The effects of leisure activities on cognitive function varied by different cognitive statuses in older adults, with RRs ranging from 0.55 (95% CI: 0.37–0.83) to 1.07 (95% CI: 0.95–1.22). Meta-regression analysis showed that compared with studies with percentage of female ≥50%, studies with female participant percentage <50% had significantly increased RR (p = 0.01). Moreover, studies conducted in European and American countries had significantly lower RR (p = 0.019), compared with those conducted in Asian countries. Our study revealed different effects of various types of leisure activities on different cognitive statuses in older adults. To make innovative recommendations for promoting cognitive function in older adults, more detailed observational longitudinal studies investigating the effects of different types of leisure activities on different cognitive statuses in older adults are needed.Abnormal cognitive aging in older adults is a growing public health problem. Previous studies showed inconsistent results pertaining to the effects of leisure activities on cognitive function in older adults. We conducted a systematic review and meta-analysis of published observational longitudinal studies to examine and synthesize the effects of leisure activities on cognitive function in older adults. MEDLINE, PubMed, EMBASE, PsycINFO (Ovid), CINAHL (EBSCO), and Web of Science databases were searched from January 2012 to January 2022. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Most studies found that leisure activities had a positive effect on cognitive function in older adults. The pooled RR for the effect of leisure activity on cognitive function was 0.77 (95% CI: 0.72–0.81,  Abnormal cognitive aging in older adults is a growing public health issue, moreover, increased life expectancy and population aging are expected to substantially increase the number of people with mild cognitive impairment (MCI) and dementia . GloballLeisure activities are defined as activities those in which individuals participate for enjoyment or wellbeing, these activities are independent from work or activities of daily living, which mainly include physical, cognitive, and social activities . A studyNumerous studies have found positive associations of physical, cognitive, and social activities with cognitive function in older adults . EffectsMoreover, most previous systematic reviews and meta-analyses have synthesized the effect of only a single type of leisure activity on cognitive function. For example, Sajeev et al. only synthesized the effect of cognitive activity on dementia , and VenThe study findings would help optimize future interventions to promote normal cognitive aging in older adults.This study was conducted and reported according to the Preferred Reporting Items for Systemic Review and Meta-Analysis Statement (PRISMA) 2020 guidelines . This syWe identified relevant studies published from January 2012 to January 2022 by searching MEDLINE, PubMed, EMBASE, PsycINFO (Ovid), CINAHL (EBSCO), and Web of Science. Search strings included suitable indexing terms  on “leisure activities” AND “cognition” AND “aged” AND “longitudinal” . After rWe included studies with the following criteria:Published in EnglishThe full text was availableParticipants were 65 years or older, and free of cognitive impairment at baselineAll or some of the outcome indicators included were cognitive function, which was assessed using neuropsychological testsThe effect of leisure activities  on the cognitive function was reportedObservational longitudinal studies with a follow-up of least 1 year.We excluded studies with the following criteria:Qualitative studies, case studies, reviews, interventional studies, or conference papersParticipants with other illnesses that affect cognitive function Insufficient data to calculate the relative risks (RRs).Two reviewers extracted the following data: country, study design, data source, length of follow-up, inclusion and exclusion criteria, sample size, mean age, percentage of females, assessments and types of leisure activities, and cognitive function. Crude and adjusted RRs representing the effect of leisure activities on cognitive decline, cognitive impairment, and dementia in older adults were extracted. Estimates adjusted for potential confounders were used for the meta-analyses where possible. Inconsistencies were resolved by consensus with the third reviewer through discussion between the two reviewers.Two reviewers independently assessed the risk of bias of each study according to the Scottish Intercollegiate Guidelines Network checklists developed by researchers in Scotland . Any dis0P; 0P, the P0 was obtained from studies with similar characteristics  or odds ratios (ORs) were reported for a study, we calculated the RR by using the HR or OR reported in the original study and the control event rate P0; . For stueristics . The regeristics .All statistical analyses were performed by Stata, version 17.0. First, RRs were combined through the fixed effect model. If the heterogeneity test was statistically significant, the random-effect model was then applied. Subgroup analyses were performed according to the type of leisure activities, and different cognitive statuses. Based on the leisure activity