Enterobacteriaceae is a serious problem. From this perspective, we analysed published data regarding ESBL-producing Enterobacteriaceae in different regions of Pakistan.South-Asia is known as a hub for multidrug-resistant (MDR) bacteria. Unfortunately, proper surveillance and documentation of MDR pathogens is lacking in Pakistan. The alarming increase in the prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae in Pakistan. A Web-based search was conducted in electronic databases, including PubMed, Scopus and PakMedi Net . Articles published  between January 2002 and July 2016 were included in the study. Relevant data were extracted, and statistical analysis was performed using the Metaprop command of STATA version 14.1.A meta-analysis was performed to determine the prevalence of ESBL-producing p < 0.001), and significant ES = 0  was found. OXA, SHV, TEM and CTX-M were the most commonly found gene variants for ESBLs in these studies.A total of 68 studies were identified from the electronic data base search, and 55 of these studies met our inclusion criteria. Pakistan’s overall pooled proportion of ESBL-producers was 0.40 (95% CI: 0.34–0.47). The overall heterogeneity was significant (I2 = 99.75%, Enterobacteriaceae is high in Pakistan. Little is known about the annual frequency of ESBLs and their prevalence in different provinces of Pakistan. No data are available regarding ESBL frequency in Baluchistan. This underscores an urgent demand for regular surveillance to address this antimicrobial resistance problem. Surveillance to better understand the annual ESBL burden is crucial to improve national and regional guidelines.The prevalence of ESBL-producing  Antimicrobial resistance has been declared a global threat to public health, as a massive increase in this problem has been observed in different parts of the world . AlthougEnterobacteriaceae has serious consequences for treatment outcomes   studies with incomplete information related to phenotypic ESBL detection methods; 2) duplicate articles, case reports, very small datasets (few strains < 15), abstracts/titles only, posters and review articles 3) studies on β-lactamases other than ESBL; 4) studies on animals and environmental strains of non-human origin. After reading the full texts, 13 further articles were removed for miscellaneous reasons [no phenotypic testing for ESBLs was performed , sample size, strains detected ESBL, phenotypic detection techniques including; the double disc synergy test (DDST), the combination disc test (CDST), the epsilometric test (E-Test) and molecular detection techniques for gene variants (PCR) Tables  and 2. DMetaprop command in STATA version 14.1  to pool the published data regarding the predominance of ESBLs in different regions of Pakistan. Statistical heterogeneity was calculated using the I2 statistic (measure of inconsistency) at the significance level of 5%. Heterogeneity was used to study the variation in studies using the I2 statistic. The p-values  were used for converting meta-analysis results to defined/known tests of statistics. Random-effects model (REM) was used to estimate the pooled prevalence and 95% CI. A funnel plot and Begg tests were performed to evaluate the publication partiality using data graphically and statistically.Statistical analysis was performed using the Electronic database searches yielded a total of 68 studies. A total of 55 articles reviewed from four provinces of Pakistan included 14 25.4%) from Punjab, 23 (41.8%) from the Islamabad/Rawalpindi, 9 (16.4%) from the KPK, while the remaining 9 (16.4%) were from the Sindh. No studies were found from Baluchistan province  had performed the double disc synergism test (DDST). However, only 13 23.6%) had performed the combination disc test (CDST), and only 5 (9.09%) had performed the epsilometric test (E-Test). None of the studies had used the broth minimum inhibitory concentration (MIC) method. Out of 55 studies, 28 (50.9%) were published in local journals while the remaining 27 (49.1%) were in international journals  out of 55 articles reported PCR-based gene detection methods. Among these, 50% of articles reported CTX-M group as the most prevalent group, and CTXM-1 as the most commonly found gene variant. Additionally, CTX-M and TEM combinations were found in 33% of selected articles. One study reported the association of 1% out of2 = 99.75%, p < 0.001), and significant ES = 0 . The pooled proportion of ESBL-production for the Punjab, the Islamabad/Rawalpindi region, the KPK and the Sindh regions was 0.33 (95% CI: 0.21–0.46), 0.50 (95% CI: 0.39–0.62), 0.26 (95% CI: 0.15–0.39) and 0.43 (95% CI: 0.27–0.60) respectively. Significant heterogeneity (I2) for four regions with p < 0.001 is 99.77, 99.46, 99.59 and 99.81% respectively. Significant ES = 0 at p < 0.001 for the Punjab, the Islamabad/Rawalpindi, the KPK and the Sindh regions is Z = 8.32, 12.65, 7.43 and 7.87 respectively . The variation in ESBL occurrence reported in this systematic report may depend on several factors, including the socio-economic status of a society and the availability of antibiotics [These results indicate an extensive and statistically significant degree of disparity in ESBL proportion estimates  have investigated the molecular characterization and presence of ESBL encoding genes , 51, 58.sistance . Howeversistance . There asistance , 75. WitThis meta-analysis indicated that there is a high ESBL burden in Pakistan. Few papers are available that address the annual frequency of ESBLs and their distribution in different provinces of Pakistan. No paper is available regarding the frequency of ESBLs in Baluchistan. Only 6 papers that reported gene detection were found. Detection of gene variants in β-lactamase-producing bacteria is essential information for the appropriate and effective treatment of patients. This underscores an urgent demand for regular surveillance to address this antimicrobial resistance issue. National and regional guidelines would be based upon such surveillance in order to understand the annual ESBLs burden. Effective measures such as the establishment of active surveillance and infection control programmes, emphasizing hand hygiene together with coherent antibiotic policies in hospitals and clinics should be implemented to stop and manage the spread of ESBLs in hospitals and communities.


VDR) gene Fok I polymorphism and susceptibility to prostate cancer (PCa), however the results remain inconclusive. To provide a relatively comprehensive account of the association, we searched PubMed, Embase, CNKI, and Wanfang for eligible studies and carry out this meta-analysis. A total of 27 case-control studies with 10,486 cases and 10,400 controls were included. In the overall analysis, Fok I polymorphism was not significantly associated with the susceptibility to PCa. Subgroup analyses showed that significantly association was existed in Caucasian population, the subgroup of population-based controls and the stratified group with advanced tumor.These results indicate that the VDR Fok I polymorphism might be capable of causing PCa susceptibility and could be a promising target to forecast the PCa risk for clinical practice. However further well-designed epidemiologic studies are needed to confirm this conclusion.Several previous studies have been reported to examine the association between Vitamin D receptor ( Prostate cancer (PCa) is now thought to be one of the most commonly diagnosed malignant tumors in old men throughout the world, and the second cause of cancer in males. It accounted for approximately 233,000 (27%) new cases and 30,000 deaths in the United States in 2014 [In vitro experiments suggested that vitamin D inhabits the growth and differentiation of prostate cancer cells, promotes cell apoptosis. It can also inhabit the invasion, metabolism and angiogenesis of tumor cell [Low levels of vitamin D are considered to be a risk factor for PCa . In vitrmor cell . A clinimor cell .VDR) [2D3), the active form of vitamin D, binds to VDR and form a heterodimer complex, which subsequently binds to the vitamin D response element and down-regulate the transcription of numerous genes that stimulating the cell growth and differentiation [The anticancer effect of vitamin D is activated mainly through the vitamin D receptor (VDR) . 1,25-Dintiation .VDR gene were reported to be associated with risk of PCa [Fok I variant (rs10735810) located in exon 2 of VDR gene is one of the most extensively studied SNPs [2D3 signal [Fok I polymorphism might accelerate the progression of PCa. However, the results are disputable and contradictory [Several single nucleotide polymorphisms (SNPs) of k of PCa . Fok I vt rs1073510 locatet rs1073510 locateadictory , 10, as A total of 277 potentially relevant studies were identified following the searching strategy. 27 studies , 12-32 wFok I polymorphism is not associated with the PCa risk in the overall populations . , dominant model  and allele-frequency genetic model  and allele-frequency genetic model   Table .In the stratified analysis by genotyping method, there was no significant association in different subgroups, which were stratified into TaqMan, PCR-RFLP, SNPlex and other subgroups. As showed in Table Fok I polymorphism is associated with the advanced tumor in homozygote model  and allele-frequency genetic model . Meanwhile, no significant difference in the genetic variants was detected between localized tumor cases or controls.A subgroup analysis based on the tumor stages was also conducted to delineate the association in more detail. As presented in Table 2=14%), Ff vs. FF: p=0.105, I2=0%; Ff/ff vs. FF: p=0.173, I2=0%; ff vs. FF/Ff: p=0.318, I2=13%; and f vs. F allele: p=0.138, I2=27%)  database searches were conducted for all the eligible papers. The following search terms were used: “VDR gene Fok I polymorphism and PCa risk; (iv) detailed genotype distribution frequency of cases and controls could be obtained or calculated; (v) and received more than four points in the Newcastle-Ottawa Scale (NOS), which was considered to be high quality.Retrieved studies screened should meet the following criteria: (i) studies on human beings; (ii) in a case-control or nested case-control design; (iii) investigated the association between The studies meeting the inclusion criteria were read carefully by two investigators independently (Yansheng Zhao and Lei Wang). The following information was extracted for reaching consensus on all of the items: the first author's name, year of publication, country of origin, ethnicity of study population, genotyping methods, source of controls, and number of cases and controls. The subjects were categorized as Asians, African and Caucasians for ethnicity; TaqMan, PCR-RFLP, SNPlex and other subgroup for genotyping method; population-based, hospital-based and Benign Prostate Hyperplasia (BPH) for the source of controls, respectively. We also divided the clinical stages into a localized group and an advanced group. Any disagreements were resolved by a third reviewer (Geng Zhao).2-test based on the Q statistic was conducted to assess the heterogeneity. The between-study heterogeneity was considered to be significant when I2>50% and p<0.1, and the random effects model was chosen to combine values from studies [2-test. All analyses were performed using STATA package version 11.0 .A χ studies . Otherwi


