflammatory, endothelial function, and anti-fibrotic properties . Statinsigration . Steatosfibrosis . Furtherfibrosis . Statin es (ROS) . Howevern of ROS ,56. Intrn of ROS ,58. It in of ROS ,60. FinaROS [Myc  and acceiRNA-145 , which uThis study is a large updated meta-analysis on this topic, including both randomized controlled trials and observational studies (case-control and cohort studies). All the included studies were of higher quality with their respective NOS scores ranging between 7 and 9. All the effect sizes ware adjusted with potential confounding factors , and theThis meta-analysis has several limitations that need to be addressed. First, all the included studies were adjusted with potential confounding factors, but these confounding factors were not the same. For example, some failed to adjust their study for factors such as the severity of liver disease (classified with the Child–Pugh score), alcohol consumption, diabetes, or different viral diseases. Second, most included studies were observational (cohort and case-control study) and the HCC patients were identified by the ICD code. Therefore, it is not clear that the HCC patients who used statins were followed properly and what was the medication compliance of these populations. Third, some studies used the same databases to assess the association between statin use and HCC risk. Even though the study duration was not the same for any of the included studies, some patients might overlap in the included studies. Our updated meta-analysis included a large number of studies with 59,073 HCC patients from diverse populations (four continents), and the pooled risk ratio was less than 0.5 with a narrow confidence interval. Our findings therefore strongly suggest that statin use has a significant and clinically relevant effect on HCC reduction, including with various conditions such as diabetes and other types of liver diseases. Recently, concern has been raised about the potential hepatotoxicity of statins, and several guidelines regarding statin use also persistently warn of these risks. However, many studies have also reported that statin-induced hepatotoxicity is extremely low . A significant amount of retrospective studies mentioned that statins are safe for use in patients with cirrhosis, even if statins are more effective in reducing liver decompensation and hepatocellular carcinoma. However, prescribing statins ubiquitously is not recommended in patients with all types of cirrhosis. A study by Kaplan et al.  suggesteOur results support the hypothesis that statins could be used as an anticancer therapy targeting the mevalonate pathway. The current study found that lipophilic statins, such as lovastatin or simvastatin, have a higher beneficial effect on HCC than hydrophilic statins such as pravastatin. Another finding from our subgroup analyses suggested that statins showed a higher beneficial effect in the Western population compared with the Asian population. Variation in genetic structure or polymorphism between Asian and Western people can influence statins’ pharmacokinetics and pharmacodynamics properties . More imNCT02968810) of the United States study, researchers are evaluating the preventive effect of statin on liver cancer in patients with liver cirrhosis. Similarly, in Taiwan, another prospective randomized clinical trial phase IV (NCT03024684) is evaluating preventive HCC recurrence after curative treatment. Since it takes a long time and is expensive to develop a new drug, drug repurposing is getting researchers’ attention in order to find new indications. Therefore, the results of these clinical trials and our updated meta-analysis bring new hope to patients with HCC. However, two large clinical trials are ongoing in the United States and Taiwan which have immense potential to justify or nullify our findings in our updated meta-analysis. In the prospective randomized control trial Phase-II  flow diagram for study inclusion and exclusion. Moreover, we also considered the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for observational studies .We systematically searched for relevant studies in PubMed, EMBASE, Web of Science, Google Scholar, and Scopus for studies published between January 1, 1990, and September 1, 2019, with no restriction of language. The following search terms were used to finds potential studies: “hepatocellular carcinoma”, OR “liver cancer”, and “statins” OR “simvastatin”, OR “atorvastatin”, OR “lovastatin”, OR “HMG-CoA reductase inhibitor(s)”, OR “pravastatin”, OR “rosuvastatin” OR “cerivastatin” OR “pitavastatin” . Our iniEligibility was restricted to large observational (≥200 participants) and clinical trials only which investigated the association between statin use and the risk of HCC as the primary outcome. Studies were included if they met the following inclusion criteria: a) a large observational study with at least a 6-month follow-up time; b) the study reported the development of HCC in adult individuals (≥18 years old) with statin use versus non-statin use; c) the study clearly defined statin exposure and the identification of HCC in patients; and d) the study clearly estimated the risk of HCC as a hazard ratio (HR), odds ratio (OR), and risk ratio (RR) with 95% CIs. However, studies were excluded if they are only review articles, letters to the editors, or case reports. Studies including fewer participants (<200 participants) were also excluded. The same two authors (M.M.I. and T.N.P.) independently screened the titles and abstracts of the previously selected literature. They followed prespecified inclusion and exclusion criteria developed through the discussion with all authors to identify relevant studies. Any disagreements during that reviewing process were resolved by the consideration of the prior guidelines; any remaining conflict was then resolved by discussion with the main investigator (Y.C.L.). The same two authors (M.M.I. and T.N.P.) independently conducted the data collection process and checked for study duplication, population sizes, and date of publications. The primary outcome measures were ORs and HRs with 95% CIs for the association between statin use and the risk of HCC. Two authors (M.M.I. and T.N.P.) identified and recorded the effect sizes reflecting the higher degree of adjustment variables for possible confounding factors. Unadjusted findings and the effect of statins on HCC with other potential diseases were also extracted. Other information extracted from the included studies were author names, publication years, study designs, number of participants, number of HCC patients, process of HCC patient’s identifications, statins user’s definitions, doses information, effects of different types of statins on HCC, follow-up times, settings, and regions.Q statistic and the I2 statistic. Moreover, publication bias was assessed by the funnel plot-based (Egger test and the Begg test).The Newcastle Ottawa Scale (NOS) was applied for evaluating the individual quality of each study . The hetp-value of less than 0.05 was considered significant. Furthermore, the random effect model was used to pool the effect size and funnel plots were drawn to present the effect sizes visually. We only considered adjusted effect sizes reported in studies for analysis to account for confounding variables.We performed statistical analyses with the Comprehensive Meta-analysis (CMA) software . The risk ratio with 95% confidence intervals (CIs) was calculated to assess outcomes, and a To our knowledge, this is the most extensive meta-analysis so far that evaluated the beneficial effects of statins on HCC. The findings of this meta-analysis provided additional evidence because they showed that statin use can provide a 46% risk reduction in HCC development. Furthermore, a larger mechanistic study is warranted to confirm or refute our findings.


The associations between maternal use of antidepressant during pregnancy and preterm birth (PTB) has been the subject of much discussion and controversy. The aim of the present study was to systematically review the association between antidepressant use during pregnancy and the risk of PTB, especially in depressed women.June 30, 2019, supplemented with a manual search of the reference lists, to identify original research regarding PTB rates in women taking antidepressants during pregnancy. A random-effects model was used to calculate the summarized relative risks (RRs) and 95% confidence intervals (CIs). The potential for publication bias was examined through Begg' s and Egger' s tests.A computerized search was conducted in PubMed, PsycINFO, and Embase before A total of 2,279 articles were reviewed, 23 of which were selected. The risk of PTB was increased in women with depression [1.58 (1.23−2.04)] and in the general pregnant female population [1.35 (1.11−1.63)] who used antidepressants during pregnancy. Similar results were observed in depressed women treated with selective serotonin reuptake inhibitors (SSRIs) during pregnancy [1.46 (1.32−1.61)]. There was no significantly increased risk of PTB observed with SSRI use in the general pregnant female population [1.25 (1.00−1.57)], and the heterogeneity of these studies was high.The results of this meta-analysis indicate maternal antidepressant use is associated with a significantly increased risk of PTB in infants. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with antidepressant during pregnancy. Preterm birth (PTB), defined as delivery prior to 37 weeks of gestation, is regarded as a global public health concern, since it is the leading cause of infant mortality worldwide . In compMany factors are thought to contribute to the increased PTB rate, including a higher mean maternal age, more frequent use of assisted reproductive technologies and a resulting increase in multiple gestations, and higher rates of preterm inductions and cesarean deliveries . InteresTherefore, in the present study, a meta-analysis of all available studies was conducted to quantitate the strength of the relationship between antidepressant use during pregnancy and PTB especially in depressed women.June 30, 2019. The search queries used are listed in The PubMed, PsycINFO, and Embase databases were searched for related articles published before Eligibility criteria were defined as: (1) articles available in English with the full text provided; (2) studies conducted in humans; (3) prospective cohort studies; (4) antidepressant use as the study exposure and PTB as the study outcome; (5) antidepressant use during pregnancy; (6) no psychotropic drug use in the control group; and (7) reported risk ratio or adequate data for the calculation of an effect size as a relative risk (RR) between antidepressant use and PTB.The study quality of eligible articles was assessed by two reviewers (X-YM and X-RX), who subsequently extracted data from each selected article including the study design, sample size, data source, criteria for inclusion/exclusion, definition of exposure, definition of outcome, outcomes with risk estimates and 95% confidence intervals (CIs), and adjusted confounders. The two reviewers extracted data independently and any disagreements were resolved by discussion with a third reviewer (QC), when necessary.For one study  that chaThe two reviewers independently performed a quality assessment using the Newcastle−Ottawa scale (NOS)  for cohoI2 value represents the percentage of total variation across studies due to heterogeneity rather than chance  was used for all statistical analyses. The mean effect size approach was used to pool estimates, which has been applied in other studies . The effn chance . Values n chance . A two-tg's test .If more than eight studies were available, potential sources of heterogeneity were explored by conducting subgroup analyses according to the following parameters: geographic location (Europe vs. North America or other regions) and adjustment for potential confounders (adjusted vs. unadjusted) including maternal age, ethnicity, maternal education, tobacco use, alcohol consumption, BMI during pregnancy, and parity. Heterogeneity between subgroups was evaluated by meta-regression analysis. To determine the influence of individual studies on each analysis of the estimated RR, sensitivity analysis was conducted that recalculated the pooled effect by omitting one study at a time. The population was divided into four groups: antidepressant use in the general pregnant female population, antidepressant use in pregnant women with depression, SSRI use in the general pregnant female population, and SSRI use in pregnant women with depression.A total of 2,278 potentially eligible articles were identified in PubMed, PsycINFO, and Embase. One additional study was added following a manual search of the reference lists. Following removal of 528 duplicate articles, the titles and abstracts were screened, and 1,577 irrelevant articles were removed. A total of 174 full-text articles were assessed for eligibility, and 23 (published between 2004 and 2019) were ultimately included in the present analysis. A flow diagram of study identification is shown in All prospective cohort studies assessing antidepressant exposure during pregnancy were included. Eight studies  were conAnalysis of the included studies using Newcastle−Ottawa criteria indicated that 21 studies were at a low risk and two studies  were at I2 = 75.8%, P < 0.001, Sixteen studies  in the gI2 = 9.7%, P = 0.365, Seven studies  in the pI2 = 85.6%, P < 0.001, Nine studies  in the gI2 = 0.0%, P = 0.432, Only four studies  in the pTo the best of our knowledge, this is the first meta-analysis of the impact of antidepressant use during pregnancy on PTB in depressed women. Our study focused not only on depressed pregnant women but also on the general pregnant female population, with 23 prospective cohort studies finally being selected. It was found that the risk of PTB was increased in depressed women treated with SSRIs during pregnancy. Similar results were observed in women with depression and in the general pregnant female population who used antidepressants during pregnancy. There was no significantly increased risk of PTB observed with SSRI use in the general pregnant female population.The focus of the present study was to explore the association between maternal use of antidepressants in depressed women during pregnancy and risk of PTB. Subgroup analysis shows that even though the use of antidepressants in the general pregnant female population significantly increased the risk of PTB, the heterogeneity was high, which may be due to the differences in population sources. There was a statistically significant difference in the European cohort study but not in the North American cohort study, which may be one of the sources of heterogeneity. Another reason for the high heterogeneity may be that there were confounding factors that influenced the conclusion. For this reason, a meta-regression analysis was conducted; when maternal age, tobacco use, and parity were defined, there was a statistically significant difference in the meta-regression, indicating that these may be confounding factors.P values were 0.27, 0.40, and 0.12, respectively, and the meta-regression was not statistically significant. Subsequently, the data were adjusted for certain confounding factors such as maternal age, ethnicity, maternal education, tobacco use, and alcohol consumption; however, the results were not ideal. Finally, a subgroup analysis of SSRI use in pregnant women with depression was performed, and it was found that the heterogeneity was 0%; therefore, a possible source of the high heterogeneity was not stipulating depression in the study population. However, there have only been four studies to date, and the present study suggests that future studies may be inclined to stipulate depression in the study population and to consider the effects of SSRIs or other antidepressants on preterm PTB, which is of great clinical significance.To further explore whether the heterogeneity originated from different drug types, subgroup analysis of SSRI use in the general pregnant female population was conducted, and it was found that the heterogeneity was elevated. A possible reason could be differences in the sources of the population. Firstly, according to geographic location, studies were divided into European, North American, and others; the P < 0.001); after limiting the population to depressed pregnant women, the OR was 1.79 (0.77−4.14). Moreover, a study by Currently, there exist four meta-analyses of the effects of antidepressant use on PTB (nearly 6 years) . The resThe present study describes a meta-analysis of 23 prospective cohort studies investigating the risk of PTB in women taking antidepressants during pregnancy, with additional analyses associated with a diagnosis of depression. The main strength is that it is a large meta-analysis including a large number of prospective cohort studies. Furthermore, to-date, evidence regarding associations between the use of antidepressant in depressed women and risk of PTB is limited. To the best of our knowledge, the present study is the first meta-analysis to investigate the associations between maternal antidepressant use in depressed women and the risk of PTB.Nevertheless, this study has several limitations, which should be considered when interpreting its findings. First, due to the limited number of included studies, the present study did not account for trimester exposure and either for duration of exposure in the analysis. Both factors may significantly modify the association between maternal use of antidepressant during pregnancy and PTB. The number of studies related to specific antidepressants are small for specific drugs  and did not allow for investigations into the dose-response. Second, heterogeneity was high among studies focusing on the associations between maternal antidepressant use in the general pregnant women and the risk of PTB. Our subgroup analysis suggested that the high heterogeneity might be attributed to differences in study locations and diagnosing of depression.The results of this meta-analysis highlights the association between maternal use of antidepressant during pregnancy and the risk of PTB. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with antidepressant during pregnancy.Y-HZ and QC designed and conducted the study. X-YM and X-XR collected, managed, and analyzed the data. QC, Q-JW, HS, and Y-HZ prepared, reviewed, and approved the manuscript. Y-HZ had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This work was supported by National Key R&D Program of China (No. 2017YFC0907403 to Y-HZ); Liaoning Revitalization Talents Program (No. XLYC1802095 to Y-HZ); Key R&D Program of Liaoning Province (No. 2019JH8/10300005 to Y-HZ); the Science and Technology Project of Liaoning Province (No. 2019JH6/10400002 to Y-HZ); Young Talents of Education Ministry of Liaoning Province (No. QN2019011 to HS). The other authors declare no conflicts of interest in relation to this study.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.


MTHFR C677T and ALDH2 Glu504Lys as risk factors for ACS in a Hakka population in southern China.Acute coronary syndrome (ACS) is the most serious type of coronary heart disease and is a global medical burden. The pathogenesis of ACS is very complex and still poorly understood. Epidemiologic studies have revealed that the manifestation of ACS are the results of the interactions between multiple environmental and genetic factors. The present study aimed to investigate the role of polymorphisms of Between September 1, 2015 and October 31, 2017, a total of 1957 individuals, including 860 ACS patients and 1097 controls were recruited. Blood samples were collected and genotypes were determined by DNA microarray chip method and direct sequencing method.MTHFR C677T polymorphism, frequencies of CC, CT, and TT genotypes were 53.60% versus 55.33, 39.53% versus 38.65 and 6.86% versus 6.02% in patients with ACS versus controls, respectively(p > 0.05). The differences in genotype frequencies between the ACS patients and controls in the three genetic model were not statistically significant. For the ALDH2 Glu504Lys polymorphism, the frequencies of ALDH2*1*1, ALDH2*1*2, and ALDH2*2*2 genotypes were 48.72, 42.67 and 8.6% in the ACS patients, respectively, while these were 53.33, 39.11 and 7.57% in the controls, respectively, showing no significant difference in the distribution of the ALDH2 genotype between the groups. Using the wild genotype ALDH2*1*1 as reference, relative risk analysis revealed a slightly increased risk for ACS in individuals with the ALDH2*1*2 plus ALDH2*2*2 genotypes (odds ratio (OR) = 1.203, 95% confidence interval (CI) = 1.006–1.438, p = 0.043). In a multivariate logistic regression model, even after adjusting for potential covariates, the association between ALDH2 *2 allele and ACS remained significant .For the ALDH2*2 variant on ACS patients in a Hakka population in southern China and our findings might help to stratify the high-risk ACS patients