However, subgroup analysis showed positive correlation of PM2.5 exposure in the second trimester with an increased risk of GDM . Among pollutants other than PM2.5, significant association between GDM and nitrogen dioxide (NO2) , nitrogen oxide (NOx) , and sulfur dioxide (SO2)  was noted. There was no significant association between exposure to black carbon or ozone or carbon monoxide or particulate matter ≤10 µm in diameter and GDM. Thus, systematic review of existing evidence demonstrated association of exposure to NO2, NOx, and SO2, and the second trimester exposure of PM2.5 with the increased risk of GDM. Caution may be exercised while deriving conclusions from existing evidence base because of the limited number and the observational nature of studies.Exposure to different air pollutants has been linked to type 2 diabetes mellitus, but the evidence for the association between air pollutants and gestational diabetes mellitus (GDM) has not been systematically evaluated. We systematically retrieved relevant studies from PubMed, Embase, and the Web of Science, and performed stratified analyses and regression analyses. Thirteen studies were analyzed, comprising 1 547 154 individuals from nine retrospective studies, three prospective studies, and one case–control study. Increased exposure to particulate matter ≤2.5 µm in diameter (PM The search strategy was further supplemented by inspecting the references of the included articles. Two reviewers (XT and YiH) completed the screening independently, and any discrepancies were resolved by discussion. This report was conducted according to the Meta-analysis Of Observational Studies in EpidemiologyThe PubMed and Embase databases and Web of Science were searched for relevant studies published until August 2019. Terms used in the search included ‘air pollution’, ‘air pollutant’, ‘particulate matter’, ‘PMStudies were considered for inclusion based on the following criteria: (1) the study was an original article published in English; (2) it defined air pollution and GDM status clearly; (3) it measured the outdoor air pollution ; (4) it used physical diagnosis of GDM, if diabetes is diagnosed in the first trimester or early second trimester with the standard diagnostic criteria of a hemoglobin A1c of 6.5% or higher, a fasting plasma glucose of 126 mg/dL or higher, or a 2-hour glucose of 200 mg/dL or higher on a 75 g oral glucose tolerance test, it was considered gestational diabetes2.5), ozone (O3), sulfur dioxide (SO2), black carbon (BC), nitrogen dioxide (NO2), nitrogen oxide (NOx), particulate matter ≤10 μm in diameter (PM10), and carbon monoxide (CO) were included. We included all studies that quantified these air pollutants as ‘per … μg/m3’ or ‘ppb’ or ‘ppm’.For the meta-analysis, only cohort studies about particulate matter ≤2.5 μm in diameter (PMTwo investigators (XT and YiH) independently extracted data from the enrolled studies, using a standard form that included publication year, country of origin, testing method, number of cases, control type, and cut-off value. Two investigators independently assessed the risk of bias for the enrolled studies (XT and FL) using the Newcastle-Ottawa Quality Assessment Scale (NOS) criteria.2 metric, and Tau2 respectively. Random effects models were performed to synthesize the association between different air pollutants and GDM in case of I2>50%. Random effects models give more weight to smaller studies and have typically wider CIs because the total effect is the average value of the real effect of each study that focuses on the studies with large samples, and pays attention to all included studies in order to balance the effect of each study. Fixed effects models were chosen in case of I2≤50%. ORs as the measure of association were pooled across all studies. If studies reported both unadjusted and covariate-adjusted ORs, we included the latter. When risk ratios and incidence ORs were reported, we directly considered them as ORs. For studies providing different methods of air pollution exposure assessments, we chose the results using spatiotemporal models. We used estimates of association and their SEs reported as ‘per 5 µg/m3’ of exposure in PM2.5, ‘per 10 µg/m3’ of exposure in PM10, ‘per 0.5 µg/m3’ in BC, ‘per 5 ppb’ in O3 and SO2, ‘per 10 ppb’ in NO2 and NOx, and ‘per 0.1 ppm’ in CO. We converted other reported quantities or units where necessary. Potential publication bias was evaluated by Egger’s asymmetry test.Heterogeneity and variance between the enrolled studies was evaluated using I2.5,3,10,2x2.23 24As per our search strategy, we identified 852 potentially relevant records, of which 229 were duplicate, and thus excluded. The remaining 623 manuscripts were subject to title and abstract screening. Further, 525 publications were removed as they were reviews, letters or conference abstracts or unrelated studies. Therefore, 98 articles were eligible for full-text review and data assessment . Finally10.1136/bmjdrc-2019-000937.supp1Supplementary dataQuality assessment using the NOS evaluation tool resulted in high ratings for all the 13 studies (score 7 or 8) .2.5 , 8 sets of data on O3 , 6 sets of data on PM10 , 4 sets of data on each of the following: NO2 , SO2 , CO , NOx , and 3 sets of data on BC . As per the heterogeneity, the random effects model was selected for analysis of PM2.5, O3, NO2, CO, and NOx, while the fixed effects model was chosen for SO2, PM10, and BC.There were 13 sets of data on PM2.5 and GDM . We further performed the subgroup analysis for PM2.5 exposure in the different periods, including the pre-pregnancy, the first trimester and the second trimester. Subgroup analysis revealed that the above non-significant association persisted in both the pre-pregnancy and the first trimester  and 1.01 (95% CI 0.96 to 1.07), respectively). However, in the second trimester, exposure to PM2.5 was associated with the increased risk of GDM   .2 with increased risk of GDM was noted . In the subgroup analysis, the positive association was consistently observed in the pre-pregnancy, the first trimester, and the second trimester , 1.07 (95% CI 1.01 to 1.13), and 1.34 (95% CI 1.01 to 1.78), respectively) (The significant relationship of exposure to SOctively) .2 and the increased risk of GDM . In the subgroup analysis, the same correlation was persistent in the pre-pregnancy and the first trimester subgroups (pooled OR=1.10 (95% CI 1.08 to 1.13) and 1.04 (95% CI 1.00 to 1.07), respectively)  .x was also related to an increased risk of GDM . In the pre-pregnancy subgroup, a positive association was noted between the exposure to NOx and GDM . However, in the first trimester, and the second trimester subgroups, the association was missing  (Exposure to NOto 1.27) .3, and PM10   . Similarctively) .2.5, PM10, and O3 were performed through single elimination of studies. The sensitivity analyses between the exposures to PM2.5, PM10, and O3 and the risk of GDM indicated no significant change in results.Sensitivity analyses of PM2.5, O3, and PM10, no significant bias exists among the studies by Egger’s test. The funnel figure of these studies showed a symmetrical inverted distribution that was consistent with the results of Egger’s test  to PM2.5 during the second trimester had a 2.63 (95% CI 1.15 to 6.01) times higher risk of having impaired glucose tolerance (IGT) than the women who had first quartile exposure. In another study, Fleisch et al2.5 exposure than the older women, at the second trimester. O3 was the other air pollutant that showed significant association with GDM in our analysis, consistent with Robledo et al,2 and NOx exposure with the risk of GDM.In the current analysis, the relationship of PMThe possible mechanisms underlying the associations between air pollutants and GDM are still unclear. Several different aspects were raised by many researchers based on their opinions, including inflammation  with GDM. Besides these eight kinds of air pollutants, there are also some other pollutants that may influence the risk of GDM.Our study had the following limitations. (1) All included studies were observational studies, thus, the causal effect between air pollutants and GDM could not be described. (2) The high heterogeneity identified for some of the pollutants may be due to differences in race, blood glucose measurement, and pollutant concentrations in different regions. (3) This article analyzed respectively the relationship between eight different air pollutants (PMFuture studies may focus on the relationship between exposure to different air pollutants before conception and GDM. The relationship between some other outdoor air pollutants, such as sulfur oxide, and GDM needs to be analyzed, and a dose–response manner should be of important consideration while analyzing the association of air pollutants with the risk of GDM. The effect of different combinations of air pollutants also needs to be studied more systematically. In addition, the distance from the main traffic road and noise are also potential risk factors for GDM,To sum up, the available evidence indicated direct association of air pollutants and GDM risk. High-quality and longitudinal studies are needed to improve our understanding of this association.


Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD.Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects.Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects.Video Abstract Celiac disease (CD) is an autoimmune enteropathy, which affects three million Americans and 1% of the population worldwide . NotablyGlobally, the incidence of autoimmune diseases including CD is expected to triple by 2050 , 11, yetBacteroides-Prevotella group [Firmicutes, Proteobacteria, and Bifidobacterium [Bacteroides and a higher abundance of Firmicutes in these subjects compared to controls [Firmicutes, Enterococcaceae, and Peptostreptococcaceae in controls from 4 to 6 months but no differences over time were observed in cases [Accumulating evidence suggests that the gut microbiota may be involved in several immune-based disorders  such as la group , Firmicuacterium  were morcontrols . Other scontrols , 30. Forcontrols  identifiin cases . While tin cases , 32, stuin cases . The onlin cases , where tin cases .While these studies have provided valuable insights into the development of the gut microbiota early in life in subjects at risk of CD, solid food has already been introduced into the infants’ diet in many of these studies without accounting for its impact on the microbiota. In addition, to the best of our knowledge, no microbiome-wide study of the effect of environmental risk factors for CD currently exists. More importantly, existing studies are primarily based on 16S rRNA amplicon sequencing, which is not capable of fully addressing how the functional characterization of the microbiota will affect CD onset. To mitigate these limitations, here, we utilize a large-scale prospective cohort study called the Celiac Disease Genomic, Environmental, Microbiome and Metabolome study (CDGEMM) , where wWe selected 31 children recruited into the CDGEMM cohort for whom stool samples were available at birth, 3 months, and 4–6 months for this study . Notably, a decreased abundance of Coprococcus has been previously reported in the gut of individuals who carry a genetic risk to develop autoimmune conditions including CD [Bacteroides and Enterococcus species, respectively, at enrollment compared to no genetic risk. These observations are in agreement with previous studies [Bifidobacterium or Proteobacteria, which were reported before [Veillonella, Parabacteroides, and Clostridium perfringens at 4–6 months after birth in infants with high and standard genetic compatibility. This observation is contrary to case-control studies that report an increased abundance of these microbes in autoimmune conditions such as autoimmune liver disease [We found that both high and standard genetic risk to develop CD are associated with a decreased abundance of several species of uding CD . Standar studies , 26; howd before , 26 was  disease , Bechet’ disease , and neu disease .p value < 0.05). These pathways include amino acid metabolism, biosynthesis of secondary metabolites, and metabolism of cofactors including ubiquinone and other terpenoid-quinone biosynthesis. Furthermore, we identified an association between high genetic risk and a number of metabolites, e.g., an increased abundance of butanoic acid and a decreased abundance of dihydroxyacteone at 3 and 4–6 months of age .In addition to association with microbial species, we found that a high genetic risk of developing CD is associated with a decreased abundance of a number of functional pathways at 4–6 months of age  compared to vaginal delivery  in agreement with previous work [Bacteroides vulgatus and Bacteroides dorei. An increased abundance of these species has been reported to lead to a decreased gut microbial production of lipopolysaccharide, which will improve immune function through mechanisms such as major histocompatibility production and T cell activation, among others [p value < 0.05). Of note, defects in folate biosynthesis have been linked to an impaired immune response to viral infections and reduced natural killer cell response possibly contributing to T1D onset [p value < 0.05). An increased abundance of hydroxyphenlacetic acid in the serum has been associated with ulcerative colitis in a previous study [We found that cesarean section delivery is associated with a decreased abundance of several species of ous work , 38–40. g others . Analysi1D onset . Finallyus study ; howeverus study .Bifidobacterium [of Bifidobacterium breve (at 4–6 months) while exclusive formula feeding is associated with an increased abundance of Bifidobacterium adolescentis compared to exclusive breastmilk feeding . We also found that exclusive formula feeding is associated with a decreased abundance of Staphylococcus epidermis (at enrollment) consistent with previous work [Ruminococcus gnavus and Lachnospiraceae bacterium (at 3 and 4–6 months), which have been linked to allergic disease [p value < 0.05). Additionally, metabolomic analysis uncovered an association between both breastmilk and formula feeding with a decreased abundance of homoserine, alpha-d-glucopyranoside, and hydrocinnamic acid (at 4–6 months) . Exclusive formula feeding is also associated with an increase in sucrose and threonine and a decrease in oxalic acid and dihydroxyacetone abundances, among others (at 4–6 months).We examined three infant feeding types in this study including exclusive breastmilk feeding, exclusive formula feeding and both breastmilk and formula feeding, the last two of which were considered environmental risk factors. Previous work shows an association between infant feeding type and distinct species of acterium , 45. Conous work , and wit disease , diabete disease , and col disease . PathwayBacteroides thetaiotaomicron (at 4–6 months of age) . This is corroborated with previous work suggesting that this species, which is an important metabolizer of polysaccharides, increases in abundance in response to amoxicillin exposure [Propionibacterium, Subdoligranulum species and a decreased abundance of Bifidobacterium merycicum and Streptococcus lutetiensis (at 4–6 months). Pathway analysis also revealed an association between antibiotic exposure and a decreased abundance of phenylalanine metabolism and an increased abundance of cyanoamino acid (3 and 4–6 months) and galactose metabolism (4–6 months) . Analysis of metabolites showed associations between antibiotic exposure and a number of metabolites including decreased sucrose abundance (at 4–6 months) .We found an association between antibiotic exposure  and an increased abundance of exposure . Other ip value < 0.05). Metabolomic analysis identified alterations such as a decreased abundance of homoserine (at enrollment and 3 months) and of 2-ketobutryic acid (at enrollment) as well as an increased abundance of ribose (peak 2) (at 3 and 4–6 months) in environmentally exposed infants compared to non-exposed infants .Here, we performed a cross-sectional (inter-subject) analysis to explore how various features of the gut microbiota  change between genetically predisposed infants who were exposed to at least one environmental risk factor noted before  vs. those who were not  Fig. . This anGiven the unique prospective study design of our cohort, we were able to perform a longitudinal (intra-subject) analysis to gain additional insights beyond a cross-sectional analysis by identifying dynamic alterations in the gut microbiota composition, function, and metabolome in the first 6 months after birth. To this end, we explored changes in the microbiota features noted above between all pairs of time points that are observed exclusively in environmentally exposed or exclusively in environmentally non-exposed infants . For example, the abundance of Anaerostipes caccae monotonically increases during the study period and that of Klebsiella species and Erysipelotrichaceae bacterium increases from enrollment to 4–6 months. Among these, Klebsiella has been associated with the autoimmune condition ankylosing spondylitis [Bacteroides uniformis monotonically increases during the first 6 months after birth, a pattern which has previously been reported in breastmilk-fed infants [Bacteroides uniformis improves immune defense mechanisms, which are impaired in obesity, by decreasing TNF-α production and increasing IL-10 production [Veillonella species from enrollment to 4–6 months in non-exposed infants. An increased abundance of Veillonella species has been associated with autoimmune hepatitis [By longitudinal analysis of microbial species, we found that the abundance of a number of species increases over time in the environmentally exposed infants . Notably, a decreased abundance of ether lipids in the serum of children with T1D compared to healthy controls has been observed, [Longitudinal pathway analysis revealed that the abundance of ether lipid metabolism increases from 3 to 4–6 months of age in environmentally exposed infants . Propionic acid produced in the colon via bacterial fermentation of fiber promotes regulatory T cell generation [Metabolomic analysis revealed a monotonic increase in erythritol abundances during the study period and a decrease in propionic acid abundance from enrollment to 4–6 months in environmentally exposed infants  as detailed in Additional File Several studies have linked exposure to a variety of genetic and environmental risk factors with the onset of non-infective chronic inflammatory diseases . This liRuminococcus gnavus and Lachnospiraceae bacterium, which are linked to allergic diseases [Bacteroides vulgatus and Bacteroides dorei and folate biosynthesis pathway along with an increased abundance of hydroxyphenlacetic acid. All of these patterns have been reported to be associated with impaired immune function [Many microbes, pathways, or metabolites that we identified in these analyses are well supported in the literature to be associated with inflammation, autoimmune disease, or immune system dysfunction, thereby suggesting that they may have similar effects in CD. For example, we found that high-risk HLA genetics and formula feeding are both associated with an increased abundance of diseases  and diabdiseases , respectfunction  and inflfunction , 43 suggKlebsiella species, a microbe linked to autoimmune disease [Bacteroides uniformis over time and decreasing abundance of lipoic acid and methane metabolism [While the cross-sectional analysis did not identify any microbial species whose abundance significantly changes between the environmentally exposed and non-exposed infants at any given time point, our longitudinal analysis yielded significant results further stressing the power of intra-subject analysis. This allows us to prospectively evaluate the impact of risk factors on the dynamics of the gut microbiota development and to link dynamics to increased susceptibility to inflammation. For example, environmentally exposed infants show an increasing abundance over time of  disease  and a de disease . In conttabolism –58, 66. tabolism , 73, furUnlike previous microbiome studies for CD that are often based on 16S rRNA amplicon sequencing, here, we use shotgun metagenomic sequencing, which is amenable to functional characterization of the microbiota. This is particularly important as previous studies have shown that functional characterization is a more robust descriptor of the status of the microbiota compared to taxonomic composition alone , 75. FurIn this paper, we utilized an ongoing prospective study and multi-omics analysis to perform an in-depth analysis of the impact of genetic and environmental risk factors on the longitudinal development of the gut microbiota in infants at risk for CD, before solid foods  are introduced. These analyses revealed several microbial species, functional pathways and metabolites that have been previously linked to inflammation or immune system dysfunction as well as several new ones that have not been reported before and could be specific to CD. In this study, we restricted our analysis to the first 6 months of life and particularly prior to the introduction of solid foods in order to proactively “regress out” the effect of gluten on the gut microbiota as a major confounder when analyzing the effect of genetic and environmental risk factors. However, while our