P = 0.02), while GG genotype carriers had a higher risk of HCC  than those with CC and CG genotypes in healthy group. Rs187238 GG genotype increased the risk from CHB to LC status , meanwhile the trend also existed by controlling confounding factors . Haplotype Crs187238Trs1946518 moderately decreased the risk of CHB carriers developing into HCC  after adjustment. In conclusion, IL-18 rs187238 GG genotype may increase the risk of HCC in healthy population and the risk of LC in CHB carriers.IL-18 polymorphisms influence the transcriptional activity of the IL-18 gene and associated with various diseases. However, their relationships with hepatitis B virus-related liver diseases had not reached a consensus. So we conducted this case-control study with a view to clarifying the association. We included four groups: healthy controls, chronic hepatitis B virus (CHB) carriers, liver cirrhosis (LC) and hepatocellular carcinoma (HCC) groups with each group of 250 persons. Odd ratios (ORs) and 95% confidence intervals (95%CIs) with or without adjustment were calculated. Haplotype analysis was also performed. The results showed people carrying rs187238 CG genotype had a lower risk of LC (CG vs. CC: OR = 0.59, 95%CI = 0.38–0.91,  From 1990 to 2013, ranking of viral hepatitis on leading death causes worldwide rose from the tenth to seventh . Genomic+ T cells depending on its cytokine milieu [+ T cells can contribute directly to disease pathogenesis and inhibit viral replication during HBV infection [Interleukin-18 (IL-18), firstly described as interferon (IFN)-gamma inducing factor, is one of the members of the IL-1 cytokine superfamily . IL-18 me milieu . CD4+ T nfection . Cytotoxnfection . IL-18 pnfection . All thenfection . Previounfection –19. Rs19nfection . Hass SLnfection . Li Y etnfection .Several researches have studied the impact of the two polymorphisms on HBV-induced liver diseases, but no consistent conclusions had been achieved –26. The P = 0.002) and diabetes history (P = 0.021), while they had no meaningful difference in smoking history (P = 0.100) and family history (P = 0.647). Furthermore, patients carrying CHB related liver diseases had higher laboratory parameters than healthy controls, including T-Bil, ALT and AST levels (P <0.001), which are evidences of liver injury [The included subjects were equally categorized into four groups with 250 participants, healthy controls, CHB, CHB-positive LC and CHB-positive HCC Table . The aver injury .P = 0.142; rs1946518: P = 0.90). A LC patient and five HCC patients were failed to detect 187328 genotype, and three patients with HCC was failed to detect rs1946518 polymorphism. For rs187238 polymorphism, as displayed in Table The alleles and genotype distributions of IL-18 polymorphisms were shown in Table P = 0.02). The genotype GG at187238 was more frequent in LC patients than CHB patients (2% vs. 0.8%) and logistic regression analyses showed a higher LC risk in CHB carriers with rs187238 GG genotype than individuals with CG or CC genotypes . However, after controlling for gender, age, smoking and alcohol consumption, the result indicated no significant difference in rs187238 polymorphism between LC and health controls  were analyzed. As shown in Table rs187238Trs1946518 moderately decreased the risk of CHB carriers developing into HCC  were suggested to associate with different expression of IL-18 by causing differences in transcription factor binding . Rs18723Recently, the association between the two polymorphisms (rs187238 and rs1946518 polymorphisms) and HBV-related liver diseases were frequently researched. Lau HK et al. included 559 healthy controls and 342 HCC patients to investigate the relationship and finally found rs187238 GC and CC genotypes not only increased the risk of HCC, but also was responsible for vascular invasion and enhanced the prognosis in HBV-related HCC . On the Different from the previous studies, we enrolled 1000 people who were at different stages from health to HCC. The four groups did differ significantly in alcohol history and diabetes history. For LC patients carrying HBV, heavy alcohol consumption is a independent increased risk of HCC . Lin CW Our results should be interpreted with caution because of several limitations. Firstly, though we recruited 1000 samples in this study, the sample size of each group was relative small which may restrict its detail subgroup analysis by the clinical index. Secondly, considering we just controlled four factors , other factors including environmental background, treatment protocols and living habits may cause some bias. Thirdly, all participants were all from Shaanxi Province, China, which may not stand for all the Chinese population. Lastly, the fundamental experiments should be further conducted to validate our results and explore the possible mechanism.In conclusion, our research revealed that rs187238 GG genotype increased the risk of HCC in healthy population and the risk of LC in CHB carriers. However, rs1946518 polymorphism had no impact on CHB-related liver diseases. These results indicated that IL-18 rs187238 polymorphism may be involved in the progression of CHB-related diseases in Northwest Chinese population.This study was approved by the Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University . The research protocol was completed according to the approved guidelines.For the current analysis, we established a case-control study of 250 healthy controls, 250 CHB carriers, 250 LC patients and 250 HCC patients. HBV infection was detected by ELISA method that requiring positivity of serum HBsAg and serum negativity for anti-HCV. LC patients and HCC patients were confirmed by pathological diagnosed. All the subjects were from the Second Affiliated Hospital of Xi’an Jiaotong University, and Xijing Hospital of Fourth Military Medical University, Xi’an, Shaanxi Province, China. Every participant was interviewed in-person including questions on age, demographics, ethnicity, height and weight, smoking and drinking habits, and medical history. Blood samples were collected after interview.The samples were centrifugated and stored in −80°C freezers for long-term storage. The genomic DNA was extracted and concentrated by the method described in our previous studies , 49. Twoχ2 test and the degree of freedom was 1 in the cases and controls. The significant difference in allele and genotype frequencies between cases and controls was determined by Pearson's χ2 test. ORs and 95%CIs were calculated with and without adjustment for gender, age, smoking and drinking. We evaluated the risk in the dominant model (AA+ Aa vs. aa), the recessive model (aa vs. Aa+AA), and the allele model (a vs. A) respectively . A two-sided P-value < 0.05 was considered statistically significant in all the tests.All the statistical analyses were completed using the SPSS software package . HWE was examined by comparing expected and observed frequencies using Alrlquin 3.1 program . The genotype frequencies of observed values were compared with expected values obtained from HWE theory . Haplotype analysis was performed by PHASE v2.1 software. The calculation was performed by


We conducted a meta-analysis of prospective studies to separately examine the associations between fish consumption and dietary intake of n-3 PUFAs with the risk of AF. A systematic search was conducted in PubMed and Embase to identify relevant studies. Risk estimates were combined using a random-effect model. Seven prospective cohort studies covering 206,811 participants and 12,913 AF cases were eligible. The summary relative risk of AF for the highest vs. lowest category of fish consumption and dietary intake of n-3 PUFAs was 1.01  and 1.03 , respectively. These null associations persisted in subgroup and dose-response analyses. There was little evidence of publication bias. This meta-analysis suggests that neither long-term intake of fish, nor of n-3 PUFAs were significantly associated with lower risk of AF.Findings on the association between long-term intake of fish or long-chain  Atrial fibrillation (AF) is one of the major threats to cardiovascular health with a lifetime risk of about 25% ,2 and a n-3 polyunsaturated fatty acids (PUFAs) is predominantly found in fatty fish and the liver of lean fish. N-3 PUFAs have received considerable interests for their potential anti-arrhythmic properties, yet evidence from clinical trials and observational studies has not been entirely conclusive [n-3 PUFAs supplementation on the prevention of AF and, overall, no substantial benefits have been observed [n-3 PUFAs and risk of AF [n-3 PUFAs in the analysis, which further complicated the interpretation of their findings. Given the limitations of the previous analyses and several new population-based prospective studies regarding the associations between dietary fish and/or n-3 PUFAs and risk of AF emerging thereafter [n-3 PUFAs intakes and risk of AF.Marine-derived long-chain nclusive ,6,7,8. Sobserved ,12,13,14sk of AF . Neverthsk of AF  and combereafter , we condn-3”, “eicosapentaenoic acid”, “docosahexaenoic acid”, “cohort”, “prospective”, and “follow-up”. Bibliographies of the retrieved full articles were also manually screened to identify any additional studies. According to the Tenth Revision of the International Classification of Diseases (ICD-10), AF was defined as atrial fibrillation or atrial flutter (code I48). The literature search was limited to records published in English.This meta-analysis was planned, conducted, and reported according to the guidelines of MOOSE  . A litern-3 PUFAs intake; (c) AF as the outcome of interest; and (d) adjusted risk estimates with corresponding 95% confidence intervals (CI) were reported. The most recent publication was included if one cohort was reported in several publications.Studies were included if they met the following criteria: (a) prospective study design; (b) exposure of interest was fish consumption or dietary For each eligible study, we extracted the first author’s name, publication year, country of origin, study name, follow-up duration, number of participants and cases, sex, age of participants, exposure, diseases excluded at baseline, and potential confounding factors that were adjusted for. We evaluated study quality with the Newcastle-Ottawa Quality Assessment Scale . Accordin-3 PUFAs intake. Subgroup analyses stratified by characteristics of included studies such as sex, region, range of intake, duration of follow-up, age at baseline, and quality scores were also conducted.We considered relative risk (RR) and 95% CI as the effect size for data synthesis, and hazard ratios (HRs) were considered equivalent to RRs ,21. A raThen, a dose-response analysis was conducted to estimate study-specific slopes (linear trends) from the natural logarithm of the extracted RRs and CIs across categories of exposure according to the method proposed by Greenland and Longnecker . The metI2 statistics  [p < 0.05 was considered significant unless specifically noted. All analyses were performed by using STATA software .Statistical heterogeneity was assessed by using the Q and geneity) . Publicageneity) ,30. A twn-3 PUFAs were also excluded. Finally, with one publication [lication  reportinlication ,25,37,38Characteristics of the included studies are summarized in p = 0.74, I2 = 0.0%)  .p = 0.60, I2 = 0.0%). Quantitative assessment  and graphical inspection (not shown) did not indicate evidence of publication bias. The observed null association persisted in the subgroup analyses carried out according to various characteristics of the included studies  when comparing the highest with lowest category of the intake . Neither Begg’s test nor Egger’s test revealed publication bias . Funnel plot also suggested absence of publication bias (not shown). Results of subgroup analysis supported the observed null association . Test for nonlinearity was not significant  for each one serving/week increment in fish intake, with low heterogeneity  for each 0.3g/day increment in the intake of n-3 PUFAs, without heterogeneity .There was evidence of a nonlinear