classification of the included studies, we divided leisure activities into three categories: physical , cognitive , and social activities . If the included studies did not classify activities, we classified activities based on the procedure used in other included studies and previous studies . The cogp < 0.05 was considered statistically significant) and I2 statistic ). For exp(β) > 1, the percentage increase in RR is calculated as (exp(β)− 1) × 100%. For exp(β) < 1, the percentage decrease in RR was calculated as (1 − exp(β)) × 100%. Furthermore, variables with p < 0.20 in univariate analysis were included in the multivariate regression model , 5 did not contain information about our primary outcome (the effect of leisure activities on cognitive function), and 3 did not calculate the effect size. Resultantly, 19 studies were included in meta-analyses of this study. The characteristics of included studies are presented in 2I = 96.8%, Q-test: p < 0.01). The effects of leisure activities on the cognitive outcomes of interest were summarized, and the forest plot is shown in p < 0.001).There was considerable heterogeneity between studies . The pooled RRs for each subgroup  were calculated; physical and cognitive activities showed pooled RRs of 0.83  and 0.66 , respectively. Studies that evaluated cognitive activity reported lower pooled RRs compared with those of activities.Eight studies  investig2I was 96.4%. The pooled RR for leisure activities on cognitive impairment was 0.67 . The pooled RRs for each subgroup  were calculated; physical and cognitive activities showed pooled RRs of 0.55  and 0.69 . Studies that evaluated physical activity reported lower pooled RR compared with those of other activities.Seven studies  investig2I was 91.9%. The pooled RR for leisure activities on cognitive decline was 0.87 . The pooled RR for the physical activity group was 0.65 .Four studies  investigexp(β) = 0.718, 95% CI: 0.548–0.941, p = 0.019) than studies conducted in Asian countries. Compared with studies with female participant percentage ≥50%, those with female participant percentage <50% had significantly increased RRs (exp(β) = 1.445, 95% CI: 1.100–1.898, p = 0.010). Follow-up, cognitive assessment intervals, cognitive assessment measures, country, and percentage of female participants can explain the heterogeneity.Univariate meta-regression analysis was performed to investigate the reason of the relatively high heterogeneity among studies . Follow-p < 0.01) and the contour-enhanced funnel plot showed the risk of publication bias . However, the findings of some reviews indicated that cognitive activity had a positive effect on the delay in the onset of dementia , and health status of older persons vary across countries . These fIn addition, previous studies have reported that factors including frequency and intensity of activity, specific type of activity, age of engagement in activity, gender, and education level may influence the effect of leisure activities on cognitive function in older adults . The effOur study has several strengths. First, all included studies were prospective cohort studies. All case–control or cross-sectional studies were excluded to minimize recall bias. Furthermore, meta-regression analysis was performed to investigate the effect of different countries on the variation in RRs. Moreover, our study examined the effects of different types of leisure activities on different cognitive statuses, which was not performed in previous reviews . In thisAlthough our meta-analysis found protective effects of leisure activities on cognitive function in older adults, some study limitations that should be considered. First, there was a high degree of heterogeneity among the included studies. Although our meta-estimates were derived from cohort studies, which may exhibit a high degree of heterogeneity, analyses of such studies provided results that can be considered similar to those of randomized trials . Second,In conclusion, the present systematic review and meta-analysis provided evidence that multiple types of leisure activities, especially physical activities had positive effects on cognitive function in older adults. Therefore, we recommend that older adults should perform more leisure activities to promote their cognitive function. Moreover, different types of leisure activities were found to elicit different effects on cognitive function in older adults. However, more data are needed to confirm these effects. Future studies should investigate the optimal type, duration, intensity, regional and gender difference of leisure activities, and the optimal age of engagement in leisure activities that preserve cognitive function in older adults.XY, XX, LG, YZ, and YL contributed to the study conception and design. Study screening, data extraction, and assessment of study quality were performed by XY, XX, LG, and YZ. Validation and data curation were performed by XY and XX. The first draft of the manuscript was written by XY, XX, and SW. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Foundation of China (grant nos. 72204075 and 72204228), the Hebei Provincial Postdoctoral Science Foundation (grant no. B2022003032), and the Science and Technology, Scientific Research Foundation Program of School of Nursing, Hebei Medical University (H2020003).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fpsyg.2022.1080740/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


