Macro‐algae products have been shown to ameliorate the metabolic disorders state. Thus, highlighting their function as supplementary therapeutic agents can be a novel strategy for clinical therapies. This systematic review and meta‐analysis of clinical trials aimed to summarize the effect of macro‐algae consumption on serum lipid profile, glycaemic control and anthropometric factors.Q test and I‐square (I2) tests were used to evaluate heterogeneity across the included studies. The meta‐analysis was conducted using random‐effects model (DerSimonian and Laird), and weighted mean difference (WMD) was considered as the pooled effect size.In this systematic review and meta‐analysis, a comprehensive search was performed for relevant studies published up to May 2023. The Cochran's p‐value = .023). There was an increase in level of high‐density lipoprotein cholesterol (HDL‐c)  which was not statistically significant. Macro‐algae supplementation reduced body mass index (BMI) , weight , waist circumference (WC) , fasting blood sugar (FBS)  and HbA1c  in intervention group.Out of 8602 papers in the initial screening, eight clinical trials with a total of 438 participants were included into this meta‐analysis. The results indicated that macro‐algae supplementation significantly decreased serum levels of total cholesterol (TC)  and low‐density lipoprotein cholesterol (LDL‐c) (WMD = −8.25 mg/dL; 95% CI: −15.38, −1.12; This meta‐analysis indicated that macro‐algae supplementation significantly decreased TC and LDL‐c level. It can also increase HDL‐c level and reduce anthropometric indices and glycaemic control factors. This meta‐analysis indicated that macro‐algae supplementation significantly decreased total cholesterol, low‐density lipoprotein cholesterol and fasting blood glucose levels, but had no significant effect on triglyceride, high‐density lipoprotein cholesterol and body mass index levels. AND . Additionally, a manual search of reference lists was performed to collect the studies that were not included by the online search.2.2After removing all duplicates reports, two authors (SH. R and S. GH) carefully screened all collected papers according the titles and abstracts to find eligible studies. Next, all eligible studies were categorized based on their findings and contents. Authors (S. GH and M. Z) carefully checked all papers independently and only studies which met the following criteria were included in this meta‐analysis: (i) articles in English language, (ii) papers which included population higher than 18 years old, (iii) RCTs, (iv) papers with enough data  parameters in the beginning and the end of study for both intervention and control participants to measure the targeted factors including glucose and lipid profiles, and (v) intervention duration was equal or higher than 1 week. The outcomes were included in the final analysis if the number of documents related to the outcome was equal or more than three documents. Studies were also excluded if they investigated animal models, published as conference abstract, book chapter, editorials, and patents, or reported insufficient data about the outcome.2.3The following data of selected articles were separately extracted by two authors (SH. R and S. GH), using a standard form included: the name of the first author, study place, the number of participants involved in both the intervention and control groups, the type and dose of supplementation with alga (g/day or mg/day), algal polyphenol concentration (mg/day), duration of intervention, the age and sex of the participants, type and design of the study, the outcomes of algal products supplementation and the related data for meta‐analysis.2.4Sh. R and Z. M assessed the quality of eligible included studies using Cochrane collaboration risk of bias tool.2.5Stata version 13.0 (Stata Corp LP) was applied to perform statistical analysis. Random‐effects model was employed with a 95% confidence interval (CI) for the calculation of the pooled weighted mean difference (WMD). The value of mean and SD was recorded for each result in the beginning and the end of the study using the calculation of the difference between the values before/after the intervention. The mean differences for the unreported SDs were calculated by applying the following formula:r was calculated and estimated between 0 and 1 values.SE×n, where n = the number of individuals in each group, was used to measure SD parameter in those cases that reported SE instead of SD. The statistical heterogeneity between trials was calculated using p < .05 and I2 > 50%. The sensitivity analysis was performed to evaluate the effects of each study on the pooled effect size by using ‘one‐study‐removed’ method  approach. This evaluation was performed by two independent investigators (Sh. R and R. T). Using this approach, the certainty of the body of evidence is assessed against factors such as the presence of risk of bias, inconsistency, indirectness, imprecision and evidence of publication bias.3The process of the identification of the related studies is presented in Figure Overall, 438 participants were included within this systematic review. The age of the participants was between 18 and 80 years old, and both of men and women were considered. One study by Shin et al.3.1p‐value = .026; I2 = 31.03%, p‐value = .29) and low‐density LDL‐c  were significantly decreased and serum level of HDL‐c increased  in the intervention group compared with the placebo group which was not statistically significant. There was no significant change in TG level .By consumption of macro‐algae, serum levels of TC  and HbA1c  in the intervention group compared to placebo group.In terms of glycaemic control, macro‐algae consumption decreased serum levels of FBS , weight  and waist circumference (WC)  were decreased in intervention group, but it was not statistically significant. The forest plots for the effect of macro‐algae supplementation on studied outcomes are shown in Figure BMI level (WMD = −0.25 kg/m3.2p Egger's = .18), LDL‐c (p Egger's = .057), HDL‐c (p Egger's = .8) and TG (p Egger's = .59).Findings from sensitivity analysis did not show considerable effects of the macro‐algae on levels of lipid profiles, glycaemic control and anthropometric indices after excluding each study from the pooled effect sizes. There was no evidence of publication bias Figure  among th3.2.1Table 4The results of this meta‐analysis of RCTs indicated that macro‐algae supplementation significantly reduced TC and LDL‐C concentrations levels. Macro‐algae supplementation also had a reducing effect on anthropometric indices and glycaemic control factors, and an increasing effect on HDL‐C level but were not statistically significant. Studies suggested that macro‐algae have particular classes of polyphenols called phlorotannins E. cava polyphenol‐rich extract could regulate lipid metabolism and inflammatory pathways.E. cava are effective agents for decreasing the blood glucose level and preventing hyperglycaemia‐induced oxidative stress. Herein, the outcomes of this meta‐analysis identified that the short‐term consumption of whole product of brown macro‐algae or its polyphenol‐rich extracts could increase the level of HDL‐C and decrease the level of TC, LDL‐C and glycaemic control profiles. In addition, these macro‐algae products also improved anthropometric factors but the result was not statistically significant.Zhao et al.In recent systematic review by Murray et al.,In addition, short‐term macro‐algae supplementation had no significant effect on triglyceride, HDL‐c and anthropometric factors. No clear mechanism has been reported in the literature, and further long‐term clinical studies will be required to accurately determine the exact effect of these compounds on anthropometric indices. Some studies failed to find the effect of algae on serum glucose and lipid profiles and anthropometric indices. Various factors such as individual characteristics of the subjects, clinical conditions of the participants, duration of the intervention, dose–response effect, and type of seaweed and polyphenols can affect the relationship between algae and health outcomes. For example, Kim et al.With the increasing interest on developing new drugs for diabetes mellitus, searching for natural drug‐like compounds opened new windows in nutritional and pharmacological studies. Studies on macro‐algae polyphenols suggested that these compounds may be beneficial in the prevention of metabolic diseases.This study had some limitations. The major limitation of this meta‐analysis was the short duration of the included studies. Another important limitation factor is the small number of participants recruited for performing clinical trials. Furthermore, not enough studies have been done on some of the important outcomes yet, and we have not been able to perform subgroup analysis. Further trials with larger populations and longer duration are needed to confirm the beneficial effects of seaweeds against the metabolic diseases.5The outcomes of the current meta‐analysis suggest that the short‐term administration of algal products either through consuming whole products or polyphenol‐rich extracts could decrease the TC and LDL‐c levels. Macro‐algae polyphenol‐rich extracts can be considered as new safe supplementary products for ameliorating complications associated with DM and obesity. However, further investigations in this field should evaluate the large‐scale clinical effect of seaweeds polyphenols to more entirely understand their potential.Shahla Rezaei: Software . Reza Tabrizi: Supervision ; validation . Saeed Ghobadi: Formal analysis . Morteza Zare: Writing – original draft . Zohreh Mazloom: Formal analysis ; software . Saeid Doaei: software , Maryam gholamalizadeh: Writing ‐ original draft .Funding for this study was provided by Shiraz University of Medical Sciences.All authors read the manuscript before the submission process, and they declared that there was no conflict of interest to list their name in this paper.The study was approved by the ethics committee of Shiraz University of Medical Sciences, Shiraz, Iran.Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.


Background: Meta-analysis is an approach that combines findings from similar studies. The aggregation of study level data can provide precise estimates for outcomes of interest, allow for unique treatment comparisons, and explain the differences arising from conflicting study results. Proper meta-analysis includes five basic steps: identify relevant studies; extract summary data from each paper; compute study effect sizes, perform statistical analysis; and interpret and report the results.Objectives: This study aims to review meta-analysis methods and their assumptions, apply various meta-techniques to empirical data, and compare the results from each method.Methods: Three different meta-analysis techniques were applied to a dataset looking at the effects of the bacille Calmette-Guerin (BCG) vaccine on tuberculosis (TB). First, a fixed-effects model was applied; then a random-effects model; and third meta-regression with study-level covariates were added to the model. Overall and stratified results, by geographic latitude were reported.Results: All three techniques showed a statistically significant effects from the vaccination. However, once covariates were added, efficacy diminished. Independent variables, such as the latitude of the location in which the study was performed, appeared to be partially driving the results.Conclusions: Meta-analysis is useful for drawing general conclusions from a variety of studies. However, proper study and model selection are important to ensure the correct interpretation of results. Basic meta-analysis models are fixed-effects, random-effects, and meta-regression.


