This umbrella review aims to provide a systematic and comprehensive overview of current evidence from prospective studies on the diverse health effects of cheese consumption. We searched PubMed, Embase, and Cochrane Library to identify meta-analyses/pooled analyses of prospective studies examining the association between cheese consumption and major health outcomes from inception to August 31, 2022. We reanalyzed and updated previous meta-analyses and performed de novo meta-analyses with recently published prospective studies, where appropriate. We calculated the summary effect size, 95% prediction confidence intervals, between-study heterogeneity, small-study effects, and excess significance bias for each health outcome. We identified 54 eligible articles of meta-analyses/pooled analyses. After adding newly published original articles, we performed 35 updated meta-analyses and 4 de novo meta-analyses. Together with 8 previous meta-analyses, we finally included 47 unique health outcomes. Cheese consumption was inversely associated with all-cause mortality , cardiovascular mortality , incident cardiovascular disease (CVD) , coronary heart disease (CHD) , stroke , estrogen receptor-negative (ER−) breast cancer , type 2 diabetes , total fracture , and dementia . Null associations were found for other outcomes. According to the NutriGrade scoring system, moderate quality of evidence was observed for inverse associations of cheese consumption with all-cause and cardiovascular mortality, incident CVD, CHD, and stroke, and for null associations with cancer mortality, incident hypertension, and prostate cancer. Our findings suggest that cheese consumption has neutral to moderate benefits for human health. This umbrella review provides a systematic and comprehensive overview of current evidence on the association of cheese consumption with 47 major health outcomes through 35 updated, 4 de novo, and 8 previous meta-analyses of prospective observational studies. Although high saturated fat and sodium in some cheeses tend to be emphasized as a health concern in dietary guidelines, cheese also provides some nutrients and bioactive compounds that may confer some benefits.2, B2, B12, and folate), and probiotics and bioactive molecules , which may provide various health benefits. On the other hand, cheese contains relatively high contents of saturated fat and salt, which are perceived as unfavorable dietary components for cardiovascular health , or not written in English were also excluded. Studies with changes in cheese consumption rather than absolute intake as exposure, using substitution analysis, or using surrogate end points  as outcomes were removed. If more than 1 article reported the results for an identical outcome from the same study population (or cohort), only the one with the largest sample size, the longest follow-up, or the most complete information was included.From each included meta-analysis, the following information was extracted and verified by three investigators : the first author’s name, publication year, outcome of interest, study population , study design of the primary studies, type of comparison (highest compared with lowest category of cheese consumption or each increment in cheese consumption), number of included studies, number of participants and cases, and the reported summary risk estimates  with corresponding 95% CIs. For meta-analyses on over 1 health outcome, each outcome was recorded separately. For original studies, the extracted data covered information on the first author’s name, publication year, study design, study population characteristics, geographic location, number of participants and cases, length of follow-up (cohort study), dietary assessment method , cheese type, categorization and amount of cheese consumption, adjustment factors, and effect size with 95% CIs.The AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews) tool  was usedThe credibility of evidence was assessed using the NutriGrade scoring system . It compWe reanalyzed previous meta-analyses to obtain necessary information for subsequent assessment of the credibility of evidence. If the existing meta-analysis included cross-sectional, retrospective, and prospective studies, we only kept the results from prospective studies in our meta-analysis. Furthermore, we incorporated newly identified original studies into previous meta-analyses to update or derive de novo meta-analyses, where appropriate. For each outcome, we recalculated the summary risk estimates and their corresponding 95% CIs for the highest compared with the lowest category of cheese consumption and/or per 30-g/d increment in cheese consumption by using the random-effects model by DerSimonian and Laird . When reI2 statistic. We also performed subgroup analyses according to adjustment for total energy intake in the models (adjusted and unadjusted) and geographical location  to explore potential sources of heterogeneity. We computed 95% prediction intervals (95% PIs) to predict the effect size range of a future original study will lie after considering both the uncertainty in the mean effect and the heterogeneity from the random-effects model [P value of <0.10 was interpreted as the presence of small-study effects. The excess statistical significance test was performed to evaluate whether the observed number of nominally statistically significant studies was larger than their expected number using the χ2 test [P value of <0.10 was considered statistically significant.Heterogeneity across studies was investigated using ts model ,23. We ats model  if ≥3 st χ2 test . A P valP value for nonlinearity was calculated by testing whether the coefficient of the second spline was equal to 0 [We further examined the nonlinear dose–response association among studies that provided risk estimates with ≥3 exposure categories using a 2-stage restricted cubic splines  analysis ,27. The . No randomized controlled trials were eligible in this analysis; thus, all results were from prospective observational studies.The evaluation of methodological quality for previous meta-analyses using AMSTAR-2 is summarized in P = 0.0052; I2 = 34%)  (P-nonlinearity < 0.001)  . In the 2 = 60%) . Nonline< 0.001) A.FIGURE P = 0.015; I2 = 34%)  (P-nonlinearity = 0.004)  . In addi2 = 42%) , the non= 0.004) C. No ass= 0.004) .P = 0.91; I2 = 1%)  . The linI2 = 1%) . In addiI2 = 1%) .P = 0.0001; I2 = 38%)   (P<0.0001) (P = 0.0013) (P = 0.0023) (P-nonlinearity<0.001)  for overall CVD risk , 12 stud2 = 38%) , CHD (RR2 = 27%) , and strI2 = 0%) . Each 30<0.0001) , CHD (RR 0.0013) , and str 0.0023) . The nony<0.001) A–C. Cheey<0.001) .FIGURE 5P = 0.29; I2 = 21%)    (Forty-six studies  comprisi2 = 21%) . Meta-an2 = 29%) . Concern2 = 29%) ; colorec2 = 29%) ; total, 2 = 29%) ; total a2 = 29%) ; and oth2 = 29%)  but was I2 = 0%) . Linear I2 = 0%) . No nonlI2 = 0%) . In addiI2 = 0%) .P = 0.009; I2 = 45%)    when com2 = 45%) . The de 2 = 66%) . Similar2 = 66%)  and over2 = 66%) .P < 0.0001; I2 = 0%)  (P-nonlinearity < 0.0001)   (P-nonlinearity < 0.001)    . The metI2 = 0%) . The dos 0.0001) . Null as2 = 71%)  for the I2 = 0%) . Meanwhi< 0.001) . The de < 0.001)  and frai< 0.001) . MoreoveI2 = 0%) . In addi2 = 29%) .Seventeen original articles  reportedOf the 184 original studies included in the meta-analyses, 149 (81.0%) studies adjusted for total energy intake in the models, and 152 (82.6%) studies were conducted in North America, Europe, and Oceania. Among the 47 major outcomes in our study, 4 outcomes were solely based on studies without energy adjustment, 18 outcomes were only based on studies with energy adjustment, and 30 outcomes were entirely based on studies conducted in Europe, North America, and Oceania .P = 0.0305; I2 = 0%; P-subgroup = 0.02)  (P-subgroup = 0.03), the null association was consistent between subgroups. Meanwhile, an inverse association was detected for CHD mortality    and was  = 0.04)  in studi = 0.03)  in studiThe credibility of the identified associations with cheese consumption is summarized in This umbrella review provides a broad overview of the existing evidence on the association between cheese consumption and 47 unique outcomes through 35 updated, 4 de novo, and 8 previous meta-analyses based on 184 prospective observational studies from 145 primary articles. Moderate quality of evidence showed that cheese consumption was associated with reduced risk of all-cause mortality, CVD mortality, and incident CVD, CHD, and stroke but not related to the risk of cancer mortality, hypertension, and prostate cancer. Low quality of evidence was observed for inverse associations of cheese intake with incidence of ER− breast cancer, T2D, total fracture, and dementia and null association with site-specific cancer mortality , CHD mortality, and incidence of overall, site-specific cancer and its subtypes , overweight/obesity, hip fracture, and fall. The nonlinear dose–response analyses additionally suggested a U-shaped association between cheese consumption and the risk of all-cause mortality and cardiovascular mortality and an L-shaped association with the risk of overall CVD, CHD, stroke, and total and hip fractures with the optimal intake at ∼40 g/d.Although cheese is theorized to have detrimental effects on blood pressure and blood lipid profile based on its high sodium and saturated fat contents, a moderate quality of evidence suggest that cheese consumption does not increase the risk of cardiovascular diseases and may even have protective associations with overall CVD, CHD, and stroke incidence and cardiovascular and all-cause mortality in our updated meta-analyses. The inverse associations are in line with findings from most previous meta-analyses ,39,40,42Results from pervious meta-analyses ,60,216 aWe found a low quality of evidence for an inverse association between cheese consumption and T2D risk in the highest compared with that of the lowest intake, which is in accordance with previous meta-analyses ,68. SubsDairy products are rich in calcium, magnesium, phosphorus, and protein, which are essential for good bone health ,222. NevAdditionally, low quality of evidence also showed that higher cheese intake was associated with a lower dementia risk in our de novo meta-analysis of 2 prospective cohort studies ,198. The2 in many regions [2 can improve cardiovascular health by inhibiting and reversing vascular calcification [The protective association of cheese consumption with mortality, CVD, bone fracture, and dementia may be attributed to the abundance of nutrients, bioactive compounds, and probiotics in cheese. Dairy products, especially cheese, are a predominant dietary source of vitamin K regions ,228. Vitfication ,230, redfication . Probiotfication , exertinfication . Additiofication . Besidesfication  because 2D3  because urate and 1,25(OH)2D3 may protect against Parkinson’s disease [It is noteworthy that a borderline positive association between cheese intake and Parkinson disease risk was observed in a previous meta-analysis of 5 cohort studies, which accords with findings from the latest meta-analysis on total dairy and milk  and 1 re disease ,243. How disease ,245. AccThis umbrella review provides the most recent evidence from prospective observational studies on the association between cheese intake and a wide range of health outcomes. Different from traditional umbrella reviews focusing only on published meta-analyses, we thoroughly and systematically resynthesized the available evidence by incorporating newly identified prospective studies into prospective studies included in previous meta-analyses. On one hand, we updated those outdated meta-analyses to reflect up-to-date conclusions with more statistical power. On the other hand, we performed de novo meta-analyses for specific health outcomes without previous meta-analyses despite enough published original studies to include as many potentially related health outcomes as possible. Furthermore, dose–response analyses were conducted to reveal further the linear and nonlinear association between cheese intake and multiple health outcomes, thereby determining the optimal consumption level of cheese.I2 ≥ 50%), probably due to the inclusion of original studies involving different populations. Also, caution should be taken when generalizing the conclusions to populations with different genetic backgrounds and dietary habits because most primary studies included were conducted in Europe and North America. Moreover, different types of cheese also vary a lot in dairy matrix and nutrient content like fat and sodium, which may deliver divergent health effects. However, the lack of information on cheese type deterred finer stratified analyses by cheese type. Finally, the