and implement appropriate strategies for this genetic subpopulation to ultimately guide the precision preventive procedures in the future.We present findings regarding the possible clinical impact of the  Acute coronary syndrome (ACS) is the most serious type of coronary heart disease and is a global medical burden . ACS refMTHFR) plays a significant role in cellular metabolism of folate, as well as in the synthesis of purine, DNA, and RNA and is essential in the methyl cycle that converts homocysteine (Hcy) to methionine [MTHFR is a crucial controlling enzyme related to Hcy metabolism and many articles connecting MTHFR single nucleotide polymorphism (SNP), mostly MTHFR C677T, with plasma Hcy levels [MTHFR C677T polymorphism on ACS are not fully understood.Methylenetetrahydro folate reductase  has been proved to responsible for oxidation and detoxification of aromatic and aliphatic aldehydes [ALDH2 gene is at exon 12, wherein glutamate acid (Glu) is replaced by lysine (Lys) at position 504(Glu504Lys) [ALDH2 allele (ALDH2*2) have dramatically deficient enzymatic activity by approximately 60 to 80% in heterozygotes and found in approximately 560 million people of East Asian descent but are virtually non-existent in other populations of the world [ALDH2 are associated with the risk for a series of diseases such as alcoholic cirrhosis, cancer, Alzheimer’s and stroke [ALDH2 causes accumulation of acetaldehyde and 4-hydroxy-2-nonenal (4-HNE) and decrease the anti-oxidative stress effects, which has been proposed to be potentially linked with coronary artery disease (CAD) [Mitochondrial aldehyde dehydrogenase 2 (ldehydes . The sigu504Lys) . Carrierhe world , 23. Numd stroke –26. Morese (CAD) –29.MTHFR C677T and ALDH2 Glu504Lys in ACS patients in a Hakka population in southern China. We hypothesized that polymorphisms of the ALDH2 and MTHFR gene that result in reduced enzyme activity may modify the risk of ACS. We tested this hypothesis in a case-control study.To the best of our knowledge, there is currently no report that evaluated the role of polymorphisms of This was a retrospective study that analyzed consecutive patients who visited the cardiovascular medicine of our hospital, which is a tertiary hospital located in urban area between September 1, 2015 and October 31, 2017. The annual patients admitted to the cardiovascular medicine were ranged from 10,000 to 12,000 patients. Participants of this study include native inhabitants in Meizhou region for at least 3 generations with no migration history, from both rural and urban origins. A total of 1957 individuals, including 860 ACS patients and 1097 controls were recruited. ACS patients were diagnosed by two senior specialists at the time of the index hospitalisation according to the same clinical criteria defined by the European Society of Cardiology/American College of Cardiology. Control subjects were free of cardiac disorders according to medical history, physical and laboratory examinations. The present study complies with the Declaration of Helsinki and was approved by the ethics committee of the Meizhou People’s Hospital , Meizhou Hospital Affiliated to Sun Yat-sen University. A prior written informed consent was obtained from patients and controls who participated in the present study before inclusion.The ACS was classified as ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UA) based on clinical, electrocardiographic, and biochemical criteria. In brief, STEMI was defined as presence of persistent chest pain along with at least one of the following: new-onset ST segment elevation ≥1 mm in at least 2 contiguous leads in the admission electrocardiogram, or left bundle branch block and elevated cardiac biomarker values above the upper limit of normal range. NSTEMI was defined as presence of persistent chest pain, absence of new-onset ST segment elevation, and/or the presence of T-wave abnormalities and elevated cardiac biomarker above the upper limit of normal range. UA was defined as worsening angina without elevated values of cardiac biomarker. Patients were excluded if they had a previous history of ACS, percutaneous coronary intervention or coronary artery bypass graft surgery, malignant tumor, blood system diseases, autoimmune diseases and severe hepatic or renal dysfunction.Information on the age, gender, smoker, and drinker, hypertension, diabetes and dyslipidemia were collected from the medical records. Smoker was defined as those daily smoking for more than 5 cigarettes. Drinker was defined as a person who drinks hard liquors at least once per week and continuously drinks for more than a year. Hypertension was defined as history of hypertension or systolic blood pressure (SBP) ≥ 140 mmHg or diastolic BP (DBP) ≥ 90 mmHg. Diabetes was defined as history of diabetes or a fasting plasma glucose level of ≥7.0 mmol/L or 2-h OGTT venous blood glucose level ≥ 11.1 mmol/L and a hemoglobin A1c level of ≥6.5%. Dyslipidemia was defined as level of triglycerides (TG) value of ≥1.50 mmol/L or LDL cholesterol (LDL-c) value of ≥3.92 mmol/L or under medication of lipid lowering drugs.ALDH2 Glu504Lys and MTHFR C677T genotyping was performed used the DNA microarray chip method and direct sequencing method as previously described [Five millilitres of venous blood was collected in ethylene diamine tetra-acetic acid (EDTA) tubes from each participant. Genomic DNA extraction was carried out with the use of a DNA extraction kit  following the manufacturer’s instructions and quantified using Nanodrop 2000 Spectrophotometer . The extracted DNA was dissolved in sterile distilled water and stored at − 20 ͦC before used. escribed . To verip value of < 0.05 was considered statistically significant.Data were collected and all statistical analyses were performed with SPSS 19.0 . Continuous variables, which were expressed as mean ± standard deviation (SD) and analysed by t test or Mann-Whitney U test. The categorical variables were expressed as percentage and analysed by Chi-square test or Fisher’s exact test. Hardy-Weinberg equilibrium (HWE) was used to assess the representativeness of the participants. Univariable logistic regression analysis was used to test the association between ACS and gene polymorphisms. To examine the association between ACS and possible confounding factors, univariate and multivariate logistic regression analysis were performed. The correlation risk was estimated by odds ratio (OR) and 95% confidence interval (95% CI). A p < 0.05). Besides, ACS patients had elder age, higher SBP and DBP, higher serum total cholesterol (TC), LDL-c and TG levels than control subjects (p < 0.05). No significant differences were found with regards to the proportion of drinkers, serum high-density lipoprotein cholesterol (HDL-c), Apolipoprotein A and Apolipoprotein B levels between the two groups .In this study, we analysed 860 ACS patients and 1097 control subjects. The demographic and baseline clinical characteristics of the study population were shown in Table MTHFR C677T and ALDH2 Glu504Lys polymorphisms in ACS patients and controls. The genotype distributions of the two SNPs in the ACS patients  and controls  were consistent with the HWE(p > 0.05). The effect of the two SNPs on the risk of ACS was also performed based on dominant , recessive  and additive  models of inheritance. For the MTHFR C677T polymorphism, frequencies of CC, CT, and TT genotypes were 53.60% versus 55.33, 39.53% versus 38.65 and 6.86% versus 6.02% in patients with ACS versus controls, respectively(p > 0.05). The differences in genotype frequencies between the ACS and control groups in the three genetic model were not statistically significant. Another, the T allele frequency difference between the two groups was also not statistically significant (p = 0.362).Table ALDH2 Glu504Lys polymorphism, the frequencies of ALDH2*1*1, ALDH2*1*2, and ALDH2*2*2 genotypes were 48.72, 42.67 and 8.6% in the ACS patients, respectively, while these were 53.33, 39.11 and 7.57% in the controls, respectively, showing no significant difference in the distribution of the ALDH2 genotype between the groups. We further analysed this association in dominant model . Using the wild genotype ALDH2*1*1 as reference, relative risk analysis revealed a slightly increased risk for ACS in individuals with the ALDH2*1*2 plus ALDH2*2*2 genotypes . However, the differences in genotype frequencies between the ACS patients and control groups in the recessive and additive model were not statistically significant. Meanwhile, there was no significant difference between the ACS patients and control groups in the ALDH2*2 allele frequencies (p = 0.052).For the ALDH2 *2 allele was an independent risk factor for ACS . As regards other covariates, age, gender, smoking status, hypertension, diabetes and dyslipidemia were independent risk factors for ACS . By contrast, drinking status and carrier of T allele in MTHFR, exerted no significant effect on ACS .We performed multivariate logistic regression analysis to identify the variables that independently and significantly contributed to the presence of ACS Table . MultivaMTHFR C677T polymorphism and ALDH2 Glu504Lys polymorphism with ACS in a Chinese Hakka population. Next we performed genotype association test with dominant, recessive, and additive models. Our results indicated that ACS patients with the mutant ALDH2 (dominant model) had an increased risk of ACS . In a multivariate logistic regression model, even after adjusting for potential covariates, the association between ALDH2 *2 allele and ACS remained significant .ACS is an important global public health issue and one of the leading causes of mortality rate, as well as a great economic burden for society worldwide . The patMTHFR is one of the most important enzymes with a pivotal role in the Hcy metabolism [MTHFR gene C677T polymorphism and plasma Hcy levels [MTHFR might be an important genetic risk factor for ischemic heart disease through its effects on Hcy metabolism [MTHFR gene in CAD pathogenesis has been extensively studied in several ethnic groups while the results were inconsistent. A meta-analysis of the risk of CAD related to the MTHFR C677T polymorphism showed that individuals with TT genotype have a significantly higher risk of CAD [MTHFR TT genotype and allele frequencies in patients with MI are higher than those in healthy individuals [MTHFR C677T polymorphism was associated with risk of MI in young and middle-aged populations, particularly among Caucasians [MTHFR C677T polymorphism and elevated risk of