Previous studies have suggested that the DRD2/ANKK1 rs1800497 C > T polymorphism plays a critical role in the risk of post-traumatic stress disorder (PTSD). However, published data are inconsistent or even contradictory. Therefore, we conducted a meta-analysis to explore the underlying correlation between the rs1800497 C > T polymorphism and PTSD risk.A total of five online databases were searched, and all related studies were reviewed up to 1 October 2022. Critical information was extracted, and quality assessment was conducted for all included studies. Multivariate meta-analyses were performed for the genetic model choice, and the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to examine the statistical power of the genetic models. In addition, heterogeneity, sensitivity, cumulative analysis, and publication bias were analyzed to guarantee statistical power.P = 0.01, I2 = 58.9%) and other specific subgroups. Moreover, similar results were observed in other genetic models using univariate analysis.Overall, 12 observational studies involving 5,515 subjects were included and analyzed in this meta-analysis. Multivariate analysis indicated that a co-dominant genetic model was most likely the best choice. Pooled results revealed an elevated PTSD risk in mutated homozygote TT carriers in the general population (TT vs. CC: OR = 1.73, 95% CI = 1.14–2.62, Current evidence suggests that the DRD2/ANKK1 rs1800497 C > T polymorphism may contribute to PTSD susceptibility. Post-traumatic stress disorder (PTSD) is one of the most important and severe mental disorders occurring in people who have been exposed to a series of traumatic events such as natural disasters, traffic accidents, war, or violent injuries  is a G protein-coupled receptor (GPCR) and is one of the most important intermediate transmitters of the dopaminergic system Ford, . This reThe DRD2 gene is located on human chromosome 11q23 and contains nine exons, several introns, and a short nucleotide repeat (STR)  statement :#1 Dopamine receptor D2;#2 DRD2;#3 rs1800497;#4 Taq1A;#5 #1 OR #2 OR #3 OR #4;#6 Polymorphism;#7 Variant;#8 Mutation;#9 #6 OR #7 OR #8;#10 Post-traumatic stress disorder;#11 PTSD;#12 #10 OR #11;#13 #5 AND #9 AND #12;All retrieved studies were screened with the following criteria for inclusion in this meta-analysis: (1) observational studies on the association between rs1800497 polymorphism and PTSD susceptibility; (2) sufficient genotype data for case and control groups; (3) published studies in English or Chinese; (4) studies with the latest or largest sample size were retained with multiple publications having similar data; and (5) subgroup analyses were conducted only when two or more studies were excluded. The exclusion criteria were as follows: (1) case report and review studies; (2) biological fundamental studies; and (3) studies without sufficient information on genotypes.p-value of the Hardy–Weinberg equilibrium (HWE) test in the control group, and NOS scores.Dr. Niu and Zhang reviewed all selected studies and extracted information independently: the surname of the author, year of publication, country and ethnic distribution, control design , genotyping method, sample sizes of case and control groups, frequencies of the genotype distribution in both case and control groups, causes of trauma, different crowds, diagnostic criteria, the A total of six departments of representativeness of cases, control design, HWE status in controls, genotyping methods, subject size, and association assessment were independently evaluated by two authors according to the modified Newcastle–Ottawa quality scale (NOS)  and OpenBUGS 3.2 (http://www.openbugs.net/w/Downloads), and a p-value of <0.05 was considered to be statistically significant (two-sided).Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the association between the rs1800497 polymorphism and PTSD susceptibility. The two pooled logORs of log (CT vs. CC) and logOR (TT vs. CC) were first calculated; then, the ratio λ was calculated using the following formula: λ = log(AG vs. AA)/log(GG vs. AA). The genetic model was inferred and calculated according to the ratio λ when the value of λ was equal to 0, 0.5, and 1, which corresponded to the recessive, co-dominant, and dominant models, respectively. An over-dominant model was adopted when the ratio λ was <0 or >1. Furthermore, the statistical power of the other genetic models was determined using univariate analysis regarding allele contrast (T vs. C), the co-dominant model (CT vs. CC and TT vs. CC), the dominant model (CT + TT vs. CC), and the recessive model (TT vs. CC + CT). Potential heterogeneity among the collected studies was examined using The screening process for the included studies is shown in p-value of HWE of the genotype distributions in the control groups was found to be statistically significant in three studies  method, whereas the others used the PCR-ligase detection reaction (PCR-LDR), TaqMan, SnaPShot, and SNPscan methods for polymorphism detection. As control sources, three studies obtained controls from the PB groups, and seven studies used controls from the TEWOP groups. Regarding PTSD causes, war and earthquakes were the most common traumatic factors . The p-vP = 0.01, I2 = 58.9%, −yes: CT vs. CC: OR = 1.38, 95% CI = 1.05–1.82, P = 0.02, I2 = 62.5%; HWE−no TT vs. CC: OR = 4.01, 95% CI = 2.01–7.99, P < 0.01, I2 = 18.9%), Asian groups , control design of TEWOP groups , groups with earthquake experience , and specific crowds of civilians   was close to 0.5, suggesting that a co-dominant genetic model (CT vs. CC and TT vs. CC) of inheritance was more appropriate. Statistical analysis indicated that TT carriers (homozygote model) were associated with elevated PTSD susceptibility in the general population  .via univariate analyses .The publication bias test was assessed, and no significant asymmetry was observed in the funnel plots  involving 5,515 subjects were included. Scientific statistical methods with multiple analyses were employed, and the co-dominant genetic model was suggested as the most appropriate choice to examine the association between the rs1800497 polymorphism and PTSD susceptibility. Overall, the pooled results indicated a significant association between the rs1800497 polymorphism and PTSD susceptibility in the general population and several specific subgroups, such as control design, causes of trauma, and crowds. For TEWOP controls, our results indicate that the mutation of the rs1800497 polymorphism might be a more dangerous triggering factor when PTSD patients and TEWOP controls face the same traumatic exposures. Considering the causes of trauma, the current results indicated that the earthquake was more strongly correlated with PTSD risk than other factors. This may be because the occurrence of earthquakes is sudden and often unpredictable. In addition, earthquakes are more destructive in depth and breadth, and this damage always involves a wider range of people, and the personnel composition is more complex. For different crowds, the stratified analysis demonstrated that civilians were more vulnerable in the face of traumatic events. This also means that the ability of civilians to tolerate and resist high-intensity traumatic events is weaker than that of military personnel who have systematic training. Moreover, in co-dominant genetic models (heterozygote model and mutant homozygote model), the pooled results revealed a statistically significant difference in the general population and subgroups, which also indicated that the rs1800497 TT genotype could increase PTSD risk with a gene dosage effect compared with the CC genotype and the CT genotype. In terms of ethnic differences, six studies focused on Caucasian and Asian descendants, and the results showed that the T allele may be an independent trigger for PTSD risk in Asians but not in Caucasians. Even so, these results should be interpreted with caution because of the small sample size and obvious heterogeneity in Asian populations.Inevitably, there were some limitations that should be addressed in our research. First, only one polymorphism locus was analyzed in this meta-analysis, and the interactions with other SNPs and the gene–gene or gene–environment synergistic effects could not be assessed due to the lack of original information. Second, moderate heterogeneity was observed in several genetic models, which might have caused bias in the current results. This heterogeneity was partially alleviated with subsequent stratified analysis, and no significant contributing factor was found in meta-regression analyses. Third, the current studies were mostly conducted with Caucasian and Asian descendants, and whether the results could be extended to the general population remains to be demonstrated. Nevertheless, some advantages of our meta-analysis should be highlighted: (1) Multivariate meta-analyses were applied in this study as a scientific statistical method to select a more appropriate genetic model, (2) complete search strategies and rigorous criteria of inclusion and quality assessment were employed, and (3) cumulative analyses and sensitivity analyses were conducted to identify potential interfering factors and to guarantee the credibility of our results.In summary, this meta-analysis suggests that the DRD2/ANKK1 rs1800497 polymorphism may increase the risk of PTSD susceptibility. Due to the insufficient quantity and quality of published research, global, high-quality studies with larger sample sizes should be conducted to further validate the current results.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The datasets generated during and/or analyzed during this study are available from the corresponding author on reasonable request.Y-MN, JZ, and Y-YH conceived the study. Y-MN, JZ, and HT searched the databases and extracted the data. Y-MN and L-HC analyzed the data. Y-MN, JZ, T-YJ, and Y-YH wrote the draft of the article. T-YJ and Y-YH reviewed the manuscript. All the authors approved the final manuscript.