limited number of prospective observational studies in meta-analyses for cheese consumption and specific health outcomes—such as cancer at sites other than colorectum, breast, and prostate, overweight/obesity, dementia, fall, and frailty—leads to insufficient statistical power and low credibility of evidence. Thus, further large-scale prospective studies are warranted to ascertain the association of cheese intake with these health outcomes.There are also some limitations in our research. Given that the original studies included in this review are all observational, some of their inherent limitations could not be excluded, such as residual confounding and reverse causality. Besides, the updated meta-analyses for some health outcomes are highly heterogeneous (Our results indicate that cheese consumption has neutral to moderate benefits for human health, particularly ≥40 g/d, with a moderate quality of evidence for inverse associations with all-cause and CVD mortality and overall CVD, CHD, and stroke incidences. Null associations were observed with cancer mortality, hypertension, and prostate cancer incidence. Although high saturated fat and sodium in some cheeses tend to be emphasized as a health concern in dietary guidelines, cheese also provides some nutrients and bioactive compounds, which potentially may confer some benefits. Environmental effects of cheese production should also be considered.The authors’ responsibilities were as follows—AF, YW: conceived the study; AF: designed the study; MZ, XD, ZH: performed the literature search and screening and extracted the data; MZ, XD: conducted the data analyses and drafted the manuscript; AF: revised the manuscript; ELG, XL: critically reviewed the manuscript; AF, ELG: had primary responsibility for final content; and all authors: contributed substantially to the interpretation of the data and read and approved the final manuscript.The authors report no conflicts of interest.All data included in this umbrella review were extracted from publicly available systematic reviews and original studies.


Anterior cruciate ligament injuries (ACLIs) are one of the most common knee injuries in sports. Although numerous factors have been related to the risk of ACLIs, it is still unclear why some individuals are more susceptible than others due to the intricate etiology of ACLIs. Several genetic factors have been identified as contributing to ACLIs. This systematic review summarizes the current evidence regarding the genetic causes of ACLIs based on the available literature. Five electronic databases were searched from 2017 to 2022. All titles, abstracts, and full texts were reviewed in detail to determine the inclusions and exclusions. The Newcastle-Ottawa Scale was used to evaluate the risk of bias. The studies' characteristics and results are presented in both narrative and tabular formats. A total of 24 studies examined 31 genes and 62 variants associated with ACLIs in the global population. Ten studies investigated seven collagens and ten SNPs for the ACL injury. The majority of studies found no significant difference in the association of the COL1A1 rs1800012, COL5A1 rs12722, VEGFA rs1570360, IL6R rs2228145, IL6 rs1800795, IL1B rs16944 and rs1143627, however, contrary results were found when nationality and gender were considered together. Conflicting evidence was found for polymorphisms rs2010963, rs699947 of the VEGFA gene in different studies. Due to a lack of data, it was impossible to determine the relationship between the anterior cruciate ligament rupture (ACLR) and the other polymorphisms. More research is required to establish a clear relationship between the ACLR and genetic variants, particularly when gender and nationality are taken into account separately. Anterior cruciate ligament (ACL) injuries are one of the most common knee injuries in sports , and morAn ACL injury is attributed to extrinsic and intrinsic mechanisms. Extrinsic factors are those that can be adjusted to decrease the risk of ACL injury such as the playing surface and exercise intensity. However, although numerous factors have been related to the risk of ACL injury, it is still unclear why some individuals are more susceptible than others due to the intricate aetiology of ACL injuries. Female athletes, for example, have a higher risk of ACL injury than male athletes  in both In recent years, there has been an increasing amount of evidence supporting the hypothesis that genetic sequence variants play a significant role in the ACL rupture occurrence , with siIn this study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for reporting . This syStudies were considered for inclusion in the systematic review if they satisfied the following criteria: a case-control, cohort, cross-section and randomized controlled experiment that investigated genetic influences on the ACL injury in humans. Studies with previous systematic reviews, animal studies, book chapters, letters, editorials, conference abstracts, and review articles were disregarded. Furthermore, studies not written in English, without full-text were eliminated. Also studies with fewer than ten participants were not taken into consideration.st of January, 2017 to the 18th of September, 2022 without language restriction, however, only articles in English were taken into consideration. The following search strategy was applied:  AND  AND (2018:py OR 20 1 9:py OR 2020:py OR 2021:py OR 2022:py).The electronic databases PubMed Central, Web of Science, Cochran Library, Embase and Scopus were searched from the 1Using the aforementioned search strategy, results were searched by the first author, and all of the results were imported into a reference manager (Endnote Vision X9.3.3) to remove duplicates. Two authors independently reviewed the results. Titles and abstracts were used as the initial criteria for selecting suitable studies. If an abstract did not provide sufficient information, full-texts were examined. In the event of discrepancies between two authors, the final decision was made by a third reviewer.Data from the included studies were extracted independently by two reviewers. Extracted data items included the author's name, the year of publication, the country or the region, ethnicity of research, the study design, the gene's name, a detailed genotype frequency of cases and controls, authors' definitions of cases and controls, sample size (case and control), sample types, training background of research subjects.To evaluate the potential risk of bias in case-control, cohort and cross-section studies, the Newcastle-Ottawa Scale (NOS)  was usedAfter analyzing the included studies, it was determined that meta-analysis was not appropriate due to the diversity of genetic variations and the heterogeneity of the risk of bias between investigations. The same genetic variants from multiple studies were compared and evaluated to determine whether genetic variables contributed to the ACLR. As a result, the findings are described in a narrative but systematic review.From all databases, a total of 392 studies were retrieved. Two authors independently assessed the titles and abstracts of 291 papers after 101 duplicates were eliminated. Next, 242 and then 25 records were excluded after reading the title/abstract and the full text, respectively. Finally, 24 full text studies that met the criteria for inclusion were examined .This systematic review included twenty-four papers published between 2017 and 2022 in English, with summary features presented in The NOS was utilized to assess the study's quality, and the rating greater than six indicated exceptional quality. Three papers received eight points, eleven articles received seven points, seven studies received 6 points, and only three studies were rated as of low quality .p > 0.05). However, when individuals of European ancestry  were combined, the rs1800012 TT genotype (TT vs. GT + GG) was significantly over-represented in the control group compared to the ACLR group , which confirmed a strong link between rs1800012 and the ACL risk (p < 0.03) (Ten studies investigated seven different collagens and ten single nucleotide polymorphisms (SNPs) with regard to the ACLR. Some studies showed the same results with no significant difference in the association of the COL1A1 rs1800012  variant ACL risk . The A a < 0.03) . Perini p = 0.006). COL5A1-IL1B-IL6 allele T-C-G combination was significantly underrepresented (p = 0.034) in the Swedish male cohort control group , and rs240736 of COL12A1 played a significant role in the ACL injury in Chinese men . COL12A1 rs970547 and rs240736 may present a high risk of the ACLR in the Chinese male population , but not in the European population . The AA p = 0.021), however, no association was found for MMP8 (rs11225395C/T), and TIMP2 (rs4789932 G/A) regarding the ACL injury.The evidence was insufficient to support the influence of MMP genes on the non-contact ACL rupture risk. p = 0.039, OR = 3.06)  .Conflicting evidence was found for polymorpsims rs2010963, rs699947 of VEGFA gene in different studies. p = 0.035, OR = 2.3).Two studies analyzed the relationship between the TNC gene and the ACL risk. p = 0.041) in Polish participants. When female and male participants were analyzed together, no significant differences in the genotype and allele distributions were noted for the DCN rs516115. In the male ACLR group, the A allele of rs1042103 (OR = 1.5) was found to be significantly over-represented, however, there were no reported significant genotype differences for the ACAN rs1516797.When gender was considered, conflicting results were found for the BGN rs1042103 and rs1126499  between the two groups. The GG genotype was more prevalent in the control group than in the ACL group . However, there were no significant differences in the genotype or allele frequency for TGFBR3 rs1805117 T > C between all groups and after sex stratification.Two studies investigated the effects of transforming the growth factor and tumor necrosis factor Adipokine and cytokine on ACL injury. The limited evidence was found for the lack of association between CASP8  , B-fibriResearchers for a long time have been interested in whether genes have a significant impact on the ACL injury. Despite the fact that numerous studies have found a link between a genetic variation and the ACL injury, conflicting results have been reported regarding the connection between single nucleotide polymorphisms (SNPs) and the ACL rupture. According to our findings, some SNPs may contribute to the ACL risk, however, more research and a larger sample size are needed for to draw a firm conclusion. This systematic review included 24 carefully designed studies published in the last six years to summarize the potential genetic variants associated with the ACL injury, and new outcomes were presented based also on previous articles by The majority of research has concentrated on the genes that encode for collagens, matrix metalloproteinases, interleukins, and cell signaling molecules. Previous studies have also shown that sequence variants with these genes are associated with other musculoskeletal injuries, for instance, rotator cuff tearing  and AchiClearly, genetic expression differences for the ACL injury exist among populations in various countries. In the Sivertsen et al.'s(2019) study, the C allele of the SNV in the COL12A1 gene differed between the Norwegian and Finnish cohorts, and the A allele of rs1800012 in the COL1A1 gene was more abundant in the Norwegian cohort than in the Finnish one. Another noteworthy finding is that studies by The limitations of this systematic review were that we were unable to assess the database using meta-analysis due to the diversity of genetic variations and the heterogeneity of the risk of bias between investigations. Additionally, some of the included studies used the same participants for analysis of different genes and polymorphisms, which was likely to increase the risk of bias in the results. When it comes to determining the risk of the ACL rupture, genetic tests can be a valuable tool, especially when it comes to assessing athletes, to determine their risk level. However, the results of candidate gene tests should only be used as part of a multifactorial risk model. To accurately assess the risk of sports injuries, we still need to identify specific genes that increase the risk of ACL injuries and use genetic screening as a diagnostic tool.More research is needed to establish a clear link between the ACL rupture and genetic variants, particularly gender and nationality, that need to be considered separately. Furthermore, these findings should be validated in a larger sample of subjects from around the world.