analysis suggests that the microbiome shifts that we observed during the first 6 months after birth increase the risk of developing autoimmune conditions including CD based on existing literature, it is unclear whether they indeed contribute to the future development of CD. Therefore, further work is required to investigate alterations in the gut microbiota over a longer period of time, including through the onset of CD. Future work should also consider other environmental factors such as viral infections, timing of solid food (gluten) introduction, amount of gluten ingested, and household exposures, e.g. family size and contact with pets, which have been reported to be associated with altered microbiomes , or withn = 18) and Italy (n = 13) with a first-degree relative with CD participating in the CDGEMM prospective birth cohort study [Thirty-one healthy infants from the USA .https://app.cosmosid.com/login) [General sequencing statistics of all samples, as well as mean sequence quality distribution for metagenomics samples were measured by MultiQC . Since tm/login) , 81, whihttps://jgi.doe.gov/data-and-tools/bbtools/) , we used the SPAdes tool [only-assembler -k 77,99,127) for the assembly of metagenomes and subsequently and after removing short contigs (length threshold = 500 bp), we used Prodigal (v2.6 using -d parameter) [appl Hamap, ProDom -p and -f tsv) to annotate the identified genes with biochemical functions based on the KEGG pathways [G is fragments per kilobase per million (FPKM) for each gene, L is the length of the gene, C is the coverage of contig in which the gene is identified, R is the read length and K is the k-mer size [After trimming the raw sequencing reads using BBDuk (des tool  (with parameter)  to identrameter)   according to manufacturer instructions. Instrumental analyses were performed with a GC-MS system . Sample analysis was performed in triplicate. Additional information related to the extraction, purification, derivatization, GC-MS analysis, and data preprocessing can be found in Additional File p value threshold of 0.05.We used the widely used multivariate statistical framework, MaAsLin , to deteU (Wilcoxon Rank Sum) test to compare the abundance of microbial species, pathways, and metabolites at each time point between the environmentally exposed and non-exposed groups . For the longitudinal analysis, we performed the paired Wilcoxon (Wilcoxon Signed Rank) test to compare the abundances of microbial species, pathways, and metabolites between each pair of time points using the same p value threshold noted above to report the significant results. Analyses of microbial species and pathways were performed in Python (using scipy.stats.mannwhitneyu and scipy.stats.wilcoxon functions) and those for metabolites were performed in R .For the cross-sectional analysis, we performed the Mann-Whitney  package  using paAdditional file 1: Clinical metadata for the subjects in this study.Additional file 2: Results of the taxonomic profiling of metagenomic samples.Additional file 3: Taxonomic composition at the genus and family level for metagenomes.Additional file 4: Results of the functional profiling of metagenomic samples.Additional file 5: Results of the metabolomic profiling of stool samples.Additional file 6: Supplementary text describing details of data analysis methods.Additional file 7: The results of association studies between significant features .Additional file 8: Functional categorization of pathways with significantly altered abundances.Additional file 9: Boxplots for significant features in the cross-sectional and longitudinal analysis


Post-operative delirium is an important, yet under-researched complication of surgery. Patients undergoing urological surgery may be at especially high risk of POD, as they are often older, and interventions can be associated with conditions that trigger delirium. The main aim of this systematic review was to evaluate the available evidence for risk factors in this patient group.Five databases were searched  between January 1987 and June 2019. The Newcastle–Ottawa Scale was used to assess for risk of bias. Pooled odds ratio or mean difference (MD) for individual risk factors were estimated using the Mantel–Haenzel and inverse variance methods.Seven articles met the inclusion criteria, giving a total population of 1937. The incidence of POD ranged from 5 to 29%. Three studies were deemed low risk of bias and four at a high risk of bias. Nine risk factors were suitable for meta-analysis, with age  and the clock drawing test  having a statistically significant association with POD in pooled analyses.Delirium is common in urological patients. This review has identified a lack of studies in this surgical population, with wide heterogeneity and high risk of bias. It also highlights a number of potential risk factors for post-operative delirium, of which some are modifiable. However, the strength of evidence is weak at present and so future research should focus on assessing comparable risk factors in this patient group in order to inform future clinical practice.Review registration The review protocol was prospectively registered with the PROSPERO database (reference CRD42017054613) Addirs (DSM) , 4. Althrs (DSM) .Delirium can be described as prevalent, i.e. found on admission, or incident, when it develops during the hospital admission. Incident delirium is a serious concern in surgical disciplines; delirium rates of over 50% have been reported in older adults undergoing major non-cardiac surgery . PreviouThere are reasons to believe that delirium may be a particular issue in Urology. Common urological diseases, including cancers and benign prostatic hyperplasia (BPH), are strongly associated with increasing age which is a generally accepted risk factor for delirium , 9. UrolA better understanding of urological POD epidemiology and risk factors could inform decisions about treatment. Multicomponent interventions may prevent delirium and if high risk patients could be identified these resources could be applied appropriately .The aim of this study was to identify risk factors for delirium in patients undergoing urological surgery. Systematic reviews of POD in other surgical areas reported small sample sizes and uncertainty in conclusions , 11–16. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines were followed for reporting and the review protocol was prospectively registered with the PROSPERO database (reference CRD42017054613). The study design used in this review was based on previous reviews related to POD in older general and vascular surgical patients , 12.A comprehensive search strategy was developed using search syntax based on medical subject heading (MeSH) terms and other controlled vocabulary relating to urological surgery, delirium and potential risk factors. The full search strategy is presented in Additional file Literature searches were undertaken between January 1987 and June 2019 inclusive. January 1987 was chosen as this coincided with the introduction of the first validated delirium assessment tools –19. LiteInclusion criteria were studies of humans published in English, using a validated delirium diagnostic/assessment tool and evaluating risk factors for incident POD. Only full papers published in a peer-reviewed scientific journal were considered. Eligible study designs were primary research evaluating risk factors for incident delirium only, cohort, case–control and cross-sectional studies. The population of interest was patients undergoing elective or emergency urological surgery. The primary outcome of interest was the development of POD Table . The outAn assessment of methodological quality and risk of bias of included studies was conducted by two independent authors using the Newcastle–Ottawa Scale (NOS) . The NOSTo analyse associations with POD, each risk factor reported in the included studies was recorded with the size of association and statistical significance. Meta-analysis was used to estimate the pooled odds ratio (OR) for dichotomous data, or mean difference (MD) for continuous data, between patients developing POD and those not developing POD. The quality of evidence for each risk factor was assessed using the GRADE criteria and presented in a summary of findings table.2 statistic, caution was highlighted where I2 was greater than 60%.Studies were pooled into a meta-analysis if study designs were considered sufficiently homogeneous and where two or more studies examined the same risk factor in a comparable manner  , 24. MetSensitivity analyses were conducted based on risk of bias (pre-specified), excluding studies at high risk of bias based on NOS score and overall assessment of bias. Sensitivity analyses were also performed based on heterogeneity of studies in terms of urological operations included.After removal of duplicates, the initial literature search identified 2331 articles. After title and abstract screening, 44 articles were fully reviewed and 5 met the inclusion criteria –30; see The main characteristics of the seven included studies are summarised in Table A range of urological procedures were included, and Table The seven studies scored between 4 to 9 on the NOS, the majority scoring 7 , 29, 30.A total of 26 separate risk factors were studied, with 14 studied in two or more analyses Table . See AddSensitivity analyses were conducted based on study overall risk of bias where possible and studies at a high risk of bias were excluded. This significantly affected the results in the pooled results of two risk factors (Age and ADL) but did not affect the overall result in the other analyses undertaken. Study heterogeneity existed in terms of the operations included within some studies. To assess their impact, sensitivity analyses were performed but the overall result was unchanged in all analyses. A Meta-regression analysis was also considered but due to lack of data and heterogeneity this was not feasible.Age as a risk factor was studied in all the included papers. Five of the studies found older age was a statistically significant risk factor for developing POD –32. One The effect of male sex was examined in all but two papers , 31, as Marriage was recorded in three papers , 29, 31,Five studies recorded co-morbidities, but only two were comparable as the others used different measurements. The Charlson Co-morbidities Index (CCI) was used in two papers , 28 but 2 of 98%. Sensitivity analysis based on type of surgery did not reach statistical significance . Excluding studies at high risk of bias in a further sensitivity analysis resulted in a significantly smaller p-value  and reduced statistical heterogeneity (I2 0%). A poor Instrumental Activities of Daily Living (IADL) score was found to be statistically significant risk factor for POD in two studies [Meta-analysis of activities of daily living (ADL) scores from three studies found no statistically significant association  , 29. HetThe mean BMI of the POD and non-POD groups were comparable in four studies , 31, 32 Only one study  assessed2 100%).Depression was included in three studies, and was found to be associated with POD in one study . Use of 2 of 96%. Excluding studies at high risk of bias in a sensitivity analysis did not significantly affect the result  but did reduce statistical heterogeneity (I2 67%). A sensitivity analysis based on operations included in the studies also did not demonstrate an association . The majority of the studies excluded patients with a pre-existing history of Alzheimer’s disease. A history of previous delirium was reported statistically significant risk factor for developing POD in one study  [Five of the seven studies recorded pre-operative MMSE, but only one found a low score to be associated with an increased risk of POD . Pooled Two studies , 30 analEducation, in years, was assessed pre-operatively in two studies , 31. PooNo statistically significant impact on risk of developing POD was seen between general and regional anaesthesia. This was the case in individual studies, in the meta-analysis , 30–32 , meta-analysis forest plots (S2), extended risk factor table (supplementary Table 1) and extending GRADE summary of findings table (supplementary Table 2).