ACS. Similar findings were also observed in ACS patients of Asian, Caucasian and African descent [MTHFR pathway, such as folate, pyridoxal phosphate (B6) or methylcobalamin (B12), or ethnic populations and genetic backgrounds exist [tabolism . Accumuly levels . Consequtabolism , 18. Thek of CAD . The stuk of CAD . Helfensividuals . Anotherucasians . However descent –36. The ds exist –39.ALDH2 with deficient catalytic activity [ALDH2*2 mutation have an increased risk for alcoholic cirrhosis, cancer and CAD [ALDH2 protects against myocardial ischemia/reperfusion (I/R) injury by removing toxic aldehydes such as 4-HNE in animal models of myocardial ischemia [ALDH2 allele were significantly more frequent in patients with MI than in the controls, indicating that ALDH2 gene is a risk factor for MI [ALDH2 Glu504Lys polymorphism may be associated with increased risk of CAD and MI in East Asians, especially among Chinese and Korean populations [ALDH2 mutant genotypes (*1/*2 plus *2/*2) might serve as an independent genetic risk factors for ACS in a Hakka population in southern China, which was consisted with a previous study in Han Chinese [ALDH2 Glu504Lys polymorphism and risk of ACS is considered multifactorial. The genetic variation in the ALDH2 gene can influence serum high-density lipoprotein-C levels and intracellular asymmetric dimethylarginine levels, subsequently increase the risk of ACS [ALDH2 genetic polymorphism was also significantly associated with alcohol consumption and increase blood pressure, and others has revealed a beneficial role of ALDH2 against alcohol, acetaldehyde and toxic aldehyde-induced reactive oxygen species formation, and tissue injury [ALDH2 is the major enzyme that eliminates exogenous and endogenous toxic aldehydes, such as acetaldehyde, 4-HNE and environmental aldehydes like acrolein . Up to 4activity . Importa and CAD , 27. Priischemia , 41. Jo r for MI . A meta-ulations , 43. Int Chinese . The undk of ACS , 45. Thee injury , 46–48. ALDH2*2 variant and the risk of ACS patients, additional studies employing larger cohorts will be needed in the future.It should be noted that the results of this observational study have some limitations. Firstly, the main study limitation was based upon the retrospective design of the study and patient selection biases could not be avoided. Secondly, this study is a single-center study and the sample size of the study may not be sufficiently large. To further validate the association between ALDH2*2 variant on ACS patients in a Hakka population in southern China. We hope our findings might help to stratify the high-risk ACS patients and implement appropriate strategies for this genetic subpopulation to ultimately guide the precision preventive procedures. However, more efforts is urgently required to confirm this hypothesis in the future.The present study showed the possible clinical impact of the


Background: It is still conflicting for the correlation between cancer susceptibility and Aurora-A V57I (rs1047972) gene variant from the published researches. This meta-analysis was performed to access the correlation between cancer susceptibility and Aurora-A rs1047972 gene polymorphism by using meta-analysis methods.Methods: Eligible studies published before Nov 1, 2019 were systematically searched in PMC, PubMed, EMBASE, Web of Science, Cochrane Library Database, China National Knowledge Infrastructure, Wanfang databases, in order to collect qualified case-control or cohort studies. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to evaluate the correlation between Aurora-A rs1047972 gene polymorphism and cancer risk. Sensitivity analysis was used to examine the stability of the results; Egger's test and Begg's funnel chart were used to assess possible publication bias. Trial sequential analysis (TSA) was used to access whether the sample size of our meta-analysis was sufficient.Results: The sample set extracted from 24 case-control studies involving 35,926 subjects  for the association of Aurora-A rs1047972 gene polymorphism with cancer susceptibility. In our meta-analysis, Aurora-A rs1047972 polymorphism was associated with an increased risk of cancer susceptibility in overall populations , and the GA/GG variant might be a risk factor for cancer susceptibility. In the stratified analysis by ethnicity, we found a significant association between Aurora-A rs1047972 variant and the susceptibility of the cancer in Caucasian population. In a subgroup analysis by cancer type, we observed a significantly increased susceptibility of lung cancer. In addition, an increased risk was found between Aurora-A rs1047972 polymorphism and cancer susceptibility in MALDI-TOF group and among population-based study (PB) patients. Our results were in a sufficiently large number of participants according to TSA and did not require more studies to confirm such association.Conclusion: Our meta-analysis revealed that the susceptibility of cancer was associated with Aurora-A rs1047972 polymorphism, especially in Caucasians. And the GA/GG variant might be a risk factor for cancer susceptibility. Aurora Kinase A (AURKA) is a serine/threonine kinase, which belongs to the Aurora kinase family The AURKA gene owns a lot of polymorphisms, so far, at least 6 AURKA polymorphism sites have been found, of which the most investigated were two common non-synonymous single nucleotide polymorphisms (SNPs) (F31I and V57I). However, there were at least four meta-analyses indicating F31I SNP was a low protective factor in the development of tumors. So we only analyzed the SNP V57I and did not analyze SNP F31I, as we needed to be sure that there was no redundancy that may be caused out of the publication of the research for SNP F31I. Gene polymorphism has been reported to be a significant factor and it might increase the susceptibility of cancer Eligible studies were systematically searched in PMC, Cochrane Library database, PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang databases. And we also performed manual search to find relevant studies. English search strategy: (Aurora-A OR BTAK OR STK15 OR AIKI OR rs1047972) AND (cancer OR neoplasm OR tumor OR carcinoma) AND (SNP or variant or genotype or polymorphism). We searched the studies published before Nov 1, 2019, and also searched relevant degree papers.(1) Case-control or cohort studies on the association between Aurora-A rs1047972 gene polymorphism and cancers risk; (2) The genotypes of the study followed with Hardy-Weinberg equilibrium (HWE); (3) Alleles or genotypes frequencies in control groups and case groups could be received from the studies; (4) English and Chinese literature.(1) Unable to extract useful data or results; (2) The Aurora-A rs1047972 polymorphism was not included or the results were not about cancers susceptibility; (3) The studies published repeatedly and the one included the largest sample size.Using the Newcastle-Ottawa Scale  to evaluate the included articles, if the score of the articles were more than or equal to 5 points, the quality of the articles was considered to be high. Two authors independently read the retrieved article titles and abstracts. After excluding the articles that did not meet the inclusion criteria, the full review of the retrieved articles probably meeting the inclusion criteria was performed to determine its qualifications for final incorporation after cross-checking by the two research evaluators. The extraction information mainly includes: the name of the first author of the studies, ethnicity, original country, the year of publication, sample size, source of controls , genotyping methods, the number of cases and controls for Aurora-A rs1047972 genotypes and so on.2 I<50%), a meta-analysis was performed by using a fixed-effect model; if there was a huge statistical heterogeneity between these studies (P<0.1 or 2I> 50%), we analyzed the results using a random-effect model, if necessary, a subgroup analysis of related factors that may lead to heterogeneity will be performed. The pooled ORs were performed for these models (1) AA vs.GG, (2) GA vs. AA, (3) AA+GA vs.GG and (4) GG+GA vs. AA, respectively. We use Egger's test and Begg's funnel chart to evaluate the publication of bias. Each time a document was removed for sensitivity analysis. Subgroup analysis was carried out, as it needed.We performed meta-analysis using STATA 12.0 software, and the count data was expressed using odds ratio (OR) and its 95% confidence interval (95% CI). The heterogeneity between the results of each included study was tested by chi-square test. When there was a small statistical homogeneity between these studies . At the same time, if the cumulative Z value crosses the RIS threshold, the results are considered statistically significant. Therefore, it can be considered the sample size of the accumulated evidence is sufficient. However, if the cumulative Z value does not cross the RIS threshold, it means the sample size is not sufficient. And it still needs more studies to confirm the results.The search strategy resulted in a total of 425 potentially relevant articles Figure . The cha24 case-control studies including 14,639 cancer cases and 21,287 normal controls were investigated. As illustrated in Table Subgroup analysis of different ethnicities was carried out. We found a significant association between Aurora-A rs1047972 variant and the susceptibility of the cancer in Caucasian population . Our results indicated that GA/GG genotype carriers have a higher risk of cancer compared to AA carriers and the AA variant might be a protective factor for cancer susceptibility in Caucasian population. However, we did not find any association between Aurora-A rs1047972 variant and cancer risk in Asian population . And the AA variant might be a protective factor in lung cancer. But for the other cancer, like breast cancer and cervical cancer, we did not find any important association in different Aurora-A rs1047972 genotype carriers Table .cancer risk inPB (population-based study) group . Our results indicated that GA / GG genotype carriers have a higher risk of cancer compared to that of AA carriers and the AA variant might be a protective factor for cancer susceptibility in PB group. However, we did not find any association between Aurora-A V57I variant and cancer risk in HB  group . Our results indicated that GA/GG genotype carriers have a higher risk of cancer compared to that of AA carriers , and the results suggesting that there was no publication bias for the association between Aurora-A