Endotypes leading to very and extremely preterm birth are clustered into two groups: infection/inflammation and dysfunctional placentation. We conducted a systematic review of observational studies exploring the association between these two endotypes and the pharmacological closure of patent ductus arteriosus (PDA) induced by cyclooxygenase (COX) inhibitors. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for gestational age (SGA) or intrauterine growth restriction.PubMed/Medline and Embase databases were searched. The random-effects odds ratio (OR) and 95% confidence interval (CI) were calculated for each association. We included 30 studies .p = 0.211) nor SGA  were significantly associated with the response to therapy. Subgroup analyses showed that the higher response to COX inhibitors in the HDP group was significant for indomethacin  but not for ibuprofen  or for the studies using both drugs . However, meta-regression showed that this difference between the drugs was not statistically significant (p = 0.404).Meta-analysis showed a significant association between exposure to HDP and increased rate of pharmacological closure of PDA . In contrast, neither chorioamnionitis (13 studies, OR 0.75, 95% CI 0.47–1.18, Our data suggest that the pathologic condition that triggers prematurity may alter the response to pharmacological treatment of PDA. The DA of infants exposed to HDP appears to be more responsive to COX inhibitors. MorphPDA in very and extremely preterm infants  is a persistent dilemma for neonatal medicine, as well as a potential morbidity and mortality contributor when hemodynamically significant , 7, 8. ALow gestational age (GA) is the main risk factor for both failure of spontaneous and pharmacologic closure of the DA , 13–15 bIndividual studies suggest that prenatal conditions such as chorioamnionitis , 17 or H2.P) exposed to chorioamnionitis, HDP, or growth restriction during pregnancy (E) have a different rate of PDA closure in response to treatment with COX inhibitors (O) than infants with no history of exposure (C)?The methodology of the present study is based on that used in our previous meta-analyses on the association of several risk factors and the incidence of PDA and/or the response to pharmacological treatment of PDA , 32–34. 2.1.ductus arteriosus, patent ductus arteriosus, PDA, Patency of the Ductus Arteriosus, Ductus Botalli, treatment, pharmacologic closure, indomethacin, ibuprofen, paracetamol, acetaminophen, cyclooxygenase, COX, chorioamnionitis, intrauterine infection, intrauterine inflammation, antenatal infection, antenatal inflammation, preeclampsia, IUGR, growth restriction, growth retardation, restricted growth, fetal growth, fetus growth, placental dysfunction, placental insufficiency, chronic hypoxia, chronic hypoxemia, small for gestational age, small for date, SGA, gestational hypertension, maternal hypertension, hellp syndrome, hypertensive disorders, toxemia, hypertensive disorders of pregnancy. No language limit was applied. The literature search was updated up to March 2022. Narrative reviews, systematic reviews, case reports, letters, editorials, and commentaries were excluded, but read to identify potential additional studies. Additional strategies to identify studies included manual review of reference lists from key articles that fulfilled our eligibility criteria, use of “related articles” feature in PubMed, and use of the “cited by” tool in Web of Science and Google scholar.A comprehensive literature search was undertaken using the PubMed and EMBASE databases. The search terms involved various combinations of the following key words: 2.2.Studies were included if they had a prospective or retrospective design, examined infants with GA below 32 weeks and reported primary data that could be used to measure the association between pharmacological closure of PDA and exposure to chorioamnionitis , HDP  or fetal growth restriction. As we did in our previous meta-analyses, we accepted small for gestational age (SGA) as a proxy for fetal growth restriction , 27. Reg2.3.Two investigators (GG-L and MB-L) extracted data on study design, demographics, and response to treatment. Another investigator (EV) checked the data extraction for completeness and accuracy. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies . This sc2.4.Q statistic and by the 2I statistic. I2 was interpreted on the basis of Higgins and Thompson criteria, where 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity, respectively , mean or median GA, median year of birth, and drug used for PDA treatment. We used the Egger's regression test and funnel plots to assess publication bias. Subgroup analyses, meta-regression, and publication bias assessment were performed only when there were at least ten studies in the meta-analysis. A probability value of less than 0.05 (0.10 for heterogeneity) was considered statistically significant.Studies were combined and analyzed using comprehensive meta-analysis V3.0 software . The odds ratio (OR) with 95% confidence interval (CI) was calculated with a random-effects model and subgroups were combined with a mixed-effects model . Statistectively . Potentiectively , 17. For3.3.1.The flow diagram of the search process is shown in 3.2.p = 0.211) (p = 0.516) and histological chorioamnionitis . Meta-regression showed that the difference in effect size between clinical and histological chorioamnionitis was not statistically significant (p = 0.400). In contrast, meta-analysis showed a significant association between exposure to HDP and pharmacological closure of PDA  (p = 0.006) but not in the preeclampsia group . However, meta-regression showed that the difference in effect size between any HDP and preeclampsia was not statistically significant (p = 0.962). Finally, the meta-analysis could not demonstrate a significant association between being SGA and response to pharmacological treatment of PDA  (p = 0.852). Neither visual inspection nor Egger's test suggested the presence of publication or selection bias for none of the three meta-analyses  . This la= 0.006) . Subgrou= 0.115) . This la= 0.115) . Meta-reanalyses .3.3.P = 404, In addition to the subgroup analysis based on the definition of the different exposures –3, we cop = 0.008). As the cohort became more modern, the effect size of the association significantly decreased  and observed that HDP was associated with a higher rate of pharmacologic closure of PDA. Moreover, subgroup analysis showed that the association between HDP and response to treatment was particularly significant for indomethacin. However, the relatively small number of studies and the moderate degree of heterogeneity that was present in some of the meta-analyses limit our results.As mentioned in the introduction, the different endotypes of prematurity are not only the trigger for preterm birth but also induce a different pathophysiological environment for the development of fetal organs and systems. Thus, the infectious-inflammatory endotype is characterized by the development of a systemic inflammatory response with elevated cytokine levels , 23, 24.Peri- and postnatal infection is classically considered a key risk factor for PDA , 61–64. The only antenatal pathology for which we have found an association with pharmacological closure of the DA was HDP. That HDP may affect the incidence of PDA has been demonstrated in several cohort studies –70. HoweSubgroup analysis showed that the association between HDP and higher rate of pharmacologic ductal closure was particularly significant for indomethacin. However, meta-regression showed that the difference between the drugs was not statistically significant. Interestingly, Louis et al. reported that the rate of ductal closure induced by prophylactic indomethacin was significantly higher in the offspring of HDP mothers . With ouThe third condition in which we have analyzed pharmacological ductal closure is fetal growth restriction. It should be noted that these results were limited because all included studies reported data on SGA and not IUGR. Although the terms SGA and IUGR are often used synonymously, SGA is a statistical definition based on BW, with the 10th percentile as the most frequently used cut-off –83. TherIn a recent meta-analysis, we investigated the association between SGA/IUGR and incidence of PDA. Although we observed a negative association, i.e., the rate of any PDA was lower in the growth-restricted group, this association only involved the subgroup in which SGA was defined using the 10th percentile threshold . MoreoveIt may be noteworthy that of the two proxies we used to represent placental dysfunction (HDP and SGA), only HDP were significantly associated with pharmacological closure of PDA. First argument that can be used to explain this difference is that not all HDP induce growth retardation and not all SGA infants are smaller because of HDP. In previous meta-analyses, we have shown that the positive association between HDP and SGA is very strong , whereas the associations between chorioamnionitis and HDP  or SGA  were strongly negative . Thus, aNeonatology is a medical specialty in constant evolution and this is also reflected in the diagnostic and therapeutic approach to PDA. Neonatologists have been debating for decades what is a hemodynamically significant PDA, what are the health consequences of the presence of a ductal shunt for the preterm newborn and when and how PDA should be treated , 7, 8. Aone size fits all is no longer an appropriate approach to perinatal medicine (In conclusion, our data suggest that the pathological condition that triggers prematurity may alter not only the incidence of PDA but also the response to pharmacological treatment. Our meta-analysis further supports the growing evidence that not all preterm infants are identical even if they are of the same gestational age. Therefore, medicine , 89–91. medicine . Further


MetS is associated with greater morbidity and mortality in relation to a number of malignancies, but its association with ovarian cancer remains contested. The present study was a systematic review and meta-analysis of case-control and cohort studies examining the association between MetS and ovarian cancer risk.The study was registered on the PROSPERO platform in January 2023 (CRD42023391830). Up until February 13, 2023, a complete search was undertaken in PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials. On the basis of inclusion and exclusion criteria, eligible studies for meta-analysis were screened to determine the association between MetS and ovarian cancer risk.2 = 92.6, P<0.05) existed between the included studies. We performed a subgroup analysis of the risk of bias and showed that only unadjusted stratification of risk of bias for smoking  and hysterectomy  demonstrated a relationship between metabolic syndrome and ovarian cancer risk. The meta-regression analysis revealed that smoking and hysterectomy excision were substantially linked with heterogeneity (p < 0.05).Five studies were included in total, including three cohort studies and two case-control studies. Meta-analysis showed no significant correlation between metabolic syndrome and ovarian cancer . Significant heterogeneity (IOur research revealed no statistically significant association between MetS and ovarian cancer risk. The prevalence of metabolic syndrome has highlighted the need of enhancing and controlling women’s metabolic health. However, the evaluation of metabolic syndrome as a cancer risk factor may be deceptive and etiologically uninformative. Its main components include hypertriglyceridemia, reduced HDL cholesterol concentration, hypertension, insulin resistance, and central obesity . CurrentWith 22,000 cases reported each year in the United States, ovarian cancer is one of the most prevalent diseases in women and the fifth largest cause of cancer-related deaths in women , 7. TherPotentially significant ovarian cancer risk factors include metabolic disorders. Numerous research has investigated the association between specific MetS components and ovarian cancer, including obesity, dyslipidemia, and diabetes –15. HoweAs a result, we conducted a methodical review and meta-analysis of case-control and cohort studies to examine the relationship between MetS and ovarian cancer risk.22.1The systematic evaluation and meta-analysis of the study were conducted in accordance with the PRISMA statement’s requirements . At the The most recent recommendations were used to conduct the literature search . The sea2.2Included in our meta-analysis were only the publications that matched the following criteria (1): cohort studies and case-control studies (2); examined the connection between MetS and ovarian cancer risk (3); provided risk estimates  and 95% confidence intervals. Articles that fit any of the following requirements were disqualified (1): reviews, conference abstracts, books, reports, and commentaries (2); studies from which exact data extraction was not possible (3); for studies that have been published more than once, data from the information with the most thorough reporting and longest follow-up. Two researchers independently reviewed titles and abstracts to exclude ineligible publications. All disagreements were settled through conversation and cooperation with a third reviewer. The examination of the full text was performed independently by the same reviewers, and all discrepancies were resolved by discussion and contact with a third reviewer.2.3Two researchers independently collected pertinent information from the included study data using a standard form that was created prior to data extraction and modified for the data extracted twice. The following data were taken out: first author, year of publication, country of publishing, study design, study period, study source, adjustment factors, mean age (or range), amount of patients, number of ovarian cancer cases, diagnostic standards for MetS, risk estimates, and 95% CIs.Using the Newcastle-Ottawa scale (NOS), two researchers independently assessed the caliber of the studies that were included . The NOS2.42 statistic. Subgroup and meta-regression analyses were conducted to identify the causes of study heterogeneity and the significance of OR variations between subgroups. Sensitivity analysis investigated if excluding a study would significantly change the total OR. We did not employ statistical techniques to test for publication bias since less than ten studies were included . As a consequence, we performed a study-by-study exclusion method to remove individual studies one by one, with no significant change in risk estimates  and hysterectomy  showed an association between metabolic syndrome and ovarian cancer risk, and its number of studies was limited. However, most of the remaining strata showed no correlation between the two. meta-regression showed a significant correlation between smoking, hysterectomy and heterogeneity among the selected study characteristics (p < 0.05). The correlation results are shown in 4Several latest studies have studied the relationship between MetS and the ovarian cancer risk with contradictory results. For the random-effects meta-analysis, we looked through PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials to find 5 studies that indicated the relationship. Our investigation revealed no correlation between metabolic syndrome and the risk of ovarian cancer. This result was durable in sensitivity analyses and was mostly consistent among subgroups defined by various research parameters. As far as we are aware, no meta-analyses have been performed to determine whether MetS raises the risk of ovarian cancer.2 . Obesity and type 2 diabetes may raise the probability of ovarian cancer, however the relationships were weak, even minor, and heterogeneous , 33. TheThis analysis has the advantage of examining the association between MetS and ovarian cancer risk by the inclusion of 5 observational studies that were carefully screened. Additionally, our findings were consolidated by sensitivity analysis. Third, our study was significantly heterogeneous. Therefore, comprehensive subgroup and univariate meta-regression analyses were conducted to determine if the results differed based on important research features. Finally, we assessed each piece thoroughly to ensure that they were of adequate quality to be included.Notably, the study is limited in several areas. First, all meta-analyses, especially those of observational studies, have historically been concerned with clinical and methodological heterogeneity . Despite5Our research revealed no statistically significant association between MetS and ovarian cancer risk. The prevalence of metabolic syndrome has highlighted the need of enhancing and controlling women’s metabolic health. However, the evaluation of metabolic syndrome as a cancer risk factor may be deceptive and etiologically uninformative.The original contributions presented in the study are included in the article/All authors are solely responsible for the content and writing of the manuscript. All authors made significant contributions to the design, data collection and interpretation, and manuscript preparation and revision of this study. All authors contributed to the article and approved the submitted version.