association (Pnonlinearity = 0.006)  b. Howeven-3 PUFAs intake and the development of AF. Such null associations persisted in subgroup analyses based on various study and population characteristics. We observed little evidence of between-study heterogeneity or publication bias. There was some evidence that very high n-3 PUFAs intake was associated with a higher risk of AF in the dose-response analysis. However, this observation was sensitive to individual studies and should be treated with great caution.In this meta-analysis of eight prospective studies with up to 12,000 AF cases occurring among more than 200,000 participants, we found no association between higher fish consumption or This meta-analysis has several strengths. First, results of sensitivity analysis and subgroup analysis are consistent, indicating the robustness of our work. Second, the prospective design of included studies provides a more conclusive relationship between dietary intake and AF and eliminates the possibility of recall and selection biases. Third, the dose-response analysis in our study can provide a more direct exhibition of the relationship.n-3 PUFAs intakes, which would likely be non-differential and attenuate a week association to be null. Last but not least, our meta-analysis is unable to specifically investigate the association of dietary supplements of fish oil with AF. However, most of the included studies [Meanwhile, several limitations should be taken into consideration. Although publication bias was not detected, we still could not rule out such bias because the number of included studies was limited. Also, our findings are based on observational studies and we could not identify causality, but only associations because methodological issues such as the impacts of residual confounding on our results cannot be ruled out. Furthermore, only two of the included studies ,17 disti studies ,17,23,37n-3 PUFAs, and fish-derived n-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) are reported to be effective on improving blood lipid profile, vascular relaxation, and plaque stability, and thereby may have anti-arrhythmic, anti-inflammatory, and anti-thrombotic properties [n-3 PUFAs intake are inversely associated with various cardiovascular diseases such as stroke [n-3 PUFAs. Higher fish consumption may also accompany higher levels of exposure to harmful substances such as polychlorinated biphenyls, methylmercury, and mercury. These substances may cause damage to the cardiovascular system, and thus counterbalance the effect of other protective factors [Fish is the major source of operties ,40,41,42s stroke , coronars stroke ,44, and s stroke . Howevers stroke , and the factors ,48. FurtN-3 PUFAs play a beneficial role in the cardiac electric activity, and moderate intake of n-3 PUFAs may exert beneficial effects on the development of AF through various biological mechanisms [n-3 PUFAs into clinical benefits has not yet been proven. Several meta-analyses of clinical trials have investigated the potential health benefits of n-3 PUFAs on AF recurrence or postoperative AF, but the findings have not been encouraging [chanisms ,42. Neveouraging ,10,13,14n-3 PUFAs intake with AF. Additional prospective studies including population with high intake of n-3 PUFAs are needed to further explore whether a high-level dietary exposure is detrimental for AF.This meta-analysis suggests no association of fish consumption or


Oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas. We explored whether residential proximity to oil and gas development was associated with risk for hematologic cancers using a registry-based case-control study design.Participants were 0–24 years old, living in rural Colorado, and diagnosed with cancer between 2001–2013. For each child in our study, we calculated inverse distance weighted (IDW) oil and gas well counts within a 16.1-kilometer radius of residence at cancer diagnosis for each year in a 10 year latency period to estimate density of oil and gas development. Logistic regression, adjusted for age, race, gender, income, and elevation was used to estimate associations across IDW well count tertiles for 87 acute lymphocytic leukemia (ALL) cases and 50 non-Hodgkin lymphoma (NHL) cases, compared to 528 controls with non-hematologic cancers.Overall, ALL cases 0–24 years old were more likely to live in the highest IDW well count tertiles compared to controls, but findings differed substantially by age. For ages 5–24, ALL cases were 4.3 times as likely to live in the highest tertile, compared to controls (95% CI: 1.1 to 16), with a monotonic increase in risk across tertiles . Further adjustment for year of diagnosis increased the association. No association was found between ALL for children aged 0–4 years or NHL and IDW well counts. While our study benefited from the ability to select cases and controls from the same population, use of cancer-controls, the limited number of ALL and NHL cases, and aggregation of ages into five year ranges, may have biased our associations toward the null. In addition, absence of information on O&G well activities, meteorology, and topography likely reduced temporal and spatial specificity in IDW well counts.Because oil and gas development has potential to expose a large population to known hematologic carcinogens, further study is clearly needed to substantiate both our positive and negative findings. Future studies should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest (e.g. benzene) near homes, schools, and day care centers; provide age-specific residential histories; compare cases to controls without cancer; and address other potential confounders, and environmental stressors. Among U.S. children ages 0–14, acute lymphocytic leukemia (ALL) is the most commonly diagnosed cancer, and non-Hodgkin lymphoma (NHL) is the most common lymphoma , 3.A number of factors, including genetic predisposition and susceptibility, as well as environmental factors, come together in the development of childhood cancers through a two step process, the first of which likely occurs in utero . EnvironU.S. oil and gas development has grown rapidly over the past 15 years. This industrial activity, which includes drilling, hydraulic fracturing, and production, has the potential to emit chemicals that may be associated with childhood ALL and/or NHL, including benzene and other hydrocarbons, polycyclic aromatic hydrocarbons, and diesel exhaust, into the air and water –18. The Previous ecological studies on the link between childhood cancer and oil and gas development are inconclusive because they aggregated cancer outcomes and exposures and did not consider latency periods and differentiate between types of leukemias , 22. ThiChildhood incidence cancer data for children diagnosed with cancer between 2001 and 2013 were obtained from the Colorado Central Cancer Registry (CCCR)  held at We used information available in the publically accessible Colorado Oil and Gas Information System (COGIS)  to buildTo protect the identity of the children in the study, CDPHE staff linked the well locations in the dataset we provided to each child’s address in the registry. Geocoded residential addresses at time of cancer diagnosis were linked to active well locations in the year of diagnosis, as well as active well locations in each of the 10 years preceding the cancer diagnosis. Distance of each residence from all active oil and gas wells within a 16.1-kilometer radius was then computed using spherically-adjusted straight line distances, to account for the Earth’s curvature. Ages were truncated into five year ranges  to further protect identity. The CDPHE staff then provided the analyst (LMM) with a de-identified dataset, containing subject diagnosis, age group, gender, race/ethnicity, income quintile at zip code level, residential elevation, maternal smoking history (from linkages with birth certificates), and distance to each active oil and gas well within a 16.1-kilometer radius.Because the number of wells is not associated with distance of the nearest well in the 16.1-kilometer radius around a child’s home , we usedBased on the latency period between exposure to benzene and diagnosis of leukemia of 1 to 10 years –27, we cChildhood cancer outcomes considered for analysis were ALL  (87 cases), and NHL nodal and extra-nodal (includes Burkitt and lymphoblastic lymphomas regardless of bone marrow involvement) (50 cases). The number of cases for other types of leukemia  was too small to analyze individually. Cases diagnosed with other leukemia types (n = 26) and those with Hodgkin lymphoma (n = 52) were excluded from the control group. Case-control analyses were conducted separately for ALL and NHL. A total of 528 controls for each of these cancer outcomes included all children reported in the CCCR with non-hematologic cancers, .a priori knowledge of their association with both exposure and outcome. We conducted tests to evaluate linear trends in binominal proportions with increasing IDW well count by treating the categorical IDW well count variable as ordinal [We used logistic regression to study associations between case-control status and IDW well count tertiles. First, we estimated the crude odds ratio (OR) associated with IDW well counts tertiles. We further investigated associations by adjusting for potential confounders, as well as child covariates, based on  ordinal . Specifi ordinal ,4, race/ ordinal , and gen ordinal . Because ordinal , may be  ordinal . We also ordinal . In a seIn secondary analyses, we explored reducing IDW well counts to an 8-kilometer buffer around the maternal residence, as well as analyzing the subset of subjects with information on maternal smoking and adjusting for maternal smoking during pregnancy. All statistical analyses were conducted using SAS® software version 9.3 . To further protect the identity of study participants we truncated counts of less than 5 to “<5” in result tables. The Colorado Multiple Institutional Review Board reviewed and approved our specific protocol for this study as exempt from human subjects research (COMIRB Protocol 14–1978). We (the researchers) only had access to de-identified data from the Colorado Cancer Registry which had been previously collected for reasons other than research and the data we analyzed anonymously.Geocoded addresses were missing for 24% of our study population, with a higher proportion missing for white Hispanics and young adults aged 19–24 years, as well as controls . The ALLBoth crude and adjusted estimates indicate an increase in odds of living near oil and gas development at the time of cancer diagnosis, as represented by IDW well counts, in children diagnosed with ALL . FurtherIn secondary analyses using an 8-kilometer radius, results for cases of ALL ages 5–24 years and ages 0–4 years were similar to the primary analysis . In secoWe observed no statistically significant associations between density of oil and gas development and NHL in either model, based on trend analysis across categorical IDW well counts  see S6  Tables.In this registry-based case-control study, we found that children aged 5–24 years diagnosed with ALL were 3–4 times as likely to live in areas with active oil and gas wells as were children diagnosed with non-hematologic cancers, and the association between ALL and residential density of oil and gas wells increased monotonically from the lowest to highest IDW well count categories after adjusting for age, race, gender, socioeconomic status, and elevation. Further adjustment for year of cancer diagnosis resulted in a slightly larger association in children aged 5–24 years. We did not observe an association between ALL and density of active oil and gas wells in children