IL16 were associated with diseases. Thus, we conducted a systematic review and meta-analysis to evaluate possible associations between IL16 rs4778889, rs11556218, rs4072111, and rs1131445 SNPs and the risk for cancer or CVD.Introduction: Interleukin-16 (IL-16) is a chemotactic cytokine that is found to increase in Cancer and cardiovascular diseases (CVD). Single nucleotide polymorphisms (SNPs) in Materials and Methods: This study was performed according to the PRISMA statement. Medline, Web of Science, and Scopus databases were systematically reviewed, and a meta-analysis was conducted.Results: The analysis comprised 6386 individuals with cancer and 2415 with CVD. The SNP rs11556218 was significantly associated with an increased risk for cancer in Chinese in different genetic inheritance models. Also, to the best of our knowledge, this is the first meta-analysis to show an association of rs4778889 with an increased risk of gastric cancer and rs11556218 with an increased risk of CVD in Chinese.IL16 were associated with an increased risk for cancer in Chinese and rs11556218 with increased risk for CVD in Chinese, highlighting the need for further studies on the impact of these polymorphisms on cancer treatment and surveillance.Conclusions: Our meta-analysis suggested that the SNPs rs11556218 and rs4778889 of  Cancer is the second leading cause of morbidity and mortality worldwide. GLOBOCAN  estimated for 2018 a total of 18.1 million people with cancer and 9.6 million deaths from this disease . CardiovAlthough cancer and CVD are considered distinct entities, they have similarities and interactions among risk factors , supporting a shared biology . AlthougCytokines are mediators of the immune response, and some, such as interferon-α (IFN-α), interleukin (IL)-2, and granulocyte macrophage colony stimulating factor (GM-GSF), are currently indicated in cancer treatment. Other cytokines, such as IL-12, -15, and -21, are undergoing clinical trials .IL16) is located on chromosome 15q26.3. The receptor of IL-16 is a CD4 molecule initially described as inhibiting the interaction between CD4 and HIV-1 [Interleukin-16 (IL-16) is a chemotactic cytokine whose gene , rs11556218 (missense mutation), rs4072111 (missense mutation), and rs1131445 (located in the 3′-UTR).Single nucleotide polymorphisms (SNPs) are common genetic variations that can alter protein composition or gene expression and thus modify the functioning of immune response components such as cytokines. These modifications may lead to changes in the immune response, cell cycle regulation and metabolism, and DNA repair associated with cancer and CVD susceptibility , 36. SNPIL16 and the risk of cancer or CVD.A better understanding of the connections between cancer and CVD is crucial for identifying and preventing short- and long-term problems in the treatment and prevention of these diseases. In the study of the association of SNPs with diseases, a major analysis tool is meta-analysis. Meta-analysis is the statistical analysis of the evidence from different individual studies, with the aim of integrating them, combining and summarizing their results . Its impIL16 was statistically associated with the risk of cancer in Chinese . Specifically, for gastric cancer in Chinese, the SNP rs4778889 was associated with risk factors for disease development . The SNP rs11556218 was also associated with the risk of CVD in Chinese . Forest plots for all statistically significant comparisons are shown in Supplementary Figure 1. For the selected studies, no statistically significant associations were observed with rs1131445 and rs4072111 and the selected disease groups. For the Iranian population, significance was not found between IL16 polymorphisms and cancer or CVD in this meta-analysis.This systematic review included a total of 6386 cancer subjects and 7395 controls in 19 studies for different types of cancer, as well as 2415 individuals with CVD and 2317 controls in 7 studies. The studied population consisted of Chinese and Iranian individuals. The results are shown in P ≥ 0.05), according to the goodness-of-fit test for HWE. These results are shown in IL16 SNP rs11556218 remain associated with the risk of cancer in Chinese  in the genetic inheritance models described in To avoid a possible bias caused by studies whose genotype frequency distribution in the control groups was not in HWE (Hardy–Weinberg equilibrium), stratified analyses were performed including only studies that met this criterion . An analysis of the covariates evaluated by CVD studies was carried out with the aim of finding a possible source of heterogeneity for the obtained results. These assessed covariates are described in Supplementary Table 2. In this sense, it was not possible to identify in this analysis which covariables could partially explain the qualitative heterogeneity observed in this CVD analysis.An association of The statistical power after HWE stratification results, considering a subtle genetic effect (1.25), showed a slight reduction for the association between rs11556218 and cancer (from 99.9% to 93.0% after stratification for HWE) but a substantial reduction for rs11556218 and CVD (90.7% to 81.0%) and for rs4778889 and gastric cancer (72.0% to 54.3%). Forest plots for all statistically significant comparisons after stratification of studies with controls in HWE are shown in Supplementary Figure 2.P > 0.05).The mean minor allele frequencies (MAF) observed among the control groups of the selected studies were 21.5% for rs4778889 , 21.3% for rs11556218 , 21.5% for rs4072111 , and 32.3% for rs1131445 . These frequencies were similar to those described in the 1000Genomes database for East Asian populations , and the Fisher test did not indicate a statistically significant difference between the allele frequencies in these populations (P ≥ 0.05), and these results are shown in Egger’s tests did not indicate possible bias in the selection of publications  is located in the 3′-UTR of the gene, and the mutation predicts disruption of the binding of a microRNA inhibitor (miR135b-mRNA) of the gene sequence, which would result in greater pro-IL-16 expression . In our Important limitations should be considered in our study. First, every systematic review presents some risk of bias, related to the difficulty of obtaining non-indexed studies, and the heterogeneity present in the selected studies. Moreover, the results obtained are limited to the populations surveyed and, therefore, lack information for a meta-analysis on the frequency distributions of these polymorphisms in other populations, although an attempt to broadly describe the literature has been made. Similarly, important covariates must be considered to explain the associations observed in these studies, thus multivariate methods of analysis can be useful, highlighting the need for detailed publication of the profile of the populations studied, although the reliability of these methods depends on 10 or more studies. From the results of this review, further studies may be necessary to clarify the role of these polymorphisms in the immunopathogenesis of cancer and CVD, also helping to clarify the relationship between these diseases.IL16 was significantly associated with an increased risk of cancer or CVD in Chinese. Additionally, the SNP rs4778889 was associated with an increased risk of gastric cancer, while the rs4072111 and rs1131445 SNPs were not associated with cancer or CVD in our study.The SNP rs11556218 of IL16 polymorphisms and cancer or CVD, the MEDLINE, Web of Science and Scopus databases were searched up to June 30, 2020, according to the strategy detailed in Supplementary Table 1. The language of publication was not defined as a search criterion, but only articles in the English language were included. All steps were performed by two pairs of reviewers in duplicate. Article screening procedures are included in The methodology of this study was performed according to the PRISMA  statement . To idenIL16 polymorphisms were included. In the next step, the 95 selected articles were evaluated by reading the full text, as to their suitability for inclusion in a meta-analysis . Thus, 55 articles were obtained that met all these criteria. All doubts regarding the eligibility of a study or not (according to the criteria described above) were discussed among all authors and resolved after consensus. After a consensus was reached between two authors working in pairs, 26 studies were selected for data collection, according to the diseases of interest. Also, the references of these studies were searched for additional studies. The studies and SNPs selected in this review are described in Supplementary Table 3. The 26 selected studies were further reassessed by a third independent pair of authors, composed of authors with more experience in the field of cytokine polymorphisms and association studies, evaluating whether all the studies and results were in accordance with the proposed criteria for this review.Articles with available abstracts were selected for title and abstract screening as to their relevance and fitness to the proposed theme. Only original human studies of Genotype frequency data were collected from the selected studies. Allele frequencies were obtained by counting the total number of alleles in all genotypes, and the number of individuals used in the meta-analysis was obtained by summing the total number of described genotypes. Distinct groups of cases or controls within the same study were combined into a single group for distinct and unrelated groups of individuals. The cancer group was analyzed by combining all cancer types or individually for each type of cancer (when a comparison was possible). Statistical analyses were performed by using the program R, version 3.5.2, with the meta-analysis package “meta” .Odds Ratio, OR) of each study in the final result are presented in two possible models according to observed heterogeneity: fixed and random. Thus, for all comparisons performed, Forest plots were constructed with a heterogeneity test (I2). When the value of I2 was greater than 50% and the test showed statistically significant results, the random OR model was chosen. When I2 was less than 50% with no evidence of significant heterogeneity, the fixed model was chosen. Six comparison groups of alleles and genotypes were used to verify the influence of genetic association with diseases. Considering “M” as the wild-type allele and “m” as the mutated allele, the combinations analyzed were (1) M vs. m alleles; (2) MM vs. Mm genotypes; (3) MM vs. mm and (4) Mm vs. mm; and also genetic inheritance models (5) MM + Mm vs. mm (recessive); (6) MM vs. Mm + mm (dominant); and (7) MM + mm vs. Mm (overdominant).The meta-analysis results are represented by the Forest plot. This chart aims to summarize the results of the pooled studies giving them a general trend. It represents the studies with the proportions of events of interest in each study for the case-control groups. The percentage values of weight and effect size (represented by the P < 0.05), as recommended for assessing study quality [https://www.internationalgenome.org/) and the comparison was made using the exact Fisher test in R. For all tests, P < 0.05 was considered to indicate statistical significance.Quality evaluation of the selected studies was performed according to the Newcastle–Ottawa (NOS) scale by two independent authors. Disagreements were resolved by consensus, and studies with a score higher than 5 were considered as good or reasonable . Possibl quality . After t quality , to eval