A high fruit and vegetable intake has been associated with reduced risk of hypertension; however, results have been inconsistent and it is unclear whether specific types of fruits and vegetables are particularly beneficial. This systematic review and meta-analysis aimed to summarize the published prospective studies on fruit and vegetable consumption and risk of hypertension.Embase and PubMed databases were searched for relevant prospective studies up to 15th May 2022. Random effects models were used to calculate summary relative risks (RRs) and 95% confidence intervals (CIs) for the association between fruit and vegetable intake and risk of hypertension. Strength of evidence was assessed using World Cancer Research Fund (WCRF) criteria.I2 = 68%, n = 8) for fruits and vegetables, 0.93  for fruits, and 1.00  for vegetables. Reductions in risk were observed up to 800 g/day for fruits and vegetables, and 550 g/day for fruits, and these two associations were considered probably causal using WCRF criteria. Inverse associations were observed for apples or pears, blueberries, raisins or grapes, avocado, broccoli, carrots and lettuce, while positive associations were observed for cantaloupe, Brussels sprouts, cruciferous vegetables, and total and fried potatoes (n = 2–5).Eighteen prospective studies  were included. The summary RR (95% CI) of hypertension per 200 g/day was 0.97 (0.95–0.99, A high intake of fruit and vegetables combined, and total fruit was associated with reduced risk of hypertension, while results for fruit and vegetable subtypes were mixed and need further study.The online version contains supplementary material available at 10.1007/s00394-023-03145-5. Hypertension is a growing public health concern worldwide and the number of people aged 30–79 years with hypertension doubled from 331 million women and 317 million men in 1990 to 626 million women and 652 million men in 2019, respectively .Dietary factors are of importance for the prevention of hypertension and a range of chronic diseases including cardiovascular disease, cancer, and type 2 diabetes, as well as all-cause mortality , 10. A hHowever, the results have not been entirely consistent. Of studies that assessed the association between fruit and vegetables combined and risk of hypertension, half of the studies reported clear inverse associations , 15, 20,This review was reported in accordance with the PRISMA  statement . Both thPubMed and Embase databases were searched for relevant studies from inception up to 15th May 2022 on fruit and vegetable intake and hypertension. The search terms used for the PubMed and Embase searches are shown in the Supplementary Text. We also searched the reference lists of previous meta-analyses , 40–42 aReference Manager version 11 was used for the literature screening. Titles and abstracts of each record were screened initially, and full texts of articles that were considered potentially relevant were obtained for a final decision on whether the study should be included. Prospective and retrospective cohort studies, nested case–control studies within cohorts and case-cohort studies which reported adjusted relative risk estimates  for the association between fruit and vegetable intake and risk of incident hypertension in generally healthy adults without hypertension at baseline were included. Retrospective case–control studies were excluded because of the potential for recall and selection biases and cross-sectional studies were excluded because of the lack of temporality between the exposure and the outcome. In addition, studies reporting unadjusted risk estimates, studies without data on fruit and vegetable consumption or hypertension or elevated blood pressure, abstract only studies, and studies reporting on blood pressure as a continuous measure, and duplicates were excluded and a list of the excluded studies and exclusion reasons is provided in Supplementary Table 1. When multiple articles were available from the same study, we used the publication with the most detailed data on fruit and vegetables and hypertension. The first part of the screening  was done by HM, and the second part of the screening (366 selected records) were done in duplicate by DA and HM. Disagreements were resolved through discussion.Relevant data was extracted from each study including: name of the first author, publication year, geographic location, name of the study, recruitment and follow-up period, sample size, age, sex, number of cases, dietary assessment method, exposure , quantity or frequency of intake, relative risks , and confounders adjusted for in the analysis. Extracted data are shown in Supplementary Table 2. The data extraction was done by HM and was checked for accuracy by DA.A modified version of the Newcastle–Ottawa scale for cohort studies was used to assess the quality of the included observational studies . The modWe used World Cancer Research Fund criteria for evaluating the strength of the evidence . This grDiagnosis of hypertension was defined in most studies as SBP ≥140 mm Hg and/or DBP ≥ 90 mm Hg, or SBP ≥ 135 mm Hg and/or DBP ≥85 mm Hg, by a medical diagnosis of hypertension or if the subject received antihypertensive drug therapy. Elevated blood pressure was defined as SBP ≥130 mm Hg, and/or DBP ≥85 mm Hg .The random effects model by DerSimonian and Laird, which take into account heterogeneity within and between studies, was used to calculate summary relative risks (RRs) and 95% confidence intervals (CIs) for the association between fruit and vegetable intake and hypertension . The metQ- and I-squared (I2) statistics [E-values were calculated to estimate the strength of an unadjusted confounder that could explain away the observed associations [E-value is defined as the minimum strength an unmeasured or uncontrolled confounder would have with both the exposure and the outcome to fully explain away the observed associations. Publication bias was assessed with Egger's test [Heterogeneity between studies was evaluated with atistics . Subgrouciations . The E-vr's test , Begg’s r's test . All staThe data extracted and analysed were from already published and ethically approved studies, thus ethical approval was therefore not needed for this review.Out of the total 17566 records screened, 366 articles were examined and evaluated in full text. Out of these 366 articles, 345 articles were excluded for not meeting the inclusion criteria (Supplementary Table 1). Eighteen cohort studies (21 publications) met the pre-specified inclusion criteria and were included in the analysis of fruit and vegetable intake and risk of incident hypertension or elevated blood pressure , 35–37 . This indicates moderately high methodological quality of the studies. The main quality issues were self-report of hypertension diagnoses and limited reporting on adequacy of follow-up.I2= 58.7%, pheterogeneity=0.01)   or with Begg’s test (p = 0.54), although there was some asymmetry in the funnel plot . There was no evidence of a nonlinear association for fruits and vegetables, Pnonlinearity = 0.23, and there was an 11% reduction in risk at an intake of 800 g/day compared to 40 g/day  with 102 395 cases among 346 613 participants were included in the analysis of high vs. low intake of fruits and vegetables and risk of incident hypertension , 22–25. I2= 62.6%, pheterogeneity=0.001)  , Begg’s test (p = 0.37), although slight asymmetry was observed in the funnel plot  due to one outlying study [Pnonlinearity = 0.23, but there was a 19% reduction in risk at an intake of 550 g/day compared to 8 g/day  with 134 798 cases among 329 029 participants were included in the analysis of high vs. low intake of fruit and risk of incident hypertension or elevated blood pressure , 24–28. I2 = 0.0%, Pheterogeneity =0.89)  , Begg’s test (p=0.25) or by inspection of the funnel plots . There was no evidence of a nonlinear association for vegetables, Pnonlinearity = 0.09  with 98 484 cases among 248 490 participants were included in the analysis of vegetable intake and risk of incident hypertension or elevated blood pressure , 27, 28.see Fig. e. The suI2 = 0%, Pheterogeneity = 0.99) for “apples or pears”, 0.84  for blueberries, 0.80  for “raisins or grapes”, and 1.09  for cantaloupe  for apples and pears and 0.91  for “raisins or grapes”. There was no evidence of nonlinearity for the associations between “apples or pears”, bananas, blueberries, oranges, “peaches, apricots, plums”, prunes, “raisins or grapes”, and strawberries and hypertension, but a suggestive nonlinear weak positive association was observed for cantaloupe, Pnonlinearity = 0.05 (Supplementary Tables 6–8).Some studies investigated the association between subtypes of fruit and hypertension  , 25  for avocado, 0.88  for broccoli, 0.90  for carrots, 0.92  for lettuce, 1.25  for Brussels sprouts, 1.11  for cruciferous vegetables, 1.11  for cabbage, 1.10  for corn, 1.04  for yams or sweet potatoes, and per 200 g/day was 1.12  for potatoes , and 1.31  for potatoes (fried)  (Supplementary Table 12). There was no evidence of nonlinearity in the analyses of the remaining vegetable subtypes and hypertension (Supplementary Tables 9–12).Among subtypes of vegetables and risk of hypertension, inverse associations were observed in the meta-analyses of intakes of avocado, broccoli, carrots, and lettuce and hypertension, while positive associations were observed between intakes of Brussels sprouts, cabbage, corn, potatoes (fried), potatoes  and “yams or sweet potatoes” and hypertension , 35–37 . There was no between subgroup heterogeneity when using meta-regression analyses, with the exception of the subgroup analysis of fruit and vegetables