aged 0–4 years. We found no indication of an association between NHL and density of active oil and gas wells.In model 2, we categorized year of cancer diagnosis into six categories each containing two to three diagnosis years . We noteOur analysis addressed the limitations of previous studies. The case-control design allowed us to evaluate individual outcomes and IDW well counts; and we considered a 1–10 year latency period and one specific type of childhood leukemia, rather that grouping all leukemias, in our analysis. An ecological study on childhood cancer incidence associated with hydraulic fracturing sites in Pennsylvania found no differences between childhood leukemia incidence before and after hydraulic fracturing began in several Pennylvania counties . That stIt is thought that less than 5% of leukemia is attributed to only inherited genetic predisposition ; that geOne possible environmental risk factor for childhood ALL that is associated with oil and gas development is exposure to benzene and other petroleum hydrocarbons. Ambient air benzene levels in Colorado areas with active oil and gas development ranged from 0.03–22 parts per billion by volume (ppbv). Median benzene concentrations ranged from 0.212–0.757 ppbv which are greater than the Environmental Protection Agency’s (EPA) risk based screening level (RBSL) of 0.102 ppbv for benzene in residential air , 47–50. Benzene is a well established cause of acute myeloid leukemia in adults . StudiesOur study benefited from the ability to select cases and controls from the same population. Because all our data were obtained from the CCCR, neither recall bias nor measurement bias affected our results. The possibility of random errors does exist in the CCCR, but in our judgment these are unlikely to affect our findings.Geocoded addresses were missing for 27% of our study population, with a higher proportion of missing addresses for white Hispanics and young adults aged 19–24 years, as well as controls. These groups are more likely to include migrant workers, college students, and undocumented residents, so our results may not be representative of these groups.Because ALL and NHL are rare diseases, there were only a small number of ALL and NHL cases in rural Colorado between 2001 and 2013. This limited number of cases affected the stability of our associations, as evidenced by wide confidence intervals, particularly for ALL in the 5–24 year and 0–4 year subsets and in the NHL analyses. Our controls were children diagnosed with a non-hematologic cancer, which may share some risk factors with NHL and ALL, including exposure to hazardous air pollutants associated with oil and gas development. This may have biased our associations toward the null , 53. We Data on covariates obtained from the CCCR were limited to basic demographic information and median incomes at the zip code level. Our inability to adjust for early common infections, nutrition, family history of neoplasms, water source, proximity to other pollutants, and daycare attendance, as well as individual income, may have resulted in residual confounding. Meta analyses indicate that children with ALL and NHL are 10% and 22%, respectively, more likely than controls to have a mother who smoked during pregnancy , 56. We Because we did not have complete residential histories, we assumed that address at time of diagnosis represented a child’s residence over the entire exposure period, so residential mobility during the exposure period may have obscured our results. A California study on residential mobility in children with leukemia found that 66% of children moved between birth and diagnosis, urban/rural status changed for 20%, and neighborhood SES changed for 35% . The lacUsing IDW well counts in absence of information on O&G well activities, meteorology, and topography likely reduced temporal and spatial specificity in IDW well counts . The oveIn this exploratory study, children aged 5–24 years diagnosed with ALL were more likely than children diagnosed with a non-hematologic cancer to live within 16.1-kilometers of an active oil and gas well, while children aged 0–4 years diagnosed with ALL were not more likely than children diagnosed with a non-hematologic cancer to live with within 16.1-kilometers of an active oil and gas well. Children aged 0–24 years diagnosed with NHL were no more likely to live in areas with active oil and gas development than children diagnosed with a non-hematologic cancer. Because oil and gas development has potential to expose a large population to known hematologic carcinogens, such as benzene, further study is clearly needed to substantiate both our positive and negative findings. Future studies should incorporate information on oil and gas development activities and production levels near homes, schools, and day care centers; provide age-specific residential histories; compare cases to controls without cancer; and address other potential confounders, and environmental stressors.S1 Table(ZIP)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.S6 Table(PDF)Click here for additional data file.S7 Table(PDF)Click here for additional data file.S8 Table(PDF)Click here for additional data file.S9 Table(PDF)Click here for additional data file.S10 Table(PDF)Click here for additional data file.


Crystalline silica is considered as one of the most common and serious occupational hazards to workers’ health. Although its association with lung cancer has been studied for many decades, the conclusion remains somewhat controversial. Our objectives are to review and summarize the epidemiological evidence on the relationship between occupational silica exposure and risk of lung cancer and to provide an update on this major occupational health concern.Eligible studies up to 29 April 2016 were identified. Pooled effect estimates were calculated according to the reported outcome and the study design. Cohort, case control and proportional mortality studies were examined separately. Studies reporting results according to silicotic status were grouped together and analyzed. Due to the significant amount of heterogeneity expected, random effects models were implemented. Subgroup and meta-regression analyses (both univariate and multivariate) were performed in an attempt to explain heterogeneity. Studies which had adequate exposure characterization were selected to find out whether there was an exposure-response relationship between silica and lung cancer.The risk of lung cancer was found to be elevated in both silicotics and non-silicotics. The pooled standardized mortality ratio (SMR) was 2.32 with a 95 % confidence interval (95 % CI) of 1.91–2.81 and 1.78 (95 % CI 1.07–2.96) respectively. The pooled standardized incidence ratio (SIR) was 2.49 (95 % CI 1.87–3.33) and 1.18 (95 % CI 0.86–1.62) respectively. Subgroup analysis showed that workers in the mining industry had the highest risk of lung cancer with a pooled SMR of 1.48 (95 % CI 1.18–1.86) and the weakest association was seen in potteries with a pooled SMR of 1.14 (95 % CI 1.05–1.23). A positive exposure-response relation was found between cumulative silica exposure and risk of lung cancer.The results of our meta-analysis supported the carcinogenic role of silica on the lungs, which was more pronounced at higher levels of exposure, in the presence of silicosis and in the mining industry. Further research is needed to evaluate whether non-silicotics are truly at risk, whether a predisposing factor would explain this potential risk, and to determine the mechanism of carcinogenicity of silica in humans.The online version of this article (doi:10.1186/s12889-016-3791-5) contains supplementary material, which is available to authorized users. Crystalline silica is one of the commonest minerals on earth and a major ingredient in sand, granite, soil and glass. Traditionally, silica exposure occurs in workplaces such as coal and metal mining, metallurgy, construction industry and manufacturing of building materials, glass and clay. Recent reports indicated that more than 33 million workers in China  and IndiThe possible carcinogenicity of silica became a subject of intense debate in the scientific community in the 1980s, especially after the publication of epidemiological studies by Westerholm in 1980  and presThe latest IARC report in 2012 reported seven meta-analyses conducted on this topic . We noteIn our paper, we have combined epidemiological data from relevant studies published till date to evaluate the risk of lung cancer due to silica dust exposure and we have attempted to explain heterogeneity through subgroup and meta-regression analyses. We have also performed an exposure-response analysis by identifying studies which had well-characterized exposure data.The meta-analysis was conceived and performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .We searched MEDLINE and EMBASE databases from January 1982 through 29 April 2016 using the search terms “lung cancer”, “silica”, “silicosis”, “risk”, “incidence” and “mortality” with variation in term construct to identify epidemiological studies published in the literature which evaluated the relationship between silica exposure and lung cancer in workers, irrespective of their silicotic status  or standardized incidence ratio (SIR) or odds ratio (OR) or proportional mortality ratio (PMR) or mortality odds ratio (MOR) or relative risk (RR) with their corresponding 95 % confidence interval.The following inclusion criteria were used for the analysis:Reviews, autopsy studies, comments, editorials, studies with insufficient quantitative data required for the analysis  and those overlapping with studies which were already considered, were excluded.When a particular study was reported in several papers, the most recently-published reference was used unless the required data was reported in a previous paper and not in the latest-published one.For each study, the following data was extracted: geographical location, year of publication, industrial setting, study design, total number of subjects, exposure assessment (including level and duration of exposure to silica dust), outcome examined, study period , person-years of follow-up, covariates adjusted for, potential occupational carcinogens including radon, arsenic, asbestos, diesel, polycyclic aromatic hydrocarbons (PAH), talc, cadmium and amphiboles, number of lung cancer cases, total number of deaths and number of deaths due to lung cancer, measure of association and effect estimates with corresponding 95 % confidence interval (CI). Two authors worked independently for study selection and data extraction. Any disagreement was resolved after a team discussion. The list of included studies was made in consensus.We used the Newcastle-Ottawa Assessment Scale (NOS) for assessing the methodological quality of observational studies . The scap value, and the variability due to heterogeneity (I2 statistic), reported as a percentage in this paper [2) was used to quantify the amount of heterogeneity accounted for by each covariate. It was calculated as the percentage of ratio of variance explained to the total amount of variance. Both univariate and multivariate meta-regression models were used to try to lower the variability due to heterogeneity (I2) to the minimum level and to bring the p value of Q close to 1. Heterogeneity should be completely absent  for an ideal comparison [Studies were pooled together according to the outcome examined which could be incidence or mortality, the study design which could be cohort or case-control or proportional mortality study design and the measure of association. When a study reported results stratified by race, gender, industrial setting and silicotic status, they were treated as