Background: Recently, radioiodine refractory differentiated thyroid cancer (RR-DTC) has received increasing attention due to its poor prognosis. The roles of clinical, pathological, and molecular features in the development of RR-DTC remain controversial and require additional investigation. This study aimed to evaluate the association between these risk factors and the occurrence of RR-DTC.Methods: We performed a systematic search for relevant literature following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in PubMed, EMBASE, Medline, SCOPUS, and Web of Science up to the July 15, 2020. Observational studies that investigated the risk factors for RR-DTC were included. Fixed- or random-effects models were used to calculate pooled odds ratios (ORs) or mean differences (MD) with corresponding 95% confidence intervals.Results: We included 13 eligible studies incorporating 1,431 cases, of which 603 were patients with RR-DTC. The pooled analysis indicated that four parameters significantly increased the risk of RR-DTC: extrathyroidal extension (ETE) , BRAFV600E mutation , TERT promoter mutation  and high-risk histological subtype , including tall cell variant papillary thyroid carcinoma (PTC), sclerosing diffuse PTC, hobnail variant PTC, follicular thyroid carcinoma (FTC) (including Hürthle cell), and poorly differentiated thyroid carcinoma (PDTC). However, there was no statistical significance regarding sex, age, tumor size, multifocality, or lateral lymph node metastasis. Subgroup and sensitivity analyses were conducted to further confirm the robustness of the results.Conclusions: Histological subtype, ETE, BRAFV600E mutation, and TERT promoter mutation could be considered clinicopathological factors and biomarkers. They could assist in risk stratification, prognostic prediction, and individual therapy options for RR-DTC. In recent decades, thyroid cancer (TC) has emerged as a striking health issue, and the global incidence of TC is 6.7 per 100,000 , respectThe American Thyroid Association (ATA) Management Guidelines for Adult Patients with Thyroid Nodules and Thyroid Cancer has classified RR-DTC in four basic ways: (i) the malignant/metastatic tissue has no concentrated RAI, (ii) the tumor tissue has lost the ability to concentrate RAI after previous evidence of RAI-avid disease, (iii) RAI is concentrated in some lesions but not in others, and (iv) metastatic disease progresses despite significant concentration of RAI . There iThe study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria.131I or radioiodine or “radioactive iodine,” refractory or negative or resistant* or fail* or resist, and predict* or factor or character* or feature or risk. The reference lists of relevant studies and review articles were hand-searched to identify any potential additional relevant articles. The literature search was conducted independently by two investigators, and any inconsistencies were resolved by consensus with a third investigator.The search for eligible studies was conducted in PubMed, EMBASE, Medline, SCOPUS, and Web of Science up to July 15, 2020, with English restriction. The following terms were used: “thyroid neoplasms” or “thyroid carcinoma” or “thyroid cancer” or “thyroid tumor,” “iodine radioisotopes” or The inclusion criteria of the literature in this meta-analysis were as follows: (1) the original research; (2) observational studies designed to evaluate the association between clinical, pathological, or molecular factors and the development of RR-DTC, including retrospective and prospective studies; (3) patients with RR-DTC were well-defined, and the data of the control group were available; and (4) the data of variables reported could be used to calculate the log odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI). Studies were excluded in cases of duplicated, unavailable, or incomplete data. Reviews, case reports, letters, editorials, and expert opinions were also excluded.Two investigators (Y.L. and H.J.) extracted key data from the included articles in a standardized Excel sheet independently, and a third independent investigator (B.M.) checked the extracted data. For each article, data were extracted on the authors, year of publication, country, study type, recruitment period, sample size, demographics (age and sex), histological subtype, case number of patients in the RAI refractory (RAIR) group and the RAI-avid (RAIA) group, and RAIR classifications. Disagreements during data extraction were resolved through discussion among all authors. Study quality was assessed by two investigators (Y.L. and W.X.) using the Newcastle-Ottawa Scale (NOS). A third reviewer (X.W.) was available for mediation. The NOS assigns a maximum of 9 points based on three quality parameters, including selection, comparability, and outcome. A score ≥ 7 indicates good quality.I2 > 50%, according to the Cochrane Handbook), but this difference will be very slight with data of insignificant heterogeneity. Thus, we conservatively conducted random models for all data to make the results as reliable as possible. In this meta-analysis, subgroup analyses were conducted to explore the source of obvious heterogeneity, and a sensitivity analysis was performed to evaluate the reliability of the associations. A publication bias test was not conducted due to the small sample size. A p < 0.05 was considered statistically significant. All analyses were performed with R software version 3.6.2.Risk factors were included in the meta-analysis when they were reported in more than two studies. We considered only adjusted estimates to minimize the impact of confounding factors on pooled effect measures. Thus, for categorical variables, we entered the ratio measures of the (adjusted) effect as a log OR and the standard error (SE) of the log OR using the generic inverse-variance weighting method . The meaAfter duplicate studies were excluded, 2,136 articles from PubMed, EMBASE, Medline, SCOPUS, and Web of Science were screened. A total of 2,090 articles were inappropriate for our study according to the title and abstracts. Forty-six remaining studies were retrieved for assessment, and a flow chart showed the process of literature retrieval . Of 13 eTERT promoter (TERTp) mutation, and BRAFV600E mutation    and BRAFV600E mutation       , lateral lymph node metastasis (LLNM), mutation , 3. In t15–3.27)  and ETE 43–3.64) . At the 74–7.46) . However74–1.38) , age (p to 3.96) , tumor sto 1.55) , multifo63–2.42) , or LLNM6–11.01) .I2 = 91%, p < 0.01), LLNM , multifocality , BRAFV600E mutation , and TERTp mutation  (Heterogeneities were obvious for the following five features: tumor size  = 0.03) , 3. Due  , 3. Due = 0.03) .I2 = 70%, p = 0.02), whereas heterogeneity showed a marked decrease in Western countries  (p = 0.43) and Western countries (p = 0.35) demonstrated a statistically insignificant association between multifocality and RR-DTC.When subanalyzing multifocality, Asian studies continued to demonstrate moderate heterogeneity ( = 0.60) . Both AsTERTp mutations in the Asian group , and the pooled estimates remained positive . Interestingly, there was no significant heterogeneity in Western countries  failed to show a significant association between the BRAFV600E mutation and RR-DTC (p < 0.01).Asian populations continued to demonstrate considerable heterogeneity, with an d RR-DTC . HoweverTERTp and BRAFV600E mutations , but there was no heterogeneity after removing the study (I2 = 0%) . For multifocality, we found that one study . However, the p-value was still statistically insignificant despite the fact that a fixed-effect model was used to replace the former random-effects model, which indicated that multifocality was not a proper predictor of the occurrence of RR-DTC. During the sensitivity analysis of LLNM, it was found that the deletion of one study (I2 = 91%) into no heterogeneity (I2 = 5%) with a statistically significant outcome .The heterogeneity of tumor size was high (I2 = 0%) . The poone study  could bene study  turned tTERTp mutation, when we removed one study (p < 0.01) to 6.13 , and the statistical heterogeneity declined , which suggested that it could be the source of heterogeneity. However, there were few changes in the statistical heterogeneity after removing the literature sequentially in the sensitivity analysis of the BRAFV600E mutation, indicating its robust outcome.At the molecular level, for ne study , the pooTERTp mutation, and BRAFV600E mutation.Recently, RR-DTC has become a tricky problem as a result of the increasing number of patients with PTC around the world. The present study of 11 observational studies synthesized and explored potential risk factors for RR-DTC. We found four risk factors, as follows: histological subtype, ETE, Generally, grades of malignancy were related to age and sex in DTCs, wherein younger and female patients have a better prognosis. Some have reported that RAI avidity has a significant inverse correlation with age , 20, 21.131I treatment (p = 0.01) with low heterogeneity . Sensitivity analysis also assessed the stability of the association.Histology has been known as an important predictor of prognosis in PTC. In patients with RR-DTC, some studies illustrated that FTC, Hürthle cell, and poorly differentiated thyroid carcinoma (PDTC) had a higher possibility of being refractory to radioiodine treatment –25. It wreatment . In the Generally, a large tumor size is a useful feature for indicating the worse prognosis of PTC , 28, butp < 0.01, OR: 2.28, 95% CI: 1.43–3.64), and the sensitivity analysis confirmed the robustness of the results. However, ETE is associated with other factors, such as histological subtype, the location of the primary lesion, and the timing of diagnosis. For example, the ETE probability of tumors is higher in the isthmus than in the thyroid gland lobe due to its anatomical position, while the incidence of RR-DTC might be similar on the assumed premise of the same clinical stage and the same histology. Thus, ETE could be a risk factor, but it needs to be combined with other factors when making clinical decisions and strategies, and further studies are urgently needed.There is no doubt that ETE correlates with poor survival of PTCs –31, wherp < 0.01, I2 = 5%) by removing one study  and TERTp  mutations were