rs1047972 gene polymorphism and cancers risk in included studies Figure .We implemented TSA to reduce the risk of type I error by keeping the overall 5% risk of a type I error and 20% risk of a type II error (power of 80%) to evaluate the RIS. As it showed, the sample size of the 18th study had crossed the TSA boundary Figure . The posIn the past 20 years, a large amount of epidemiologic researches were centered on correlation between Aurora-A rs1047972 gene polymorphism and cancers risk, but the conclusions are still controversial. Based on it, this meta-analysis was performed to investigate whether the Aurora-A rs1047972 gene polymorphism was correlated with the susceptibility of cancer. In this meta-analysis, a total of 24 case-control studies including 14,639 cancer cases and 21,287 normal controls were investigated. Our results demonstrated that a significant association was observed for Aurora-A rs1047972 gene polymorphism in overall population. And the AA genotype carriers have a slightly lower incidence of cancer compared to that of GA/GG carriers and the GA/GG variant might be a risk factor for cancer susceptibility in overall populations.In a stratified analysis by population, we found a significant association between Aurora-A rs1047972 variant and the susceptibility of the cancer in Caucasian population. Our results indicated that GA/GG genotype carriers have a higher risk of cancer compared to that of AA carriers and the AA variant might be a protective factor for cancer susceptibility in Caucasian population. However, we did not find any association between Aurora-A rs1047972 variant and cancer risk in Asian population. In a stratified analysis by cancer type, our results indicated that Aurora-A rs1047972 polymorphism has an increased risk for lung cancer.Our results were consistent with the study by Gu et al. We also carried out subgroup analysis by SC and GM. In a stratified analysis by SC, we found significant association between Aurora-A rs1047972 polymorphism and increased risk of PB group. In a stratified analysis by GM, we observed significant association between Aurora-A rs1047972 polymorphism and increased risk of MALDI-TOF group. Our results indicated that different genotype methods might have an important affect in different studies.2 = 55.4%) but not in our meta-analysis (I2 = 0%), so this might distort their results.A previous meta-analysis conducted by Tang et al. It is very important for us to pay more attention to the heterogeneity, because huge heterogeneity might have the bad influence on our results of the present meta-analysis and neglect the heterogeneity might lead to mistakes. In the present meta-analysis, the contrast model of Aurora-A rs1047972 polymorphism did not have significant heterogeneity. Therefore, it can be considered the results we performed were reliable in a way. In addition, we carried out the subgroup analysis of other related factors in order to study the relationship between more factors and cancer susceptibility.Moreover, our meta-analysis has some advantages. Firstly, we have carried out TSA to reduce the article risk of type I error to promote scientific preciseness. Secondly, we have revealed a lot of factors which exert influence on the association between Aurora-A rs1047972 polymorphism and the susceptibility to cancer. Thirdly, strictly based on the search strategy, articles included in our meta-analysis are more than 20 studies which may enhance the authenticity and reliability of the analysis. Fourthly, the subgroup analysis is sufficient and reveals the difference among diverse populations. In addition, Egger's tests and funnel plot were used to find potential publication bias. No significant publication bias was found.Nevertheless, there are still some limitations which cannot be avoided in our present meta-analysis. First, some unpublished studies might not be included. Second, we did not include studies in other races such as Africa, so it cannot fully reflect the influence of different races and regions. Third, this study did not reveal gene environment and gene-gene interactions, due to the original information of the included studies was not sufficient. Fourth, this study failed to include an independent cohort study into our meta-analysis; therefore, more cohort studies should be performed to refute the association between the risk of cancer and Aurora-A rs1047972 polymorphism in the future. Despite the above limitations, this study ensures the reliability of the results by setting a careful research plan to minimize the bias.In summary, the findings from this systematic review and meta-analysis indicate that the susceptibility of cancer was associated with Aurora-A rs1047972 polymorphism, especially, in Caucasians. And the AA genotype carriers have a slightly lower incidence of cancer compared to that of GA/GG carriers and the GA/GG variant might be a risk factor for cancer susceptibility. Our study has certain guiding significance for Aurora-A rs1047972 polymorphism and cancer research, and contributes to the development of ARUKA inhibitors. Of course, due to the research we included in this meta-analysis was the only case-control study, more prospective study should be performed to refute the association between the risk of cancer and Aurora-A rs1047972 polymorphism in the future.


Opium and its pyrolysates have been investigated as potential carcinogenic material through several studies in different body systems; however, the results were controversial and no consensus was achieved with this regard. Thus, we aimed to systematically review and meta-analyze all existed evidence regarding association between opium consumption and cancer.Four major electronic databases including ISI Web of Science, PubMed, Scopus, and Embase along with Magiran and SID were searched thoroughly for all published articles from inception up to September 25, 2020. All studies were appraised critically by Newcastle Ottawa Scale (NOS) checklist. Relevant demographic data and the intended results of the selected studies were extracted and their Odds ratios (OR) were pooled using Comprehensive Meta-analysis (CMA). The cumulative risk of opium for developing different cancers was calculated.34 studies comprised of 18,230 individuals were entered in our systematic review and finally 32 publications were enrolled in meta-analysis. Overall, using the random effects model, opium consumption was associated with increased rate of malignancies in both minimally[OR = 4.14 95%CI = (3.32–5.15)] and fully adjusted [OR = 4.35 95%CI = (3.36–5.62)] analyses. Moreover, using random effects fully adjusted model, the subgroup analysis revealed increased risk for larynx [OR = 9.58 95%CI = (6.31–14.53)], respiratory [OR = 9.02 95%CI = (6.27–12.96)], head and neck [OR = 8•03 95%CI = (4.03–16.00)], and colon [OR=5.58 95%CI = (3.14–9.92)] cancers for opium consumers compared to non-consumers.Opium consumption is highly associated with all reported types of cancers, especially in fully adjusted model; however, basic pathophysiology should be further investigated.None. Taking into consideration different reports that assessed the carcinogenicity of opium, we tried to pool all available studies in a systematic review and meta-analysis. ISI web of science, Scopus, Embase, PubMed, and Persian databases including Magiran (magiran.com) and SID (sid.ir) were searched for identifying all the studies published until September 25, 2020 without any time or language limitation. The main outcome measure was the association between opium addiction and the risk of cancers. The odds and hazard ratios were pooled in Comprehensive Meta-analysis (CMA) software and the pooled results were reported.Several studies have reported different odds ratios for the carcinogenic impact of opium use on different cancers but making all these studies together can provide a more robust result. Our findings showed that after adjusting for different confounders, opium use was associated with a 4.35-fold increased risk of malignancy. This addictive substance was associated with a 9.02-fold higher risk of respiratory cancer, 8.03-fold increased risk of head and neck cancer, and 3.03-fold higher risk of gastrointestinal malignancies. In fact, these findings are a summary of 32 different studies and have an added value compared to each individual study.This study can have several implications. Our meta-analysis gives a final odd ratio for the risk that opium poses on cancer development, and could thus generate awareness if highlighted in the guidelines, online resources, text books and practitioners’ databases. Moreover, with a glance to our final outcomes, the heavy cancerous role of opium can be concluded, even comparable with cigarette smoking. Besides clinicians and healthcare practitioners, policy makers should also be warned about the health burden imposed by opium use to take necessary actions, particularly in countries where opium is widely used.Alt-text: Unlabelled box1Cancer is the second leading cause of death and is responsible for one out of every six mortality cases, globally Opium is a highly addictive substance extracted from the opium poppy and is widely used for recreational purposes, especially in the Middle Eastern countries Regular opium abuse is considered a risk factor for developing cancer. Previous studies indicated the association between opium consumption and increased risk of laryngeal ,24, oralTaking into account the association between opium consumption and increased risk of cancer, we aimed to perform a systematic review and meta-analysis to evaluate this correlation more precisely with meta-analyses.2Our review was designed to answer two questions; 1. Can opium consumption increase the risk of cancer? 