The association between vitamin C intake and breast cancer is unclear. This meta-analysis aimed to precisely assess the association of vitamin C intake with breast cancer risk and mortality. We searched the PubMed, Embase, and Web of Science databases up to June 2020 and found 69 studies relevant to breast cancer risk (54 studies) and survival (15 studies). Relative risks and 95% confidence intervals were calculated using the random-effects models. Pooled results suggested that the highest versus lowest vitamin C intake was significantly associated with a lower risk of breast cancer incidence . Dietary vitamin C but not supplements was found to reduce breast cancer risk . For the highest versus lowest vitamin C intake, the pooled hazard risk for breast cancer-specific mortality was 0.78 , totality mortality was 0.82 , and recurrence was 0.81 . Our analysis suggests that higher vitamin C intake is significantly associated with reduced breast cancer incidence and mortality. However, the intake of vitamin C supplements has no significant effect on breast cancer prevention. According to the latest study conducted by the International Agency for Research on Cancer, there were 18.1 million new cancer cases and 9.6 million cancer-related deaths globally in 2018 . Thus, iP = 0.00]) ) . To date= 0.00]) , 2000 [1= 0.00]) , and 201= 0.00]) . A recen= 0.00]) . However= 0.00]) . TherefoThe flow chart for the selection of publications from the existing literature is shown in The characteristics of these studies on BC risk published between 1991 and 2016 are presented in P < 0.001) and showed evidence of heterogeneity . Significant publication bias was observed according to the Begg’s test (P < 0.001) and Egger’s test (P = 0.006). The funnel plot was a little asymmetrical  and 0.86 , respectively.metrical . Sensitimetrical . The usemetrical . The pooP < 0.001) and a non-significant inverse association in cohort studies  (P = 0.004) but not with supplements  (P < 0.001) but not in Europe and America (P = 0.025) and postmenopausal women  . The detailed results are summarized in = 0.295) . When th= 0.678) . In subg America . Further= 0.045) .P < 0.001) and showed non-significant heterogeneity (2I = 2.6%) in 6 studies. A significant reduction in the risk of mortality  was observed when comparing the highest versus lowest quintile of VitC intake in 7 studies. For BC recurrence, the combined HR of the 2 relevant studies was 0.81 .While 10 articles (15studies) were selected for analyzing the association of VitC intake with BC prognosis, 7 articles of 10 were chosen to examine its association with total mortality (26347 cases and 3733 deaths) –31. MeanSeveral studies have assessed the association between antioxidants and the incidence or prognosis of BC , 35, 36.Our meta-analysis included the most up-to-date and comprehensive studies (69 studies) on VitC intake and BC. Previous meta-analyses included other dietary elements  to assess the risk of BC , 20. HowHowever, there are some inconsistencies between our findings and those of earlier reports. Howe et al.  in 1990 Several studies have assessed the association between VitC and BC survival; however, the results have been discordant. A previous study found that the risk of recurrence and disease-related mortality were reduced among women taking VitC for more than 3 years . AnotherSubstantial evidence has supported the beneficial effects of VitC. Because of its antioxidant effects, VitC protects cells from oxidative DNA damage, thus preventing cancer , 44. VitIn subgroup analyses, an inverse association was found between VitC intake and BC risk in case-control studies but not in cohort studies, which was in agreement with a previous meta-analysis . This maOur subgroup analysis also showed an inverse association between dietary VitC and BC. However, this association was not significant for VitC supplement intake in our meta-analysis. These findings are inconsistent with those reported by Hu et al. in 2011 . Many moSignificant heterogeneity was observed in this meta-analysis. Sensitivity analyses suggested that the stable pooled RR was not significantly affected by any single study. We also performed subgroup analyses stratified by confounding factors  to identify the sources of heterogeneity. The consistent results and sensitivity obtained from several subgroup analyses confirm the robustness and reliability of our study.Like all meta-analysis, this study had potential limitations that need to be acknowledged. First our results showed greater heterogeneity, the source of which remains unknown even after subgroup and sensitivity analyses. This may be attributed to other factors such as different races, different stages of BC, outdoor physical activities, bias in the collection of dietary information, and diverse periods before interview across the included studies. Second, obvious publication bias was admitted, possibly because studies with negative results are more difficult to be published. Third, we did not perform a stratified analysis by hormone status because limited information was available and additional studies are needed. Finally, the interactions between VitC and other vitamins may reinforce the associations with BC, but our estimates of further potential interactions are limited by the lack of raw data from related studies.In conclusion, the results from this meta-analysis suggest that a high intake of total VitC appears to be significantly correlated with a reduced risk of BC incidence, mortality and recurrence. However, additional VitC supplementation should be cautiously considered for BC prevention.We searched PubMed, Web of Science, and Embase databases for relevant English publications up to June 2020. The terms “breast cancer(s)” [Title/Abstract], “breast tumor(s)” [Title/Abstract], “mammary cancer(s)” [Title/Abstract] and “breast neoplasm(s)” [Title/Abstract] in combination with “Ascorbic Acid” [Mesh], “ascorbic acid” [Title/Abstract], “Vitamin C” [Title/Abstract], “Vitamin C supplement(s)” [Title/Abstract], “antioxidant(s)” [Title/Abstract], “Vitamin(s)” [Title/Abstract] were used in the search. We also identified additional relevant studies by scanning the reference lists of all eligible articles and reviews. Only full-length original articles published in English were included. Two researchers independently read the retrieved documents, screened relevant publications based on the exclusion criteria, and deleted all duplicate studies. Any disagreement between the two authors was resolved by discussion.The inclusion criteria for publications were (1) an original article, (2) a cohort or case-control study in design, (3) the exposure of interest was the use of dietary or supplementary VitC (ascorbic acid), (4) the dependent variable of interest was BC, (5) relative risk (RR), hazard risk (HR), or odds ratio (OR) with a 95% CI was provided, and (6) the results were adjusted at least for age. The exclusion criteria were as follows: (1) case reports, reviews, animal studies, and in-vitro studies; (2) studies reporting insufficient statistics or results; (3) repeated or overlapping publications; (4) studies that assessed VitC in combination with other nutrients; (5) studies assessing the association for blood levels of VitC; and (6) studies in which low/no intake of VitC was not the reference category.Data on the study population characteristics, including author names, year of publication, geographic locations, study design, age, assessment of diet and supplement type, duration of follow-up, sample size, and RR (95% CI) for each category of VitC and confounding factors that were adjusted, were independently extracted by two investigators. From each study, we extracted the RR with the most adjusted potential confounders. If the two researchers disagreed regarding the eligibility of data, a consensus was reached with the help of a third reviewer.Two authors independently assessed the quality of each included study based on the Newcastle-Ottawa Quality Assessment Scale . The con2 statistics [P values <0.05 in the Q statistic or at I2 values ≥50%. We performed subgroup analyses based on menopausal status, study type, geographical location, and VitC source to explore potential origins of heterogeneity. Sensitivity analyses were performed to assess the effect of individual studies on the results [The pooled measure was calculated as the inverse variance-weighted mean of the logarithm of RR with 95% CI to assess the association between VitC intake and BC. A random-effects model was used to combine the study-specific RR (95% CI), which considered both within-study and between-study variations , 62. Hetatistics  and was  results . Egger’s results .For the dose-response analysis of results across the different categories of VitC intake, methods reported by Greenland  and OrsiSupplementary FiguresSupplementary Table 1Supplementary Table 2


XRCC1) and 8 Oxo guanine DNA-glycosylase 1 (OGG1) genes are implicated in the repair of single-stranded breaks (SSBRs) and base excision repair (BER) pathways. Common polymorphisms in DNA repair genes are supposed to decrease the capability of DNA repair and cause genetic instability. This study was designed to investigate the association between XRCC1 (rs25487) and OGG1 (rs1052133) polymorphisms and susceptibility to colorectal cancer (CRC) in the Ahvaz city, south-west Iran. X-ray cross-complementing group 1 . XRCC1 (rs25487) is significantly higher in colorectal cancer patients, compare to controls . Significant increased risk of cancer was observed in XRCC1 (rs25487) genotypes , while no association was found between OGG1 (rs1052133) and colorectal cancer risk (p = 0.6). Our results indicate that the frequency of the Gln (A) allele of XRCC1 (rs25487) polymorphism might be associated with an increasing risk of CRC in Ahvaz. It also demonstrates positive correlation between the XRCC1 (rs25487) genotypes and demographic characteristics, such as smoking and increased age in patients and control groups.Our study suggests that  XRCC1) and 8 Oxo guanine DNA-glycosylase 1 (OGG1) polymorphisms have been frequently studied as potentially related with susceptibility to the incidence of several cancers . The DNA repair gene XRCC1 is implicated in the repair of single-stranded breaks (SSBRs) and base excision repair (BER) that has been mapped to the human chromosome region 19q13 . Another DNA repair gene that has an essential role in base excision repair is OGG1 that is located in the chromosome region 3p26. This glycosylase enzyme removes damaged bases by way of reactive oxygen. XRCC1 has unknown enzymatic activity and is considered to operate as a scaffold protein for base excision repair activities . XRCC1 has been reported to interact with other crucial proteins such as DNA polymerase