risk factors for RR-DTC. However, according to the results of the cumulative meta-analysis, we found an obvious decreasing tendency of the prediction effect of the BRAFV600E mutation, which could be used to explain the considerable heterogeneity of the BRAFV600E mutation. Over the past few decades, an increased incidence of BRAFV600E mutations has been reported in PTCs, especially classic papillary PTCs , defined as a tumor of 1 cm or less in size. Based on the available information, the 2015 ATA suggested that BRAF had a limited role in increasing the recurrence risk of patients with PTMC . The possible explanation could be that the control group was the RAIA group without distant metastasis, within whom the TERTp mutation would be much lower. It could be improved if the control group had a similar ratio of local recurrence and distant metastasis to the RAIR group.Molecular analysis provides useful insight into the role of predicting the occurrence of RR-DTC, and u et al.  reportedogenesis , 37. Secogenesis . Tavarespression . Currentn of NIS –42. The ary PTCs –45. In tith PTMC , 48. ThuTERT/BRAF mutations, the predictive power seems to be better. Vuong reported that concurrent TERT/BRAF mutations were associated with increased tumor aggressiveness than were PTCs with BRAFV600E or TERTp mutation alone, and TERTp mutation was more high risk than BRAFV600E in terms of tumor aggressiveness , and PDTC. In contrast, tumor diameter and multifocality were not predictors according to our results. Meanwhile, other factors, including age, sex, and LLNM, may be useful and valuable predictors, but their values in RR-DTC need to be further investigated.This meta-analysis indicated that high-risk histological subtypes, ETE, All datasets generated for this study are included in the article/YW: conceptualization, supervision, and project administration. YL: methodology. YL, HJ, WX, XW, and BM: acquisition, analysis, curation, and validation of data. YL, HJ, WX, XW, BM, and TL: writing—original draft preparation, review and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The genetic variants of Mannose-Binding Lectin, a vital component of innate immunity have been studied with acute/recurrent vaginal infections ((R)VVI) and presented inconclusive findings. Therefore, a systematic review and meta-analysis of published data were conducted to assess the possible role of these variations in (R)VVI. A comprehensive search was made using PubMed, Web of Science and Google scholar till June 18, 2019. A total of 12 studies met the specified criteria and were included in the analysis. Different comparisons were made on the basis of the outcome of interest that resulted in the filtering of studies for the pooled analysis to find an association using the standard genetic models. Odds ratio (OR) with 95% confidence interval (CI) was chosen as the effect measure for the data synthesis. The trim and fill technique was applied to adjust the publication bias. The meta-analysis revealed the significant association (p < 0.05) of rs1800450 polymorphism with RVVI risk (OR ≥ 3.5) in all the genetic models. The subgroup analysis identified the same association in Caucasian and Mixed ethnicity. Quantitative synthesis based on RVVC showed>3.5 fold risk of disease development accredited to rs1800450. A combined evaluation of Exon1 variants showed no association with (R)VVI. This meta-analysis suggests rs1800450 polymorphism as a genetic predisposing factor for RVVI, but to reinforce, further studies with a larger sample size are warranted. However, the important issues are their high recurrence rates (RVVI) and the associated severe pregnancy outcomes as well as infectious diseases2. High proportion of opportunistic pathogens, which are either normally dwelling or transmitted sexually have been suggested as the reason behind the development of VVI and RVVI, collectively abbreviated in this study as (R)VVI2. Nevertheless, universal presence of asymptomatic cases implies that the shared risk factors of (R)VVI including excessive sexual activity, antibiotics/contraceptives use and ethnicity are simply responsible for increasing the vaginal colonisation of potentially dangerous microbial species but not disease3. Hence, the presence of symptomatic/asymptomatic (R)VVI cases are mainly accredited to the differences in women’s immunity, conferred partially or wholly by genetic variations1. Therefore, genetic exploration of immune mediators that ultimately decides the host susceptibility to symptomatic (R)VVI is necessary.Vulvovaginal infections (VVI) account for a huge fraction of gynaecological outpatient visits by woman of childbearing age and include about 10 to 20% of consultations only. Bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) and trichomoniasis (TV) are the frequently encountered VVI in clinical practice4. It’s a multimeric soluble protein encoded by MBL2 mapped to 10q21.1. Evidences have been provided regarding MBL binding to the molecular patterns of (R)VVI pathogens and thus its important role in first line of vaginal defense ranging from direct opsonophagocytosis, activation of C system with subsequent indirect opsonisation, phagocytosis, ROS production and pro-inflammatory signaling7. Moreover, MBL levels has been assessed in vaginal fluid/serum of (R)VVI cases that has suggested its effective role in acute phase defense, although defective MBL production attributed to genetic variations appears to be predisposing women to (R)VVI12.One such important mediator is human Mannose-Binding Lectin (MBL), which is a vital component of systemic as well as mucosal innate immunityMBL2 have been suggested to have potential functional consequences on encoded protein and its levels, even though only six of them are functionally recognised and widely studied13. Three variant alleles in Exon 1 of MBL2 including T, A and A of rs5030737 (codon 52 and C > T transition), rs1800450 (codon 54 and G > A transition) and rs1800451 (codon 57 and G > A transition) single point mutations respectively, often pooled together as “O” owing to their similar effect in the collagenous region of MBL monomers that results in non-functional high order oligomers, while their wild type alleles  are referred as “A”14. These variants together with three promoter variants including rs11003125 , rs7096206  and rs7095891 , the other well-known protein expression regulators, form haplotypes including HYPA, LYPA, LYQA, LYPB, LXPA, LYQC and HYPD, which have been documented to alter soluble MBL levels by interfering in its transcription as well as translation15. Therefore, analysis of MBL2 genetic variations could be informative in identifying the women at risk of developing (R)VVI and to validate the therapeutic possibility of emerging MBL substitution therapy for this condition.Several genetic variations of MBL2 polymorphisms in susceptibility to (R)VVI in different populations24. Nevertheless, owing to ethnic diversity and underpowered study design, the conclusions provided by these reports are still controversial, demanding further in-depth investigation to establish the relationship between the two. Therefore, in order to provide scientifically rigorous summarised information, a systematic review of hitherto literary evidences and the quantitative synthesis of data thus obtained, were performed in this study by applying a well recognised statistical method—a meta-analysis, making the current investigation a primary approach towards it.Thus, by considering the importance of gene in view, studies have examined the possible association between 25. Whereas, the condition of RVVI is defined as the repetition rates as high as 30–50% within 3 months for recurrent BV (RBV), while ≥4 repetitive episodes of VVC in 12 months for recurrent VVC (RVVC)2. Similarly, cases of recurring TV (RTV) should have recurrence rates as high as 5–8% within 2 months of initial diagnosis26. VVI or RVVI denoted as (R)VVI are the primary study outcome, while different categories (R)BV, (R)VVC and (R)TV are the secondary study outcome in the present study.The outcomes of interest were women, who have experienced either at least one episode of any of the common vaginal infections (VVI) or its repeated episodes (RVVI) as per the original definitions. For VVI, the standard clinical symptoms and laboratory based diagnosis positive for BV, VVC and TV should be in consistent with European (IUSTI/WHO) guidelines on vaginal discharge management27. All those retrieved studies were incorporated that met the following criteria: (i) it must have assessed an association between MBL2 gene polymorphisms and (R)VVI  susceptibility; (ii) conducted under a case-control design; (iii) had a clear description of (R)VVI cases (as aforementioned) and controls  must have an accessible genotype distribution in cases and controls; (v) must be published in English language or have an English abstract; (vi) Data collected and analysis performed should be valid from statistical point of view.The study was performed in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelinesin-vivo/in-vitro analysis; (v) duplicates; (vi) review articles, comments or animal studies.The studies were excluded if: (i) they did not have an accessible genotype information; (ii) involved evaluation of MBL protein levels or vaginal microbiota distribution only, under a case-control design; (iii) case only studies without a comparison group; (iv) functional studies involving MBL2 polymorphisms and risk of (R)VVI. The combination of terms used were: “MBL” OR “MBL2” OR “mannose binding lectin” OR “mannose-binding lectin” OR “mannose binding lectin 2” OR “mannose-binding lectin 2” AND . We searched the electronic databases from inception to June 18, 2019 without any restrictions. The reference lists of resulting articles were also screened to find out the relevant publications that could have been missed in the initial search. Moreover, the cited literature in review articles was manually scanned for possible studies.The electronic databases including PubMed (MEDLINE), Web of Science and Google scholar were used to retrieve articles that have studied an association between the 28. Those studies that scored ≥5 stars were ranked from moderate to higher methodological quality. Contradictions in regard to data extraction, study eligibility and quality assessment were resolved by systematic discussion in the presence of third reviewer (JS).By stringently following the inclusion/exclusion criteria, an independent extraction of data from the selected studies was performed by three investigators  on a customised data extraction e-form (MS Excel). For each study, the following information was collected: first author, year and country of origin, ethnicity, study type, sample size, age distribution of cases and controls, polymorphisms detected, genotyping methods, genotypes distribution for each polymorphism in both cases and controls, and association