and hypertension stratified by number of cases, where studies with a lower number of cases showed stronger associations than those with a larger number of cases, and for the subgroup analysis of fruits and hypertension stratified by cut-off values for hypertension, where a stronger association was observed among the studies that used lower cut-off values than among the studies using a higher cut-off value (Supplementary Table 13).E-values for the highest level of intake based on the nonlinear dose–response analyses were 1.49 (lower CI 1.24) for fruits and vegetables combined (800 vs. 40 g/d) and 1.76 (lower CI 1.40) for total fruits (550 vs. 8 g/d).The estimated Using World Cancer Research Fund criteria for evaluating evidence (42) (Supplementary Table 4), we considered the overall evidence to be supportive of a probably causal relationship between fruit and vegetable intake combined and total fruit and the risk of hypertension, and limited-no conclusion for vegetables (Supplementary Tables 14–15). A justification for these judgements is found in Supplementary Table 14 and included clear inverse associations for fruits and vegetables combined and for fruits in high vs. low, linear and nonlinear dose–response analyses, moderate heterogeneity driven mainly by differences in the size of the effect estimates, and results were in general robust in subgroup and sensitivity analyses. In addition, biologically plausible mechanisms exist and there is data from randomized controlled trials that fruits and vegetables and certain nutrients found in fruits and vegetables can reduce blood pressure. These data are also consistent with randomized trials on dietary patterns high in fruit and vegetables, such as the DASH-diet, Mediterranean diet, and vegetarian and vegan diets which have been shown to reduce blood pressure. Subtypes of fruits and vegetables were in the category of limited-suggestive and limited-no conclusion, mainly because of the few studies available.The findings from this meta-analysis of 18 cohort studies suggest that high vs. low intakes of fruit and vegetables are associated with a 9–11% reduced risk of hypertension. Inverse associations were observed both for intake of fruit and vegetables combined and for total fruit in the dose–response- and high vs. low analyses, whereas the results for vegetables were null. There was no evidence of nonlinearity, but there was an 11% reduction in risk at an intake of 800 g/day compared to 40 g/day for fruit and vegetables combined, and a 19% reduction in risk at an intake of 550 g/day compared to 8 g/day for fruit. Several subtypes of fruits were inversely associated with risk of hypertension in the dose–response analyses including “apples or pears”, blueberries, and “raisins or grapes”, while a positive association was observed for cantaloupe. Among subtypes of vegetables, inverse associations were observed in the dose–response analyses for avocado, broccoli, carrots, lettuce, and positive associations were observed for Brussels sprouts, cruciferous vegetables, fried potatoes, total potatoes and hypertension. Nonlinear positive associations were observed for cantaloupe and fried potatoes.The findings from this meta-analysis are consistent with the results from two previous meta-analyses that also found inverse associations between fruit and vegetable consumption combined and risk of hypertension , 40. ComThis study summarizes the findings from prospective cohort studies, which have the advantages of being less prone to selection bias and avoids recall bias. Combination of results from multiple cohort studies increases the statistical power to detect associations as several individual studies may have been too small and underpowered to detect an association. All the studies were considered to have moderately high methodological quality (see Supplementary Table 3). The dose–response relationship between fruit and vegetable intake and hypertension was investigated using both linear and nonlinear dose–response analyses and the results persisted across multiple subgroup and sensitivity analyses, suggesting that the overall findings were robust.E-values for the highest level of fruit and vegetable intake combined was 1.49 (lower CI 1.24) (800 vs. 40 g/d), and for total fruit was 1.76 (lower CI 1.40) (550 vs. 8 g/d), respectively, suggesting that an unadjusted confounder would have to have a moderate to strong association with both fruit and vegetable intake and hypertension to fully explain away the observed association. On the other hand, although BMI is often considered a confounder in such analyses, it is possible that BMI could be a mediator as high fruit and vegetable intake has been associated with lower risk of general and abdominal obesity, and lower weight gain over time [The study also has some potential limitations as it could be affected by biases that can affect observational studies. Confounding by other risk factors that have not been adjusted for or by unknown confounders is difficult to completely rule out. Fruit and vegetable consumption is typically associated with other health behaviors, such as physical activity, lower prevalence of smoking and alcohol consumption, and other dietary factors, that may themselves be associated with reduced hypertension risk, and could potentially confound the association between fruit and vegetable consumption and hypertension. Many of the included studies adjusted for a range of confounding factors and most of the results persisted in subgroup analyses when stratified by adjustment for confounding factors, and there was no evidence of heterogeneity between subgroups. In addition, some risk factors that were adjusted for in the statistical analyses may to some degree correlate with other unadjusted confounders, thus indirectly capture adjustment for some unknown or unadjusted confounders. The estimated ver time –34. If aThere is also the risk of publication bias because studies that have statistically significant results are more likely to be published than studies with non-significant findings. Publication bias was assessed using Egger’s and Begg’s test and by inspection of funnel plots. There was no evidence of publication bias with the statistical tests used in the analyses of fruit and vegetables and hypertension, but there was indication of potential publication bias in the high vs. low analyses for fruit and hypertension, and vegetables and hypertension, however, this appeared to be driven by 1–2 outlying studies which did not substantially alter the results when excluded. There were few studies included in the analyses of subtypes of fruits and vegetables with only 2–5 studies included in each analysis. Further studies are therefore needed of specific subtypes of fruits and vegetables and hypertension risk.The studies used different methods to assess the exposure and the outcome, and this may have influenced the results. Both measurement errors in dietary intake and changes in diet during follow-up is likely to lead to bias toward the null in cohort studies, resulting in underestimation of the association between dietary intake and the outcome of interest. However, there can also be measurement errors in the confounders, which sometimes can lead to residual confounding and overestimation of the association between the main exposure and the outcome, but presumably measurement of other risk factors such as weight, height, smoking and physical activity is less complex than diet, which typically includes 100–200 or more food items, thus potentially resulting in less error than measurement of diet. Most of the studies excluded participants with unrealistic energy at baseline that were likely to have substantially misreported their dietary intake. There were also some differences in the ways the outcome was measured. Blood pressure was either measured by the investigators or relied on self-report. Self-reported diagnosis of hypertension can be a potential limitation because there are no symptoms and cases could be underreported; however, some studies suggest the validity of this measure . AlthougSeveral possible mechanisms could explain the association between fruit and vegetable consumption and reduced risk of hypertension , includiThis meta-analysis provides a summary of the available evidence on fruit and vegetable consumption and risk of hypertension, and can be useful in further refining dietary guidelines given the global rise in hypertension prevalence. The results provide further support for dietary guidelines that recommend increasing the consumption of fruit and vegetables, and suggest a clear dose–response relationship with increasing intake up to 800 grams/day, which is consistent with data on other outcomes . CliniciThis meta-analysis found that a high intake of fruit and vegetables combined and total fruits, but not total vegetables, was associated with reduced risk of hypertension, and supports dietary recommendation to increase the consumption of fruit and vegetables as part of strategies to prevent hypertension. The association appeared to be linear up to an intake of 800 grams per day for fruits and vegetables combined. Specific types of fruits and vegetables appeared to be beneficial including apples and pears, avocado, blueberries, raisins or grapes, broccoli, carrots, lettuce, and onions, while cantaloupe, potatoes, and Brussels sprouts were associated with increased risk, however, further cohort studies are needed before firm conclusions can be drawn regarding subtypes of fruits and vegetables.Supplementary file1 (PDF 792 KB)Supplementary file2 (PDF 1323 KB)Below is the link to the electronic supplementary material.