Multiple genetic variants have been studied for years to try to find anassociation with polycystic ovary syndrome (PCOS). This meta-analysis willinvestigate if there are associations between increased risk of PCOS andrs6165 polymorphism in follicle stimulating hormone receptor (FSHR) gene andrs2479106 polymorphism in differentially expressed in DifferentiallyExpressed in Normal and Neoplastic Development Isoform 1A (DENND1A)gene.Studies were identified from PubMed library, and case-control studies withcorrect polymorphisms and available genotype frequencies were included. Thestatistical analysis is done in Review Manager 5.3, and odds ratio (OR) withcorresponding 95% confidence interval (CI) was calculated to see if anyassociation with PCOS exists.p=0.18),recessive  nor thedominant  model. Thers2479106 polymorphism in DENND1A gene included 10 studies with 3627 casesand 20325 controls. Only the Asian subgroup in the recessive model  showed a positive relation withPCOS, while associations were not found within the overall results in theallelic , recessive or the dominant model.In the study of FSHR gene, eight articles with 1539 cases and 1877 controlswere included. No relations were found between PCOS and rs6165 polymorphismin neither the allelic (OR=1.07, 95% CI=0.97-1.19, This meta-analysis suggests that rs2479106 polymorphism in DENND1A gene isassociated with increased risk of PCOS in the Asian population. No relationswere found with increased risk of PCOS and rs6165 polymorphism in FSHRgene. Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders inwomen of reproductive age with 12 to 18% affected worldwide  gene, also called differentially expressed innormal and neoplastic development isoform 1A gene. It has been identified as a riskmarker for PCOS and is located at chromosome 9q33.3. This is a poorly characterizedprotein that regulate Rab-mediated membrane trafficking pathways  found that DENND1A.V2 is elevated in thecacells in PCOS patients. They tried to force an overexpression of DENND1A.V2 innormal theca cells, which resulted in an increased androgen synthesis compatiblewith the elevated androgen profile we can find in PCOS women. Contrarily, when theytried to reduce these levels, the androgen synthesis was decreased, and the authorsconcluded that DENND1A plays a role in hyperandrogenemia in women with PCOS  case-control study where patients are not related to controls; (2) rs6165 orrs2479106 polymorphisms; (3) clear criteria of diagnosis; (4) genotypefrequencies of genes were available, both patients and controls; (5) thefrequency genotype distribution was consistent with Hardy-Weinberg equilibrium(HWE). Studies with these criteria were excluded: (1) animal studies; (2)foreign languages; (3) meta-analysis, reviews, family studies; (4) notsufficient data; (5) other polymorphisms.The meta-analysis is registered in the International prospective register ofsystematic reviews (PROSPERO) under designation CRD42021229235.The extracted data from each study included: the name of the first author, yearof publication, country and ethnicity of the population in the study, diagnosiscriteria of PCOS, sample size of patients and controls, mean age and body massindex (BMI) of patients and controls and distribution of genotype- and allelefrequencies.p-value.P-values <0.05 is considered significant. To find thepooled OR calculation, each polymorphism had three genetic models; allelic model, recessive model  and dominant model .In this research, Review Manager 5.3 (provided by Cochrane Collaboration) wasused to make forest plots for each of the polymorphisms. The association betweenpolymorphism of interest and PCOS was evaluated by odds ratio (OR) withcorresponding 95% confidence interval (CI) and 2value and its corresponding p-value. The choice of forest plotmodel depends on the heterogeneity results, and according to Cochrane handbook,I2<50% and p≥0.1 show noheterogeneity, and a Mantel-Haenszel fixed-effect model is chosen.I2≥50% and p<0.1 are indications ofheterogeneity and random-effects model are preferred. If a model showsheterogeneity, subgroup analysis based on ethnicity will be investigated to seeif this is the reason for variability.Heterogeneity is tested with Cochrane´s Q test, which will give a I2Goodness-of-Fit test. P-values <0.05 are not consistent withHWE, and are not included in this analysis.Hardy-Weinberg Equilibrium (HWE) is tested in all controls by comparing theobserved genotypes frequencies to the expected ones in χPublication bias is also estimated in this study, and studies that are notstatistically significant but have positive results, may bias the result in ameta-analysis and can lead to a false-positive result. In this analysis, afunnel plot made in Review manager is used to estimate publication bias.In the identification of articles concerning FSHR and DENND1A polymorphisms, atotal of 65 studies from Pubmed were identified. 30 of these were excluded afterreading the title and abstract due to irrelevance to the chosen genes orpolymorphisms. 35 full-text texts were assessed for eligibility, and 16 articleswere excluded because of family study (n=1), review (n=2), no information aboutgenotype (n=4), not relevant to topic (n=4) or not correct polymorphisms (n=5).Finally, 19 articles have been used in this meta-analysis , patients with PCOS had to haveall the three diagnostic features  to be included.The polymorphism related to FSHR gene is rs6165 (Ala307Thr). A total of 1539cases of PCOS patients and 1877 controls from eight studies are included, andthe articles were published from 2009 to 2018. Extracted information includelast name of author, year of publication, country, ethnicity, the definitioncriteria, sample size, mean age and BMI for both PCOS patients and controls. 2/8 stuetal. (2012) include populations from Boston, Chicago and Iceland,but they are separately analyzed in this paper. The articles were published from2011 to 2020, and extracted information is first name of author, year ofpublication, country and ethnicity of PCOS patients and controls, definitioncriteria, sample size, mean age and mean BMI for both PCOS patients and controlsused the NIH criteria which includes the presence of chronic anovulation andhyperandrogenism . A fixed model was used in each of thembecause the heterogeneity test did not show significant heterogeneity . Because of these values, subgroupanalysis was not necessary.The association between rs6165 polymorphism in FSHR gene and the risk of PCOS hasbeen analyzed based on allele and genotype frequencies with HWE values , and pooIn the study of rs2479106 polymorphism in DENND1A gene, 10 studies are includedin the analysis of allele frequencies, while only five of the articles areincluded in the study of genotype distribution (p=0.10).Because p=0.09 in the heterogeneity test, a random model wasused. Furthermore, a subgroup analysis was done by ethnicity, and neither theAsian subgroup  nor theCaucasian subgroup  showed asignificant association with PCOS. In this subgroup analysis, the study ofDallel et al. (2018) was not included since it was the onlystudy with an Arab ethnicity. The heterogeneity in the Caucasian subgroupdisappeared , while it remained inthe Asian subgroup .In the allelic model , individp-value=0.41, which suggest thatan association with PCOS was not found in patients with this genetic model. Theheterogeneity test showed heterogeneity , and a subgroup analysis was done to study the possiblecause. In the subgroup analysis, an association with PCOS risk was discovered inthe Asian population , butnot in the Caucasian population .In the recessive model , pooledp=0.05). Because of the mild heterogeneity foundin this analysis , random model wasused and a subgroup analysis was done. These results also indicated that thispolymorphism neither has an increased risk of PCOS in Asians  nor in Caucasians . The heterogeneity disappeared in theCaucasian population , but remainedin the Asian population .No association with PCOS was found in the dominant model  of rs247etal. (2013) was removed . A weak association was also seen when removingthree different studies in the recessive model: Gu et al.(2010): OR=1.27, 95% CI=1.01-1.59, p=0.04; Fu etal. (2013): OR=1.34, 95% CI=1.04-1.71, p=0.02;p=0.04. On the otherhand, no individual study affected the pooled OR (95% CI) in the dominant modelof this polymorphism.In the sensitivity analysis of the allelic model of rs6165 polymorphism in FSHRgene, the result was mildly associated with PCOS when the study of Fu p=0.04). The result isstatistically significant because p<0.05. The removal of thesame study changed also the result in the recessive model  and indicated a more obvious associationwith this polymorphism and the risk of PCOS. In the dominant model, Xiaet al. (2019) changed the overall results after it wasremoved , and theassociation with PCOS and the polymorphism disappeared.Results changed when single studies were removed in every genetic model in thesensitivity analysis of rs2479106 polymorphism in DENND1A gene,. In the allelicmodel, a very mild association with PCOS risk appeared when In the evaluation of funnel plots of both rs6165 and rs2479106 polymorphisms, noobvious asymmetry was found in any of the genetic models.FSHR gene is a familiar gene that has been studied for years. The first study thatinvestigated the coding region of this gene back in 2001, found no mutations inChinese Singapore patients with PCOS, and controls and patients showed similardistributions of variations in alleles  in the allelic model, a mildly association with PCOSappeared, and a mildly association was also the result after removing three studies,one by one  investigated some of them. They foundrelations with PCOS and polymorphisms rs10818854 and rs10986105, while thepolymorphism in our study, rs2479106, only had an increased risk of PCOS in Asianpatients , only one study (vs. GA+AA) and dominant model (GG+GAvs. AA).A significant association with PCOS and polymorphism rs2479106 was not found in theallelic and recessive model. In the dominant model, 95% CI=1.00-1.71 andp=0.04, but since 95% CI=1.00-1.24, it is insufficient toconclude because of these values. A stronger association appeared in the recessivemodel  when removing the study ofLerchbaum et al. (2011), while the association from the dominantstudy, disappeared completely when removing the study of Xia et al.