status with (R)VVI. Furthermore, the quality of selected studies were independently evaluated by two reviewers (NK and MK) using star-rating system (from 0–9) of Newcastle-Ottawa Scale (NOS) for quality assessmentMBL2 polymorphisms. The OR-estimates were pooled based on allelic, homozygote, heterozygote, dominant and recessive genetic models for each comparison. χ2–based Cochran’s Q statistics were used to assess heterogeneity between studies, which signifies its presence at p-value < 0.05. To further quantify the amount of variability between studies, I2 index was used to represent the presence of low, moderate and high inconsistency with increasing value of I2 index i.e. < 25%, 50% and >75% respectively29. To account for observed significant (p < 0.05) heterogeneity among studies, the random-effects model was applied. However, in case of no heterogeneity (p > 0.05) a fixed-effects model was used for pooling results. Moreover, the publication bias was assessed by visually interpreting the funnel plots and the quantification of it was performed by the Egger’s linear regression test and Begg & Mazumdar’s rank correlation test, wherein the p < 0.05 depicts statistically significant publication bias30. Further, to adjust the observed publication bias, trim and fill technique was used for recalculating the effect size (ES) of the genetic models31. Sensitivity analyses was also carried out to evaluate the contribution of each study to the pooled OR estimates by sequentially removing one study at a time and re-computing the summary ES for the rest of the outcomes. Distinct ethnicities were considered as moderators and the pooled results were stratified and compared among subgroups of Asian, Caucasian, Egyptian and Mixed population formed because of it. The countries of Latin America, particularly Brazil, Mexico and Colombia have widespread racial mixing , hence generally regarded as of Mixed ethnicities. All these statistical analysis was performed by ProMeta software v 3.0 . Hardy-Weinberg equilibrium (HWE) in the controls was determined using χ2 test. The adequate sample size needed to achieve the statistical power of each MBL2 polymorphism was calculated by genetic association study power calculator  using global minor allele frequency of each polymorphism. Bonferroni’s correction was applied to control inflation of the type I error rate. p < 0.05 was considered statistically significant.Odds ratio (OR) with 95% confidence interval (CI) was chosen as the effect measure for the quantitative synthesis conducted on the basis of combination formed from different (R)VVI and 24 met the specified inclusion and exclusion criteria and thus incorporated in the present study , 143 from Google Scholar and 21 from Web of Science core collection. However, only 16 studies were found potentially eligible after careful evaluation of titles/abstracts and removal of duplicate studies. Finally, only 12 studies22 provided sufficient data (comprising 577 controls and 644 RVVI cases) for the pooled analysis to find an association. Homogeneity between studies was observed in homozygous (BB vs AA) and recessive (BB vs BA + AA) genetic models  = 3.54; 95% confidence interval (CI) = 1.69–7.43), homozygous , heterozygous , dominant  and recessive   Fig. , with an57) Fig.  in homoz57) Fig. . HoweverMBL2 rs1800450 polymorphism with RVVI in different ethnic groups , homozygous , heterozygous  and dominant  genetic models. However, the observed significant risk effect was lost in the homozygous (p = 0.1) and heterozygous (p = 0.06) genetic models, when correction for multiple testing was applied. Moreover, high inconsistency was also found in heterozygous and dominant genetic models for Caucasian population. Additionally, Mixed ethnic group with 2 successfully included case-control studies showed an association with RVVI risk in all the genetic models including allelic contrast , homozygous , heterozygous , dominant  and recessive  even after Bonferroni correction with no observed heterogeneity at all. However, no significant (p > 0.05) association of rs1800450 polymorphism with RVVI susceptibility was found for Asian ethnicity in any genetic models  for the pooled analysis of MBL2 rs1800450 polymorphism and RVVC risk. Homogeneity between studies was observed in homozygous and recessive genetic models , homozygous , heterozygous , dominant  and recessive  genetic models. The overall ES indicated no significant association of rs1800450 polymorphism with RBV in any genetic models  to calculate the summary effect of rs1800450 polymorphism in susceptibility to VVI. No heterogeneity was observed among the included studies in any genetic models  and recessive  genetic models  for the analysis of association between MBL2 rs1800450 polymorphism and VVC risk. No heterogeneity was found , homozygous , heterozygous , dominant  and recessive  genetic models. The overall ES did not show significant association of rs1800450 polymorphism with BV in any genetic model , homozygous , heterozygous , dominant  and recessive  genetic models. The overall ES did not show significant association of rs1800450 polymorphism with RVVI in any genetic model , homozygous , heterozygous , dominant  and recessive  genetic models. The overall ES did not show significant association of rs1800450 polymorphism with RVVI in any genetic model  due to the inclusion of newly published literature than the previous meta-analysis (175 participants) to precisely access the role of rs1800450 polymorphism in (R)VVC. Nevertheless, the study20, used Taqman detection method, which has been suggested of producing false positive results, therefore the results should be interpreted with care34.In absence of inter-study heterogeneity, stratified meta-analysis based on VVC and BV revealed no significant association with codon 54 polymorphism, the former includes the same three independent publications as that of VVI but with different sample size while the later includes two independent studies16 of same ethnicity (Caucasian) as well as genotyping method (Melting temperature assay) did not show any notable association either with enhanced or reduced risk of disease. Though, the sample size was large enough, the result for this analysis might have experienced low power accredited to the low Global MAF  of MBL2 rs5030737 of Exon 1 variant. In addition, other MBL2 genetic polymorphisms, rs1800451, rs11003125, rs7096206, rs7095891, rs10824792, rs2120132, rs2120131, rs2165813, rs2099903, rs2099902, rs11003124, rs7084554, rs36014597 and rs11003123 could not be investigated due to the absence of multiple studies in response to the same infection. Nevertheless, studying the combined effect of MBL2 structural and promoter gene variations in pathogenesis of (R)VVI is important, which further assures the study to be performed in a generously proportioned scale given that more studies regarding the association should be available in the literature.Meta-analysis of combined Exon1 polymorphisms with RVVI  and BV  involving two independent studieset al.22 was not in accordance with HWE, which may be attributed to the population stratification/selection pressure or the reason could be other prevailing infectious diseases or genotyping error. However, it is of note that, omission of this study22, did not alter the results of quantitative synthesis, suggesting the robustness of results. Fourth, our pooled ORs were based on un-adjusted data for potential confounding factors, such as the well-known risk factors for mucosal vaginal infection, which might have affected the accuracy of the data, though no sufficient information was available in this regards. Fifth, some ethnicity based sub-group analyses, might lack sufficient statistical power to identify the authentic relationship in different ethnic groups and hence demands more such studies to be published for the up-dated quantitative synthesis. Finally, the caveat for dealing with multiple comparisons with Bonferroni correction is the risk for false negative outcomes hence, caution should be taken while interpreting the results.Although, meticulous methodology was used for the systematic evaluation of results, yet the present analysis has some limitations to be cared for. Firstly, the study might have experienced the publication bias owing to the inclusion of English literature only, which could have limited the published evidences. Secondly, sensitivity analysis indicated that the statistical significance of rs1800450 in association with VVC altered on exclusion of a study, further suggesting that the pooled estimates for this association may be short on strength. Third, the control group of study by Kalia i.e. PCR-RFLP, which is important to avoid variation in results that may arise due to differences in performance and sensitivity of different detection methods. Fourth, except for one comparison, the sensitivity analysis showed potency in the present study’s conclusions. Fifth, the random-effect model was used to minimize the problem that may arise due to the observed inconsistency by obtaining wider confidence intervals. Hence, the present study may contribute significantly to the understanding of (R)VVI pathogenesis.Albeit of aforementioned limitations, this meta-analysis offered several substantial advantages to the field. Firstly, the included studies were stringently checked for quality assessment by applying NOS scale and each study found to be of good quality with clear descriptions of the inclusion criteria. Secondly, in order to achieve consistent results, a meticulous procedure for the identification of study, statistical methodology adopted, and data selection was used to minimize the possibility of bias. Moreover, the analysis of publication bias was performed using the three well known criteria and the two of them indicated no bias in the majority of results. Third, almost all the studies involved in the present meta-analysis used one mode of genotyping MBL2 including 5′-promoter and 3′-UTR variants in response to (R)VVI, restricted the pooled analysis of these variants. Thus, the study demands more such studies to confirm MBL substitution as novel immunotherapeutic approach in order to replace traditional non-specific anti(R)VVI treatments. Furthermore, future studies involving the extensive screening of MBL2 variants with regard to (R)VVI susceptibility are warranted to decode the potential molecular markers underlying the pathogenesis.In conclusion, the present investigation evaluated 12 case-control association studies, whose quantitative synthesis provided strong evidence in favour of rs1800450 polymorphism as a genetic predisposing factor for RVVI and RVVC in various ethnic groups. Interestingly, no evidence of association was found between the combined effect of Exon 1 polymorphisms and (R)VVI. Moreover, the lack of sufficient literary evidences for many of the important polymorphisms of Supplementary information.