two separate reports for analysis. Studies which gave risk estimates according to silicotic status were grouped and analyzed separately. Statistical analysis was performed on the natural logarithm (ln) of the risk estimate so as to approximate its sampling distribution to a normal one. The difference between the upper and lower limits of the confidence intervals was transformed to the log scale and the standard error was calculated by dividing the transformed interval by 3.92 . Random is paper . We perfis paper . The promparison . Differemparison . Based omparison . For themparison  with themparison .The levels of significance for all statistical tests were assumed to be equal to or less than 0.05, except in the case of heterogeneity testing whereby the level of significance was assumed to be equal to or less than 0.10 .The PRISMA flowchart for the selection of studies is shown in Fig. After categorization of the studies by outcome assessed, study type and measure of association there were 63 cohort studies reporting mortality due to lung cancer in the form of SMR as measure of association, 19 cohort studies reporting incidence of lung cancer in the form of SIR, 1 cohort study reporting incidence in the form of RR, 3 case-control studies reporting mortality in the form of MOR, 9 case-control studies reporting incidence in the form of OR, 5 case-control studies reporting mortality in the form of OR and 2 proportional mortality studies or PMR. The characteristics of all included studies are shown in Additional file Most studies comprised males only and a mere few included both males and a small proportion of females around 10 %). Only exceptions were the studies of Zhang et al.  and Smai0 %. OnlyThe results of the study quality assessment are presented in Additional file p = 0.024 for Egger’s regression test) but no evidence of publication bias for studies reporting incidence in the form of SIR (p = 0.238) and OR (p = 0.457).As demonstrated graphically by the funnel plots in Additional files p < 0.05) except in the category of PMR studies (p = 0.38). The results of the SMR, SIR and OR studies with incidence as outcome are illustrated in forest plots in Figs. 2 of 96 %, 87 % and 75 % respectively. PMR and OR studies with mortality as outcome showed lower between-study heterogeneity (I2 62 % and 51 % respectively), which was statistically insignificant . No heterogeneity was observed in the meta-analysis of OR studies with incidence as outcome. Studies conducted in silicotic subjects yielded a significantly higher pooled SMR of 2.32 (95 % CI 1.91–2.81) and SIR of 2.49 (95 % CI 1.87–3.33) as compared to non-silicotic studies which gave a resulting estimate of 1.78 (95 % CI 1.07–2.96) for SMR studies and 1.18 (95 % CI 0.86–1.62) for SIR studies. Between-study heterogeneity was statistically significant in silicotic and non-silicotic studies with SMR as risk measure (I2 = 94 % with p < 0.0001 and I2 = 74 % with p = 0.013 respectively) but they were found to be lower and statistically insignificant in silicotic and non-silicotic studies with SIR as measure of association (I2 = 25 % with p = 0.377 and I2 = 41 % with p = 0.192) respectively.Using the random effects model, the pooled estimate was 1.55 (95 % CI 1.38–1.75) for SMR studies, 1.68 (95 % CI 1.45–1.96) for SIR studies, 1.10 (95 % CI 0.89–1.36) for PMR studies, 1.69 (95 % CI 1.26–2.26) for MOR studies, and 1.34 (95 % CI 1.24–1.46) for case-control studies reporting incidence as outcome and 1.82 (95 % CI 1.25–2.66) for case-control studies reporting mortality as outcome. The risk estimate in each category was statistically significant (p > 0.10) in the subgroups of potteries (I2 = 0 % and p = 0.273), construction industries (I2 = 0 % and p-0.656) and in the subgroup including studies done in Australia (I2 = 20 % and p = 0.265). In all other subgroups, between-study heterogeneity remained significant. Out of 63 SMR studies, only 2 adjusted for smoking [Subgroup analyses were carried out individually for SMR and SIR studies. We could not perform similar subgroup analysis for the few remaining studies reporting other measures of association due to their limited number. Since the level of between-study heterogeneity was found to be 0 % in the group of OR studies reporting incidence as outcome, we did not perform any further analysis to explore heterogeneity. Subgroup analysis for SMR studies showed a positive association between silica dust exposure and lung cancer in all subgroups except in the subgroup of cement industries which had a pooled risk estimate of 0.87 (95 % CI 0.42–1.82). Heterogeneity became non-significant . Much of the between-study heterogeneity could be explained by sub-grouping the SIR studies and in most of the subgroups, it became statistically insignificant (p > 0.1). None of the SIR studies adjusted for smoking. Detailed main statistical analysis, subgroup analyses for SMR and SIR studies and statistical analysis of silicotic and non-silicotic studies are shown in Table Subgroup analysis for SIR studies showed a positive relation between occupational silica exposure and risk of lung cancer in all subgroups, with statistically significant risk estimates in all subgroups except that including studies conducted in Canada (2 = 37 %). As for the SIR studies, univariate analysis showed that total number of deaths accounted for the highest amount of heterogeneity (R2 = 100 %) and a combination of number of subjects and NOS score corrected the maximum amount of heterogeneity (R2 = 15 %) in multivariate analysis. Regarding the silicotic studies, the combination of year of publication and total number of deaths corrected 43 % of between-study heterogeneity. Detailed results of meta-regression analyses are shown in Table Separate meta-regression analyses were performed for SMR studies, SIR studies and silicotic studies reporting SMR as risk measure. These were done using both univariate and multivariate models. In the univariate meta-regression analysis of SMR studies, NOS score was the most important covariate accounting for 19 % of heterogeneity while in the multivariate analysis, the combination of industrial setting, year of publication, geographical location and number of subjects accounted for the maximum amount of heterogeneity R2 = 7 %. As fp value of the estimate was statistically insignificant for the second, third and fourth quartiles (p > 0.05). A high level of between-study heterogeneity was also noted especially with rising quartiles of cumulative silica dust (p < 0.0001).For the exposure-response analysis of the relationship between silica dust and risk of lung cancer, reference was made to the subgroup analysis of SMR studies by average level of cumulative silica dust exposure. Nineteen studies were included. It was found that the risk of lung cancer increased with rising exposure level (risk estimate rose from 1.19 (95 % CI 1.02–1.39) in the first quartile to 1.36 (95 % CI 0.87–2.13) in the fourth quartile). However, the Sensitivity analyses showed that omission of any study did not significantly influence the pooled estimates.The present meta-analysis, which combines the results from 85 different studies, supports the carcinogenicity of respirable crystalline silica dust on the lung. This positive trend was observed independent of the measure of association and of the level of heterogeneity. The pooled risk estimates in the silicotic studies, which were 2.32 (95 % CI 1.91–2.81) for SMR studies and 2.49 (95 % CI 1.87–3.33) for SIR studies, were found to be higher than those in non-silicotic studies, which were 1.78 (95 % CI 1.07–2.96) for SMR studies and 1.18 (95 % CI 0.86–1.62) for SIR studies. Both silicotic and non-silicotic studies include subjects who are exposed to silica dust. Our results support the hypothesis that silicosis has a stronger association with lung cancer morbidity and mortality than silica exposure on its own. The positive association between silica dust and lung cancer in non-silicotic subjects could probably be due to genetic factors which predispose these individuals to lung cancer with only a minimal exposure to silica dust.Previous meta-analyses have found a positive association between crystalline silica dust and lung cancer in silicotics and silica-exposed workers, but in non-silicotics, the association was either negative or weakly positive , 106–111Based on the year of publication, we observed a gradual decline in the pooled risk estimate with time from a pooled SMR of 2.37 (95 % CI 1.76–3.19) and a pooled SIR of 2.32 (95 % CI 1.50–3.58) in publications before 1991 to a pooled SMR of 1.30 (95 % CI 1.16–1.46) and a pooled SIR of 1.54 (95 % CI 1.40–1.70) in papers published after 2000. Though some of the papers are updates of older ones, the difference between them is the extended follow-up period in the more recent ones. The lowering risk of lung cancer in recent years may be due to more objective outcome assessment and exposure ascertainment by direct measurement and also due to lower dust concentration as a result of the improvement and stricter implementation of dust control measures.p = 0.714) was observed between cement dust exposure and lung cancer mortality in cement factory workers in this meta-analysis. A reverse trend was observed among SIR studies in the subgroup of cement industries. Possible explanations could be that cement dust is weakly carcinogenic and cement factory workers are immediately removed from the high-risk job as soon as they are diagnosed with any respiratory problems, thereby decreasing the chance of progress to more severe disease and mortality.Our study also showed that the risk of lung cancer differed among various industries. In the SMR studies, the highest pooled risk estimate of 1.48 (95 % CI 1.18–1.86) which was statistically significant was observed in the mining industry. Possible reasons may be due to the higher level of silica exposure and longer duration of time spent in dust-laden environment. In the same subgroup, the lowest risk of lung cancer was observed in the pottery factories with a risk estimate of 1.14 (95 % CI 1.05–1.23). This may be because clay coatings decrease the biological availability of the toxic crystalline silica surfaces, thereby diminishing or deferring the disease risk. Harrison et al. found that the percentage of clay coating silica particles was 45 % in pottery worksites, 18 % in tin mines and 13 % in tungsten mines . StudiesWhen conducting a meta-analysis of epidemiological studies, significant heterogeneity in risk across studies reflects differences in workplace exposures, assessment of exposure, data collection processes, population being studied and, in the case of silica, in the biological activity of the silica particles. It has been suggested that a variable biological activity of silica particulates might be related to particle size, time since fracture and presence of other minerals or dust components that might cover the silenol radicals on the surface of the silica particles . We wereThe exposure-response analysis showed that the higher the level of cumulative silica dust exposure, the more is the risk of lung cancer. However, the high level of heterogeneity limits any inference of causality. Wrong estimation of the level and duration of exposure of workers, varying measurement methods and incorrect data collection may lead to significant between-study heterogeneity in the determination of an exposure-response relationship. Similar findings were obtained in the dose-response meta-analysis of silica and lung cancer using 4 cohort and 6 case-control studies performed by Lacasse et al. .The first strength of our meta-analysis is that we have tried to include the maximum number of relevant studies