2. Which cancers are more associated with opium addiction? The current study has been conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement 2.1sid.ir) was performed in order to identify all studies published from inception until September 25, 2020. No language and time limitations were posed to the study. Moreover, Google scholar was checked using Opium and cancer as key words.A systematic search of several databases such as ISI web of science, Scopus, Embase, PubMed, and Persian databases including Magiran (magiran.com) and SID (Two independent researchers (M.Z.B. and S.H.H.) performed all searches. A third researcher (M.S.) was also involved as a decision-maker for any disagreements. Also, in order to increase sensitivity of the search, reference list of the relevant studies was hand searched. All articles retrieved from the databases were exported to EndNote (Version X.9). Our final search strategy based on free-text words and controlled vocabulary terms using medical subject headings (MeSH) regarding Opium and cancer was as follows: (“Opium” OR “Papaveretum” OR “Omnopon” OR “Pantopon”) AND After excluding the duplicate studies, a team of two reviewers (M.Z.B. and S.H.H) independently screened the title and abstract of identified publications for potential eligibility, and any disagreement was settled by the third reviewer (M.S.). Our systematic review included observational studies that investigated the role of opium addiction in cancer development. All case reports, case series, commentaries, letter to editors, published abstracts, unpublished trials, position papers, unstructured papers, dissertations, and animal studies were excluded.2.2After checking for eligibility, full texts of the included studies were acquired, and the qualified studies underwent full-text review and were read, tagged, and hand-noted by two reviewers (M.Z.B. and S.H.H.). Then, any disagreement was verified by a third reviewer (M.S.). Two independent reviewers (M.Z.B. and S.H.H.) assessed the methodological quality of all studies using the Newcastle-Ottawa scale (NOS) 27, and the third reviewer verified the assessment (M.S.). NOS scores of 1–3 were categorized as low-quality, 4–6 as moderate quality, and 7–10 as high-quality studies The eligible studies underwent data extraction by two independent authors (M.Z.B. and S.H.H.) using predetermined forms. Data extraction table included the information regarding the first author name, journal name, study location, publication year, study design, number of cases and controls separated by age and sex, and the procedure of selection, inclusion and exclusion criteria, risk ratio, odds ratio and hazard ratio. The main outcome measure was the association between opium addiction and the risk of cancers.2.3The odds ratios were pooled based on different classifications of cancer sites using International Classification of Diseases for Oncology, third version (ICD-O-3) 2.42 index. A cut-off more than 50% was considered as significant level of heterogeneity. Moreover, a funnel plot was designed for included studies, in order to assess the risk of bias of the studies. All analyses were performed by Comprehensive Meta-Analysis , and a p-value of < 0•05 was considered statistically significant.To assess the association between opium use and cancer development, data from separate studies were pooled. The intended effect sizes were odds ratio (OR) and 95% confidence intervals (CIs). In order to statistically minimize the role of confounders, studies were categorized into two groups: studies that were adjusted for only age and sex  and studies that were adjusted for age, sex, and some additional factors (fully adjusted). Furthermore, heterogeneity assessment was conducted using Cochran's Q- test and I2.5There is no funding source associated with this study.33.1Totally, 244, 256, 305, and 357 studies were identified through performing a comprehensive search in Web of Science, PubMed, Scopus, and Embase databases. As most of our included studies were from Iran, Iranian databases, including SID and MagIran, were also searched for all eligible researches, and 198 papers were included in our primary assessment. No additional relevant studies were entered in our study using Google Scholar and reference screening. Seven hundred thirty-five studies were remained after excluding duplicates and were gone under the title and abstract screening. Therefore, 302 studies were selected for full-text assessment, and finally, 34 and 32 publications were included in our qualitative and quantitative synthesis, respectively. Our study selection procedure is summarized in the PRISMA flowchart .Fig. 1PR3.2The detailed data of the included papers such as methodology and population's demographic are summarized in 3.3NOS scores of all of the included studies were between 5 and 9. Medium and high quality studies were included, which were qualified enough to be included in our systematic review and meta-analysis 3.4p < 0•001) (p < 0•001)  -A1. Simi< 0•001) -B1. Inde3.5To test the power of our finding about association between opium consumption and cancer development in minimally adjusted model, we recalculated the joined consequences of primary investigation by barring one examination. The overall pooled range showed that exclusion of any studies did not change our result (ranged from 3.97 (95% CI = 3.20–4.92) to 4.29 (95% CI = 3.46–5.31)) -A2. Also3.6p-value (two-tailed) = 0.789 in Egger's regression intercept that show publication bias does not exist minimally adjusted studies. The results of fully adjusted funnel plot are presented in 3.72 = 60.99; p = 0.012) was conducted. The results revealed that Opium use was significantly associated with GI cancers . Random effect analysis was carried out on six studies with a sample size of 2588 concerning upper GI (UGI) cancers; Thus, a significant association was observed . It should be indicated that as ICD-O, IARC, and NCI did not categorized oral cavity cancer in GI or UGI malignancies, we omitted Naghibzadeh Tahami et al. p < 0•001; I2 = 0•00). Oral cavity cancers were also found to be associated with opium use ) in random-effect analysis and minimal adjustment level. Moreover, we detected a significant association between opium use and bladder cancer in both minimally (M) and fully (F) adjusted random effects model ). Random effects model analysis of 5 studies with fully adjusted odds ratios and a population of 4580 participants revealed considerably increased odds of laryngeal cancer following opium use . In addition to laryngeal cancer, our meta=analyses concluded that respiratory (OR = 9.02 95%CI = (6.27–12.96)), head and neck (OR = 8.03 95%CI = (4.03–16.00)), colon (OR = 5.58 95%CI = (3.14–9.92)) cancers were also significantly associated with the consumption of opium in random-effect fully-adjusted models. Random-effect model also revealed that lung cancer ) involvement is also associated with opium consumption. Furthermore, random effects model analysis of minimally adjusted odds ratios showed a significant association between opium use and lung cancer . Random effects model analysis of eight gastrointestinal (GI) cancer studies with 3593 participants and medium heterogeneity  system. Our results in fully adjusted odds ratio model showed that opium addicts have around 2•72 times more risk of GI cancers. Moreover, we found that opium consumption makes the person 2•42 times more susceptible to upper GI (UGI) cancers, especially around two times more prone to esophagus cancer and 2•6-fold more prone to oral cavity malignancies. It is reported that morphine, as a dominant alkaloid of Opium, inhibits clearance of Salmonella typhimurium strains S Typhimurium strains, which is reported to be even at higher rates than those for cigarette condensates Moreover, opium and morphine pyrolysates showed mutagenic activity through frameshift mutations in Besides being carcinogenic for digestive tract, opium is found to be responsible for respiratory tract cancers including malignancies of the larynx and the lung. We found that this substance can increase the risk of larynx and lung cancers by 8.41 and 4.19 folds, respectively. Intra-tracheal use of Opium and Morphine pyrolysates has shown to be carcinogenic in hamsters and can cause tracheal carcinoma Opium is also responsible for bladder cancer. The hypothesis proposed for bladder cancer in the exposure of Opium is similar to those of the other discussed cancer. In fact, the urinary retention caused by Opium can further prolong the exposure to the carcinogenic material ,66. We fSukhte is one of them. Sukhte can be boiled in order to produce another substance named Shireh. Sukhte is usually ingested, but Shireh can be ingested or smoked Several remnants are also derived from Opium that can be abused. The burned residues of the smoked Opium named Furthermore, the role of the confounders should not be ignored. Many of the opium users usually smoke cigarettes and use alcohol that both of them are carcinogens Nokhod-day or Nokhod year unit, but it still needs more workup [Nokhod has an amount of 0•2 mg of Opium Drug dealers usually add lead, as an impurity, to the Opium that is also a carcinogen compound and may play a part in this issue ,71. Furte workup ,73. It ith January 2021) and up to our knowledge, this study is currently in press and as we know, they had thoroughly reviewed all studies regarding the carcinogenicity of opium in their Monograph; However, we found that no meta-analyses were done in this review as we done in our study to quantify the potential of opium in development of different cancers Recently, a news published by The Lancet Oncology has reported the work of a group of scientists at International Agency for Research on Cancer (IARC) in which they had performed a thorough review on the opium carcinogenesis. Until now (19Due to the high heterogeneity regarding the route of opium administration between the included studies, our study was limited to this factor. We tried to minimize the confounding, especially smoking and alcohol consumption, by statistical adjustment, and our results showed a strong relation between Opium and various cancers. What remains little-known is the underlying pathophysiology of carcinogenesis with opium consumption. Future animal and biological studies should further work on the carcinogenesis of Opium. Moreover, small number of the included studies had reported the route of opium administration in their target population and so we recommend future researches to investigate and report it more accurately. In addition, they have to consider that in Islamic countries like Iran, heavy smokers are more vulnerable to break the religious prohibitions and consume alcohol, illegally; Thus, the researchers should keep these factors in mind as they are proven to be strongly associated with cancer development.We concluded that Opium could be a carcinogen material that can cause various cancers in GI, urinary, and respiratory systems. In fact, we can say that opium consumption can cause different cancers from the oral area to the anus. Yet, the underlying pathophysiology of this carcinogenesis is not fully discovered. More animal studies should be conducted to entirely describe the pathways that lead to carcinogenesis.The authors have nothing to disclose.