β, DNA ligase III, poly (ADP-ribose) polymerase, APE1, and OGG1 in base excision repair pathway . One of the common genetic polymorphism in the XRCC1 gene is Arg399Gln (rs25487) at amino acid residue 399 (Arg to Gln) of exon 10: this substitution can alter the functionality of XRCC1 protein and damage its DNA repair activity . The OGG1 is an important DNA repair gene that encodes a DNA glycosylase for removal of the 8-oxoG adduct of oxidatively damaged DNA . Although many polymorphisms have been reported, Ser326Cys (rs1052133) polymorphism at the codon 326 of exon 7 (Ser to Cys) in OGG1 gene is the most studied polymorphism . It has been reported to affect the OGG1 function and is linked to increased risk of different cancers . Therefore, this study was designed to investigate the association between the polymorphisms of DNA repair genes, including XRCC1 (rs25487) and OGG1 (rs1052133) given their susceptibility to colorectal cancer in the Ahvaz city, south-west Iran.Colorectal cancer (CRC) is one of the most common malignancies and the fourth leading cause of death by cancer in the world . The incidence of colorectal cancer seems to have increased in Iran: occurrence of CRC has increased with age and highest rates have been observed in the older peoples . CRC is a complex disorder caused by the composite of genetic susceptibilities and environmental factors. Diet, smoking, and alcohol consumption are environmental factors that have shown association with CRC risk . Candidate genes considered susceptible to CRC are implicated in tumor suppressor genes, oncogenes, methylation mechanism, and genes involved in DNA repair pathways . In mammalian cells, four important mechanisms of DNA repair have been recognized: nucleotide excision repair (NER), base excision repair (BER), double-strand break repair, and mismatch repair . Some common genetic polymorphisms in DNA repair genes are supposed to decrease capability of DNA repair and genetic instability that may contribute to the development of cancers such as CRC . Among the established polymorphisms of the DNA repair genes, the X-ray cross-complementing group 1  with mean age 54.89 ± 13.5 SD and 150 controls  with mean age 55.09 ± 11.5 SD. Informed consent was obtained from all participants for their participation in the study. The ethics committee of the Jundishapur University of Medical Sciences approved the study. An organized questionnaire was applied to collect information from study subjects about lifestyle habits . Patients include subjects with positive colonoscopic findings for malignancy and histologically accepted as carcinomas of colorectal. The control subjects were picked among individuals who refers to hospital with no evidence and history of cancer. Patients and controls were matched were age and gender. Our exclusion criteria for control group are personal history of all cancers and chronic diseases such as hypertension, diabetes mellitus, and nephritic disorder. Patients who were receiving neoadjuvant chemotherapy and suffered from autoimmune and metabolic diseases were excluded from the study. DNA extraction and genotypingDNA for genotyping was isolated from whole blood samples (5 ml collected into EDTA tubes) taken from CRC patients and control subjects. DNA extraction was performed by DNA Extraction Kit  conforming to the manufacturer’s procedure.Genotyping was carried out by restriction fragment length polymorphism (RFLP) after polymerase chain reaction (PCR); detailed information of procedures for PCR-RFLP is shown in Statistical analysisXRCC1 and OGG1 gene polymorphisms between clinical features within the cases and controls were analysed using the Chi-square test. Association between these polymorphisms and CRC was calculated with 95% odds ratios (OR) and confidence intervals (CI). p value < 0.05 was considered statistically significant. Adjusted Odds ratio (OR), 95% confidence intervals (CIs), and p-values were determined by logistic regression in order to evaluate the association between each genotype and risk of CRC. The binary logistic regression model included age, gender, and smoking. All statistical analysis was performed using the SPSS software for Windows version 18.0 .The differences of genotype frequencies of the XRCC1 (rs25487) and OGG1 (rs1052133) polymorphisms are shown in Out of 150 patients, 49 patients (32.7%) had less than 50 years and 101 (67.3%) had more than 50 years old, compare to 46 controls (30.7%) less than 50 years and 104 controls (69.3%) more than 50 years (p= 0.7). 82 patients were male and 68 were female (54.7% and 45.3% respectively), while 70 healthy controls were male (46.7%) and 80 were female (53.3%). 40 out of 150 patients were smoker (26.7%) and 44 out of 150 controls (29.3%) were smoker. There were no significant differences in parameters of mean age (p= 0.8), gender (p= 0.16) and smoking (p= 0.7) between the patients and controls. In 85 patients cancers located in colon (56.7%) and 65 patients suffered from rectal cancer (43.3%); 74 cancers were in stage I and II (49.3%) and 76 in stages III and IV (50.7%). Among 18 patients metastasis were detected (12%), while in 132 ones, metastasis did not reported (88%). Representative PCR-based restriction analyses for the XRCC1 (rs25487) and OGG1 (rs1052133) polymorphisms in patient and control groups are represented in XRCC1 (rs25487) was significantly higher in CRC patients than in controls . Also, frequency of the Gln/Gln genotype of XRCC1 (rs25487) was higher in CRC patients than in controls. No significant association was found between the Cys allele and the Ser/Cys genotype of OGG1 (rs1052133) in CRC patients as compared with controls. Furthermore, the associations of genetic models with CRC risk in each polymorphism were evaluated. For XRCC1 (rs25487) polymorphism, significantly increased cancer risk was seen in the recessive genetic model. Influence of interaction between demographic and clinical characteristics of CRC and XRCC1 (rs25487) (OGG1 (rs1052133) (data not shown) polymorphisms have been displayed. Our results demonstrate a positive correlation between XRCC1 (rs25487) genotypes and some demographic characteristics in patient and control groups, such as smoking and age more than 50 years. Simultaneously, no differences in frequencies of the OGG1 (rs1052133) genotypes were found in patient and control groups in all demographic features. In addition, association between XRCC1 gene polymorphism and pathologic characteristics is shown in OGG1 (rs1052133) polymorphism the data is not shown.The distributions of the genotype and allele frequencies for rs25487)  and OGG1XRCC1 and OGG1 genes encode proteins that play critical roles in the base excision repair pathway . In this study, we aim to test the hypothesis that whether polymorphism in these genes influences the risk of CRC. The outcomes of some investigation about the association of XRCC1 (rs25487) polymorphism with colorectal cancer risk have been contradictory. For example, two recent studies indicated association with increased risk of colorectal cancer , while a case-control study in Sweden found no association with CRC risk . Also, other findings about the association of OGG1 (rs1052133) polymorphism with susceptibility to CRC remain controversial . The results of our study demonstrate that the frequency of the Gln allele is significantly higher in CRC patients than in controls and is associated with the risk of colorectal cancer. Individuals with 399Gln homozygote genotype have more than 5 folds greater risk of colorectal cancer than those with the homozygous 399Arg genotype. Significant interactions were found between this polymorphism and smoking in smoker patients as compared to smoker controls and also with age more than 50 years. Our findings are consistent with the results of Fouad et al. in Egypt: they observed increased risk of colorectal cancer associated with the 399Gln allele . In contrast, a study in the Italian population reported no differences among the XRCC1 (rs25487) allele and the risk of colorectal cancer . The DNA repair system has an important role in conserving genetic stability. Polymorphisms in DNA repair genes can decrease the repair capacity of DNA, which may lead to development of different cancers including CRC . DNA damage can be caused by endogenous oxidation, deamination, or alkylation, these are repaired mainly by the base excision mechanism. The XRCC1 polymorphism and smoking in colorectal cancer risk is probable. Cigarette smoking is a plentiful source of genotoxins such as reactive oxygen species and chemical carcinogens that can cause single and double-stranded breaks and base adduct formation . Smoking has been shown to be associated with increased risk of colorectal cancer consistent with our study .The biological interaction between OGG1 (rs1052133) polymorphism. Zou et al., (2016) in a meta-analysis found no major difference in that genotype distribution between patients and controls, this confirms our results. In contrast to our findings, OGG1 (rs1052133) polymorphism had significant association with increased risk of CRC in the Polish population according to Kabzinski et al., (2018). Based on our results, XRCC1 polymorphism may be considered a substantial biomarker for cancer screening in high risk persons and for supporting these patients by prophylactic interventions and specific therapeutic methods. Due to our limited sample size, further studies with large sample size across diverse ethnic populations should be performed to elucidate the association between XRCC1 (rs25487) and OGG1 (rs1052133) polymorphisms and CRC in the Iranian population.Our data analysis revealed no significant difference between CRC patients and controls in the genotypic and allelic frequencies of the