Shift work with circadian disruption has been considered as a carcinogenic risk factor for skin cancer. The few prior studies that investigated the association between shift work and skin cancer have inconclusive results. Our main objective was to evaluate the associations between shift work and the risks of different types of skin cancer. We systematically searched PubMed, Web of Science, Cochrane Library, EMBASE and Science Direct until October 2018 for studies that included a relationship between shift work and skin cancer. Our search yielded 193 articles and 9 studies met the criteria for our review. The included studies involved 3,579,147 participants and 17,308 skin cancer cases. Overall, ever shift work, was associated with increased risk of melanoma  and a significant decrease in the risk of BCC . No association between shift work and the risk of SCC was detected. Interestingly, our dose response analysis demonstrated that the risk of melanoma cumulatively increases by 2% for every year of shift work . In conclusion, shift work is associated with increased risk of melanoma and deceased risk of BCC. Further studies are needed to confirm our findings and to elucidate the related potential biological mechanisms. According to the most recent data from the Bureau of Labour Statistics, approximately 15 million Americans work night shifts, and that number is expected to grow rapidly3. Although such work imposes significant costs on workers, including many hazardous impacts not only on their relationships, social lives and sleep patterns but also on their overall health, it is unavoidable and is taken for granted by many companies. Indeed, the International Agency for Research in Cancer (IARC) considered shift work that involves circadian disruption to be a probable carcinogenic factor in humans (Group 2 A carcinogen)4. The desynchronization that occurs in circadian rhythms with respect to sleep cycles and melatonin production predisposes employees to have a higher susceptibility to cardiovascular, neuropsychiatric and endocrine disorders and to the development of neoplastic growths5. A recent meta-analysis showed that shift work increases the risks of multiple primary cancers, such as breast, prostate and digestive system cancers6.Shift work is increasingly common, especially in industrially developed countries. It includes a wide range of schedules, such as evening work; night work; split, extended or rotating shifts; weekend work; and on-call work7. It can be classified into melanoma skin cancer, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The last two subtypes are grouped together as non-melanoma skin cancer which is the most frequently diagnosed cancer in white populations8. Both BCC and SCC have a good prognosis when detected in their early stages. While most non-melanoma skin cancer are rarely fatal, they can result in considerable morbidity which presents an increasing burden on the healthcare services9. On the other hand, while invasive melanoma accounts for only a small percentage (~4%) of all skin cancer cases, it is responsible for the vast majority of deaths due to skin cancer8. The main risk factor for all types of skin cancer is exposure to ultraviolet light. However, many other risk factors have been reported to predispose patients to skin cancer, such as family history of the disease, fair skin and shift work11.According to the last annual report by the Skin Cancer Foundation, skin cancer is the most commonly diagnosed cancer in the USA15, while others have failed to reveal any significant correlation17. In this context, identification of the associations between shift work and the risks of different types of skin cancer would be of the utmost interest. In the present study, we conducted a meta-analysis to summarize the results of published case-control and cohort studies exploring the association between shift work and the risk of skin cancer. More specifically, we sought to assess the effect of increased duration of shift work on the risk of skin cancer.Previous studies that examined the relationship between shift work and skin cancer risk have provided inconclusive results. Some studies have demonstrated a significant association between shift work and skin cancer21 evaluating the associations between shift work and the risks of different types of skin cancer that were published before 30 October 2018 with a total of 17,308 skin cancer cases and 3,579,147 participants.The detailed process of eligible article identification and selection is depicted in Fig. 18. Approximately half of the included studies were conducted among nurses and health professionals, one study was conducted among flight attendants, and three studies were conducted among different types of workers. In terms of skin cancer types, nine studies reported melanoma, two studies reported SCC and two studies reported BCC. Of note, articles that included different types of skin cancers, sexes and multivariate models were considered independent entries. The number of adjustment factors in the individual studies ranged from 2 to 22. Eight studies adjusted for >3 covariables and only one adjusted for ≤3 covariables. For exposure assessment, four studies used databases, three adopted questionnaires, one study used interviews, and one study used all three instruments.The descriptive data from the studies included in our meta-analysis are summarized in Table 22. Overall, most studies were of good quality with a NOS score ranging from 6 to 9 with a mean of 7.6, as shown in Supplementary Table 23. Among the 8 cohort studies included in this meta-analysis, we found that the potential flaws were detected in three items of the population selection that includes “representativeness of exposed cohort”21, “selection of non-exposed cohort”18 and “outcome of interest history”21.New castle Ottawa scale (NOS) was used to estimate the quality of the included studies according to a predefined set of criteria2 = 66.1%, p < 0.001), BCC , and SCC .We performed a meta-analysis and calculated the pooled effect estimates across the enrolled studies. The multivariate-adjusted relative risks (RRs) of each study were combined using the random effects model to identify the associations between shift work and the risks of different types of skin cancers Fig. . The oveTo expand on the results obtained from the pooled RRs analysis and to explore the heterogeneity, subgroup analyses were performed for each type of skin cancer based on geographical regions , assessment of exposure , quality score , high quality (NOS ≥ 7)), study design , occupation , sex , and studies adjusted to the exposure to UV radiation in the multivariate analysis .2 = 74.73%). In the analysis stratified by exposure assessment, a positive relationship between the risk of melanoma and shift work was observed when conducting a study using a database . Nevertheless, no relationship was found when conducting the study using questionnaires  and in the interview group . In the subgroup analyses stratified by quality score, study design, occupation, sex and using the exposure to UV radiation as a covariable in the multivariate analysis, non-significant associations were observed between shift work and an increased risk of melanoma in all subgroups, as shown in Table For melanoma subtype, our results of the subgroup analysis stratified by geographical region suggest that shift work caused a significant increase in the risk of melanoma in Europe , while no association was found in the America . However, only the Americas group tended to have significant heterogeneity  and  Table . For SCC21. All the four studies included melanoma, two studied SCC and only one for BCC. Our results demonstrated that every extra year of shift work is causing a significant increase of 2% of melanoma . Moreover, exposure to shift work does not have an impact on the risks of both BCC  and SCC  14 study was omitted in the melanoma group, as the heterogeneity changed from  to . The same occurred in the other two groups of BCC and SCC after excluding the Heckman 201715 Lie 200721 studies, respectively, as heterogeneity changed from  to  for BCC and from  to  for SCC.To evaluate the robustness of our results, we performed a leave-one-out-sensitivity analysis in which the meta‐analysis was serially repeated after sequentially leaving out exactly one study at a time. Our results demonstrated that none of the included studies unduly influenced the pooled estimate, as it remained stable, which confirmed that our findings were not driven by a single study. However, we did find that the heterogeneity was significantly reduced if the Schernhammer 2011Egger’s regression test and a funnel plot were used to assess the existence of publication bias among the included studies. For melanoma, BCC and SCC, the funnel plots had symmetrical distributions, and no evidence of publication bias was detected by Egger’s test  and the effect estimate was ,  and  respectively. For BCC, two possible missing studies were imputed by the trim-and-fill method and the effect estimate was . However, no imputed studies were detected for both melanoma and SCC.15 and an increased risk of melanoma among flight attendants, especially pilots25. In contrast, our results are clearly at odds with the observations of other studies that showed a reduced risk of melanoma in cohorts of chemical workers and nurses20. However, other previous studies have reported that no relationship can be detected between shift work and the risk of melanoma18.This meta-analysis summarized the results of one case–control and eight cohort studies that investigated the associations between shift work and the risks of different types of skin cancer and involved 3,579,147 participants and 17,308 skin cancer cases. Our analysis demonstrated positive associations between shift work and the risk of melanoma . In contrast, an inverse significant association in the risk of BCC  and a non-significant inverse association in the risk of SCC  were detected. Our findings are consistent with previous observations by others reporting a significant association between a longer duration of night shifts and a decreased risk of BCC32. The results presented herein, together with the findings of the previously mentioned studies, suggest that longer exposure to shift work increases the risks of different types of cancers. Moreover, one might assume that shift work is not a real problem in short-term, but its effect accumulates with time. One possible justification is that long-term circadian disruption associated with prolonged duration of shift work may play a role in development of melanoma.Our dose-response analysis demonstrated that every extra year of shift work is causing a significant increase of 2% of melanoma. Similar results were demonstrated in several studies that showed higher risks of colorectal, breast, lung and prostate cancers with an increased duration of shift work33. Melatonin, which is considered a marker of the circadian rhythm, is a natural antioxidant with immunoenhancing properties34. Several in vitro studies speculated that melatonin derivatives exhibited antitumourigenic effects through their ability to inhibit melanoma and breast cancer cell proliferation36. There is now growing evidence that circadian disruption can interfere with cell proliferation, apoptosis, DNA damage repair, and immune functions37. It has been recognized that disrupting the expression of circadian genes, which oscillates according to the circadian rhythm, increases the risks of different types of cancer38. Indeed, both exposure to LAN and melatonin suppression are associated with an imbalance in the regulation of melanocyte function and the inhibition of melanin secretion in the skin with a subsequent loss of the protective effects against carcinogenic agents, such as exposure to UV radiation39. This type of radiation is known to have multiple effects on skin tissue, including inflammation, DNA damage and immunosuppression41. According to the Skin Cancer Foundation, approximately 86% of melanomas and 90% of non-melanoma skin cancers are associated with exposure to solar UV radiation7. Therefore, the increased risk of melanoma with longer duration of shift work detected in our results can be explained by intense intermittent exposure to UV radiation, which could be related to shift work. In addition, the association of lower risk of BCC with shift work demonstrated in our results can possibly be explained by shorter duration of exposure to UV radiation. Another important point that should be highlighted is the association of certain occupations, which include shift work in their schedules, such as nurses and pilots, with the risk of skin cancer. One might surmise that there are other potential factors related to these occupations that increase the risk of skin cancer, such as exposure to cosmic radiation that can cause genetic and cytogenetic damage42. Therefore, it is difficult to determine whether shift work alone or in association with other occupational factors is responsible for the increased risk of certain type of skin