published till date. The number and variety of studies included in a meta-analysis are sometimes reduced to increase the homogeneity of the studies evaluated. However, this potentially reduces the amount of information on factors that influence the outcome of individual studies. To our knowledge, our meta-analysis is the largest one conducted on this topic. Secondly, we conformed to the PRISMA guidelines for a systematic and objective data analysis. Thirdly, subgroup and meta-regression analyses have allowed us to explore in more detail the issue of heterogeneity which, as expected was substantially high. Fourthly, we have been able to explore the exposure-response relationship between occupational exposure to silica dust and risk of lung cancer.p < 0.05) for SMR studies. The most important factors that can account for confounding bias in the interpretation of the results are cigarette smoking and occupational carcinogens including radon, arsenic, PAH, diesel, talc, cadmium and asbestiform fibers. When we compared the pooled risk estimate of smoking-adjusted SMR studies with that of the unadjusted studies, we found that cigarette smoking does not account for increased risk of lung cancer among silica-exposed workers. We obtained similar results by subdividing SMR studies into those with potential exposure to occupational confounders and those excluding their presence. These findings imply that the presence of other potential lung carcinogens in silica-exposed jobs does not suggest a confounding effect on the positive relationship between silica and lung cancer. Observational studies are also prone to biases due to selection of study population and loss to follow-up. It is, however difficult to completely control or eliminate all bias when designing or performing an observational study [Two main limitations of our study should be noted. First is the ensuing risk of bias of the included studies. Although publication bias was not detected from funnel plots and by Egger’s regression test of OR and SIR studies, it was found to be significant (al study . Our metWe have shown, through this meta-analysis that the risk of lung cancer is higher in workers exposed to crystalline silica dust but the exact mechanism of carcinogenicity in human beings are yet to be determined. Three mechanisms have been proposed based on experimental studies in animals. First, exposure to crystalline silica impairs alveolar-macrophage-mediated particle clearance thereby increasing persistence of silica in the lungs, which results in macrophage activation, and the sustained release of chemokines and cytokines. In rats, persistent inflammation is characterized by neutrophils that generate oxidants that induce genotoxicity, injury and proliferation of lung epithelial cells leading to the development of lung cancer. Second, extracellular generation of free radicals by crystalline silica depletes antioxidants in the lung-lining fluid. Third, crystalline silica particles are taken up by epithelial cells followed by intracellular generation of free radicals that directly induce genotoxicity. The IARC considers the first mechanism as the most prominent based on the current experimental data using inhalation or intratracheal instillation in rats, although the other mechanisms cannot be excluded. More research has been recommended in this particular field .To conclude, this paper supports the positive association of crystalline silica and lung cancer and the existence of an exposure-response relationship between these two, with a high degree of heterogeneity in the analyses. The risk tends to be more pronounced in the presence of silicosis and in the mining industry and is not significantly affected by the presence or exclusion of occupational confounding factors or by adjustment for cigarette smoking. A gradual reduction in the risk with time has also been noted. Further research is needed to find out whether non-silicotics are truly at risk, whether a predisposing factor would explain this potential risk and to determine the mechanism of carcinogenicity of silica in humans.


The development of male infertility increased rapidly worldwide, which coinciding with the epidemic of obesity. However, the impact of weight abnormalities on sperm quality is still contestable. To assess the correlation between BMI and sperm parameters, we searched relevant articles in PubMed, Embase, Web of science, and Wanfang database published until June 2015 without language restriction. Otherwise, we also recruited some participants who attended fertility clinic as well as some general populations in this report. We performed a systematic review and meta-analysis about BMI and sperm parameters containing total sperm count, concentration, semen volume and sperm motility . Metabolomic analysis of seminal plasma was performed to explore the mechanism from a new perspective. This study found standardized weighted mean differences (SMD) in sperm parameters  of abnormal weight groups decreased to different degree compared to normal weight. Dose-response analysis found SMD of sperm count, sperm concentration and semen volume respectively fell 2.4%, 1.3% and 2.0% compared with normal weight for every 5-unit increase in BMI. Metabolomic analysis of seminal plasma showed that spermidine and spermine were likely to play a vital role in the spermatogenesis progress. This systematic review with meta-analysis has confirmed there was a relationship between BMI and sperm quality, suggesting obesity may be a detrimental factor of male infertility. The development of assisted reproductive technology and its exponential increase usage have reflected, to a certain extent, infertility has become a serious worldwide problem. Forty-eight point five million couples were infertile in 2010, and about 50% infertility is caused by male factors , 4. AlonWe summarized these new studies combined with the past as well as our personal data, and conducted this study to investigate the effect of overweight and obesity on several sperm parameters. Besides, because obesity is a metabolic disorder phenomenon, a proper understanding of small molecule metabolites in human seminal plasma will provide biological information on mechanism underlying spermatogenesis. Therefore, we also performed the metabolomic analysis of seminal plasma in this study.The search strategy identified a total of 31524 articles, including 9382 from PubMed, 11515 from Web of Science, 9277 from Embase and 1350 from Wanfang; however, 31089 studies were excluded because 14242 were reduplicative and 16847 articles had no relevance to the primary research. We selected 42 articles that providing BMI and sperm parameters data after review of 435 abstracts. Among these, 24 articles studying the relationship between BMI and sperm parameters seemed potentially appropriate to be included in the meta-analysis  of sperm parameters of abnormal weight group was calculated Table . And, foTo reduce the heterogeneity between these studies, random effected models were performed in this meta analysis. Then, we conducted the sensitive analyses to access whether modification of the inclusion criteria affected the final results. The results showed that the SMD of progressive motility in obese group changed when eliminated data from Aggerholm et al 2008) , while t , while Subgroup analyses were conducted based on the ethnicity of participants. The results showed that the sperm parameters were different in Caucasian and Asian population in some BMI groups, such as total sperm count, semen volume and sperm motility in the obese group, but the effect of BMI was similar Figure .Using Egger's test and Begg's funnel plot to evaluate the publication bias of studies, the results provided no evidence in each sperm parameter of different groups Figure .We used trial sequential analyses to calculate the required information size of different sperm parameters in different groups. The results showed that none of the numbers included in the meta-analysis exceed the required information size except semen volume of obese group and some boundary TSA ignoring due to too little information use Figure . Among thttp://www.metaboanalyst.ca/). The results showed 5 metabolic pathways were significantly changed, among which the three lowest P values were of arginine and proline metabolism, beta-alanine metabolism and glutathione metabolism  and normal sperm parameters; AA: abnormal BMI (obese) and abnormal sperm parameters) were used to perform the metabolomic analysis. . We got the preliminary significant changed metabolites profile compared the results of group AA with NN. After eliminated the different ones between group NN and NA, as well as some changed ones between group NN and AN, we caught the final different metabolites list Table , and anaIn the meta-analysis, we found that high BMI decreased sperm quality such as sperm count, concentration, and semen volume rather than sperm motility . Meanwhile the trial sequential analyses confirmed the relationship to some extent according to the calculation of the required information size.Our result for the association between BMI and sperm quality is consistent with some large studies , 8, 20, The effect of obesity on the traditional sperm parameters is thought to be multifactorial and the proposed pathophysiological mechanisms underlying these sophisticated relationships have been raised from endocrinology to psychology. First of all, probably of more concern is the changes of hypothalamic-pituitary-gonadal (HPG) axis. Aromatization activity increased by the elevated white adipose tissue of obese men converts testosterone to estrogens, and the enhancive leptin coming from the same source decreases the production of testosterone from Leydig cells . BesidesThere are several limitations to our study. First, we didn't obtain the original data through contacting the corresponding authors. All the information in the meta-analysis relied on published articles only. It is inevitable that the unity and credibility of data is disturbed to a certain extent because of the variety of BMI categories, statistical approach and outcomes. We used the SMD and converted data format by the accepted formula to reduce the influence as far as possible. Besides, due to the limitation of data sources, the use of different boundaries for normal, overweight and obese in Chinese studies was different from others, which may affect the final results. However, because people of different ethnicities experience various extrinsic factors and they have different genetic sources, the physique is different between Asians and Western populations and we have conducted subgroup analyses based on the ethnicity of participants and different classification standards to reflect the impact of such difference brought about. Second, considering the data processing and statistical aggregation, some relevant articles accessing effect of BMI on sperm quality were excluded even though they maybe provide useful information. In order to verify the reliability of the results, we performed the trial sequence analyses, which confirmed the validity of the present meta-analysis though the sample size didn't meet the requirement. Third, BMI was considered as the unique surrogate of body fat content to evaluate the influence of obesity on sperm quality, and other information such as the relationship between waist circumference , 18, or Our results have confirmed that obesity is a pernicious factor of sperm quality. While we look forward to springing out large sample researches to further validate about the relevance between obesity and sperm motility and morphology. According to the conclusion, it would be natural to assume that weight loss will have