Background: The association between left atrial size and the risk of stroke has not been fully understood. We performed a meta-analysis of prospective cohort studies to determine whether left atrial enlargement (LAE) is associated with an increased risk of stroke.Methods: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library through May 2019. Prospective cohort studies were included if they reported hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of stroke with respect to LAE. All meta-analyses were performed using a random-effects model.Results: Six studies involving 66,007 participants and 3,549 stroke events were included. Compared with patients without LAE, those with LAE had an increased risk of stroke . There was also a graded association with stroke relating to LAE . Furthermore, for each increase of 1 cm in left atrial diameter, the odds of stroke were increased by 24% .Conclusions: Our meta-analysis demonstrated that LAE is associated with an increased and graded risk of stroke. Stroke is a catastrophic condition with a great burden of disability and death. Furthermore, as the world population is aging, the global burden of stroke will increase dramatically . And it Studies have found that left atrial size was associated with an increased risk of ischemic stroke and all-cause of deaths despite of controversy –5. AdditAmong various quantification methods of left atrial size, the European Society of Cardiology recommends that left atrial volume indexed to body surface area (LAVi) should be used to predict all-cause mortality and ischemic stroke because of its accuracy and reliability , consideThis meta-analysis was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement . It was * AND “cerebral embolism” OR stroke OR “Apoplexy” OR “Brain Vascular Accident” OR CVA OR “Cerebrovascular Accident*” OR “ischemic infarction” OR embolism* OR thromboembolism* OR thrombosis. The Medical Subject Headings (MeSH) search and free-text terms search were conducted with our search strategy. Furthermore, we hand-reviewed reference lists of included studies and review articles to search for more studies. Only those that were published as full-length articles and in English were considered. Two investigators (YCX and LMZ) independently performed the literature search.We searched PubMed (from inception to May 2019), EMBASE (from inception to May 2019), Web of Science, and the Cochrane Library Databases (May 2019). The following search terms were used: “left atrial volume” OR “left atrial size” OR “left atrial dimension” OR “left atrial diameter” OR “left atrial dilatation” OR “left atrial hypertrophy” OR “left atrial enlargement” OR “left atria volume” OR “left atria size” OR “left atria dimension” OR “left atria diameter” OR “left atria dilatation” OR “left atria hypertrophy” OR “left atria enlargement” OR “left atrium volume” OR “left atrium size” OR “left atrium dimension” OR “left atrium diameter” OR “left atrium dilatation” OR “left atrium hypertrophy” OR “left atrium enlargement” OR “enlarged left atrium” OR “enlarged left atria” OR “heart atrium enlargement” OR atriomegaWe removed duplicates, screened the titles and abstracts for relevance, and accessed full text to identify eligibility. For inclusion, studies had to fulfill the following criteria: have a prospective cohort design with follow-up >1 year; report relative risks or hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of stroke relating to left atrial enlargement (LAE).Two authors (YCX and LMZ) independently collected data from all included studies using a standard form. The following information was extracted from each included study: first author, year of publication, country of the study, participant number and characteristics, sex, AF status at baseline, exposure definition, mean length of follow-up, number of stroke events, and covariates in the fully adjusted model.We assessed the quality of each cohort by using the Newcastle–Ottawa Scale . This scWe described associations using HR or risk ratio (RR) for prospective studies. RR was considered equivalent to HR .Q statistic and the I2 statistic. The I2 statistic is used to estimate the proportion of total variation across studies due to heterogeneity rather than chance (ranging from 0 to 100%). An I2 value > 50% indicates significant heterogeneity. We also performed subgroup analyses according to LA size to further determine the relationship between LAE and the risk of stroke. To evaluate the publication bias, we constructed a funnel plot to visualize possible asymmetry (P < 0.05 was considered statistically significant.We pooled the adjusted HRs and corresponding 95% CIs from each study using a random-effects model. We assessed heterogeneity across studies using the symmetry . All staOur initial search yielded 5,436 records. After screening titles and abstracts, we obtained 44 articles for full-text reviewing. Finally, six studies were eligible for inclusion  7, 13–1–113–17.The characteristics of the included studies are shown in Compared with patients without LAE, those with LAE had an increased risk of stroke (five studies; adjusted HR 1.68, 95% CI 1.36–2.07; Our meta-analysis of five prospective cohort studies indicates that LAE is associated with increased risk of stroke. Additionally, we found that the risk of stroke became higher with the increase of the LAD. For each increase of 1 cm in LAD, the odds of stroke were increased by 24%.The mechanisms related LAE to stroke have not been fully understood. Some hypotheses have been proposed, which might partially explain the association between LAE and stroke. First, LAE may predispose the development of AF , which iThe investigation of the association between LAE and stroke may have several clinical implications. First, much evidence has been found that the left atrial structure and function were strongly associated with the risk of new-onset AF , 23 and Several limitations of this study should be considered. First, the differences of population in the included studies could result in inconsistency between studies. And it might be a significant limitation of our study. However, we only included prospective cohort studies, which helped minimize heterogeneity. Second, as we only included studies published in English, we might neglect studies published in other languages and produce bias. Third, the methodological quality of the selected studies was not uniform. Fourth, we considered that RR was equivalent to HR owing to the small number of the included studies in the present meta-analysis. So the findings of our study should be interpreted cautiously.In conclusion, our meta-analysis demonstrated that LAE is associated with an increased and graded risk of stroke. Future studies should explore the risk and benefit of thromboprophylaxis in general populations with LAE.The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the article.YX conceived the study, participated in the design, collected the data, performed statistical analyses, and drafted the manuscript. LiZ participated in the design, collected the data, performed statistical analyses, and drafted the manuscript. LvZ and YH performed statistical analyses and helped to draft the manuscript. PW and SY performed statistical analyses and helped to revise the manuscript critically for important intellectual content. All authors read and approved the final manuscript.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.


Stroke is the major cause of death and disability worldwide. ABCA1 R219K has been suggested as a risk factor for ischemic stroke, but the results remain inconclusive in the Chinese population. This study aimed to assess the association between ABCA1 R219K and ischemic stroke using meta-analysis. A systematic literature search was conducted to select eligible studies and the pooled odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of association. Fourteen studies containing 2865 cases and 3227 controls were included in the meta-analysis and the results suggested that there is a strong association between ABCA1 R219K and the ischemic stroke risks . Subgroup analysis revealed that significant association was found for the 4 genetic models (p<0.05) in the Southern population, while in the northern population significant association was only found under the dominant model . This meta-analysis suggested that ABCA1 R219K polymorphism might be a protective factor against developing IS, indicating this SNP may contribute to the pathogenesis of ischemic stroke and might be potentially used as a biomarker to predict the susceptibility to ischemic stroke. In partIt is well accepted that the serum high-density lipo-protein cholesterol (HDL-C) level is an independent risk factor of vascular disease with the increased HDL-C providing a protective effect against vascular disease incidence. ATP binding cassette subfamily A member 1(ABCA1) is a key regulator of cholesterol efflux and plays a pivotal role in the synthesis of HDL-C and reverse cholesterol transport (RCT) . The ABCR219K in exon 7, also known as rs2230806, is a common variation of the ABCA1 gene. The G to A substitution causes the change from Arg to Lysine at 219 site of the peptide. Although the impacts of protein function caused by this mutation is not clear, genetic studies have found that R219K variation is associated with either increased HDL-C and/or decreased risk of CAD . AnotherAbundant studies have also been performed to investigate such an association in the Chinese population. Xiao and colleagues first reported the ABCA1 R219K might be a protective factor for IS in a Southern Chinese population . Notably22.1The relevant literature, published before August 2019, was searched across the electronic database of Pubmed, WangFang and China National Knowledge Infrastructure (CNKI) in English or Chinese. The following key terms were used for the literature searching: “ischemic stroke”, “cerebrovascular accident”, “cerebrovascular disease”, “cerebral infarction”, “polymorphism”, “gene mutation” and “ABCA1”. A manual search was also carried out on the references of the literature to identify additional eligible studies.The following criteria was used to select eligible studies for the meta-analysis: (1) studies evaluating the association between ABCA1 and ischemic stroke; (2) studies containing data from the Chinese population; (3) Clear diagnosis of ischemic stroke patients; (4) R219K polymorphism was genotyped and detailed frequency data available. Accordingly, studies that did not meet the above criteria were excluded. If there was more than one case-control study reported, they were treated independently.2.2Two authors performed the data extraction independently and any disagreements were resolved by discussion with a third author. Following information was extracted from the included studies: the surname of the first author, year of publication, region of the study (South or North China), numbers of controls and cases, genotype methods and distribution of alleles and genotypes. Additionally, P values of Hardy-Weinberg equilibrium (HWE) test for the controls were also extracted or calculated based on the genotype data.2.32 test and p<0.1 for the I2 was considered statistically significant for the heterogeneity test. The Begg’s and Egger’s test were employed to test the potential publication bias and p<0.05 indicated significant publication bias. In addition, the funnel plot was also drawn based on the Begg’s test. Subgroup meta-analysis was also performed based on the region of population and Hardy–Weinberg equilibrium (HWE) test.The meta-analysis was performed as previously reported . The ana33.1Through literature searching, 68 publications relevant to ABCA1 gene and ischemic stroke were identified. Follow-up title and/or abstract reading excluded 42 studies as they were irrelevant to the meta-analysis. After further abstract reading, 11 studies were excluded because there was no data from Chinese population (n=3), no R219K data, and not case control studies (n=2). Subsequently, full texts readings were performed on the 15 studies and 1 study was further excluded due to duplicated data. Finally, 14 studies, containing 2865 cases and 3227 controls, investigating the PD-L1 R219K C>G and the risks of ischemic stroke were included in the present meta-analysis  14, 15,, 27, 28.3.2As shown in By considering that genetic background between Southern and Northern Chinese population might be different, stratified analysis was conducted based on the region of the study. In the Southern population, significant association was found for the 4 genetic models (p<0.05); in the northern population, significant association was found under the dominant model , but not under the allelic model, homozygotic model and recessive model (p>0.05). However, heterogeneity were still found in the allelic model, the homozygotic model and the recessive model (p<0.05) in both Southern and Northern populations. Taking together, the meta-analysis revealed that ABCA1 KK+RK carriers might have decreased risk of ischemic stroke in Chinese populations.3.3Begg’s funnel plots and Egger’s tests were employed to evaluate the potential publication bias. The results of Begg’s and Egger’s tests are shown in 3.4Sensitivity analysis was performed by replicating the analysis after omitting one study at a time to evaluate the effect of quality of studies on the final findings. A representative picture for the dominant model is shown in 4ABCA1 plays an important role in the development of IS. ABCA1 is a major regulator of cellular and systemic cholesterol homeostasis. It is widely expressed and contributes to reverse cholesterol transport (RCT) by exporting cholesterol out of cells to extracellular acceptors to form HDL-C. Through the above mentioned RCT, ABCA1 exerts its protective role in atherosclerosis (AS), which is believed to be an initial step in the IS pathogenesis. R219K is a common variation in the ABCA1 gene. Several studies investigated the association between ABCA1 R219K and IS susceptibility in Chinese population, but the results are inconsistent. The present meta-analysis included 14 eligible original studies containing the data of 2865 cases and 3227 controls. The main findings of this meta-analysis are that the allele K might be a protective factor for the IS and the ABCA1 KK+RK carriers might have decreased risk of ischemic stroke in Chinese populations. Subgroup meta-analysis shows a stronger association between ABCA1 R219K and IS in the Southern Chinese population than the Northern Chinese populations.Hou and colleagues conducted a meta-analysis on the association between ABCA1 R219K and IS in the Chinese population in 2014 . This stMore recently, a meta-analysis was carried out in the Asian and Caucasian populations and have found that homozygous RR of R219K was significantly associated with increased IS risk  , which iAnother question is how to explain the protective role of ABCA1 R219K in IS risk in the Chinese population. It is generally accepted that HDL-C is a protective factor against vascular disease . As a kind of cerebral vascular condition, increased serum HDL-C has been linked to decreased IS risk. Recent studies found that ABCA1 gene polymorphisms are associated with elevated blood lipid levels, in particular, the serum HDL-C levels. Considering the important regulatory role of ABCA1 in cholesterol homeostasis, it is likely that the protective role of ABCA1 R219K in IS is due to the elevated HDL-C. However, how the R219K variation affects the function of ABCA1 protein is unclear, and requires much more investigation in the future.The present meta-analysis should be interpreted with caution due to several limitations. First, we only focused on R219K variation in the ABCA1 gene, while not evaluating other genes or environmental factors. It is possible that the potential roles of ABCA1 R219K are diluted or masked by other gene-gene or gene-environment interactions. Second, we only conducted the meta-analysis in the Chinese population, and so far only 2 studies have been published in Caucasians populations. Whether there is such association in Caucasian populations merits further investigations. The last but not the least, heterogeneity still exists even if we perform subgroup analysis based on the region of the Chinese populations. The association between ABCA1 R219K and IS should considered with caution when applied to a specific population.5This meta-analysis suggests that ABCA1 R219K polymorphism might be a protective factor against developing IS. However, the strength of association might vary among populations, and larger and well-designed studies are warranted to validate our findings.