It has been reported that patients with inflammatory bowel disease (IBD) are more susceptible to periodontitis. However, data regarding the risk of periodontitis in IBD patients are scarce, and results from individual studies remain controversial. The aim of this study is to investigate the risk of periodontitis in IBD patients.  Web of Science, PubMed, and Embase were searched for studies investigating the risk of periodontitis in the IBD patient population from Jan. 2000 to Nov. 2020. Articles were included if they contained the number of people with IBD diagnosed with periodontitis  compared with a control group. Case reports, reviews, animal studies, and articles without available abstracts were excluded. A pooled odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association between periodontitis and IBD. I2 = 27%). In particular, Crohn's disease (CD) and ulcerative colitis (UC) were both linked to an increased risk of periodontitis .  Six studies were included in the meta-analysis. The overall risk of periodontitis was significantly higher in IBD patients than controls (OR: 2.10, 95% CI: 1.60-2.74;  IBD patients are at higher risk of periodontitis than controls. After subgroup analysis, the elevated risk remained significant when analyzing CD or UC alone. UC patients were at higher risk of developing periodontitis than CD patients. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut, which includes Crohn's disease (CD) and ulcerative colitis (UC) . UC mainUp to 9% of patients with IBD present with oral manifestations , 7, of wSeveral studies have found that IBD is often associated with a higher prevalence of periodontitis. Brito et al. have shown that the prevalence of periodontitis is higher in patients with IBD than in healthy subjects . In addiThis meta-analysis was reported according to the instructions of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement  and condWeb of Science, PubMed, and Embase were extensively searched from Jan. 2000 to Nov. 2020. The following medical subject heading terms were used: “inflammatory bowel disease,” “Crohn's disease,” “ulcerative colitis,” “periodontal disease,” “periodontitis,” and “gingivitis.” All items were searched as key words or medical subject headings (MESH) where available. The electronic search strategy for PubMed, for example, was as follows: (“inflammatory bowel disease” or “Crohn's disease” or “ulcerative colitis”) and . The search was performed in English. Based on titles and abstracts, the records were screened, and relevant studies were selected for full-text assessments. References of the eligible studies were also checked for studies not identified by the primary search strategy. The inclusion and exclusion criteria for published studies are shown in A study was deemed eligible if it met all the inclusion criteria and none of the exclusion criteria. From each study enrolled, three authors  extracted information related to the name of the journal, names of authors, year of publication, location of study, study design, study population, sample size, and periodontal manifestations. Disagreement or uncertainty was resolved by discussion among the authors. In these studies, periodontitis was assessed using different markers and indices, such as the plaque index, gingival index, bleeding on probing, pocket depth, clinical attachment loss, gingival recession, and periodontal index. If the information provided in the study was insufficient, the corresponding author of the article was contacted for the missing data. However, all studies provided sufficient information about outcomes.The Newcastle-Ottawa Scale  was used to assess the quality of the enrolled studies . BrieflyI2 statistic, with I2 > 50% indicating substantial heterogeneity [p value < 0.05 was considered statistically significant.The association between periodontitis and IBD was calculated using odds ratios (ORs) extracted from individual studies. A random-effects model was used to obtain the pooled ORs with the 95% confidence interval (CI). Heterogeneity was evaluated using the Cochrane ogeneity . Subgrouogeneity  and metaogeneity . A two-sThe literature search process is summarized in All 6 studies ranked between 7 and 9 stars according to the Newcastle-Ottawa Scale ; they weI2 = 27%) (I2 = 0%) (I2 = 85%)  . BecauseI2 = 0%) , whereas2 = 85%) .I2 statistic was highest when analyzing the UC subgroup . The potential effects of any single study on heterogeneity were investigated by sensitivity analysis. Briefly, each study was removed sequentially to obtain the OR. When analyzing the remaining studies, we found that the heterogeneity across studies significantly decreased after removing the study by Zhang et al. [I2 = 49%, p = 0.16), suggesting it was the source of the heterogeneity. The OR of periodontitis for UC after exclusion of the Zhang et al. study was 1.71   .I2 = 27%), which was in agreement with previous publications [I2 = 0% for CD vs. OR: 2.39, 95% CI: 1.19-4.80; I2 = 85% for UC).In recent decades, the association between IBD and periodontitis has been recognized on account of their similar etiologies. Both diseases involve dysbiotic microbiota, deregulation of the immune response, and chronic inflammation in genetically susceptible individuals –28. Our ications –32. NotaThe number of publications included in the current meta-analysis is relatively small because of limited relevant research and the strict inclusion criteria. Because this study is aimed at calculating the risk of periodontitis in the IBD population, only publications with clear diagnosis of periodontitis were selected. Two studies that investigated the community periodontal index of treatment needs (CPITN) and loss of attachment at sites with maximal periodontal pocket depth (LA-PPD) were not included in this study , 22. DesLeptotrichia, Prevotella, Bulleidia, and Atopobium, were significantly increased [12 oral bacteria in swallowed saliva can enter the gut and affect the gut's microbial composition [Microbiota play important roles in the pathogenesis of IBD and periodontitis . A dysbincreased . Howeverncreased . Every dposition , 40, whiposition . Future α, IL-1β, and IL-6 were found in patients with active CD, and elevated salivary TNF-α and IL-6 correlate with specific oral lesions [The aberrant immune response during IBD could cause inflammation of the oral cavity. IBD is an autoimmune disease, whereas poor oral health is associated with an overly aggressive immune response in local periodontal tissues . Elevate lesions . TNF inh lesions . Similar lesions , 47. ThiDespite their similar etiologies, it is likely that IBD and periodontitis could trigger one another. That is, periodontitis, as one of the extraintestinal manifestations of IBD, could present before or after the onset of intestinal symptoms. There were limited studies that evaluated the risk of IBD in patients with periodontitis , 49. A cCertain limitations must be considered when interpreting the results of this study. First, there were some differences in the definition of periodontitis in the included studies, which may have caused some bias. Furthermore, the use of studies including self-reported periodontitis could have introduced measurement error. The risk of developing periodontitis in IBD subjects may be higher in fact. Second, the risk of developing periodontitis among patients with IBD was not adjusted for relevant factors, especially medications and smoking habits. The use of antibiotics, immunomodulatory drugs, and corticosteroids are possible confounders for evaluating the risk of periodontitis in IBD patients. Smoking is a risk for periodontitis , whereasThis meta-analysis showed that IBD patients are at higher risk of developing periodontitis than controls. After subgroup analysis, the increased risk remained significant when analyzing CD or UC alone. UC patients were at higher risk of developing periodontitis than CD patients. Additional large-scale, prospective studies incorporating professional dental care and IBD centers are essential to clarify the relationship between periodontitis and IBD.


To explore the association between cesarean section (CS) and risk of autism spectrum disorder (ASD), and evaluate the possible factors influencing this association.In total, 950 patients diagnosed with ASD and 764 healthy controls were recruited in this study. Socio-demographic characteristics and prenatal, perinatal, and neonatal characteristics were compared between the two groups. Univariate and multivariable conditional logistic regression analyses were applied to adjust for confounders. Further stratified analyses based on sex and miscarriage history were similarly performed to explore the factors influencing the association between CS and ASD.β = − 0.68, Wald χ2 = 7.5, df = 1, p = 0.006)) was similarly defined as influencing ASD.CS was evidently associated with an elevated risk of ASD  = 1.311–1.969). Unlike regional anesthesia (RA), only CS performed under general anesthesia (GA) consistently elevated the risk of ASD  in females and males in further stratified analysis. The risk of children suffering from ASD following emergency CS was apparently increased in males , whereas a higher risk of ASD was observed among voluntary CS and indicated CS subgroups  in females. Moreover, the interaction term of CS and past miscarriage history (The exposure of children to GA during CS may explain the possible/emerging association between CS and ASD. In addition, sex and miscarriage history could equally be factors influencing the association between CS and ASD. Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which the exact mechanism remains unclear and is characterized by impairment in social communication, alongside restricted interest and repetitive behaviors . ASD hasThe CS is a surgical procedure of delivering a baby to prevent a risk to the health of the mother or baby accompanied by vaginal delivery. Emergency CS is usually performed in an urgent situation due to complications, such as fetal distress which could occur spontaneously . On the Although the association between CS and ASD has been established in several previous studies, the effect size is heterogeneous when allowing for the adjustment for different confounding factors , 28. DatEmerging evidence has suggested an association between the types of anesthesia and risk of ASD development , 31. CSsThere could be variation in the observed correlation based on concomitant confounding factors or confounding by indications; this indicates that ASD may be related to the indications and concomitant confounding factors of ASD, rather than the surgical procedure . ConsideThis study was conducted following the recommended guidelines prescribed by the Second Xiangya Hospital Ethics Committee. All subjects gave written informed consent following the Declaration of Helsinki. In this case-control study, both cases and controls were ascertained from two-stage data collections from training centers and special education schools across the country. The first and second stage recruitment of subjects and data collection were performed from 2012 to 2016 and 2016–2018, respectively. The data collection was conducted in two stages because scale entries were further refined and more detailed gestational and obstetric confounding factors were included in the second stage. Subjects in the first stage who were diagnosed with Autistic Disorder or Pervasive Developmental Disorder - Not otherwise specified (PDD-NOS) in accordance with the criteria established in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM- IV) were eligible for this study. These diseases, as mentioned earlier, fulfilled the diagnostic criteria of DSM-5 for ASD. For subjects in the second stage, the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-5) was