(2019) . Because the models weresensitive to the removal of only one study, additional research have been done tostrengthen the result.When single studies were removed in the sensitivity analysis of this polymorphism,all the models had some changes. In the allelic model, a mild association appearedbecause Other meta-analysis have also been investigating this polymorphism. A study from 2016indicated that patients with rs2479106 polymorphism have increased risk to get PCOScompared to controls in allele-, heterozygote- and dominant genetic model , and subgroup analysis was done in each of them. In theallelic model, four articles were included in the Asian population, while five ofthem had Caucasian background. No association was found with PCOS in any of them.The heterogeneity did disappear in the Caucasian one, while the Asian populationwent from moderate to high heterogeneity , which must be due to other reasons than ethnicity.All three models did show moderate heterogeneity , while it remained a moderateheterogeneity in the Caucasian subgroup (I2=57%). The Asian populationconsisted of three studies, while only two populations were Caucasian, which is anextremely low number to have in a subgroup analysis. In addition, the value of theoverall heterogeneity in the subgroups (I2=78.3%), indicate that thesubgroups are different from one another, and that there are still differences inthe same ethnicity. Low number of studies were also the case in the dominantsubgroup analysis based on ethnicity, and the heterogeneity remained in the Asianpopulation.In the subgroup analysis in the recessive model, the Asian population showed anassociation with increased risk of PCOS (95% CI=1.19-2.85). The heterogeneitydisappeared in the Asian subgroup . A low number of studies can weaken the statistical power of theanalysis and can increase the false negative or false positive results, and it needto be interpreted with caution. Third, the ethnicities of the included articles wereonly Asian and Caucasian. No studies from Africa were found, and a broaderinvestigation based on ethnicity should be done in the future to see if geneticorigin matter. Fourth, only English articles were included, and relevant articlesand results can therefore be missed. A search in multiple languages, especially inChinese, could have improved the outcome due to their broad research in thisfield.To conclude, DENND1A rs2479106 polymorphism was the only gene in this study with arelation to PCOS, but it was only seen in the recessive model in patients with Asianethnicity. It is unclear to say, since only one model was affected, if this gene isa part of the pathogenesis of PCOS or not. On the other hand, no associations werefound between PCOS and rs6165 polymorphism in FSHR gene. Limitations like smallsamples sizes, heterogeneity within ethnicities and variable results fromsensitivity analysis can be found within the polymorphisms, and these results mustbe interpreted with caution. Absence of ethnicities other than Asian and Caucasianwill narrow down the diversity of patients and can increase the false negative orfalse positive results in a global perspective. In future researching, lessheterogeneity and bigger sample sizes with a broader ethnic origin should beincluded to strengthen the statistical power and to get a better understanding ofthis common heterogenous syndrome found in reproductive women.


Diabetes has reached epidemic proportions in recent years with serious health ramifications. The aim of this study was to evaluate the strength and validity of associations between diabetes and anti-diabetic interventions and the risk of any type of gynaecological or obstetric conditions.Design: Umbrella review of systematic reviews and meta-analyses.Data sources: PubMed, Medline, Embase, Cochrane Database of Systematic Reviews, manual screening of references.Eligibility criteria: Systematic reviews and meta-analyses of observational and interventional studies investigating the relationship between diabetes and anti-diabetic interventions with gynaecological or obstetric outcomes. Meta-analyses that did not include complete data from individual studies, such as relative risk, 95% confidence intervals, number of cases/controls, or total population were excluded.I2 heterogeneity index between studies, excess significance bias, small study effect and sensitivity analysis using credibility ceilings. Interventional meta-analyses of randomised controlled trials were assessed separately based on the statistical significance of reported associations, the risk of bias and quality of evidence (GRADE) of included meta-analyses.Data analysis: The evidence from meta-analyses of observational studies was graded as strong, highly suggestive, suggestive or weak according to criteria comprising the random effects estimate of meta-analyses and their largest study, the number of cases, 95% prediction intervals, A total of 117 meta-analyses of observational cohort studies and 200 meta-analyses of randomised clinical trials that evaluated 317 outcomes were included. Strong or highly suggestive evidence only supported a positive association between gestational diabetes and caesarean section, large for gestational age babies, major congenital malformations and heart defects and an inverse relationship between metformin use and ovarian cancer incidence. Only a fifth of the randomised controlled trials investigating the effect of anti-diabetic interventions on women’s health reached statistical significance and highlighted metformin as a more effective agent than insulin on risk reduction of adverse obstetric outcomes in both gestational and pre-gestational diabetes.Gestational diabetes appears to be strongly associated with a high risk of caesarean section and large for gestational age babies. Weaker associations were demonstrated between diabetes and anti-diabetic interventions with other obstetric and gynaecological outcomes.https://doi.org/10.17605/OSF.IO/9G6AB).Open Science Framework (OSF) (Registration The online version contains supplementary material available at 10.1186/s12916-023-02758-1. Diabetes mellitus (DM) affects 223 million women (20–79 years) worldwide according to 2019 estimates, a number which is expected to rise to 343 million by 2045 [The epidemiological burden of diabetes in women is accompanied by a wide spectrum of adverse gynaecological and obstetric outcomes. Reports have associated diabetes with endometrial and ovarian carcinogenesis affecting both incidence and mortality –7, and tUmbrella reviews aim to critically assess the totality of evidence provided by systematic reviews and meta-analyses and test the validity of reported estimates. In this study, we performed an umbrella review of systematic reviews and meta-analyses on the association between diabetes and anti-diabetic interventions, including drug, dietary and lifestyle interventions, and the risk of any type of gynaecological or obstetric morbidity with the aim to evaluate the strength of available evidence and guide future healthcare policies.A literature search was performed on PubMed, MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to March 2020 for systematic reviews and meta-analyses published in English on the association of diabetes with gynaecological and obstetric morbidity, i.e. adverse outcomes related to conditions of the female genital tract and pregnancy. Diabetes encompassed diabetes type 1, type 2 and gestational diabetes. The search algorithm did not include diabetes as part of metabolic syndrome. We further searched for meta-analyses of randomised or non-randomised controlled trials that investigated the impact of anti-diabetic regimens on gynaecological and obstetric outcomes. All primary and secondary outcomes related to gynaecological and obstetric morbidity were extracted from original meta-analyses. The search algorithm can be found in Additional material . We additionally excluded meta-analyses that lacked a comparison arm, meta-analyses assessing diabetes as an outcome and meta-analyses with study-specific data  missing from original papers and which could not be retrieved after contacting authors. In cases where more than one meta-analysis existed for the same exposure-outcome association, the meta-analysis with the largest number of cohort studies was selected. In a sensitivity analysis, we further assessed whether there were any differences in the summary findings of duplicate meta-analyses.The robustness of evidence of the reported associations in observational studies was assessed based on previously described criteria , 20, whiTo assess the methodological quality of observational meta-analyses, we used the AMSTAR (A MeaSurement Tool to Assess Systematic Reviews) 2 tool, which uses 16 measures to classify systematic reviews into high, moderate, low or critically low quality . To asseOur primary analysis focused on meta-analyses of cohort studies that represent the most reliable evidence among observational studies. We additionally performed sensitivity analyses that included both cohort and case-control studies. Furthermore, we applied the credibility ceilings threshold to account that any single observational study cannot give more than a maximum certainty, c%  that the true effect size is in a different direction from the one suggested by the point estimate .P value < 0.05), for which the quality of evidence, as assessed by GRADE, was extracted and presented from original meta-analyses. All statistical analyses were performed using Stata version 15  (StataCorp 2015) [P values were two tailed. Figure Evidence from interventional meta-analyses of randomised controlled trials was analysed separately and included only statistically significant studies (random rp 2015) , and allWe extracted data from 21 eligible publications, consisting of 63 meta-analyses with 478 study estimates, which investigated the effect of diabetes on gynaecological and obstetric morbidity  meta-analyses of cohort studies, while the summary random effects was significant in 33/47 (70%). At a significance cut-off of P < 0.001, 27/47 (57%) and 19/47 (40%) meta-analyses yielded significant results using the fixed and random effects model respectively, whereas at a more stringent threshold of P < 10−6, 22/47 (47%) and 7/47 (15%) of meta-analyses produced significant results. The 7 meta-analyses with strongly statistically significant summary random effect estimates (P < 10−6) identified a relationship between GDM and increased risk for caesarean section, large for gestational age (LGA) babies, macrosomia and brachial plexus palsy as well as a relationship between pregestational diabetes and increased risk for major congenital malformations, and congenital heart defects  of the summary random effect estimates fell between 1.2 and 2. The largest summary random effect  was noted for the risk of major congenital malformations in women with diabetes type 1 or 2 . Table S1A reports the effect of the largest study included in each meta-analysis. Fifty-five percent (26/47) of these effects were nominally significant at Q test and I2 index as measures of between-study heterogeneity to account for variation in study outcomes between studies that cannot be attributed to chance. The Q test was significant (P ≤ 0.10) for 40% (19/47) of meta-analyses. Moderate to high heterogeneity (I2 = 50-75%) was noted in 8/47 (17%) of meta-analyses, while substantial heterogeneity (I2 > 75%) was observed in 10/47 (21%). We further calculated 95% prediction intervals and found 10 associations in which the null value was excluded  were found to be present in five meta-analyses for associations between diabetes and postnatal depressive symptoms (GDM vs non-GDM), congenital malformations , brachial plexus palsy (GDM vs non-GDM), cervical cancer screening (DM vs non-DM) and neonatal mortality  . These included the associations between gestational diabetes and postnatal depressive symptoms and pre- or gestational diabetes with respiratory distress syndrome of the newborn. Using the random effects estimate, the association of GDM with breastmilk energy was additionally highlighted with excess significance bias, while