cancer in this population. Taken together, these factors could contribute to the progression and development of many cancers, including all types of skin cancer. Notably, the differences in the risks of BCC, SCC, and melanoma as related to shift work history suggest a variable role played by this type of work in the carcinogenesis of different types of skin cancers.The relationship between shift work and the risk of all types of skin cancer has some biological plausibility. One of the possible explanations is that shift workers are mostly exposed to light at night (LAN) that could trigger the inhibition of melatonin secretion with serious perturbations of the circadian rhythm2 tests demonstrated statistically significant heterogeneity in the group of melanoma , BCC  and SCC . In subgroup analyses of melanoma, we found that heterogeneity could be avoided among studies performed in Europe, studies that included subjects who were self-employed and workers, studies that included only males and, in the groups assessed by interview and databases. This suggests that those studies could provide more reliable evidence and that using interview and databases outperforms the use of questionnaires in the assessment of exposure. Of note, high heterogeneity in studies done in America may reflect methodological and clinical heterogeneity such as differences in the design, conduct of the studies and variations in participants’ characteristics , interventions, exposures or outcomes evaluated44. We carried out a meta-regression analysis to assess the possible sources of heterogeneity among the variables in every study. Our results showed that only geographical region and exposure assessment might explain the heterogeneity among the enrolled studies for both melanoma and SCC. Using the leave-one-out sensitivity analysis, we found that the heterogeneity was significantly reduced if the Schernhammer 2011 study14 was omitted in the melanoma group, the Heckman 2017 study15 in the BCC group and the Lie 2007 study21 in the SCC group.The quantified Q and I45. Third, eight of the enrolled studies were of high quality (NOS ≥ 7), and only one study was of low quality (NOS = 6). Finally, the included studies were conducted in different countries, which increases the generalizability of our results. Nevertheless, our study encountered many limitations. First, there was no standard definition of shift work across the enrolled studies. One of the included studies considered an employee who employed for at least one year as a flight attendant to be a shift worker16. Another study defined shift work as working between 1:00 AM and 2:00 AM for at least 6 months19. This lack of consistent definition of shift work might lead to a certain degree of misclassification and dilution of the pooled RR26. Second, the significantly high heterogeneity can be explained by the substantial variability in the definition of shift work, geographical region, study design, occupation, sex and exposure assessment tools. It is interesting, however, to note that these discrepancies were captured during NOS scoring as it assesses the risk of bias in each study. Therefore, our results should be interpreted with caution. Finally, four studies were included in the dose-response meta-analysis, hence limiting the reliability of the result. Because of the limited number of included studies and the high degree of heterogeneity, further well-designed large cohort studies are still warranted to confirm the findings of our analysis.To the best of our knowledge, this is the first meta-analysis comprehensively focused on the associations between shift work and the risks of different types of skin cancer. There are several strengths in this meta-analysis. First, the large sample size of the studied populations collected from the included studies could help ensure more precise risk estimation and enhance the statistical power of our results. Of note, five of the included studies used databases such as the Nurses’ Health Study and Norwegian board of health’s register, which provide an excellent opportunity to study a population across these countries with high rates of follow-up. Second, eight of the included studies had a cohort design, which is well known to give more credible and valuable results when compared to case-control studiesIn conclusion, this meta-analysis demonstrated that shift work was potentially associated with increased risk of melanoma and decreased risks of BCC. No association between shift work and the risk of SCC was detected. Our results indicated that the risk of melanoma increases cumulatively by 2% for every year of shift work. Taken together, our findings suggest that more efforts are needed to protect the health of shift workers, such as regular follow-up in this population. Clearly, experimental studies and large cohort studies with long-term follow-up are needed to confirm our results and to elucidate the potential biological mechanisms that are related to shift work.http://www.crd.york.ac.uk/prospero/) with the registration number [CRD42019119583]. We planned and conducted this systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines46. An extensive systematic literature search updated to October 2018 was carried out. We used the following electronic databases: PubMed, Web of Science, Cochrane Library, EMBASE and Science Direct. Searches were performed using the following keywords: (“shift work” OR “night shift” OR “circadian”) AND . We evaluated all possible articles by checking the titles and abstracts, and those that met the eligibility criteria were retrieved. Furthermore, we hand-searched the reference lists of the identified reviews and articles to further select any potentially relevant studies. Only articles written in English were included in our study, and no other limits were applied.The protocol of this systematic review was published before starting the review process on the publicly accessible website PROSPERO (The included articles were identified according to the following inclusion and exclusion criteria. The inclusion criteria were as follows: 1) studies with a cohort or case-control study design; 2) studies evaluating the possible relationships between shift work and the risks of different types of skin cancer; 3) studies with defined and quantified shift work, 4) studies with results that included the risk estimates, such as RRs, Odds rations (ORs), hazard ratios (HRs), and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) or that provided sufficient data to calculate them. The exclusion criteria were as follows: 1) studies written in language other than English; 2) studies including recurrent skin cancer; 3) studies with the same population included in more than one study; however, in the latter case, the study with the largest number of patients was selected. Investigators were divided into two groups that worked independently to evaluate articles for inclusion. In cases of doubt, full-text articles were discussed between the two groups to solve any discrepancies.The titles and abstracts of all identified articles were screened to identify all potentially eligible studies based on the predefined data extraction form. The following data were extracted: first author’s last name, year of publication, study location, study design, number of cases/number of all subjects, sex, age, occupations of participants, type of skin cancer, range of shift work, definition of shift work; tool of exposure assessment; and variables of adjustment Table . Two rev22. It includes eight items that allows for evaluating population selection (4 items), comparability of study groups (1 item) and exposure assessment (3 items) in case-control studies. However, in cohort study, it allows for evaluating population selection (4 items), comparability of study groups (1 items) and outcome evaluation (3 items). A study can be awarded a maximum of one star for each item within the selection, exposure and outcome categories. A maximum of two stars can be given for comparability. The total number of the stars that quantitatively indicates the quality of the study is 0–9. For each paper the scores are consisting of a letter  that represents illustrative item for the NOS quality coding item list, and a number (0 or 1) indicating the score value for this illustration . Studies included in this meta-analysis reported different durations of shift work  as “ever” and compared it to “never” exposure to shift work. However, only one study compared short sleep duration to 7 hours of sleep every day49. P <0.05 suggested that there was evidence of publication bias. In addition, the trim-and-fill procedure was used to search for studies missing in the meta-analysis50. This test assumes a normal distribution of the effect sizes of all included studies around a central point of a graph. If asymmetry is detected, then it adjusts for the possible effect that unpublished studies could have on the result. For the dose response meta-analysis, we selected studies that included at least three categories of shift work and supplied the number of the cases in each category26. For this analysis, the risk estimates and the doses were re-summarized via the method proposed by Greenland and Longnecker51. We assigned the dose of exposure in each category as the midpoint of the lower and upper boundaries. If the upper boundary of the highest category was not provided, the scale of the interval was supposed to be the same as in the preceding category.We conducted Egger’s regression test and constructed funnel plots to assess the publication bias of the enrolled studies for each subtypes of skin cancerSupplementary information.


Background: Numerous published studies have shown that S100A4 is frequently overexpressed in various human cancers. However, the association between S100A4 expression and prognosis or clinicopathological parameters in non-small cell lung cancer (NSCLC) remains unclear. Therefore, a meta-analysis was performed to identify the significance of S100A4 in NSCLC.Methods: Systematic literature search was conducted using PubMed, Embase, Web of Science, the Cochrane Library, the Chinese National Knowledge Infrastructure database (CNKI), and the Wanfang database to obtain relevant articles. A combined hazard ratio (HR) and its corresponding 95% confidence interval (CI) were used to evaluate the association between S100A4 expression and prognosis in NSCLC patients. Pooled odds ratio (OR) and 95% CI were calculated to assess the association between S100A4 expression and clinicopathological features in NSCLC.Results: NSCLC patients with overexpression of S100A4 had a worse prognosis than patients with low expression of S100A4 . Additionally, overexpression of S100A4 was significantly correlated to patients’ age , tumor differentiation , lymph node metastasis (LNM) , Tumor-Node-Metastasis (TNM) stage , and pathological subtype . However, there was no association between S100A4 expression and other clinicopathological features in NSCLC, including gender, tumor size, and smoking.Conclusion: S100A4 overexpression was associated with tumor progression and poor prognosis in NSCLC patients. Hence, S100A4 might serve as a potential prognostic biomarker in NSCLC. Lung cancer is the most commonly occurring cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases, and NSCLC is classified into the following pathological subtypes: squamous cell carcinoma (SCC), adenocarcinoma (ADC), and large cell lung carcinoma . DespiteP=0.0269). In contrast, in Bai et al.’s [S100A4 , a member of the S100 family of calcium-binding proteins, is a small-molecular-weight 12 kDa) protein with two domains: an S100 domain and a calcium-binding domain . S100A4  kDa protet al.’s  meta-anaet al.’s  demonstret al.’s  extracteet al.’s  and Chenet al.’s  based onet al.’s . Thus, wThis meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . A systeThe inclusion criteria were as follows: articles describing the relationship between S100A4 expression and survival outcome or clinicopathological parameters in patients with NSCLC; adequate data provided to calculate the odds ratio (OR), HR, and 95% CI; and the expression of S100A4 in NSCLC tissues determined by immunohistochemistry (IHC).The exclusion criteria were as follows: articles pertaining to the case report, review, letter, and conference abstract; articles describing overlapping studies; or studies with insufficient data.Two reviewers (Jing Zhang and Guichuan Huang) independently extracted the relevant data from included studies. The following data were obtained from each included study: the name of the first author, publication year, country, language, sample size, detection method, clinicopathological parameters of NSCLC patients, HR, and corresponding 95% CI. If the required data were not provided directly but were provided as Kaplan–Meier curves, then the relevant data were obtained from graphical survival plots based on the described method . Further2I statistics were applied to assess the heterogeneity among the studies. For the chi-square test, if P<0.05 or 2I > 50%, it indicated the