employed. Children with ASD following the criteria set out in DSM-5 were enrolled in this study. ASD was diagnosed by two experienced pediatric psychiatrists, according to DSM- IV or DSM- 5 criteria.Children with severe physical diseases such as congenital heart disease or hematological diseases, or the first diagnosis is other psychiatric disorders, such as schizophrenia or Intellectual Disability, were excluded. Autistic patients with chromosomal abnormalities, such as Fragile X syndrome and Down’s syndrome, were equally excluded. Since previous studies have shown that gestational age may be a significant influencing factor of ASD, newborns of gestational age <37 or >42 weeks were excluded from this study. Similarly, patients who underwent assisted delivery, including the use of forceps, vacuum, and oxytocin were excluded from this study.Controls were recruited from neighborhood kindergartens and in the same city. Typically developing children were recruited by adapting a survey questionnaire that include basic information and a screening test for preliminary screening of neurological or neurodevelopment disorder. Other exclusion criteria are similar to those in the autism group. Five hundred fifty-one patients and 874 healthy controls were recruited in the first stage, while 739 patients and 64 healthy controls were recruited in the second stage. In total, 1290 patients and 938 healthy controls were recruited in current study. However, 174 controls and 340 children with autism were excluded from analysis due to missing data. Ultimately, 950 children with autism and 764 controls were enrolled for the subsequent data analyses, the research process is shown in Fig. Details of data collection have been described in a previously published study . In summt-test when the data were normally distributed. In addition, categorical variables were compared using the chi-square or Fisher exact tests. The univariate conditional logistic regression models were used in the assessment of the univariable association of various prenatal, perinatal and neonatal characteristics with ASD. Further multivariate conditional logistic regression models were conducted to evaluate the adjusted effect of CS on the risk of ASD . The variables that were obviously correlated with ASD  were considered potential confounders and included in this model. Subgroup analyses were performed to assess the influence of various CS types on the risk of ASD. CS deliveries were stratified to different types according to the type of anesthesia and the indications for CS. The associations were analyzed by sex separately to evaluate the sex-specific relationship between CS and ASD and to remove the effects of an unbalanced sex ratio. Similarly, the analysis was separately conducted according to the history of miscarriage because it is a significant risk factor for ASD in current studies [Data analyses were performed using SPSS version 18 . The socio-demographic characteristics, as well as the correlations of CS and maternal, perinatal, and neonatal characteristics with the risk of ASD, were assessed via appropriate bivariate statistical tests. In the event data did not follow a normal distribution, we used a Mann-Whitney test. We used a  studies .p <0.001). Apart from CS, other variables that were associated with the risk of ASD included: parity number (p <0.001), history of miscarriage (p <0.001) and infant’s weight at birth (p = 0.001). Behavioral characteristics of the samples are presented in Table In total, 950 ASD cases and 764 subjects (as controls) were included in this study. The median age of the ASD cases and controls were 4.0 and 4.8 years, respectively. Majority of the ASD cases were male 792/158), whereas the sex distribution in the controls was balanced (407/357). Table 58, wherep < 0.05) in this study  as an influencing factor for ASD.Univariate conditional logistic regression analyses revealed that CS was significantly associated with ASD . This association was equally observed between CS and the parity number, and past history of miscarriage. Further multivariate conditional logistic regression models revealed an association between the risk of CS delivery  and ASD. After adjusting for prenatal, perinatal or neonatal confounding factors that were associated with ASD (p>0.05).In order to further explore the mechanism underlying the association between CS and ASD, the sample was stratified according to different surgery indications and types of anesthesia; the same conditional logistic regression models were applied in these subgroups Fig. . After ap>0.05). The children delivered by CS under GA demonstrated a 44% higher risk of developing ASD than those delivered vaginally . Notably, this model indicated no statistical difference in the risk of ASD between children delivered by CS under RA and those delivered vaginally (p = 0.966).Given the unbalanced sex distribution in the ASD cases, separate analyses were conducted according to sex Fig. , after cp>0.05). Similarly, an increased risk of ASD was correlated with CS under GA , unlike CS under RA(p >0.05), after adjusting for potential risks.Unlike males, a higher risk of ASD was observed among the voluntary CS and indicated CS subgroups  in females. However, the analysis revealed no significant difference in the risk of developing ASD in the emergency CS subgroup compared to vaginal deliveries subgroup (p = 0.999). In addition, further subgroup analysis equally revealed no significant association between different types of CS and ASD . In line with the results above, CS is a significant risk factor for ASD in subjects without a history of miscarriage . In addition, the OR of ASD risk following emergency CS  versus vaginal delivery was obviously higher than indicated CS  and slightly higher than voluntary CS . The neonates delivered by CS performed under GA had approximately two times higher risk of suffering from ASD than those birthed by vaginal delivery . Similarly, no association was observed between ASD and CS performed under RA (p >0).Due to the interaction between miscarriage history and CS in the risk of developing ASD, further stratified analysis, according to miscarriage history, was similarly performed in this study Fig. . Fifty-nThis study demonstrated that the correlation between CS and ASD is exclusive to CSs performed under GA, with an evident heterogeneity in different surgical indications and sex. In addition, CS may interact with miscarriage history to influence the development of ASD.According to this study, delivery by CS was associated with a higher risk of ASD in children, even after adjusting the potential confounding factors. The result was supported by previous well-established observations that increased risk of ASD was associated with delivery by CS , 27, 29.The results supported the original hypotheses that emergency CS is associated with a higher risk of ASD than voluntary CS and indicated CS, and the risk of ASD following indicated CS is slightly higher than the risk following voluntary CS. Consistent results were observed in previous studies that both indicated CS (elective CS or planned CS) and emergency CS were associated with an increased risk of ASD, contrary to this study , 29, 31.In males, emergency CS were associated with an increased risk of ASD in comparison with vaginal delivery, which was consistent with the conclusion drawn from the result of the total study population. On the contrary, no association was observed between emergency CS and ASD in females; instead, both voluntary CS and indicated CS significantly increased the risk of ASD. The rationale behind these discrepancies is yet to be accurately clarified as previous stratified analysis regarding surgical indications is limited. It was speculated that different surgical indications may exert distinct impact on the risk of ASD between males and females. A complex interaction of surgical indications and sex plays a pivotal role in the development of ASD. In addition to the ‘interaction’ hypothesis, another explanation regarding these discrepancies is that the small sample size of female subjects made it difficult to draw accurate conclusions. Thus, the contribution of different surgical indications to the unequal risk of development of ASD among females relative to males require further exploration.Another crucial finding is that CS performed under GA were related to a higher risk of ASD than CS under RA or vaginal delivery, following adjustments for potential confounders consistently between males and females in further analysis stratified by to sex. This finding is in accordance with previous research which reported a significantly higher risk among children who were delivered by CS under GA , 31; howA novel finding in this study is that an interaction between miscarriage history and CS contributes to ASD risk. Only one previous study has reported miscarriage as a specific risk factor of ADHD and ASD , which iThis study has some limitations. Limited known prenatal and perinatal risk factors of ASD were detected in this study; therefore, sufficient potential confounders could not be adjusted in multivariate analysis, such as crying, color at birth, convulsions at birth and jaundice, especially APGAR index is not available in many families given the retrospective study. Consequently, the findings could have been influenced by potential unmeasured confounding factors. However, the CS is a major exposure factor and therefore unlikely to be seriously affected by this shortcoming. Next, the imbalance in sex distribution could have affected the accuracy of the research results, although further sex-specific analysis was conducted; the small sample size of female subjects limited the number of strata used in the subgroup analyses. In addition, a sibling analysis was not performed in this study, and we were unable to further adjust for familial confounding factors. All data obtained were self-reported. Therefore, the results may be influenced by potential recall bias and exposure misclassification. Nevertheless, the exposure factor (CS) is a dominant event and is therefore unlikely to be influenced by recall bias; in addition, it was sufficient to investigate most of the hypotheses. It is also worth mentioning that the only diagnostic criterion, DSM-4, was adopted in our study, and the failure to use ADOS is another shortcoming. Lastly, our study does not further explore the possible correlation between the CS and the level of autistic symptoms, and further exploratory studies are needed in the future.Our current research shows that CS is associated with ASD; and CS performed under GA were related to a higher risk of ASD than CS under RA. The associations between different types of CS and ASD is influenced by sex and miscarriage history.