Although the association between maternal exposure to antibiotics and the risk of atopic dermatitis (AD) in childhood has been studied extensively, there still is a lack of clarity on the topic. The aim of this study was to summarize the published data and to examine if maternal exposure to antibiotics increases the risk of AD in childhood.Systematic search was performed in PubMed, Scopus, Web of Science, and Embase for all types of studies on the review subject independent of any language restrictions and published up to 28th December 2022. Data was analyzed using random-effects model and presented as pooled odds ratio (OR) with 95% confidence intervals (CI).I2 = 85%, p = 0.0003). The significance of the results was not affected by the location of the study (Asia or Europe). While subgroup analysis based on exposure assessment or diagnosis of AD demonstrated a tendency of increased risk of AD, the association was not statistically significant in multiple subgroups. Segregating data based on the timing of exposure did not affect the significance of the results for studies on all trimesters. However, there was no association between antibiotic exposure in the third trimester or just before delivery and the risk of childhood AD.A total of 18 studies  were included. Maternal exposure to antibiotics was associated with an increased risk of AD in childhood (OR: 1.14, 95% CI: 1.06, 1.22, The results of this meta-analysis suggest that maternal exposure to antibiotics may lead to a modestly increased risk of AD in offspring. The evidence is limited by high interstudy heterogeneity and bias in exposure and outcome assessment. Future studies are needed to explore if the timing of exposure, the dose, the number of prescriptions, and the type of antibiotic affect this association.https://www.crd.york.ac.uk/prospero/, identifier CRD42023387233. Atopic dermatitis (AD) is a common, chronic, and recurring inflammatory skin disease of childhood. It is characterized by intense itching, dryness, and eczematous lesions . StudiesDuring the last decade, clinicians focused on identifying risk factors for AD which can be modified to reduce disease prevalence. One such factor is maternal exposure to antibiotics which has been linked with several allergic diseases –8. WomenThe relationship between maternal exposure to antibiotics and the risk of AD has been a subject of research in multiple studies –8 but wiThe PROSPERO registration (No. CRD42023387233) of the review was completed before the beginning of the study. The review conformed to the standard instructions of the PRISMA statement .The search strategy was completed independently by two reviewers. Systematic electronic literature search of PubMed, Scopus, Web of Science, and, Embase was done. Since these databases are not comprehensive, a Google Scholar search was also conducted for gray literature. The search was independent of any language restrictions and publication dates, and was completed on 28th December 2022. The terms “eczema”; “atopic dermatitis”; “pregnancy”; “maternal”; “prenatal”; “antimicrobials”; and “antibiotics” formed the various search strings used for the literature search . The seaPopulation- Mother-child pairsExposure- Exposure to antibiotics before birthComparison- No exposure to antibioticsOutcome- AD in childhood (<18 years of age) [Outcome was to be reported as adjusted effect size with 95% confidence intervals (CI)]Study type- All typesExclusion criteria were: (1) studies not specifically on AD and reporting data on all allergic diseases combined (2) studies not reporting adjusted outcomes (3) studies not reporting exclusively on AD in childhood (4) studies with overlapping or duplicate data. In such cases, the study with the largest sample or the most comprehensive data was selected.The standardized PECOS inclusion criteria were used to select eligible studies. The criteria for each domain were as follows:Two authors extracted the following data in separate forms: author's last name, database of the study, country of origin, study type, sample size, children's age range, method of antibiotic exposure assessment, the timing of exposure, diagnosis of AD, factors adjusted in the data analysis, and effect size. If studies reported multiple ratios of the association for different subgroups, these were combined using the meta-analysis software to generate a single combined ratio. No restrictions were placed on the method of exposure assessment, the timing of exposure, or the diagnosis of AD. All methods reported by the studies were acceptable.Quality assessment was conducted using the Newcastle-Ottawa scale (NOS) . Every sI2 statistic tool was used for inter-study heterogeneity. Values of >50% indicated high heterogeneity. Funnel plots were used for publication bias. The robustness of the results was checked by excluding one study at a time in a sensitivity analysis. P-values <0.05 were considered statistically significant. Subgroup analyses were conducted based on study location, study type, sample size, exposure assessment, diagnosis of AD, and timing of exposure.The meta-analysis was performed using “Review Manager” . Effect ratios from the studies were combined in a random-effects model to calculate pooled odds ratio (OR) with 95% confidence intervals (CI). The κ = 0.9).Systematic literature search across all databases resulted in 1,238 studies. Of them, 844 were removed as duplicates. Of 394 articles, 31 studies were selected for complete text review. Thirteen studies failed to meet the eligibility criteria. Finally, 18 studies were included in the review , 20–31 . The intAll 18 studies were from Asian or European countries . Most ofI2 = 85%, p = 0.0003)  . The fun 0.0003) . There wThe results of subgroup analyses are shown in Lactobaccillus and Bifidobacterium  heterogeneity. This inter-study heterogeneity may be explained by the varied study populations and methodological differences in the included studies. Multiple subgroup analysis that was performed to assess the source of heterogeneity showed that the results were not affected by the study location and sample size. A slightly increased risk of AD was noted in Asian vs. European studies (53% vs. 12%) but this could be due to a smaller proportion of Asian studies in the review. Also, most of the studies included in the review were predominantly prospective cohort studies. The risk of AD was increased in both study types but just lost statistical significance in the case of only prospective studies.Assessment of exposure and outcomes can also be a major source of bias. Assessment of antibiotic exposure from medical records and clinical diagnosis of AD is more reliable that self-reported data which can be a subject of recall bias. There is always a possibility of mistaken reporting of drugs used by the women, or reporting other symptoms for AD. However, no marked difference was noted in the subgroup analyses, and all results remained statistically significant or showing a tendency of increased risk of AD.According to the altered gut microbiota theory, the timing of maternal antibiotic exposure should be an important variable influencing the risk of AD. Theoretically, very early exposure to antibiotics should have minimal impact as there is still enough to restore the maternal microbiota. However, research shows that certain classes of microorganisms, eliminated by antibiotics, are not restored even after nine months . LiteratThis review should be interpreted with the following limitations. The pathophysiology of AD is complex with a number of confounding factors such as maternal smoking, socioeconomic status, parental history of allergy, infant gender, birth weight, delivery mode, breastfeeding, pet contact, etc., . While oIn terms of the clinical significance, our review demonstrated that while maternal exposure to antibiotics led to a higher risk of AD in offspring, the increased risk was modest at 14% (6%–22%). Given the high inter-study heterogeneity and bias in the included studies, our results do not recommend avoiding antibiotics in pregnancy. The prescription of antibiotics in pregnancy should be carefully considered after evaluating the risk vs. benefit ratio. Most of the times antibiotics are needed for improving the overall health of the female and prevent any adverse effects of the infectious disease on the fetus. However, mothers should be advised that any intake of antibiotics during pregnancy may lead to a small risk of AD in the child who needs to be closely monitored for early diagnosis and treatment.The results of this meta-analysis suggest that maternal exposure to antibiotics may lead to a modestly increased risk of AD in childhood. The evidence is limited by high interstudy heterogeneity and bias in exposure and outcome assessment. Future studies are needed to explore if the timing of exposure, the dose, the number of prescriptions, and the type of antibiotic affect this association.


Several recent studies have suggested an association between proton pump inhibitors and the development of cognitive changes.To assess the existence of this association.A comprehensive literature search was conducted including guidelines, meta-analyses, systematic reviews, observational and experimental studies published between February 2011 and February 2021.The initial research identified 393 articles, 28 of which were included: 8 systematic reviews, 1 clinical trial, 15 observational studies, 3 case-control studies, and 1 cross-sectional observational study.Most studies classified with the highest level of evidence found no statistically significant association between the use of proton pump inhibitors and the development of cognitive impairment or dementia. Up to 1 in 5 older adults takes PPIs – and frequently – on a long-term basis.Various studies worldwide have pointed to the inappropriate prescription of these drugs, either in excessive dosage, inappropriate prolonged duration, or in the absence of medical recommendation.Along with the generalization of its use, there has been a growing concern about its adverse effects, widely disseminated through the media. Published scientific evidence on the safety profile of these drugs supports an association between long-term use of PPIs and an increased risk of developing acute and chronic kidney disease, Clostridium difficile infection, community-acquired pneumonia, bone fractures, hypomagnesemia, vitamin B12 deficiency, among others.These effects are more pronounced among the elderly, for which the American Geriatrics Society Beers Criteria, updated in 2019, advise against the use of PPIs for more than 8 weeks, except in situations of erosive esophagitis, Barrett esophagus, hypersecretory pathology or demonstrated need for treatment maintenance.In recent years, some studies have suggested an association between the use of PPIs and the development of cognitive impairment. One of the mechanisms focuses on the decrease in vitamin B12, which has been associated with cognitive decline and neurological damage, probably due to decreased synthesis of deoxyribonucleic acid and homocysteine neurotoxicity. There is evidence that PPIs (e.g. lansoprazole and omeprazole) cross the blood-brain barrier; therefore, several intracerebral mechanisms have been studied. A possible factor for the effect of PPIs on cognition is through direct interaction with brain enzymes. A recent study by Badiola et al. found that PPIs, such as lansoprazole, increase levels of amyloid beta peptide (Aβ) in an amyloid cell model and in the mouse brain. Aβ peptides are one of the main pathological signs of Alzheimer's disease and are also cytotoxic to endothelial cells. Another mechanism described