a beneficial effect on fertility of obese men. However, the truth is still unknown. Several relevant articles have been published about weight loss through dietary, exercise interventions, or bariatric surgery and male fertility. Most reports paid more attention to the effect on the reproductive hormones rather than sperm parameters and the results were ambiguous. Niskanen et al  and KaukBased on this study, sperm quality decreases along with BMI increasing, suggesting obesity may be a detrimental factor of male infertility, though lacking of the raw data may influence the accuracy of the results. Further research is required to identify the role of obesity in male sterility.We searched relevant studies published until June 2015 about BMI and sperm parameters from PubMed, Embase, Web of Science, and Wanfang database without language restriction. The following combined text and MeSH terms were used:  AND . We also searched the references of key articles to identify other relevant studies.After a primary screen of all titles retrieved from the database, we excluded reviews, studies without BMI or sperm data or studies without results on the relationship between BMI and sperm parameters, experimental or interventional studies, mechanism articles, female researches, studies restricted to men with a particular pathology (such as a varicocele) and studies comparing exposed/non-exposed men. Then the full texts of potentially eligible articles were retrieved, regardless of population size, origin, age or ethnicity. Two review authors independently examined these articles and extracted the data. Any disagreements were resolved by discussion between them. Data retrieved included study characteristics and sperm parameters.We recruited 1711 and 653 participants from infertility clinic and maternity clinic respectively to collect semen samples by masturbation and got their basic information  by self-report. Semen analysis was carried out according to the WHO laboratory manual (2010). After eliminated participants with 1. known azoospermia; 2. other reproductive diseases such as varicocele; 3. BMI < 18.5; 4. data incomplete, 2106 individuals were involved in the analysis finally (including 1461 infertile men and 645 fertile men). We computed the relationship between BMI and sperm parameters on the whole personal participants by regression analysis. Then, we calculated the odds risk (OR) under WHO reference lower limits (5th percentiles)  in different BMI groups of total participants, fertile men and infertile men respectively.Meta-analysis was performed using studies that including one or more sperm parameter in the BMI categories as following: mean or median total sperm count, sperm concentration, semen volume, sperm motility, or sperm progressive motility. Data were converted to the form of mean and standard deviation in order to facilitate the calculation. BMI was divided into three levers by WHO criteria: 18.5-24.9 , 25.0-29.9 (overweight) and above 30 (obese) kg/m2, except in some Chinese studies that defining 24.0, and 28.0 as boundaries. Participants with a BMI between 18.5-24.9 or 18.5-23.9 were deemed as the reference group. Each sperm parameter of each abnormal weight group was compared to the reference group using SMD, which were calculated by mean, standard deviation and sample size using Stata version 12.0. Then, we performed the dose-response analysis about normal weight, overweight and obese with the data reported in these studies . The valThe I2 statistic was performed to assess possible heterogeneity between studies. We used the random-effect model to evaluate SMD if the P value for heterogeneity was ≤ 0.10 or I2 ≥ 50% that demonstrating a high extent of heterogeneity between studies . FurtherThe seminal plasma of infertile participants of our own participants were used to perform the metabolomic analysis according to the previous study . Briefly


An initial screen by abstracts and titles was performed, and relevant full articles were then reviewed and assessed for their methodologic quality. Crude effect estimates were extracted from the included articles and a pooled estimate was obtained using a random effects model.3Five articles were selected from an initial pool of 4,123 articles. Use of antidepressant drugs was associated with a significant twofold increase in the odds of some form of cognitive impairment or dementia (OR = 2.17). Age was identified as a likely modifier of the association between antidepressant use and some form of cognitive impairment or AD/dementia. Studies that included participants with an average age equal to or greater than 65 years showed an increased odds of some form of cognitive impairment with antidepressant drug usage (OR = 1.65), whereas those with participants less than age 65 revealed an even stronger association (OR = 3.25).4Antidepressant drug usage is associated with AD/dementia and this is particularly evident if usage begins before age 65. This association may arise due to confounding by depression or depression severity. However, biological mechanisms potentially linking antidepressant exposure to dementia have been described, so an etiological effect of antidepressants is possible. With this confirmation that an association exists, clarification of underlying etiologic pathways requires urgent attention. ADAlzheimer diseaseMAOmonoamine oxidaseSNRIsserotonin noradrenaline reuptake inhibitorsSSRIsselective serotonin reuptake inhibitorsQUIPSQuality of Prognosis Studies in Systematic Reviews1Our increasing lifespan has led to an increased prevalence of diseases of the brain, including Alzheimer disease (AD), a progressive, neurodegenerative disorder with significant cognitive and behavioral deficits, which accounts for almost 80% of cases of dementia , lifestyle, and environmental risk factors  reviewed the full‐text articles for relevance and agreement guided by predetermined inclusion and exclusion criteria. Third, methodologic quality was assessed by two reviewers (CN and JM) independently using the Quality of Prognosis Studies in Systematic Reviews (QUIPS) tool  it was published in the English language, (b) full text was available, (c) it had a comparative design with two groups; one being exposed to antidepressant drug use and the other group being antidepressant naïve (as reported), (d) it was not older than 10 years, and (e) it had quantifiable odds ratios describing the effect size. Articles were excluded from analysis if: (a) it described a study with a single arm or without a comparison group, and/or (b) it did not describe a clear categorization of the outcome as dementia or cognitive impairment.2.3Odds ratios and their associated 95% confidence intervals (CIs) were obtained (if given) or calculated (when not directly available) from the articles. Other relevant information extracted from each study included: the study design, presence of depression at baseline, specific type of outcome (dementia vs cognitive impairment), predominant sex of study participants, average age of study participants and the use of other psychotropic medications.2.4The outcome of interest was the occurrence of dementia or any other cognitive disorder. Use of antidepressant drugs was the primary predictor of interest. The natural log of the odds ratios and the natural log of their associated 95% confidence intervals were computed for each study. The included studies were categorized for subgroup analysis based on the study duration into studies greater than or equal to 10 years and those less than 10 years. Categorizations were also made based on the average age of the included participants in the studies using a cut‐off point of 65 years of age.Yi = μ + ui + εi, was used to obtain a pooled estimate of the effect . This allowed for an estimation of the amount of variation both within and between studies. We assumed a logit link function for binary outcome.Given the nature of the research question and the likelihood of clinical heterogeneity, a random effects model defined by the equation P values less than 5%.Statistical analysis for heterogeneity was carried out using Higgins I‐squared    while those that focused on mild cognitive impairment or any other type of cognitive impairment .Overall, the pooled estimates from the five studies showed that the use of antidepressants was associated with a significant twofold increase in the odds of dementia/cognitive impairment  Fig.  and thos2I = 0%), was less than that for the groups without a documentation of depression at the start of the study, i.e. OR = 2.36 ; however, this difference was not statistically significant  for the studies with predominant female participation. The single study  whereas those with participants aged less than 65 years . Studies that factored in the use of other psychotropic medications  while those that did not Two studies involved participants with baseline depression , which was similar to the pooled estimate of OR = 2.00 (95% CI: 1.21–3.29) obtained when the study with the greatest effect estimate  suggesting publication bias was unlikely. However, it should be noted that the statistical tests for funnel plot symmetry usually suffer from low power when the meta‐analysis includes a small number of studies  or by inhibiting serotonin reuptake/removal from the synapse. Depressed women tend to respond better to MAO inhibitors, while men tend to respond better to reuptake inhibitors  indicate that the SSRI fluoxetine can restore the depletion of serotonin, which appears to prevent the loss of dendritic arborization . Interestingly, the APOE ε4 status is also associated with clinical depression, but only in women  and specific antidepressant drug usage , biological sex and whether one carries the ε4 allele of the Limitations of note include the small pool of included studies, the presence of clinical and statistical heterogeneity, and the fact that some of the studies did not look at this association as their primary hypothesis. Thus, adjustments were not commonly made for other explanatory variables and therefore, it was difficult to confidently exclude the effect of within study confounding. This latter issue is particularly worrisome in pharmacoepidemiology, where confounding by indication and severity pose serious methodological challenges. Often, questions in pharmacoepidemiology can be addressed by meta‐regression, but such an analysis would normally require approximately 10 studies per determinant of heterogeneity. The paucity of relevant studies in the literature precludes any such study design. The best way to deal with the issue of confounding would be randomization, which, again, would rely on a greater number of studies. Often (when randomized studies are not feasible) advanced methods such as propensity score analysis are necessary to deal with these forms of bias. This is not possible in a meta‐analysis such as this one, in which only unadjusted estimates were consistently available for pooling. An association, in itself, does not confirm causation, but a strong association that is consistently observed, in which temporality of the association is clear and which is biologically plausible may represent an etiologic effect Hill, . The exi5In conclusion, our meta‐analysis suggests that individuals with cognitive impairment or AD/dementia are more likely to have been prescribed an antidepressant drug and that this is more evident if antidepressant drug treatment began before the age of 65. This increased association is strong, is biologically plausible, and is consistent across the various studies examined. The risk‐benefit trade‐offs of antidepressant treatment cannot be fully understood until the etiological basis of this association is more fully elucidated.