using the summary fixed effects estimate no further meta-analysis was highlighted  meta-analyses demonstrated evidence of excess significance bias using the largest study estimate as the plausible effect size .Only two out of 47 (4%) meta-analyses fulfilled the criteria of strong evidence of an association with diabetes; these reported an association between GDM and increased risk of caesarean section  and LGA . Highly suggestive evidence was presented by two meta-analyses (4%), which reported associations between pre-gestational diabetes and increased risk of major congenital malformations  and congenital heart defects . Nine meta-analyses (19%) described suggestive evidence for associations between diabetes and several outcomes, including pre-eclampsia, stillbirth (> 20 weeks or > 400 g), postnatal depression, respiratory distress syndrome, introduction of breastmilk substitute before hospital discharge and endometrial cancer. An additional 20 meta-analyses (43%) described weak evidence, whereas 14 meta-analyses (30%) showed no association , which was upgraded from suggestive and the association of DM and infrequent cervical cancer screening, previously classified as weak evidence. The association of GDM and brachial plexus palsy was upgraded from weak to highly suggestive, while the association of GDM with respiratory distress syndrome was upgraded from weak to suggestive  or because another study included a larger number of cohort studies  with a credibility ceiling of 5%. With ceilings of 10%, 15%, and 20%, 24 (51%), 9 (19%), and 4 (8.5%) meta-analyses remained significant, respectively  met nominal significance  and 200 randomised controlled trials, which examined the effect of anti-diabetic interventions on gynaecological and obstetric conditions  were cohort studies, 44 (17%) case-control studies, while the rest represented other study types. There were two to 16 individual studies combined per meta-analysis with a median of 6. The median number of cases and total population in each meta-analysis was 121 and 638 respectively. The lowest number of cases in a meta-analysis was 8 and the highest was 8723, whereas the smallest total population or controls was 103 and the highest was 5,295,969.P < 0.05 as a statistical significance threshold, the summary fixed effects estimate reached significance in 17/49 (35%) meta-analyses of cohort studies, while the summary random effects was significant in 11/49 (22%). At a significance cut-off of P < 0.001, 9/49 (18%) and 5/49 (10%) meta-analyses yielded significant results using the fixed and random effects model respectively, whereas at a more stringent threshold of P < 10−6, 4/49 (8%) and 2/49 (4%) of meta-analyses produced significant results. The two meta-analyses with strongly statistically significant summary random effect estimates (P < 10−6) reported a decreased risk of ovarian cancer occurrence in metformin users of DM2 versus non-metformin users and a decreased risk of congenital malformations in women with PGDM who received preconception care  for 16% (8/49) of meta-analyses. Moderate to high heterogeneity (I2 = 50–75%) was noted in 4/49 (8%) of meta-analyses, while substantial heterogeneity (I2 >75%) was observed in 3/49 (6%)  was found to be present in one meta-analysis, consisting of only 3 individual studies and describing a reduced risk of preterm delivery in type 1 diabetics treated with multiple daily insulin injections versus continuous subcutaneous infusion , which reported deceased risk of congenital malformations in women receiving preconception care and decreased risk of preeclampsia in DM1 patients using continuous subcutaneous insulin infusion (vs multiple daily injections). Using the random effects estimate, the association of metformin use with increased endometrial cancer occurrence and survival were also highlighted with excess significance bias, while using the summary fixed effects estimate no further meta-analysis was highlighted  of all the included papers was graded as low and fifteen (15/16) as critically low quality  between anti-diabetic interventions and gynaecological/obstetric outcomes.With regard to anti-diabetic interventions, no association was supported by strong evidence, while a single 1/49) meta-analysis presented highly suggestive evidence reporting a decreased risk of ovarian cancer in metformin users of DM2 versus non-metformin users . Suggestive evidence was presented by one meta-analysis demonstrating improved endometrial cancer survival in diabetic patients using metformin versus other anti-diabetics . Nine meta-analyses (18%) described weak evidence for several outcomes, including metformin use and decreased cervical cancer occurrence, preconception care in PGDM and decreased rate of congenital malformations, perinatal mortality and preterm delivery  with a credibility ceiling of 5%. With a ceiling of 10%, 3 (6%) meta-analyses remained significant, whereas no meta-analysis survived the 15% and 20% credibility ceilings  met nominal significance (n = 20), dietary interventions (n = 25), exercise (n = 4), oral anti-diabetics and/or insulin (n = 110) and omega-3 supplements (n = 4) on 37 outcomes.We retrieved 200 meta-analyses of randomised controlled trials from 38 publications describing the effect of lifestyle interventions  in 40/200 (20%) meta-analyses for 16 associations on 16 separate outcomes: between lifestyle interventions and reduced rates of LGA, macrosomia and shoulder dystocia; between metformin (vs insulin) and reduced rates of LGA and macrosomic babies, caesarean section, gestational hypertension, pregnancy-induced hypertension, preeclampsia, neonatal intensive care unit (NICU) admission, neonatal hypoglycaemia and hyperbilirubinaemia; between any specific/intensive treatment and reduction of neonatal hypoglycaemia, preeclampsia, shoulder dystocia, hypertensive disorders of pregnancy, LGA, macrosomia and increased rates of induction of labour  reached statistical significance for both outcomes that met the strong criteria in observational studies. Metformin and internet-based self-monitoring were found to reduce the risk of caesarean section among women with GDM versus insulin and usual care respectively. Decreased rates of LGA were also demonstrated when metformin or GDM treatment were used versus insulin and usual antenatal care respectively. No RCTs have been published for highly suggestive outcomes , but one observational interventional study showed weak evidence of preconception care reducing the risk of congenital abnormalities in patients with PGDM. With regard to suggestive outcomes, metformin or any treatment were nominally significant in reducing the risk of preeclampsia when compared to insulin and no treatment respectively. No RCTs were retrieved on diabetes and gynaecological outcomes.Altogether, 16 out of 17 publications that yielded statistically significant results assessed the risk of bias of the included studies . Strong evidence of association was observed for only two outcomes; women with GDM seem to be at higher risk of caesarean section and LGA. LGA is explained pathophysiologically by the Pedersen hypothesis according to which maternal hyperglycaemia leads to fetal hyperglycaemia and hyperinsulinaemia, which incites fetal overgrowth . When caEight obstetric outcomes were supported by suggestive evidence including preeclampsia, postnatal depression, and neonatal respiratory distress syndrome. Increased oxidative stress, placental endothelial dysfunction and dysregulated angiogenesis underpin both preeclampsia and GDM suggesting a potential link . SurprisSuggestive evidence supported increased endometrial cancer incidence among diabetic patients and increased endometrial cancer survival in metformin users, while the evidence showing an association of diabetes with endometrial cancer mortality was weak. The results are consistent with the 2018 report of the World Cancer Research Fund Continuous Update Project (WCRF CUP), which identifies glycaemic load as a probable cause of endometrial cancer . InteresThe association of ovarian cancer incidence and mortality with diabetes was supported by weak evidence irrespective of exposure . However, ever use of metformin demonstrated highly suggestive evidence for a lower ovarian cancer risk . A proposed mechanism of the antineoplastic effect of metformin is by diminishing cell growth and proliferation through the regulation of the mitogenic IGF1/AKT/mTOR pathway . On the Forty out of 200 meta-analyses of randomised controlled trials (20%) exploring the impact of anti-diabetic interventions on gynaecological and obstetric adverse outcomes reached nominal significance for 18 outcomes. GDM treatment is associated with a reduced risk of preeclampsia, macrosomia, LGA, shoulder dystocia, neonatal hypoglycaemia; insulin is associated with decreased rates of macrosomia versus diet and increased neonatal intensive care unit admission versus metformin; metformin is linked with reduced rates of hypertensive disorders in pregnancy, caesarean section, hyperbilirubinaemia, LGA, neonatal hypoglycaemia and NICU admission compared to insulin; lifestyle interventions correlate with reduced birth weight, LGA, macrosomia and shoulder dystocia, while dietary interventions  with reduced birth weight.This umbrella review represents the most comprehensive overview of published literature to date investigating associations between diabetes or anti-diabetic interventions and the risk of any type of obstetric or gynaecological morbidity. The strength and validity of meta-analyses of observational studies was assessed against a transparent and replicable set of statistical criteria that categorised observational evidence as strong, highly suggestive, suggestive and weak, while randomised controlled trials were evaluated based on the statistical significance of associations and reporting of risk of bias and quality of evidence by the original meta-analyses.Our review has a few inherent limitations that should be considered when interpreting the findings. Our analysis relied on previously published meta-analyses and literature searches performed by the authors of meta-analyses; therefore, some individual studies might have been missed. Nevertheless, this is unlikely to have significantly influenced our findings because the assessment of duplicate meta-analyses on the same associations between exposure-outcome pairs reported similar summary results. In addition to this, reporting bias by the authors of meta-analyses could have led to underreporting of associations that did not reach statistical significance or did not conform with general knowledge and expectations , 91. FurEven though a wide range of statistical tools was used to explore risk of bias in individual primary studies of a meta-analysis, other types of biases may have been overlooked and not detected by the statistical tests used. For example, confounding bias may have undermined the reliability of associations , 93. AbsThis umbrella review provides a comprehensive summary of the published body of evidence on gynaecological and obstetric ramifications of the diabetes epidemic. There is a strong association between GDM and increased risk of caesarean section and LGA, while interventional studies demonstrated that metformin