presence of heterogeneity, then a fixed-effect model was used. On the contrary, if P≥0.05 or 2I ≤ 50%, a random-effect model was used. Begg’s test and Egger’s test were used to evaluate the potential publication bias. The trim and fill method was applied for correcting any publication bias identified in this meta-analysis [P-value of less than 0.05 was considered statistically significant.In this meta-analysis, all statistical analyses were performed using Stata-SE software (version 15.0). Also, HR and corresponding 95% CI were combined to evaluate the strength of the association between S100A4 expression and prognosis in NSCLC patients. Similarly, pooled OR and corresponding 95% CI were used to evaluate the association between S100A4 expression and clinicopathological parameters in NSCLC patients. Cochran’s Q (chi-square) test and analysis . A sensiThe article selection process is presented in The characteristics of the included studies published between 2000 and 2017 are presented in P=0.056, 2I= 38.2%) was found, and thus, a fixed-effect model was utilized for the combined HR and 95% CI. The results indicated NSCLC patients with overexpression of S100A4 had a worse OS than patients with low expression of S100A4 .Of the 24 included studies in this meta-analysis, 17 studies including 1730 patients reported data on S100A4 expression and OS in NSCLC. As shown in P=0.010, OR = 0.67, 95% CI: 0.49–0.91, 2I = 44.5%), tumor differentiation (poorly vs. well and moderately) , LNM (yes vs. no) , TNM stage (III/IV vs. I/II) , and pathological subtype (ADC vs. SCC) . However, no significant association was identified between overexpression expression of S100A4 and other clinicopathological parameters, including gender  , tumor size (>3 vs. ≤3 cm) , and smoking (yes vs. no) .The relationship between S100A4 expression and clinicopathological parameters in NSCLC patients is illustrated in 2I = 44.5%, HetP=0.03), a random-effect model was used. We found that the heterogeneity was obviously reduced  without a change in combined outcome  after removing Zhang et al. [Owing to significant heterogeneity that existed in age analysis  and pathological subtype (Supplementary Table S3) were also conducted to identify the sources of heterogeneity on the basis of publication year, sample size, and ethnicity. However, heterogeneity remained practically unchanged, indicating that heterogeneity probably did not result from publication year, sample size, and ethnicity.To test whether a single study affected the pooled HR or OR, a sensitivity analysis was performed. After removing individual study, the corresponding pooled HR and OR was not significantly changed, indicating the robustness of our meta-analysis results (data not shown).P=0.044 for Begg’s test; P=0.013 for Egger’s test) , suggesting that this observed publication bias may not influence the pooled results.Begg’s test and Egger’s test were conducted to evaluate the publication bias in this meta-analysis. As shown in ’s test) . After aS100A4 belongs to the S100 family of calcium-binding proteins, and this multifunctional protein is presented in the cytoplasm, nucleus, and extracellular space . PreviouNumerous studies have indicated that S100A4 is associated with tumor progression. Liu et al.  reportedA total of 23 articles involving 24 studies with 2307 patients were included. Of the 17 studies reporting datasets of S100A4 expression and OS in NSCLC, 5 studies results indicated that S100A4 expression was not associated with prognosis in NSCLC. However, pooled results of this meta-analysis indicated that S100A4 overexpression was significantly associated with poor OS in NSCLC patients. In addition, present meta-analysis results indicated that overexpression expression of S100A4 was associated with clinicopathological characteristics, including patient’s age, tumor differentiation, LNM, TNM stage, and pathological subtype. However, no significant relationship was found between S100A4 expression and gender, tumor size, and smoking.Of the 16 studies reporting datasets of S100A4 expression and patients’ age in NSCLC, four studies results suggested a negative association between S100A4 expression and NSCLC patients’ age. The pooled results of this meta-analysis also proved this negative association between NSCLC patient’s age and S100A4 expression. Young-age patients with NSCLC had a greater extent of malignancy and mortality rate than elderly patients , and mosThere are several limitations that should be considered in the present meta-analysis. First, due to a lack of original data for some studies, HRs were extracted from the Kaplan–Meier survival curves. Second, the cut-off values for defining S100A4 expression are different among the included studies, which may result in heterogeneity. Third, obvious heterogeneity was observed in the analysis of age, tumor size, LNM, TNM stage, and pathological subtype, which may reduce the reliability of results. Fourth, publication bias was found in the analysis of tumor differentiation, although results remained unchanged after adjustment by the trim and fill method. Finally, most of the included studies in this meta-analysis were retrospective studies, which caused the selection bias. Hence, the results should be interpreted cautiously.Overexpression of S100A4 is associated with clinicopathological features of NSCLC, including age, differentiation, LNM, TNM stage, pathological subtype, with a tendency for poor prognosis. Hence, S100A4 may serve as a potential prognostic biomarker for patients with NSCLC.Click here for additional data file.


Background: Previous studies had been published to explore the association about carbohydrate intake on esophageal cancer risk, with inconsistent results. This meta-analysis aimed to assess the association between dietary carbohydrate intake and the risk of esophageal cancer.Methods: Suitable studies were carefully searched with the databases of PubMed, Embase, the Cochrane Library, and Wanfang Database. A random-effects model was used for combined odds ratio (OR) and 95% confidence interval (CI). Stata software 14.0 was adopted for the analysis.I2 = 59.9%, Pfor heterogeneity = 0.001). The results for carbohydrate intake on the risk of esophageal adenocarcinoma  and esophageal squamous cell carcinoma  were consistent with the overall result. A positive association was found in European, Asian, North American populations, instead of South American populations.Results: At the end, 13 publications were included in our study. Pooled results suggested that highest category versus lowest category of carbohydrate intake could reduce the risk of esophageal cancer (summarized OR = 0.627, 95% CI = 0.505–0.778, Conclusions: In conclusions, dietary carbohydrate intake may have a protective effect against the risk of esophageal cancer. Cancer is a crucial health problem on a global scale that has become one of the primary causes of death. According to Globocan estimates in the year 2018, an estimated of 9.6 million were deaths from cancer  that mayWe used the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines in the present study .Two authors independently performed a literature search in databases of PubMed, Embase, the Cochrane Library, and Wanfang Database. All suitable studies published from beginning to July 1, 2019 were considered to be included. The associated medical subject headings and terms were ‘diet’ OR ‘dietary’ AND ‘carbohydrate’ OR ‘sugar’ AND ‘esophageal cancer’ OR ‘esophageal tumor’ OR ‘esophageal carcinoma’ OR ‘esophageal adenocarcinoma’ OR ‘esophageal squamous cell carcinoma’. Divergence in the search results was resolved by discussion.The studies were included in our meta-analysis if they met the following criteria: (1) the studies were with case–control design or cohort design or cross-sectional study; (2) studies assessing the associations between dietary carbohydrate intake and the risk of esophageal cancer; (3) studies reporting in humans; (4) available odds ratio (OR) in case–control studies or relative risk (RR) in cohort studies and 95% confidence interval (CI) for highest category versus lowest category of dietary carbohydrate intake.Overlapped studies or populations, conference reports, editor comments, reviews, case reports, and academic dissertations were excluded for the analysis.Two authors independently extracted the following data from each eligible study: first author’s name, publication year, research location, sample size, average cases age, disease type, study design, OR or RR and 95% CI of dietary carbohydrate intake, assessment of intake, adjusted or matched for factors. Divergence in the extraction was resolved by discussion.The Newcastle–Ottawa Quality Assessment Scale was used to assess the quality of the included studies .I2 statistic was used to estimate the degree of heterogeneity among the studies [P value less than 0.05 were considered statistically significant.Association analysis between dietary carbohydrate intake and the risk of esophageal cancer was performed using a random-effects model. The effect size was estimated by calculating the summarized OR or RR and its 95% CI . The I2  studies . Meta-re studies . Further studies  and Begg studies  were perOur research returned 5213 articles from the above mentioned databases. Three articles were identified from the references of the relevant articles. After removing the duplicates from the different databases, 2515 articles were reviewed with titles and abstract. Then, 2473 articles were excluded due to not suitable for our analysis while reviewed the titles and/or abstract. The full texts of 42 articles were assessed. Twenty-nine articles were further excluded with reasons, which showed in the In our included articles, there are five texts  reported both esophageal adenocarcinoma and esophageal squamous cell carcinoma about dietary carbohydrate intake. Therefore, 13 articles with 18 studies were used for the analysis.I2 = 59.9%, Pfor heterogeneity = 0.001)  . The resP = 0.107) detected no publication bias. Sensitivity analyses (In the publication bias assessment, the results from funnel plots  and Eggeanalyses  showed nNumerous of studies about dietary carbohydrate intake and esophageal cancer had been published, with conflicting results. However, no meta-analysis was performed to obtain a definitive conclusion. Therefore, we conducted this study to clarify whether dietary carbohydrate intake had some inverse effects on the development of esophageal cancer. In total, our results suggested that dietary carbohydrate intake had significant association on the lower development of esophageal cancer.In the current meta-analysis, people with higher carbohydrate intake may reduce the risk of esophageal cancer. On the one hand, carbohydrate intake was negatively correlated with fat intakes. Therefore, people who were with higher carbohydrate intake may also have lower intake of fat, then explained its inverse association with esophageal cancer . On the 2I was reduced to 47.1% when we leaved one study by Wolfgarten et al. 2001 [We found significant between-study heterogeneity in the whole pooled results of dietary carbohydrate intake and esophageal cancer risk. As introduced in the methods, we used meta-regression to explore the causes of heterogeneity for covariates of publication year, disease type, study design, geographic locations, assessment of intake and number of cases. Results from meta-regression suggested that no covariates increased the high between-study heterogeneity. Moreover, between-study heterogeneity also exited in the subgroup analyses by disease type, study design and geographic locations. We then used leave-one-out analysis to reduce the between-study heterogeneity. The al. 2001  (about tThe present study still had several limitations. First, all the included studies were case–control studies. As well as known, the selection bias, recall bias and some other confounding factors cannot be excluded in the case–control studies. Hence, it is requirement for evidence from prospective cohort studies. Second, all the included studies were with English language and this may omit other languages studies. Meanwhile, the papers which had been published in the journal or online were searched and included in our analysis. Those papers which published in the meetings or unpublished were not searched. However, we did not detect any publication bias in our meta-analysis. Third, we only assessed the association between dietary total carbohydrate intake and the risk of esophageal cancer, and did not assess the association between carbohydrate type and esophageal cancer risk due to the limitation data provided in all the included original articles. Hence, more articles with detailed carbohydrate type are warranted to further assess the risk of esophageal cancer.In summary, our results indicated that dietary intake of carbohydrate may contribute to the lower development of esophageal cancer. As some limitations existed in our analysis, large scale prospective studies with detailed type of dietary carbohydrate intake are needed to verify our results.