Telomere length (TL) has become a biomarker of increasing interest within ecology and evolutionary biology, and has been found to predict subsequent survival in some recent avian studies but not others. Here, we undertake the first formal meta-analysis to test whether there is an overall association between TL and subsequent mortality risk in vertebrates other than humans and model laboratory rodents. We identified 27 suitable studies and obtained standardized estimates of the hazard ratio associated with TL from each. We performed a meta-analysis on these estimates and found an overall significant negative association implying that short telomeres are associated with increased mortality risk, which was robust to evident publication bias. While we found that heterogeneity in the hazard ratios was not explained by sex, follow-up period, maximum lifespan or the age group of the study animals, the TL–mortality risk association was stronger in studies using qPCR compared to terminal restriction fragment methodologies. Our results provide support for a consistent association between short telomeres and increased mortality risk in birds, but also highlight the need for more research into non-avian vertebrates and the reasons why different telomere measurement methods may yield different results.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’. TelomThere is a rapidly growing literature exploring telomere dynamics and their significance for organismal function and fitness in non-human vertebrates and, in particular, in wild bird systems –17. TL hSeveral studies have reported significant associations between average blood cell TL and the risk of subsequent mortality in both wild and captive populations –25. Howe2.(a)Data for our meta-analysis were collected using ISI Web of Science and SCOPUS databases with the following search string: ‘telom* AND surviv* OR longevity/lifespan/life span/life expectancy/mortality/fitness'. Additional papers were identified in two ways: (i) backward and forward searching was carried out on citations of the first paper showing an association between TL and survival in a non-model vertebrate ; (ii) scSince our focus was on non-model vertebrate systems, we excluded studies involving human subjects, genetically modified or inbred laboratory strains of mice and non-vertebrate species. We excluded studies that did not report original empirical data (i.e. reviews or computer simulations) and those in which an association between TL and mortality or longevity was not reported. Our initial screening based on titles and abstracts of papers in the database led to the exclusion of 4077 papers (mostly studies of humans and model laboratory organisms), with 75 papers retained for more detailed interrogation of eligibility . To maximize our ability to detect an overall association between TL and survival across studies, and to identify the factors responsible for variation in this association among studies, we decided to obtain raw data for each study and analyse the TL–mortality relationship in a standardized way. For studies in which raw data were not available online, we contacted the corresponding authors requesting either that they provided us with the raw data used in the relevant analyses, or that they performed standardized analyses using an R script that we provided . We were able to obtain raw data or standardized measures of TL–mortality risk associations from 27 studies identified from 20 different species: 17 bird species, three reptiles and one mammal .Table 1(b)survival [For each of the 27 included studies, the following data were available: individual identity, age at blood sampling, sex, TL at sampling, sampling date, final date where survival was determined and survival status . Within each study, TL was mean centred and standardized to unit standard deviation prior to inclusion in analyses to create similarly scaled TL distributions among studies. We then applied Cox proportional hazard regression analysis in R using the package survival  includin(c)metafor package [2 as weighting factor [Q-tests to evaluate study heterogeneity.We conducted our meta-analysis using the  package  in R, tog factor , where shttp://genomics.senescence.info/species/). To crudely test for a phylogenetic signal, we tested class, order and species separately as moderators , the age group of the study animals (categorized as ‘young’ if ≤1 year and ‘adult’ if >1 year), the length of the follow-up period in years after TL measurement, and the log transformation of each species' maximum recorded lifespan  and the Kendall's tau statistic became non-significant . We also applied the ‘trim and fill’ method [p = 0.083).Overall, the hazard ratio associated with TL was significantly negative, supporting a decreased mortality risk with increasing TL across studies  = 77.77; p < 0.001) indicating substantial variation in TL–mortality risk associations among studies. We investigated the extent to which phylogeny, study follow-up period, sex, TL measurement method and age group at sampling reduced the observed study heterogeneity. We tested species, order and class as phylogenetic moderators in separate models and, although none was significant overall (QM(d.f.=19) = 20.88; p = 0.405 and QM(5) = 6.035; p = 0.419 and QM(2) = 3.89, p = 0.143, respectively), post hoc comparisons within the class model suggested that the strength of the association was marginally weaker in reptiles than birds . The fact that there were only three reptile studies in our meta-analyses meant there was limited power to dissect this trend further, but visual inspection of Liasis fuscus) [p = 0.22) and there was no significant relationship with maximum lifespan , follow-up period  or age at sampling  . We did p < 0.001; Q = 52.41, p < 0.001), while there was no significant overall association or evidence for heterogeneity in TRF studies . Since we detected a non-significant trend for a weaker TL–mortality risk association in reptiles, but have very limited power to differentiate effect sizes in non-avian classes (p < 0.001), but the method moderator effect became weaker and marginally non-significant in this dataset , suggesting that the strongly positive TL–mortality risk estimate from the python study was at least in part responsible for the method effect we observed.To explore this further, we split the data by method and ran separate models without moderators. Within the qPCR studies, the TL–mortality risk association was highly significantly negative with significant heterogeneity among studies  [Our results provide support for the prediction that shorter TLs are associated with increased mortality risk in birds, but an important further question raised by this is what processes are responsible for this pattern. The association could be the result of individual differences, associated with genetic, epigenetic or developmental variation, which generate consistent differences in both TL and mortality risk across the lifetimes of individuals. In addition, cumulative experience of environmental stress or investment in growth and reproduction could simultaneously drive telomere shortening and increase mortality risk. The importance of among-individual differences in TL versus telomere shortening as predictors of mortality risk, while not mutually exclusive, remains a major question for researchers interested in telomere dynamics at the whole organism level. The human literature reveals TL to be moderately to highly heritable  and thatguttata) . In due


Nine eligible studies were retrieved for detailed evaluation. The pooled estimates indicated that the GG genotype of VEGF rs2010963 polymorphism significantly decreased RCC risk . There was also a significant association between VEGF rs3025039 polymorphism and RCC susceptibility . Furthermore, a significant association between VEGF rs699947 polymorphism and RCC susceptibility was detected . Subgroup analysis revealed that these associations held true especially for Asians. Our meta-analysis suggested that there may be a relationship between the VEGF rs2010963, rs3025039 and rs699947 polymorphisms and RCC susceptibility.Several studies have reported an association between vascular endothelial growth factor (VEGF) gene polymorphisms rs2010963, rs3025039 and rs699947 and renal cell carcinoma (RCC). However, the results remain inconclusive and controversial. We therefore conducted a meta-analysis to evaluate this association. Electronic databases were searched for relevant case-control studies up to November 2016. RevMan 5.2 software and STATA version 12.0 were used for statistical analysis in our meta-analysis. Heterogeneity was assessed using the I Renal cell carcinoma (RCC) has around 350,000 newly diagnosed cases every year and is one of the most common histologic types of kidney cancer. At the same time, the mortality of RCC is more than 140,000 per year worldwide . HoweverThe VEGF gene is located on chromosome 6p21.3 and consists of 8 exons . It playRecently, a series of case-control studies focusing on the associations between gene mutations (particularly SNPs) and the risk of RCC have been extensively studied –21. HoweA total of 550 articles were identified through a literature search in PubMed, ISI, Wangfang, Google Scholar and CNKI databases. Nine eligible studies were retrieved for detailed evaluation Figure . The quaP = 0.01; I2 = 11%); GG vs. GC ] ; GG vs. GC ] ] Table . Subgrou)] Table .P = 1.000; Egger's test: P = 0.723); GG+GC vs. CC ; GG vs. GC+CC ; GG vs. CC ; GG vs. GC ;GC vs. CC ] ; CC vs. TT ] ; CC+CT vs. TT ; CC vs. TT ] ] ] Table . Subgrou)] Table . BecauseP = 1.000; Egger's test: P = 0.409); CC+CT vs. TT ; CC vs. CT+TT ; CC vs. TT ; CC vs. CT ; CT vs. TT ] ; AA+AC vs. CC ; AA vs. AC+CC ; AA vs. CC ; AA vs. AC ;AC vs. CC ] ] Table .P<0.01; I2 = 47%); AA+AC vs. CC ; AA vs. AC+CC ; AA vs. CC ; AA vs. AC ;AC vs. CC ] ; AA+AC vs. CC ; AA vs. AC+CC ; AA vs. CC ], even in the Asian population  ] Table . BecauseP = 1.000; Egger's test: P = 0.825); AA+AC vs. CC ; AA vs. AC+CC ; AA vs. CC ; AA vs. AC ;AC vs. CC ]  in VEGF are associated with RCC susceptibility especially in the Asian population. These SNPs in VEGF may be biomarkers for clinical evaluation. Nevertheless, additional well-designed studies including larger sample size and different ethnic groups are needed for re-evaluation of these associations.PubMed, Institute for Scientific Information (ISI), Wangfang, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI) databases were searched for all articles describing an association between the VEGF polymorphisms and RCC risk up to November 2016. The key words used were “VEGF”, “renal cancer/renal cell carcinoma”, and “polymorphism/variant”. The electronic search was supplemented by checking reference lists. All of the original studies had to meet the following criteria: (1) case-control design; (2) evaluate the association between the VEGF polymorphisms and RCC risk; (3) provide sufficient data for estimating an odds ratio (OR) with a 95% confidence interval (95% CI).Two of the authors extracted all data independently following the selection criteria. The following details were collected from each study: first author's name, publication year, country of study, ethnicity, number of cases and controls, genotyping method, and OR.The methodological quality of each study was assessed by the Newcastle-Ottawa Scale (NOS), which uses total NOS scores (range from 0 to 9) to judge the quality of all included studies. Studies with seven or more points were considered to be of high quality.2 value. The pooled OR was calculated for each study using only the random-effects model, considering the random-effects model is more conservative and will provide better estimates with wider confidence intervals [The OR with 95%CI was used to assess the association between the VEGF polymorphisms and RCC based on the genotype frequencies in cases and controls. For each VEGF polymorphism, the meta-analysis examined the genetic susceptibility in 5 genetic models, including allelic, homozygote, heterozygote, dominant model, and recessive model. The heterogeneity among the studies was checked by using the Intervals . Subgrountervals  and Beggntervals . Quantit