for the increase in Aβ peptide deposits by PPIs refers to the possible modulation of their degradation by lysosomes in microglia, since this process is pH-dependent and induced by lysosome acidification. This acidification has been described as mediated by the vacuolar proton pump adenosine triphosphatase and it is thought that PPIs will have an inhibitory action on these and may contribute to the inhibition of Aβ degradation and thus increase its deposit.Several mechanisms have been proposed to explain the possible association between PPIs use and the development of dementiaThis review aimed to assess whether there is an association between the use of PPIs and the development of cognitive impairment or dementia, according to the currently available scientific evidence.The authors performed a literature search of meta-analyses, systematic reviews, randomized controlled trials, cohort studies, case-control studies, and guidelines published in the following databases: PubMed, Cochrane Library, Database of Abstracts of Reviews of Effects, Guidelines Finder, Canadian Medical Association Infobase e National Guidelines Clearinghouse.We used the following MeSH terms: PPI, PPIs, proton pump inhibitors, omeprazole, pantoprazole, esomeprazole, lansoprazole or rabeprazole and cognitive impairment or dementia.Articles published between 02/18/2011 and 02/18/2021, in English, Portuguese or Spanish, that met the following criteria were included in the review:Population: adults without a previous diagnosis of mild cognitive impairment or dementia;Intervention: use of PPIs;Control: placebo, H2 receptor antagonists, or no drug; andOutcome: development of mild cognitive impairment or dementia. Repeated articles and those that did not meet the eligibility criteria and purpose of the review were excluded.For article selection, the authors proceeded to three phases of exclusion: regarding the title, level of evidence classification of each article, and strength of the abstract. Afterwards, the full article was read. Each one was read by two authors, resorting to the third in situations of disagreement between the first two.The methods for the diagnosis of dementia were heterogeneous. In some studies, the diagnosis of dementia was based on cognitive tests , brain imaging , and dementia symptoms. Often the diagnosis was confirmed by a board-certified psychiatrist or neurologist, based on the criteria of Diagnostic and Statistical Manual of Mental Disorders (DMS)-IV. In other studies, the authors assumed the diagnosis as documented based on the International Classification of Diseases (ICD) codes or prescription records for medication for treating dementia.The association of dementia and use of PPIs could have been assessed as categorical variables, such as adjusted hazard ratio (HR) and adjusted odds ratio (OR) or relative risk (RR).Some studies used adjusted ratios .Strength of Recommendation Taxonomy (SORT) system was used.From the initial search, 393 articles were obtained. After the selection process , 28 arti. The group of patients using pantoprazole presented an OR of 1.20 and 95% confidence interval (CI) 0.81–1.78 for the development of dementia, without statistical significance.A single randomized clinical trial was identified, which compared the use of pantoprazole 40 mg versus (vs.) placebo in patients with atherosclerotic disease 27. The. Two of the prospective studies found an increased risk of developing dementia associated with PPI use, both conducted in Germany. Haenisch et al. evaluated the effect of using any PPI compared with no use of these drugs in a population aged 75 years and over, with a HR of 1.38 for all-cause dementia and 1.44 for Alzheimer's disease.The literature search yielded six prospective and nine retrospective cohort studies 14,15,16 followed a cohort of individuals under regular use of PPIs with at least one prescription per quarter and also concluded the existence of this slight increase in risk (HR 1.44) compared with non-use.For seven years, Gomm et al..The remaining prospective studies did not demonstrate the existence of this association, either in comparison with placebo or with H2-antagonists studied two cohorts of twins in different age groups (middle-aged and elderly), comparing PPI users and non-users, and had no statistically significant difference in cognitive decline between groups in both cohorts. When studying the effect of PPIs over the time of use or adjusted for cumulative dose, there was also no increase in the risk of developing dementia.In Denmark, Wod et al. found an association between the use of these drugs and cognitive decline. In Spain, Torres-Bondia et al. found a slight increase in the risk of non-Alzheimer dementia compared with PPI non-users (adjusted odds ratio [aOR] 1.20), with no dose-dependent effect, which was not observed for Alzheimer's disease. In the United States of America (USA), Welu et al. showed a 51% increase in the risk of developing dementia in a cohort of more than 23,000 war veterans with PPI consumption for more than 30 days compared to an equal number of veterans who had never been prescribed PPIs, although without correlation to the duration of the treatment or cumulative dose. A South Korean population cohort with about 1 million people was used for a study that found an increased risk of developing dementia in PPI users (adjusted sequence ratio [aSR] of 1.21) after 3 years of use, which was more pronounced with omeprazole (aSR 1.24). In this study, different latency times of 1, 2, and 3 years were applied and the results showed that the relative risk decreased with the rise of latency time: adjusted incidence rate ratio (aIRR) of 1.13, 1.02, and 0.89, respectively; without application of latency time, the aIRR was 1.27. A study in Taiwan on people over 65 years of age, showed an increase in this risk , in a dose-dependent manner. In contrast, two retrospective studies by Cooksey et al.(in Scotland) and Goldstein et al. (in the USA) showed a decrease of about 30% in the risk of dementia in PPI users , either with regular or intermittent consumption of these drugs. Park et al. evaluated the risk of dementia in PPI users compared to anti-H2 users, this time not verifying the harmful effect associated with the former, contradicting their own findings published in 2018. The remaining retrospective studies considered in this research did not show an increased risk, either in continuous or intermittent use or in comparison with anti-H2.Regarding retrospective studies, four of them. Taipale et al. studied the development of Alzheimer's dementia associated with PPI use with 3-year lag window applied between exposure and outcome  compared with no use, with higher doses use  and with longer duration of use , revealing no increased risk. Another case-control study, carried out in Germany, which main outcome was the development of dementia dependent on predefined risk factors, concluded that there may be a modest protective effect of PPIs on the development of dementia , along with statins and antihypertensives  and vascular dementia (VD) associated with prolonged PPI use in individuals over 65 years of age, and found no increased risk for either of these conditions compared with non-users , which remained the same when the analysis was done for each of the different PPIs or for their combined usetensives 41..The only observational cross-sectional study obtained encompassed more than 7 billion surveys conducted in North American patients and did not demonstrate the existence of any association between PPI use and the development of dementia 42.. A systematic review published in 2017 included 11 studies with different methodologies and great heterogeneity, suggesting an increased risk of dementia with PPIs, but meta-analysis was not performed. One of the identified meta-analyses encompassed six cohort studies and found a slightly increased risk of dementia as a result of PPI use, with a HR of 1.29, and 95%CI 1.12–1.49.The search resulted in eight systematic reviews, seven of them comprising meta-analysis 12,13,17 meta-analysis are covered by Khan et al. meta-analysis.There is some overlap of studies included in meta-analyses, notably all cohorts included in Zhang's et al.. Among the most recent ones, the review by Khan et al., which included 11 observational studies with 642,949 individuals, found a HR for dementia from all-causes of 1.11 and 95%CI 0.88–1.37, and for Alzheimer's disease a 95%CI 0.72–1.55.None of the six remaining meta-analyses in review excluded in this research presented evidence to support the association between PPIs and dementia, information about the pattern of drug use was not consistently available. In the meta-analysis by Zhang et al., only cohort studies were included and there was substantial heterogeneity between studies; different indicators (OR and HR) were included as measures of similar effect, which constitutes a bias. In these studies, the most expressive measure of effect was a HR of 1.44, 95%CI 1.36–1.52  which was obtained in a prospective cohort study in a population aged 75 years and over. Five studies with level of evidence II found an increased risk , where the highest risk measure was an OR of 1.55. The study by Batchelor et al. had several limitations, namely data heterogeneity, variability in study designs, and clinical diversity, with an important risk of bias.Overall, this evidence-based review identified nine studies classified as level of evidence I  and eight studies classified as level of evidence II  that found no statistically significant evidence of a relationship between PPI use and the development of dementia. Three level of evidence I studies  found an association between PPI use and dementia. In the study by Haenisch et al. highlighted the importance of applying a window time after the start of PPIs, during which cases of dementia may arise in patients without a previous diagnosis, although without an etiological relationship with the drug, thus reducing the protopathic bias. The decrease in IRR with increasing time window weakens the evidence for the association between PPI use and dementia. In three studies with level of evidence II there was a decrease in the risk of developing dementia, with the lowest HR recorded 0.67, 95%CI 0.65–0.67 (p<0.01) and resulting from a retrospective cohort study, where it was not possible to assess the duration of use or dosage of PPI.The study by Park et al.Regarding the strengths of this review, the expressive sample size of the included studies stands out, comprising data from different countries and continents. The selected outcome included cognitive impairment and dementia of all etiologies, not limited to Alzheimer's disease. Only level of evidence I and II studies were included, with most of the more robust ones were classified as level I.As the main limitation, we highlight the great heterogeneity among the results, which are somewhat contradicting. Only one experimental study was identified, with a predominance of observational studies. Other limitations are the lack of methodological consistency of the intervention  and the outcome , and the fact that it was not considered a window time in most studies. Additional research is needed because there is biological evidence that PPIs could affect the brain and increase the risk of dementia and AD.In conclusion, although the available evidence is discordant, most level of evidence I studies have not found a statistically significant association between PPI use and the development of dementia or cognitive impairment. Therefore, we believe further studies on this topic are needed, particularly randomized clinical trials.