mitigates the risk for both outcomes. Moreover, metformin displayed superiority to insulin in reducing the risk of hypertensive disorders in pregnancy, hyperbilirubinaemia, neonatal hypoglycaemia and NICU admission. Highly suggestive evidence supports the association of PDGM and increased risk of major congenital malformations and heart defects. Weaker associations were demonstrated for remaining outcomes that could still be valid but mandate further investigation.The identification of robust relationships between diabetes and gynaecological and obstetric outcomes, following stringent scrutiny of studies against clearly defined statistical criteria that account for small sample size and potential bias, is crucial to reveal actionable risk factors and best interventional strategies. This umbrella review may help guide targeted prevention initiatives, further epidemiological studies with standardised design and reporting of analysis but also future studies designed to investigate the underlying molecular mechanisms of diabetes-induced adverse outcomes.Diabetes represents a global public health issue and has been associated with a number of adverse obstetric outcomes and gynaecological conditions.Several randomised controlled trials have investigated the effect of anti-diabetic lifestyle, dietary or drug interventions on a number of these outcomes.Although some of the proposed associations may be causal, methodological pitfalls, inherent bias and differences in the quality of evidence of observational and interventional meta-analyses might obscure true associations.This umbrella review includes 117 meta-analyses of observational cohort studies and 200 meta-analyses of randomised clinical trials that evaluated 317 outcomes and provides the most comprehensive appraisal of the literature to date exploring the strength and validity of the published associations between diabetes and anti-diabetic interventions on obstetric and gynaecological morbidity.We found strong evidence to support the association between gestational diabetes with risk of caesarean section and large for gestational age babies, while supportive evidence linked diabetes with endometrial cancer incidence.High-quality evidence supported an association between gestational diabetes treatment and reduced rates of large for gestational age babies and macrosomia.Metformin use in gestational or pregestational diabetes is linked with reduced rates of hypertensive disorders in pregnancy, caesarean section, hyperbilirubinaemia, large for gestational age babies, neonatal hypoglycaemia and neonatal intensive care unit admission compared to insulin.This study will inform clinical practice by highlighting the obstetric and gynaecological outcomes that are robustly linked to diabetes and the type of interventions that have proven efficacy in preventing its deleterious effects.Additional file 1. Search Algorithm.Additional file 2: Table S1A. Description of 47 meta-analyses results investigating the association of diabetes with gynaecological and obstetric morbidity- cohort studies only.Additional file 3: Table S1B. Evaluation of heterogeneity, small study effects, excess significance bias and credibility ceilings in the 47 meta-analyses investigating the association of diabetes with gynaecological and obstetric morbidity– cohort studies only.Additional file 4: Table S2. AMSTAR 2 methodological quality assessment for observational systematic reviews investigating the association of diabetes and anti-diabetic interventions with gynaecological and obstetric morbidity- cohorts only.Additional file 5: Table S3. Details of evidence grading for meta-analyses associating diabetes and anti-diabetic interventions with risk of obstetric and gynaecological morbidity– cohort studies only.Additional file 6: Table S4. Details of evidence grading for meta-analyses associating diabetes and anti-diabetic interventions with risk of obstetric and gynaecological morbidity– all study types included.Additional file 7: Table S5. Duplicate and excluded meta-analyses and meta-analyses included instead on the effect of diabetes on gynaecological/obstetric outcomes- cohorts only.Additional file 8: Table S6A. Description of 49 meta- analyses results investigating the association of anti-diabetic interventions with gynaecological and obstetric morbidity–cohort studies only.Additional file 9: Table S6B. Evaluation of heterogeneity, small study effects, excess significance bias and credibility ceilings in the 49 meta-analyses investigating the association of anti-diabetic interventions with gynaecological and obstetric morbidity– cohort studies only.Additional file 10: Table S7. Meta-analyses including only statistically significant* RCTs over the effect of any anti-diabetic intervention on the incidence of any obstetric or gynaecological disease.Additional file 11: Table S8. Risk of bias in the included interventional meta-analyses (RCTs).


Nevertheless, recurrence rates remain high. Epicardial adipose tissue (EAT) has been associated with AF pathogenesis and maintenance. However, the literature has provided equivocal results regarding the relationship between EAT and post-ablation recurrence.(2) Purpose: to investigate the relationship between total and peri-left atrium (peri-LA) EAT with post-ablation AF recurrence. (3) Methods: major electronic databases were searched for articles assessing the relationship between EAT, quantified using computed tomography, and the recurrence of AF following catheter ablation procedures. (4) Results: Twelve studies (2179 patients) assessed total EAT and another twelve (2879 patients) peri-LA EAT. Almost 60% of the included patients had paroxysmal AF and recurrence was documented in 34%. Those who maintained sinus rhythm had a significantly lower volume of peri-LA EAT . On the contrary, no significant difference was documented for total EAT . No differences were revealed between radiofrequency and cryoenergy pulmonary venous isolation. No publication bias was identified. (5) Conclusions: Only peri-LA EAT seems to be predictive of post-ablation AF recurrence. These findings may reflect different pathophysiological roles of EAT depending on its location. Whether peri-LA EAT can be used as a predictor and target to prevent recurrence is a matter of further research.  Atrial fibrillation (AF) is the most common tachyarrhythmia in the clinical practice . It affePulmonary venous isolation is the most acceptable targeted method for the catheter ablation of drug-refractory AF . NeverthEpicardial adipose tissue (EAT) is an active organ, in direct contact with the myocardium, which contains ganglionated plexuses and adipocytes . This tiThese findings, along with the widespread use of imaging technologies to better guide the management approach of AF patients , motivatThis systematic review and meta-analysis was performed in accordance with the PRISMA guidelines . The preA systematic search of the literature was performed, up to September 2022, in three databases: Medline (via PubMed) and Scopus, using the following search strategy based on keywords  OR  OR  AND ). An additional hand search was also performed using the references of the articles that were identified as relevant . No date restriction was used. Articles not available in English were excluded.All articles obtained through the initial search were screened by two independent reviewers (M.K. and N.P.) on title and abstract level. Potentially eligible studies were further reviewed for inclusion in the final analysis based on the full text. Any disagreements were resolved after consensus with an expert (G.G.). The eligibility criteria for inclusion were (a) prospective or retrospective studies including patients with paroxysmal or/and persistent AF who underwent endocardial pulmonary venous isolation with radiofrequency catheter ablation or cryoballoon ablation, (b) preprocedural quantification of EAT  using computed tomography and (c) a follow-up of at least 6 months for the detection of post-ablation recurrence. Recurrence was defined as AF/AT episodes, allowing a blanking period of 3 months, in most of the studies.Data of interest were extracted in a predesigned Microsoft Office Excel 2007 form by two independent reviewers (M.K. and N.P.) and crosschecked for any disagreements, which were resolved after consensus with a senior (G.G.). In the case of missing data or any other uncertainties, we contacted authors electronically (via email) to obtain the required data. Risk of bias, concerning the outcomes of interest, was assessed in duplicate with the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies , modifie2, with values between 50% and 90% representing substantial heterogeneity [Continuous variables were summarized as the mean (standard deviation). When the available data were summarized as the median with interquartile range, the median was assumed as the mean and the standard deviation was obtained by dividing the interquartile range by 1.35. Topool the outcomes of interest, the standardized mean differences (SMD) with the corresponding 95% confidence interval (CI) in pre-ablation total and peri-LA EAT, between patients with and without post-ablation AF recurrence, we performed a meta-analysis based on aggregate data. To allow for expected effect size dispersion between studies , a random effects (DerSimonian-Laird) model was adopted. Heterogeneity was assessed using Iogeneity . To expl861 articles were retrieved by the electronic search. The flow of study selection is depicted in p = 0.82 for total EAT and p = 0.19 for peri-LA EAT).Five studies were classified as being high quality, while the rest presented a moderate risk of bias , mainly because of the lack of power analysis . A visua2: 92%, p = 0.07, Twelve studies (2179 patients) analyzed the relationship between total EAT and AF recurrence. The mean (SD) pre-ablation total EAT was 124.28 (55.82) mL in the group of patients who experienced arrhythmia recurrence and 120.3 (49.86) mL in the non-recurrence group. Meta-analysis of aggregate data revealed a non-statistically significant standardized mean difference .No significant confounding effect of body mass index, gender or the number of patients with hypertension and paroxysmal AF was revealed in the meta-regression analysis. On the contrary, increasing age was found to significantly increase SMD . A subgroup analysis based on the method used for pulmonary venous isolation  analyzing peri-LA EAT, the mean pre-ablation values in the groups of patients with and without AF recurrence were 26.11 (18.22) mL and 23.93 (14.35) mL, respectively. Meta-analysis revealed a statistically significant standardized mean difference  and meta-regression analysis, using the same patients’ characteristics as above, did not reveal any significant sources of heterogeneity. In the subgroup analysis based on the duration of follow-up, a statistically significant difference was demonstrated only for the subgroup of studies which followed patients for more than 12 months . Finally, because of the findings above, we performed an additional, not preplanned, analysis, where we included only studies that provided information for both total and peri-LA EAT. In this analysis of ninestudies with 2023 patients, again only peri-LA and