Research Design and Methods. We searched in PubMed, Embase, and Web of Science for English-language medical literature published up to 12 May 2019. Cohort studies were only included in the search. Abdominal subcutaneous fat thickness, waist circumference, waist-hip ratio or body fat distribution were elected as measures of maternal central obesity, and all diagnostic criteria for GDM were accepted. The random effect meta-analysis was performed to evaluate the relationship between central obesity and the risk of GDM.  Nowadays, body mass index (BMI) is used to evaluate the risk stratification of obesity-related pregnancy complications in clinics. However, BMI cannot reflect fat distribution or the proportion of adipose to nonadipose tissue. The objective of this study is to evaluate the association of maternal first or second trimester central obesity with the risk of GDM. I2 = 14.4, P = 0.307). The subgroup analyses showed that heterogeneity was affected by selected study characteristics (methods of exposure and trimesters). After adjusting for potential confounds, the OR of adjusted BMI was significant .  A total of 11 cohort studies with an overall sample size of 27,675 women and 2,226 patients with GDM were included in the analysis. The summary estimate of GDM risk in the central obesity pregnant women was 2.76  using the adjusted odds ratio (OR). The degree of heterogeneity among the studies was low ( Our findings indicate that the risk of GDM was positively associated with maternal central obesity. Gestational diabetes mellitus (GDM) can be defined as different levels of abnormal glucose intolerance that occur for the first time during pregnancy . It has There is a growing prevalence of maternal obesity worldwide . NowadayAlthough some studies and meta-analyses have noted a relationship between BMI and GDM –30, therCRD42019137445.The meta-analysis followed the recommendations of the PRISMA group. The meta-analysis was registered at PROSPERO on 31 July 2019, with registration number A search was conducted using PubMed, Embase, and Web of Science to find English-language medical literature published up to 12 May 2019. Our search comprised different keywords and Medical Subject Headings (MeSH) terms, and the search strategy for all literature databases includes “Obesity, abdominal” or “Obesity, abdominal” or “Waist circumference” or “Waist circuit” or “Waist-hip ratio” or “Body fat distribution” or “Body fat index” and “Pregnancy” or “Pregnant women” and “Diabetes, gestation” or “Gestational diabetes” or “Gestational diabetes mellitus” ; women having been investigated for GDM during their pregnancy were eligible for inclusion.We excluded non-English-language medical literature; women with previously diagnosed diabetes (type 1 or 2); studies that had not reported the odds ratio (OR), relative risk (RR), confidence interval (CI), and exposure measurement or inadequate data to calculate such values; and case reports, letter to editor and previous systematic reviews, and meta-analyses.In this study, all relevant publications were inserted in NoteExpress software and reviewed independently by two authors (YD and ZH). When two reviewers disagreed, the literature was resolved by a third reviewer (WQJ). Then, qualified papers were obtained for full-text screening. After the final evaluation, we extracted information including author's name, publication year, country, study design, study population, ethnicity, exposure measurement, GDM diagnosis criteria, matching/adjustment variates, and risk estimates and 95% CIs. All extracted data were then entered into Excel software. A total of 11 cohort studies with an overall sample size of 27,675 women and 2,226 patients with GDM were included in the analysis. To assess study quality, we used the Newcastle–Ottawa quality assessment scale (NOS) for cohort studies. In the meta-analysis, the NOS guideline-modified studies which achieved five or more stars were considered of high quality .I2 was applied to determine the degree of heterogeneity between the studies [I2 > 50% [P < 0.05.The summary effect analysis was performed using Stata 11.2. After extracting and sorting the article data, we evaluated the ORs and 95% CIs for the highest level of maternal central obesity with those of the lowest level of maternal central obesity. Fixed and random effect models were applied to produce the summary estimates to determine the relationship between the exposure to maternal central obesity and the risk of GDM . Higgins studies . The resI2 > 50% . We evaln = 2) or owing to ecological studies (n = 7), or editorials (n = 4), and noncohort study (n = 3). Finally, a total of 11 cohort studies with an overall sample size of 27,675 women and 2,226 patients with GDM were included in the analysis.Searching the three databases produced 4,511 potential studies. There were 1,743 duplicated studies and 2,721 excluded based on titles and abstracts. When checking the records and removing the duplicates, 47 were fully reviewed and 14 articles were identified that met inclusion criteria . In 47 an = 10) and BMI (n = 9). However, fewer studies adjusted for ethnicity (n = 6), family history of diabetes (n = 6), parity (n = 6), smoking (n = 4), and education level (n = 5).The baseline information of each included study is presented in The modified NOS method for evaluating article quality showed that 11 studies had five or more stars .I2 = 14.4, P = 0.307) (P = 0.069)  . A total= 0.307) . Besides= 0.069) .I2 = 81.5, P = 0.020). After stratifying by trimester, the OR of the first trimester  was similar to that for the second trimester group . When stratified by assessment of outcome, the summarized OR of WHO screening criteria  was higher than the Carpenter/Coustan diagnostic criteria .The results of all subgroup analyses according to study characteristics are shown in n = 9) adjusted for confounders, and the OR of adjusted BMI was significant .When adjusted for confounders, most ORs for factors showed slight decreases. However, for the factor of BMI in the risk of GDM, most studies . Of note, one study found a positive correlation between increasing FMP and the risk of GDM in overweight and obese women, and the OR increased 8.8-fold in the highest quartile of FMP compared with the lowest quartile [In subgroup analyses, different measures differed only slightly, and VAT measured by ultrasound had the highest OR. This suggests that VAT may play an important role in GDM. As illustrated in existing studies, WHR and WC may be better predictors than BMI for cardiometabolic outcomes, including diabetes . A crossquartile . Hence, quartile . In a prquartile , as alsoquartile . Proposequartile , 47. OurOur subgroup analyses showed that a higher level of maternal central obesity had a similar GDM risk in the first and second trimester of pregnancy. A retrospective study provided some evidence that maternal central obesity at midpregnancy (18–22 weeks) was superior to BMI in identifying the risk of obesity-related pregnancy complications . Howeverα, IR was positively correlated with the decrease of adiponectin and lipase [According to previous studies, adipose tissue is a storage area for energy and acts as an endocrine and immune organ that releases signals , 10. Excd lipase . Howeverd lipase .One of the strengths of this meta-analysis is that it is the first to evaluate the association between increased maternal central obesity and the risk of GDM and included a large number of GDM cases. All included studies were of high quality . Another strength of this meta-analysis is that it included cohort studies, which decreased recall bias and provided a strong ability to test the etiological hypothesis and association.This meta-analysis also had several limitations. First, one of the main limitations is a lack of levels of central obesity data. Although we identified many studies to assess the relationship between maternal central obesity and GDM, we also need a linear test to define linear or nonlinear relationships. Second, the included studies used varying measures for central obesity in women and GDM; thus, the summary estimates would not exactly reflect the same comparison for all studies. However, after performing subgroup analyses, the ORs for comparisons between different measures were fairly consistent among studies, suggesting that the definitions had no major effects on these findings. Third, various other risk factors may have contributed to the risk of developing GDM, such as ethnicity, BMI, family history of diabetes, parity, smoking, and several other variables. However, the included studies did not use multivariate analysis to adjust for all these potential confounders, which may result in confounding bias. In addition, when adjusting BMI for confounders, we found that the summarized OR of adjusted BMI was higher than nonadjusted BMI. Besides, the group of nonadjusted BMI was two article; it may influence the summarized OR. When adjusting for other confounders, the summarized OR of adjusted factors was lower than nonadjusted factors. The result indicated that the risk of GDM was positively associated with central obesity independently of BMI. Finally, this meta-analysis may have had inclusion criteria bias due to excluding non-English literature. In addition, because one included study used self-reporting of GDM, this may have introduced a response bias into our analysis.Our findings indicate that the risk of GDM was positively associated with maternal central obesity. Therefore, this study can improve the efficiency of early screening of GDM for pregnant women in evaluating central obesity based on the measurement results. These findings can strengthen the scientific background for public health interventions for the control of the first or second trimester maternal central obesity independent of BMI.