IgA nephropathy may recur in patients receiving kidney transplantation due to IgA nephropathy induced renal failure. The risk factors for recurrence are still at issue. The aim of this study was to conduct a systematic review and meta-analysis to assess risk factors and outcomes for IgA nephropathy recurrence.We used PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, CNKI, WanFang, VIP and CBM to search for relevant studies published in English and Chinese. Cohort or case-control studies reporting risk factors or outcomes for IgA nephropathy recurrence were included.Fifty-eight studies were included. Compare to no recurrence group, those with IgAN recurrence had younger age , younger donor age (MD=-2.19 years), shorter time from IgA nephropathy diagnosis to end stage renal disease , shorter time on dialysis (MD=-3.14 months), lower human leukocyte-antigen (HLA) mismatches (MD=-0.11) and HLA-DR mismatches (MD=-0.13). HLA-B46 antigen (RR=0.39), anti-IL-2-R antibodies induction (RR=0.68), mycophenolate mofetil (RR=0.69), and pretransplant tonsillectomy (RR=0.43) were associated with less IgAN recurrence. Of note, male recipient gender (RR=1.17), related donor (RR=1.53), retransplantation (RR=1.43), hemodialysis (RR=1.68), no induction therapy (RR=1.73), mTOR inhibitor (RR=1.51), angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (RR=1.63) were risk factors for IgAN recurrence. Recurrence increased the risk of graft loss (RR=2.19).This study summarized the risk factors for recurrence of IgA nephropathy after kidney transplantation. Well-designed prospective studies are warranted for validation.https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=377480, identifier CRD42022377480. Kidney The identification of risk factors for IgAN recurrence is crucial in pre-transplant evaluation, and many studies have been conducted to investigate this issue. However, the results are inconsistent, with some studies indicated that younger age, high human leukocyte-antigen (HLA) matching, and related donor are risk factors, while others found no significant association –9. The dTo date, no studies have systematically evaluated the risk factors for IgAN recurrence after KT. Therefore, the present systematic review and meta-analysis aimed to identify risk factors for IgAN recurrence and quantify its impact on clinical outcomes.2The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) statement and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines , 11. The2.1English or Chinese literature from the following databases were considered: PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, CNKI, Wanfang, CBM, and VIP . We developed a search strategy for each database  Studies published in languages other than English or Chinese.Studies were included if they met the following criteria: (1) Patients: those who received a KT due to IgAN induced renal failure; (2) Exposure: various potential risk factors for IgAN recurrence, such as donor and recipient characteristics, primary disease characteristics, immunosuppressive therapy, biomarkers, etc.; (3) Outcome: recurrence of IgAN in kidney allografts; (4) Study design: prospective/retrospective cohort studies or case-control studies. Studies reporting the effect of recurrence on clinical outcomes were also included. The excluded criteria were as follows: (1) Excluded study types: reviews, systematic reviews, case reports, case series, animal studies, comments, conference abstracts, and letters without detailed data, (2) Difficult to differentiate the IgAN recurrence and 2.3Two researchers (YL and YT) independently screened all relevant titles and abstracts of retrieved publications to identify eligible studies. The inclusion and exclusion criteria were then applied to the full text screening. A third reviewer (TS or TL) was consulted to resolve disputes and reach a consensus. The quality and methodological strength of the included studies were assessed by two researchers (YL and YT) using the Newcastle-Ottawa Scale (NOS) . Scores 2.4Following items were extracted from selected studies: the name of the first author, year of publication, location, research design, demographic characteristics, inclusion and exclusion criteria, follow-up time, and effect of recurrence on outcomes. Number of events and total or associated effect sizes of all reported risk factors were extracted, and those risk factors assessed only by single publication were omitted. Zero counts in a two-by-two table were replaced by 0.5 according to continuity correction. For categorical variables, risk ratios (RRs) and 95% confidence intervals (CIs) were calculated independently by two researchers if reported as number of events and total. Considering that overlapping cohort studies may report different risk factors, the data for each risk factor was screened for overlapping cohort studies and only the studies with the largest sample size were included.2.5For categorical variables, the pooled RRs and 95% CIs were calculated using the Inverse variance method. For continuous variables, mean differences (MDs) or standardized mean differences (SMDs) and 95% CIs were used to pool the differences between the recurrence and non-recurrence groups. The mean and standard deviation were estimated based on data reported as median (interquartile or full range) , 14. Het33.1The study selection process is summarized in 3.2The characteristics of the included studies are summarized in 3.3The risk of bias was assessed using the NOS and the results are presented in 3.4The results of meta-analysis examining risk factors for IgAN recurrence are presented in 3.4.1The study found that recipients with recurrent IgAN were younger at KT than those without recurrence . The pooled RR showed that the risk of recurrence decreased by 4% for each increase in age of 1 year at KT . The donor age was also found to be younger in the recurrent group , but the pooled RR of 389 participants from 3 studies was not significant . Male recipients had a 17% increased risk of recurrence compared to female recipients . There were no significant differences between the recurrence and non-recurrence groups with respect to recipient body mass index or donor sex.3.4.2There was no difference in the risk of recurrence among recipients with living donors compared to those with deceased donors . Recipients with related donors had a higher risk of recurrence compared to those with unrelated donors . Further analysis found that recipients with living related donors had a higher risk of recurrence compared with those with living unrelated donors .3.4.3The age at diagnosis of IgAN did not differ between the recurrence and non-recurrence groups. However, the time from IgAN diagnosis to ESRD was shorter in the recurrence group compared to the non-recurrence group, with an MD of -1.84 years . The RR value for the time from diagnosis to ESRD showed each additional year was associated with a 6% reduction in recurrence . This suggests that patients with a faster progression of primary disease were more susceptible to recur.3.4.4Recurrent group had short dialysis duration  and hemodialysis  were identified as risk factors for recurrence, while pre-emptive transplantation was not found to be a significant risk factor.3.4.5In patients with recurrent IgAN, lower total HLA mismatches  and lower HLA-DR mismatches  were observed, but no significant difference was found in HLA-A and B. The pooled RR showed an increased risk of recurrence in recipients with HLA full match . However, compared with more than 1 mismatch, HLA-A, B, or DR full match were all found to have no effect on recurrence. For specific HLA antigens, HLA-B46 reduced the risk of recurrence , while HLA-A2, HLA-B35 HLA-DR3, and HLA-DR4 had no effect. ABO incompatibility, donor-specific antibodies, and panel reactive antibodies did not affect recurrence.3.4.6Patients without induction therapy had an increased risk of recurrence . The use of anti-IL-2-R antibodies was found to reduce the risk of recurrence by 32% , while antithymocyte globulin and anti-CD20 antibodies had no effect. For maintenance agents, mycophenolate mofetil (MMF) reduced the risk of recurrence  and use of mTOR inhibitor is associated with a higher risk , while steroids, tacrolimus, cyclosporine, and azathioprine had no significant effect. Pretransplant steroids or immunosuppressant exposure did not affect recurrence.3.4.7Recipients with recurrent IgAN were more likely to use angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) . Patients who had tonsillectomy before KT had a 57% lower risk of recurrence . Plasma exchange had no effect on recurrence.3.4.8Recipients with KT history had a 43% increased risk of recurrence compared to those with first KT . Factors such as graft rejection, hypertension, diabetes, cold ischemia time, delayed graft function, cytomegalovirus or BK virus infection, did not have an impact on recurrence.3.4.9Our findings indicated that serum immunoglobulin G autoantibodies (IgG), IgA, and galactose-deficient IgA1 (Gd-IgA1) levels for recurrence were not predictive of IgAN recurrence Table 3.3.5The level of hematuria was found to be higher in patients with recurrence one year after transplantation, compared to those without recurrence . Additionally, patients with recurrence were more likely to have hematuria, regardless of the time of occurrence . However, there was no significant difference in hematuria levels between the 3-year and 5-year follow-up periods. Urinary protein levels were also higher in patients with recurrence, and this difference was significant at follow-up periods .3.62, 95% CI: -17.25 to -7.49, I² = 0.00%; serum creatinine: MD = 0.49 mg/dL, 95% CI: 0.35 to 0.64, I² = 37.90%)  Table 2.3.7The majority of the P values of Egger’s test were not significant, indicating that there was no significant publication bias Table 2.4In the present systematic review and meta-analysis, our aim was to evaluate the risk factors associated with the recurrence of IgAN and provide a comprehensive summary of the outcomes based on relevant articles published until now. The immediate consequence of IgAN recurrence is an increased risk of graft loss, and similar to primary IgAN, treatment options for recurrent IgAN are limited. Thus, by studying the risk factors and employing appropriate risk stratification and preventive measures, it is possible to determine the likelihood of IgAN recurrence at an early stage and consequently reduce the recurrence rate. Although some previous studies have explored the risk factors for IgAN recurrence, their findings have been controversial due to variations in selection criteria, sample size, and study design. Therefore, in this meta-analysis, we aim to identify potential risk factors for IgAN recurrence, with key findings summarized in IgAN is a systemic autoimmune disease which affects both the native and allograft kidney with a high recurrence . The “muThe first step in the pathogenesis is an increase in circulating abnormal IgA (Gd-IgA1). The serum level of Gd-IgA1 was found to be elevated in patients with native IgAN . AdditioAnti-glycan immunoglobulin G autoantibodies (IgG) bind to abnormal IgA to form circulating immune complexes . HoweverIn the final stage of pathogenesis, mesangial deposition of circulating Gd-IgA1-antiglycan IgG immune complex in the renal allograft results in cell activation and glomerular injury, ultimately leads to recurrence. Transferrin receptor 1 (TfR1) was identified as an IgA1 receptor expressed on human mesangial cells and has affinity with the immune complex formed by Gd-IgA1 and IgG . Our obsOther risk factors were also identified in our study. Male recipients were more likely to recur, consistent with the higher prevalence observed in males in native IgAN . The donThis study has several limitations. All the studies included in this meta-analysis are retrospective studies, which may introduce inevitable biases. Furthermore, the overall quality of the studies is rated as medium. All the patients included in the analysis had a biopsy-confirmed diagnosis of IgAN, which could potentially result in selection bias and underestimate the recurrent incidence of IgAN. Additionally, some of the analysis is based on univariate data, which could be influenced by confounding factors. A number of the identified risk factors are based on limited studies and small sample sizes, so further research is required to verify these findings. Moreover, most of the results from Egger’s test showed p-values greater than 0.05, indicating no significant publication bias in the included literature. However, we were unable to analyze publication bias for the analysis with less than 10 included articles. This limitation arises from the fact that the power of Egger’s test greatly decreases when the number of studies is small. Additionally, we restricted the study to articles published in English and Chinese, potentially excluding studies in other relevant languages and introducing publication bias. As a result, it is advisable to exercise caution when interpreting the results of this meta-analysis.In conclusion, this meta-analysis has identified several factors associated with IgAN recurrence after KT. As patients with recurrence had poor graft outcomes, our findings may improve pre-transplant evaluation of individuals with IgAN induced renal failure. By properly stratifying risk and implementing appropriate interventions, it might be of help to enhance long-term outcomes in this population.The original contributions presented in the study are included in the article/YL: data curation, formal analysis, investigation, methodology, software, visualization, writing – original draft. TY: writing – original draft, data curation, formal analysis, investigation. TL: funding acquisition, supervision, validation, writing – review & editing. TS: supervision, validation, writing – review & editing, conceptualization, funding acquisition, project administration, software.