not total EAT was associated with AF recurrence .This study is a meta-analysis assessing the relationship between EAT and AF recurrence following catheter ablation. We analyzed both total and peri-LA EAT, quantified using computed tomography. The main finding is that only peri-LA, and not total, EAT is associated with arrhythmia recurrence. Patients with higher peri-LA EAT volume seem to have less chance atmaintaining sinus rhythm following pulmonary venous isolation. According to the subgroup analysis, this association seems to be mainly driven by studies that followed patients beyond 12 months, while no association with the body mass index was documented. Interestingly, in the analysis restricted to studies that assessed both total and peri-LA EAT, the results remained similar. Thus, the initial findings do not seem to be attributed to discrepancies between the studies’ population and methodology. All of the results should be interpreted with caution because of the existing heterogeneity. Previous meta-analyses in this topic have provided equivocal results, especially regarding the role of total EAT. Shamloo et al. synthesized four studies and concluded that both total and peri-LA EAT volumes differed significantly between patients with and without recurrence . On the Various researchers have examined the role of EAT in the pathogenesis of AF. Nowadays, it is well established that EAT is an active organwith rich secretome leading to adverse mechanical and electrophysiological cardiac remodeling. The production of various profibrotic factors promotes tissue fibrosis ,41. ThisBeyond the mechanical remodeling, EAT has been also associated with electrical remodeling. Adipocytes seem to increase sodium and potassium depolarizing currents, while reducing the repolarizing potassium ones, leading to a prolongation of the refractory period . MoreoveThe strategy of early rhythm control in patients with newly diagnosed AF was associated with fewer adverse cardiovascular events when compared to the rate control strategy in EAST-AFNET 4 trial . The choEven though our findings are not sufficient to modify the current clinical practice, they provide several interesting implications for future research. Being the largest analysis, it strengthens our knowledge regarding the role EAT in post-ablation AF recurrence, proposing a potential role of peri-LA EAT in the pathophysiology of AF recurrence. Thus, it could serve as a target for the so-called upstream therapies, which use non-anti-arrhythmic agents to reverse atrial remodeling and further reduce recurrence . In a poOn the other hand, we found that total EAT volume did not differ significantly between patients with and without recurrence. This observation may be of special interest, as it may reflect some pathophysiological insights. Inour opinion, this finding highlights the importance of the local role of EAT. One hypothesis may be that at least in patients with already established AF, its maintenance might be associated mainly with the regional alterations which peri-atrial EAT confers. Local paracrine activity, along with the remodeling induced by the direct fibrofatty infiltration and the electrical connection between EAT and myocardiac cells, as described above, may play a key role in the explanation of our findings. This hypothesis is supported by the findings of Gaborit et al. who investigated the genome of EAT samples collected from different places. They reported significant differences between samples collected from the atriae when compared to those collected from EAT surrounding the ventricles and the coronary arteries, concluding that there is a specific transcriptomic signature of EAT which depends on its location .This study has also some limitations. First, most of the studies were of retrospective nature and were judged as beingmoderate quality. Moreover, we were not able to perform diagnostic accuracy meta-analyses due to data unavailability. Additionally, older, overweight, non-Asian patients, as well as those with persistent AF and those who underwent cryoballoon ablation, were under-represented in this analysis; consequently, no robust conclusions couldbe drawn for these subgroups. Furthermore, no details regarding the distribution of EAT around the LA were available for additional analyses, while both analyses seemed to suffer from heterogeneity, which could not be adequately explained by the subgroup and meta-regression analyses. Finally, the included studies lacked information about the pathophysiological background of AF. It is known that many comorbidities such as hyperehyperthyroidism , as wellOnly peri-LA EAT seems to be associated with AF recurrence following catheter ablation, with higher volumes decreasing the chance to maintain normal sinus rhythm. Interestingly, total EAT does not seem to be associated with the ablation outcome. Limited literature data, further corroborated by our findings, support that behind these observed differences may lie the location-specific genome of the EAT, but this remains a matter of future research. Moreover, given that cardiac computed tomography is routinely performedprior to ablation for the characterization of pulmonary venous anatomy, it would be of clinical interest whether peri-LA EAT could play a prognostic role. More studies are needed for the derivation of a cut-off value which might identifypatients who will benefit more from transcatheter pulmonary venous isolation. Finally, as there is an ongoing interest in therapies that target EAT reduction, it should be further investigated whether this pathophysiological mechanism could help our effort to reduce post-ablation AF recurrence.


JC Polyomavirus (JCV) is a human polyomavirus encoding T-antigen protein, which is implicated in carcinogenesis. JCV is prevalent in the upper and lower gastrointestinal track. Several studies have reported JCV associations with the risk of developing colorectal cancer (CRC), however, these findings remain controversial. Since JCV DNA may be present in healthy tissues as well as transformed tissues, JCV T-antigen expression could be a more useful measure of JCV’s association with cancer development. The aim of this study is to conduct a meta-analysis of case-control studies to investigate if there is a significant association between JCV T-antigen protein expression and risk of CRC. A systematic review was performed to identify studies reporting JCV DNA prevalence in CRC and JCV T-antigen expression. The strength of the association was estimated by odds ratios (ORs). Five (of 66) studies satisfied analysis inclusion criteria, and spanned years 1999 to 2022. Random effects meta-analysis of CRC cases versus controls showed an 11-fold increased risk of CRC development in JCV DNA positive samples with JCV T-antigen expression versus normal tissues . The results of this meta-analysis of JCV infection followed by JCV T-antigen protein expression for the risk of CRC support the argument that JCV infection significantly increases the risk of colorectal cancer in tissues where the JCV T-antigen protein is expressed. Further research with JCV T-antigen expression in relation to CRC development is needed. Helicobacter pylori and Epstein-Barr virus have been confirmed as causative pathogens in gastric cancer and, recently, H. pylori has been reported to increase the risk of CRC . Th. Th63]. 2 was low (i2 = 22.22%), fixed effects analysis was also conducted, however, the effect was similar.Meta-analysis of all included studies  was condThere was a low probability of publication bias based on the visualization of the funnel plot, which did not reveal a significant asymmetry . StudiesTo our knowledge, this is the only meta-analysis on the association between JCV T-antigen protein expression and colorectal cancer development using all up-to-date published case-control studies. Progress in establishing the infectious origin of human cancers has been slow and controversial despite the evidence that infection plays a role in many naturally occurring cancers in animals , 64–66. In this meta-analysis of crude ORs calculated from 5 case-control studies, we found that JCV T-antigen protein expression was significantly associated with increased risk of CRC and adenomas development. Selgrad et al. used two separate populations of LTR and non-LTR patients for their IHC analysis, hence our meta-analysis contains six distinct populations from five published studies . TissuesAs noted by Bae and Kim, different types of control tissue can cause heterogeneity in the assessment of an association between cancer and infection . HoweverRecent meta-analyses showed a significant association between the presence of JCV DNA in cases versus controls –49. Only2 = 22.22%, although the confidence intervals were wide. We retained the random-effects model as the fixed-effects model did not alter the results. The signal in this meta-analysis indicates an important finding that needs to be confirmed. It should be noted that all controls in the IHC studies showed 0% T-antigen protein expression versus cases [P = 0.0002) [Since JCV DNA is found in normal tissue as well as in neoplastic tissue, albeit at different levels, Selgrad et al. asserted that JCV T-antigen protein expression would be a more convincing implication of JCV’s role in carcinogenesis than just JCV DNA alone . Consideus cases , 60–63.  0.0002) . The 50% 0.0002) , 61, 63. 0.0002) –33, 40.There is evidence that immunosuppression plays a role in JCV pathogenesis , 36, 40.A review by Gallia et al. points out that JCV is neurotropic as well as lymphotropic, and probably crossing the blood-brain barrier in infected B-lymphocytes . The stuPolyomaviruses are known to express T-antigen protein, most of which are capable of binding and inactivating p53 and pRb, the tumour suppressor proteins, including JCV and SV40 , 64. TheThree studies in literature reported on JCV viral loads , 70, 71.Large prospective case-control and cohort studies with age-adjusted multivariate analyses (according to tumour histology and tumour differentiation for example) with consistent methods (including topoisomerase I treatment) are needed. The goal is to confirm that JCV DNA with JCV T-antigen protein expression under immunosuppression are implicated in CRC development. Research into discovering which immunosuppressive agents or events have the highest impact on JCV re-activation is also important. Potentially, anti-JCV-T-antigen protein antibodies could be researched as possible CRC treatment in the future as well as developing anti JCV vaccines for CRC prevention. Much is still to be learned about JCV and its role in cancer development. However, it seems that JCV research may be following in HPV’s footsteps into the future , 75. ThiThe results of this first meta-analysis of JCV infection and the risk of CRC support the argument that JCV infection along with JCV T-antigen protein expression increases the risk of colorectal cancer. If confirmed in larger studies, knowing the risk associated with JCV infection and CRC development could be used to develop therapeutic and preventative measures, including vaccines, building on the success of the HPV vaccination developed to prevent cervical cancer .S1 Checklist(DOCX)Click here for additional data file.