Isoflavones are phenolic compounds with a chemical structure similar to that of estradiol. They are present in several vegetables, mainly in legumes such as soy, white and red clover, alfalfa and beans. The most significant food source of isoflavones in humans is soy-derived products. Isoflavones could be used as an alternative therapy for pathologies dependent on hormonal disorders such as breast and prostate cancer, cardiovascular diseases, as well as to minimize menopausal symptoms. According to the results gathered in the present review, it can be stated that there is scientific evidence showing the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis on postmenopausal women, although the results do not seem entirely conclusive as there are discrepancies among the studies, probably related to their experimental designs. For this reason, the results should be interpreted with caution, and more randomized clinical trials are required. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering some types of cancer, such as breast and endometrial cancer, but further studies are needed to confirm these results. Finally, isoflavones could be useful in reducing hot flushes associated with menopause. However, a limitation in this field is that there is still a great heterogeneity among studies. Lastly, with regard to isoflavone consumption safety, it seems that they are safe and that the most common adverse effect is mild and occurs at the gastrointestinal level. Phenolic compounds are secondary metabolites, which are produced by plants as a defense mechanism against infection, water stress, cold stress, ultraviolet radiation and high visible light, among others ,2. PhenoIsoflavones have received attention due to their putative healthy properties. In this sense, it has been described that both isoflavones and other estrogenic molecules could mediate their beneficial effects due to two different mechanisms: the classical estrogen receptor (ER)-mediated signaling pathway and the activation of intracellular pathways such as protein tyrosine kinase, phospholipase C and mitogen-activated protein kinase (MAPK) ,6. In thFabaceae family) such as soy, white and red clover, alfalfa and beans [Isoflavones are found in several vegetables, mainly in legumes  in women who are at this stage in their life. Regarding this topic, three systematic reviews and three meta-analyses were analyzed .In the systematic review reported by Perna et al. (2016), nine studies addressed to menopausal women and focused on bone health were analyzed . The autWith regard to the published meta-analysis, the studies included were restricted to randomized controlled trials. The work reported by Lambert et al. (2017) included 26 trials with 2652 participants . It suppIn view of these results, we can conclude that there is scientific evidence that supports the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis in postmenopausal women. However, the results do not seem entirely conclusive, for there are discrepancies among the studies, probably related to their experimental designs. For this reason, the results should be interpreted with caution, and more randomized clinical trials are required.Although the mechanisms of action of isoflavones are not completely understood, it seems that isoflavones not only reduce the rate of bone resorption but also increase the rate of bone formation. The enhanced bone formation is due to the stimulation of osteoblastic activity mainly through (a) the activation of estrogen receptors because they bind to nuclear estrogen receptors and exhibit estrogenic activity due to its similarity to 17β-estradiol, and (b) the promotion of insulin-like growth factor-I (IGF-I) production ,55 Figu.In some Asian countries, isoflavone intake, usually derived from soy consumption, can be associated with a lower prevalence of cardiovascular diseases (CVDs). In this revision, three systematic reviews and five meta-analyses were included to explore the association of isoflavones and markers related to CVDs .n = 139) and post-menopausal (n = 1268) women, Perna et al. (2016) suggested that a daily intake of soy isoflavones, ranging from 20 to 100 mg/day, reduced total cholesterol and triglyceride plasma concentrations, as well as some markers of oxidative stress , thus reducing cardiovascular risk [n = 406 healthy, postmenopausal or obese participants aged 50–79 years) either in diastolic or systolic blood pressure, after a supplementation with soy-protein.In their systematic revision, which included 1307 menopausal , low evidence of isoflavones was shown in the prevention of cardiovascular diseases . The autTwo meta-analyses, which covered prospective cohort studies, showed that soy isoflavone consumption was not associated significantly with mortality linked to cardiovascular events ,62. IndeAdditionally, Yan and co-workers, in their meta-analysis with a total of ten prospective cohorts and seven case-control studies , observed that the consumption of soy foods, but not that of isoflavones, was associated with a lower risk of total cardiovascular disease (including coronary heart disease and stroke) . This fan = 802) [Lastly, Abshirini et al. (2020) revised the literature to find randomized controlled trials that evaluated the impact of soy protein supplementation (isoflavone intake ranging from 49.3 to 118 mg/day) on endothelial function parameters in postmenopausal women (n = 802) . Apparenn = 802) . Furthern = 802) . Howevern = 802) . The phyn = 802) . HoweverTaken as a whole, all these results suggest that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. It follows that additional high-quality, large-scale randomized controlled trials are needed.As far as the mechanisms of action involved in the decrease in triglyceride concentration are concerned, it has been reported that hepatic lipase and/or lipoprotein lipase activity may be increased as a result of isoflavone presence. Indeed, some authors speculate that hepatic and lipoprotein lipase activity may have been altered after variable isoflavone intake from soybean, although no experimental data were provided . Since hSome epidemiological studies indicate that the incidence of some types of cancer is lower in eastern countries than in western ones. This fact does not seem to be influenced by genetics since migrating from eastern to western countries appears to cause the loss of this protective effect. In this section, 16 meta-analyses have been revised: Nachvack et al. (2019) conducted a meta-analysis where 23 prospective studies with a total of 330,826 participants were included. The authors observed that soy isoflavone consumption was inversely associated with cancer deaths. Moreover, a higher intake of soy isoflavones was associated with a lower risk of mortality from gastric, colorectal, and lung cancers. Indeed, they reported that an increase of 10 mg/day of soy isoflavones consumption was associated with a 7% lower risk of cancer mortality .Regarding breast cancer , the samAnother meta-analysis, conducted by Zhao et al. (2019), included 16 prospective cohort studies involving 11,169 breast cancer cases and 648,913 participants . The autEndometrial cancer , as wellHua et al. (2016) conducted a meta-analysis aimed at ovarian cancer, which affects women exclusively . In thisWith regard to prostate cancer, it has been proposed that it might be affected by isoflavone consumption due to its effect on hormone metabolism. Four meta-analyses have been reported to address this issue. Pérez-Cornago et al. (2018) published a meta-analysis of seven prospective cohort studies  . In JapaDue to the high prevalence of colorectal cancer, three meta-analyses addressing this issue are included in the present review. He et al. (2016) conducted a meta-analysis of 18 studies involving 16,917 colorectal cancer cases in 559,486 participants . The resversus the lowest (0.01–20.1 mg/day) categories of dietary isoflavone intake. In this sense, the authors suggested that the composition of the gut microflora may influence isoflavone absorption and metabolism and could affect the production of isoflavone metabolites, which, in turn, could mediate their biological activity.Lastly, the association between dietary isoflavone intake and the risk of developing gastric cancer has also been analyzed. You et al. (2018) performed a meta-analysis of 12 studies, where six were cohort studies, and six case-control studies, with a total of 596,553 participants . The resOverall, evidence regarding the use of isoflavones in cancer prevention suggests that they may be useful in reducing the risk of suffering from some types of cancer, such as breast and endometrial cancer, two of the types for which the association between isoflavone intake and cancer risk has been studied more in-depth. However, all the authors agree that further studies are necessary so as to confirm these results. Indeed, the dose levels of dietary isoflavones require a better definition, and the measurements of isoflavone consumption should be provided in quantifiable terms.With regard to the mechanisms by which isoflavones act to reduce cancer risk, it has been suggested that the effects are due to the similarity of the isoflavone molecule to estradiol. This chemical feature confers estrogenic or antiestrogenic effects to isoflavones, depending on the cell type and the binding to α- or β-estrogen receptors. In this regard, it has been reported that isoflavones have a higher affinity to the β-estrogen receptor , which, Menopause is characterized by a decrease in estrogen levels and is often accompanied by a range of symptoms. Among these, vasomotor symptoms comprising hot flushes and night sweats are the most common and bothersome, which, in turn, have a negative impact on women’s quality of life. Hormone replacement therapy has been proven to be effective in reducing vasomotor symptoms, although isoflavones have gained popularity as an alternative treatment to hormone replacement therapy to relieve menopausal symptoms. This is mainly due to their potential adverse effects, which range from increased coronary heart disease to stroke and cancer ,85. ConcThe six meta-analyses show a slight improvement in the frequency and intensity of hot flushes. In the meta-analysis reported by Chen et al. (2015), the authors examined the efficacy of phytoestrogens in reducing hot flushes . The metSimilarly, Li et al. (2015) concluded that soy isoflavones have both a slight and slow effect in attenuating menopausal hot flushes . A totalDaily et al. (2019) studied whether equol supplementation could benefit equol nonproducer subjects in lowering the incidence and severity of hot flushes . Equol iAnother meta-analysis explored the effects of several pharmacological and non-pharmacological treatments in the relief of vasomotor symptoms, taking into account not only hot flushes but also night sweats . Non-phaFranco et al. (2016) also studied whether there was an association between different types of interventions and the reduction in hot flushes and night sweats . They peThe two systematic reviews conclude that isoflavones have an important role in reducing hot flushes ,53, althIn general, evidence regarding the use of isoflavones on vasomotor symptoms suggests that they could be useful in reducing hot flushes. However, there is still a great heterogeneity among studies, which makes the current data inconclusive. Regarding the mechanisms by which isoflavones act to alleviate vasomotor symptoms, is has been proposed that they bind to estrogen receptors and activate endothelial nitric oxide synthase (eNOS) transcription, leading to eNOS synthesis and nitric oxide production, the main mediator of vasodilatation, which allows cutaneous heat dissipation  Figure .Potential health adverse effects in the intake of isoflavones have been postulated due to their estrogenic activity, especially in relation to breast cancer. However, it is important to mention that this connection has been established based on pre-clinical studies, whereas data derived from clinical trials have not demonstrated such association . In factFinally, it is important to mention that despite the fact that potential isoflavone adverse effects have been widely studied, little is known about the side effect of the bacterial metabolite equol. As it has been stated in the Bioavailability section, microbiota composition in humans makes equol production very variable, which yields high interindividual differences. Reproductive and developmental toxicity studies have stated that 1 g and 2 g of equol per day is safe , althougIn view of the results gathered in the present review, we can conclude that there is scientific evidence that reveals the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis in postmenopausal women. Nevertheless, the results do not seem entirely conclusive, as there are discrepancies among the studies included in the systematic reviews and in the meta-analyses, probably related to their experimental designs. For this reason, the results should be interpreted with caution, and more randomized clinical trials are imperative. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering from some types of cancer, such as breast and endometrial cancer, although further studies are needed to confirm these results. In the end, isoflavones could be useful in reducing hot flushes associated with menopause. However, a limitation in this field is that there is still a great heterogeneity among studies. Altogether, these results show that further studies are needed in order to find stronger conclusions.Considering the isoflavone chemical structure, potential health adverse effects of these compounds related to their estrogenic activity have been postulated, despite the scientific opinion offered by EFSA indicating that isoflavone intake was safe.