The results of the meta-analysis showed a potential protective effect of PA on prevalent and incident depression.Depression is a major contributor to the overall global burden of disease, with high prevalence and relapse rate. Several factors have been considered in order to reduce the depression burden. Among them, physical activity (PA) showed a potential protective role. However, evidence is contrasting probably because of the differences in PA measurement. The aim of this systematic review with meta-analysis is to assess the association between objectively measured PA and incident and prevalent depression. The systematic review was conducted according to methods recommended by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant papers published through 31 August 2019 were identified searching through the electronic databases PubMed/MEDLINE, Excerpta Medica dataBASE (Embase), PsycINFO, Scopus, Web of Science (WoS), and the Cochrane Library. All analyses were conducted using ProMeta3. Finally, 42 studies met inclusion criteria. The overall Effect size (ES) of depression for the highest vs. the lowest level of PA was −1.16 [,  Depression is one of the major leading causes of disability worldwide, affecting approximately 400 million people , with 9%Current studies are focusing on the important role played by lifestyles and in particular physical activity (PA), in both preventing and treating depression . SeveralTwo recent meta-analyses focusing on prevalent depression and incident depression found an inverse association between prevalent depression and PA , while tWe performed a systematic review with meta-analysis of the evidence from the literature to assess the relation between physical activity objectively measured and incident and prevalent depression.https://www.crd.york.ac.uk/prospero/).We conducted this systematic review according to the methods recommended by the Cochrane Collaboration  and to tStudies were identified searching through the electronic databases PubMed/MEDLINE, Embase, Scopus, Web of Science (WoS), PsycINFO and the Cochrane Library. We combined the search strategy of free text terms and exploded MESH headings for the topics of depression, physical activity, objective measurements, and type of study. The strategy was firstly developed in PubMed/MEDLINE and then adapted for use in the other databases . StudiesWe considered studies that investigated the relation between physical activity objectively measured and depression, both as a continuous and as a binary variable. Adult participants of both sexes were considered. As done before ,21, bothIdentified studies were independently reviewed for eligibility by two couples of authors  in a two-step process: a first screening was performed based on title and abstract, while full texts were retrieved for the second screening. At both stages disagreements by reviewers were resolved by consensus. Data were independently extracted by three authors  and supervised by a senior author (VG) using an ad-hoc developed data extraction spreadsheet. The data extraction spreadsheet was piloted on 10 randomly selected papers and modified accordingly. As done before ,24,25, bThe quality evaluation of the included publications were independently assessed by two authors using the New-Ottawa Scale  for obse®  software. Due to heterogeneity, a random effects meta-analysis was employed. In order to reduce the heterogeneity, two sensitivity analyses were conducted, considering the following items: (i) study design, (ii) participants’ comorbidities. Moreover, a subgroup analysis by gender was conducted in order to estimate potential different effects among the two groups. We assessed publication bias with the visual inspection of a funnel plot  based on 37,408 participants . A potential publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . However, the ES estimated did not change after the trim and fill method , icipants a, with hl method b.p-value < 0.001] based on 33,812 subjects. High statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering patients with chronic obstructive pulmonary disease (COPD), included 6 datasets, and the pooled ES was −1.08  based on 683 subjects. High statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering obese participants, included 5 datasets, and the pooled ES was −0.35  based on 1354 participants. High statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering participants with (any type of) cancer, included 5 datasets, and the pooled ES was −1.79  based on 955 participants. High statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test .The sub-group analysis considering only the general population (without diseases), included 21 datasets, and the pooled ES was −1.32  based on 34,764 participants. High statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering only cross-sectional analysis, included 27 datasets, and the pooled ES was −0.23  based on 17,191 participants. A high statistical heterogeneity was found . A publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering only cohort datasets, included 6 datasets, and the pooled ES was −2.61  based on 17,515 participants. High statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering only interventional studies , included 8 datasets, and the pooled ES was −2.63  based on 2644 participants. High statistical heterogeneity was found . Potential publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test .The sub-group analysis considering only observational studies , included 34 datasets, and the pooled ES was −0.99  based on 1415 participants. High statistical heterogeneity was found . Potential publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test . The sub-group analysis considering only men, included three datasets, and the pooled ES was −0.11  based on 928 participants. A high statistical heterogeneity was found . However, no publication bias was found by the visual assessment of the funnel plot and confirmed by the Egger’s linear regression test .Considering The sub-group analysis considering only women, included seven datasets, and the pooled ES was −1.91  while, in the subgroup analysis including only cross-sectional datasets, the risk of prevalent depression was estimated on 17,191 participants and the ES was −0.23 . In subgroup analysis including only longitudinal datasets, the risk of incident depression, estimated on 17,515 participants, was lower −2.61 [.The current systematic review with meta-analysis—which included 43 studies in qualitative evaluation and 42 studies in the quantitative analysis—provided data on the association between objectively measured PA and the risk of depression. Since some studies expressed data separated for gender, a total of 42 datasets have been considered. The pooled ES based on 37,408 subjects indicated a significantly protective effect of PA on depression [−1.16 , With the purpose of deeply understanding the strength of the association between objectively measured PA and depression, a sub-group analysis by participants’ comorbidity has been conducted. When studies assessing the association among participants with comorbidities were considered, the ES were not statistically significant (apart for COPD participants). However, prescription of adapted PA among participants affected by co-morbidities should be considered . To the These results are extremely important considering that depression is one of the leading causes of disabilities worldwide . In the 2 remained extremely high. However, a I2 value higher than 90% means that heterogeneity is directly due to heterogeneity among studies, instead of sampling error [2 [In the last decades, several studies have shown that a healthy lifestyle, in particular the intensity and length of physical activity ,73, are ng error . Moreoveerror [2 . Another2 value that might reduce the generalizability of our results. Most studies are observational and based on cross-sectional analysis. Nevertheless, we performed sensitivity analyses only including trials and longitudinal studies, increasing the robustness of our results. Due to the high heterogeneity in reporting the level of PA performed by participants in original studies, it was not possible to identify a recommended level of PA. The inability to estimate an association between severity of depression and PA is another important limitation. The main strengths of this review are being systematic in nature and its comprehensive way to include the entire scientific evidence published so far on the main medical-scientific databases. Furthermore, the pooled ES was significantly large, based on 37,408 participants, and sub-group analyses have been conducted based on participants’ comorbidity and study design. In the primary studies, diagnosis of depression was consistently based on the DSM criteria and was established by trained investigators using validated assessment scales mainly with interrater reliability.The main limitation of this systematic review is the high ITo conclude, the results of this systematic review and meta-analysis clearly show a statistically significant protective effect of objectively measured PA on prevalent and incident depression. An increased PA is associated with lower risk of depression. The advantages of our study are several. Firstly, this study offers a systematic overview of previous studies assessing objectively measured PA and depression. Secondly, this study highlights the usefulness of objectively measured PA compared to self-reported one. Objectively measured PA is not only more precise in estimating duration, total amount, and intensity of PA, but indirectly it can also better strengths the association with some diseases, as depression. Thirdly, this study shows the importance to promote physical activity forasmuch it can help to reduce the high burden of depression in our society. Lastly, our findings are relevant for both policy makers and clinicians as physical activity is one of the cheapest, non-pharmacological treatment that might be prescribed to the general population with potentially major public health impact. Physical activity is important across ages and should be integrated into daily life.