Incidence rates of thyroid cancer have increased. Recent studies findings suggest that women who underwent a hysterectomy have an elevated relative risk of thyroid cancer. The aim of our meta-analysis is to summarize the evidence about the association between hysterectomy and thyroid cancer risk.PubMed, Web of Science, and Scopus database were searched for studies published up to 5 September 2023. The PRISMA statement was followed. Heterogeneity was explored with Q statistic and the I2 statistic. Publication bias was assessed with Begg's and Egger's tests.p = 0.156). Hysterectomy without oophorectomy was a stronger predictor of risk than hysterectomy with oophorectomy. The pooled analysis of data regarding hysterectomy without oophorectomy showed a statistically significant increment of thyroid cancer risk by 59%. Hysterectomy with oophorectomy was associated with an increase of thyroid cancer risk of 39% . Significant publication bias was not detected.Sixteen studies met the criteria. The pooled analysis showed a significantly 64% increment of thyroid cancer risk in association with any hysterectomy (OR 1.64, 95% CI 1.48–1.81; I2 = 28.68%, Our findings help with decision making around these surgeries. •This meta-analysis is the first to evaluate the association between hysterectomy and thyroid cancer risk.•Risk of thyroid cancer was increased for women undergoing hysterectomy.•the number of thyroid cancer asoociated with hysterectomy has important implications for public health guidance. Thyroid cancer (TC) is the most common endocrine malignancy. Incidence rates of thyroid cancer have increased considerably during the last two decades. It is threefold as common in women as in men . In both sexes, incidence rates were five times higher in high and very high Human Development Index countries than in low and medium Human Development Index countries ,3. ThereHysterectomy is the most common gynaecologic surgery performed in women worldwide. Although it is the elective surgical procedure for treatment of uterine cancer, over 90% of procedures are associated to symptomatic benign gynaecological conditions  . Often hCaini and colleagues have found that hysterectomy may play a role in the aetiology of thyroid cancer. Their review included four studies and didn't stratify hysterectomy by oophorectomy status .Recently, several epidemiological studies have investigated the possible effect of hysterectomy, with or without BSO, on thyroid cancer risk with contrasting results.Therefore, the present systematic review and meta-analysis was carried out to summarize and better understand the published epidemiologic evidence regarding the association between hysterectomy and thyroid cancer risk.We conducted this systematic review and meta-analysis according to the “preferred reporting items for systematic reviews and meta-analyses” (PRISMA) . This rewww.zotero.org).A comprehensive literature search, without restrictions, was carried out until 5 September 2023 through PubMed, Web of Science, and Scopus databases to identify all the original articles on the association between hysterectomy and thyroid cancer risk. The following key words were used: hysterectomy AND (cancer OR tumour OR neoplasia OR “neoplastic disease” OR neoplasm) AND thyroid. In addition, to identify additional relevant publications, we manually examined the reference lists of included articles and recent relevant reviews. Study search results, initial duplication, search review and study selection were managed using Zotero ;-Comparison: No hysterectomy;-Outcomes: thyroid cancer, in particular, to search the databases, we used the following words: (cancer OR tumour OR neoplasia OR “neoplastic disease” OR neoplasm) AND thyroid;-S: case–control, prospective, or cross-sectional study design;-Finally, we included only articles, which reported a risk estimation  with 95% confidence intervals (CIs).The inclusions criteria, organized on PICO model, were: was the association between hysterectomy and thyroid cancer in women. In particular:-article not in English;-some article type, such as case studies, commentaries and reviews;-not reporting the association and/or the risk estimate between hysterectomy and thyroid cancer risk.The exclusion criteria were:When there were several publications from the same study, the one with the largest sample was selected. Foreach potentially included study, two investigators independently conducted the selection, data abstraction, and quality assessment. Disagreements were resolved by discussion or in consultation with a third author. Although it is useful to have background information, reviews and meta-analyses were excluded. No studies were excluded based on weakness of design or data quality.The study quality was assessed by a 9-star system, based on the Newcastle-Ottawa Scale (NOS) method ; the maxFrom the included studies, we extracted the following information: first author's last name, year of publication, country, study design and name, sample size , duration of follow-up for cohort studies, population characteristics ,whether the surgery included also unilateral/bilateral salpingo-ophorectomy (USO/BSO), age at surgery, risk estimates for the different categories of surgery (OR/RR/HR) with 95% CI sand adjustment of confounding factors. When multiple estimates were reported in the article, we abstracted those that adjusted for the most confounding factors. The outcome of interest in this study is thyroid cancer (TC).The association between hysterectomy and thyroid cancer risk in women was evaluated by version 3.0 of the ProMeta statistical program . For overall estimation, the relative risk and hazard ratio were taken as an approximation of the OR, and the meta-analysis was performed as if all types of ratio were ORs. We used the random effects model to calculate the summary OR and 95% confidence interval. Stratified analysis by study design (cohort and case-control studies), surgery categories  and age at surgery (in the case of hysterectomy without oophorectomy) was also performed.p-value <0.05.The chi-square-based Cochran's Q statistic and the I2 statistic were used to evaluate heterogeneity in results across studies . The I2 n = 183), Web of Science (n = 131) and Scopus (n = 541) databases, and after removing duplicates (n = 260), we identified 595 records for title and abstract revision  for cohort studies (2: 31.32)  (2: 49.94)  B Table : 49.01 f: 31.32) . The poo= 0.049) . An incr: 49.94) C Table : 49.01 f: 49.94) .p < 0.0001), omitting the study of Guenego et al. [Sensitivity analyses investigating the influence of a single study on the thyroid cancer risk estimates suggested that these were not substantially modified by any single study. Indeed, the thyroid cancer risk estimates associated to “any hysterectomy” ranged from 1.60  and oestrogen receptor beta (ERβ) .ERs belong to the nuclear receptor superfamily, which act as transcription factors. Oestrogen binding to the nuclear receptors is responsible for a nuclear translocation, with the consequent activation of genomic pathways and the transcription of multiple target genes. ERα promotes DNA transcription, while ERβ inhibits it; ERα plays a role in tumorigenesis by stimulating cell proliferation, while ERβ seems to have a significant antitumor activity .In a study that examined association of endogenous sex hormone levels with hysterectomy, oophorectomy status, age or years since menopause, it was demonstrated that androgen levels were greatly decreased in women who undergo simple hysterectomy in comparison with natural menopause. In addition, testosterone levels were 40% lower in hysterectomized women with bilateral oophorectomy compared to not hysterectomized women, with intermediate levels of testosterone observed in hysterectomized women with ovarian conservation .These results demonstrate that ovaries remain a critical source of androgen throughout the lifespan of a woman. Since both hysterectomy with oophorectomy and hysterectomy without oophorectomy have the potential to induce evident changes in hormone levels, they can also influence the risk of hormones related cancers. Further studies are needed to evaluate the effects of hormone replacement after oophorectomy.The adverse association between hysterectomy and thyroid cancer may be a consequence of the underling conditions leading up to hysterectomy. The most common diagnosis associated with hysterectomy are uterine fibroids, abnormal uterine bleeding, prolapsed, endocrine disorders and endometriosis . Indeed,The carcinogenic potential of conditions that lead to a hysterectomy is poorly understood, but hypothesized to be multidimensional in aetiology, involving hormonal, genetic and immunological factors .Finally, it is necessary to consider that women undergoing hysterectomy are more medicalized and therefore more in touch with the health care system and more concerned about their own health, so they may have a higher likelihood of being diagnosed with thyroid cancer than the general population.Sensitivity and publication bias analyses revealed that our results are stable. Moreover, in our systematic review have been included many cohort studies, of good quality, that reinforce our results. It is important to notice that the number of people that have been considered by our systematic review is 7.575.968 and that the meta-analysis showed a consistently results of 64% increment of thyroid cancer risk in association with any type of hysterectomy.The principal weakness of our study, instead, is that, even if a high agreement was registered between self-reported hysterectomy data (i.e. year of surgery) and hospital records in studies that validated exposure information, for several studies the hysterectomy status was not verified with medical records and it is self-reported only . ActuallOophorectomy or hysterectomy should be proposed to women who have a high-penetrance susceptibility genes for ovarian cancer and/or endometrial cancer, because of the high life-time risk of developing these types of cancers , while wOur review was able to account risk factors for thyroid cancer, however, other confounding factors should be taken in consideration, such as indications for hysterectomy, type of hysterectomy  and an eventual substitutive hormone therapy given in case of ovariectomy, which can influence woman cancer history. Despite challenges, additional studies are needed to determine the biological mechanisms of these associations and cohort studies with prolonged follow-up are essential to verify our findings.In conclusion, our findings from this meta-analysis suggest that women undergoing hysterectomy have an increased relative risk of thyroid cancer. This relative risk depends on frequency of hysterectomy and thyroid cancer, however, the proportion of thyroid cancers attributable to hysterectomy may be substantial, given that approximately 45% of women are estimated to undergo this procedure by the age of 70 years.all authors have contributed significantly. F.R. provided the idea and was responsible for the study design. Authors C.M. and F.R. performed the review and C.M. and G. I. wrote the article. Author F.R. and R.P. analysed the data, edited pictures and performed the statistical analysis. C.M and G.I. performed reference collection. All authors revised the manuscript and approved the final version. All authors are included in the author list and are aware that the manuscript was submitted.The authors received no financial support for this research.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.