NPHS2 is the coding gene of podocin. This study aims to investigate the association between NPHS2 p.R229Q (rs61747728), the most frequently reported missense variant of NPHS2, and focal segmental glomerular sclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) based on typing the variant in a Chinese FSGS/SRNS cohort and conducting a meta-analysis.We recruited patients with FSGS or SRNS and healthy individuals. To conduct a meta-analysis, all studies on p.R229Q and FSGS/SRNS were searched from public databases.P < 0.001). However, the subgroup analysis showed that the association between p.R229Q and FSGS/SRNS was true only in Caucasians  and in early-onset patients .In total, we enrolled 204 patients with FSGS, 61 patients with SRNS , and 100 healthy controls. Unexpectedly, p.R229Q was absent in the patients from our cohort. By meta-analysis of 21 studies including 2,489 patients with FSGS/SRNS and 6,004 healthy controls, we confirmed that the A allele of p.R229Q was significantly associated with increased risk of FSGS/SRNS (allelic OR = 1.9, 95% CI = 1.44-2.52, NPHS2 p.R229Q may play an important role in enhancing the susceptibility of FSGS/SRNS, especially in ethnicity of Caucasian and age of early-onset patients. Idiopathic nephrotic syndrome (INS) is clinically characterized by edema, massive proteinuria, hypoalbuminemia, and hyperlipidemia. Although steroid is widely used for treatment of INS, about 10-20% of children , accountNPHS2) had been found to play a significant role in SRNS, consisting of approximately 20 to 40% of familial and 10% of idiopathic childhood SRNS in different regions of the world  age between 18 to 65 years old, (2) newly diagnosed nephrotic syndrome without previous usage of immunosuppressive agents within 1 month before the recruitment, and 3) renal biopsy-proved FSGS, minimal change disease (MCD), or IgA nephropathy (IgAN). We included patients with IgAN treated with full-dose prednisone as their initial therapy. SRNS was defined as less than 50%reduction in urine protein compared to baseline or urine protein higher than 3.5 g/d after treatment with a full dose of prednisone  for at least 12 weeks. Healthy controls were defined as having serum creatinine bellow 100 umol/L without proteinuria or hematuria by urine routine test. All the individuals recruited in this study self-reported as having a Chinese Han origin. Informed consent was obtained from all the study participants before enrollment. The study protocol was reviewed and approved by Ruijin Hospital Human Research Ethics Committee.NPHS2 were amplified by polymerase chain reaction (PCR)  . Primerson (PCR)  (Supplemon (PCR) . The PCRNPHS2,” “rs61747728,” “686G > A,” and “Arg229Gln.” Additional studies were also searched by reviewing the references cited in the retrieved articles.Relevant studies published until 1 March 2021 were searched through electronic databases of PubMed, SCOPUS, Cochrane Library, and Web of Science and using the search terms “R229Q,” “Studies eligible for inclusion in our meta-analysis had to fulfill the following criteria: (1) studies discussing about the association between p.R229Q and SRNS (or FSGS) , (2) original data of genotype frequencies available, (3) SRNS was defined as patients who do not achieve complete remission within 12 weeks of glucocorticoid treatment, (4) early onset was defined as onset age ≤18 years, late onset was defined as onset age >18 years. Studies were excluded from our analysis if: (1) there was no control group, (2) genotype data were not available, (3) they were a duplicate of previous publication, and (4) they were reviews, editorials, or unpublished reports.All the data were extracted independently by two reviewers (Qiongxiu Zhou and Xiaoyan Zhang) according to a standard protocol. The following information was extracted from the eligible studies: first author’s surname, year of publication, ethnicity of subjects, sample size, age, and distribution of p.R229Q genotype and allele frequencies in case and control groups.In the current meta-analysis, the associations between p.R229Q and FSGS/SRNS was analyzed by calculating the pooled odds ratios (ORs) and their 95% confidence intervals (CIs) using a random-effects model. Three genetic models were used for the association study: the allelic model (A vs. G), the dominant model (GA + AA vs. GG), and the recessive model (AA vs. GG + GA) , 26. Sub2) for goodness of fit to compare the observed and expected genotype frequencies with controls using a previous meta-analysis as reference, and a P-value < 0.01 was considered as significant deviation from HWE. As deviation from HWE in subjects may bias the estimates of genetic effects in a meta-analysis, a sensitivity analysis was conducted by removing one study and recalculating the pooled OR and 95% CI to assess the stability of the results. Potential publication bias was estimated by Begg’s funnel plot. All statistical tests were performed with the STATA 11.0 software . Two-sided P < 0.05 was considered statistically significant.Hardy-Weinberg Equilibrium (HWE) was tested by chi-square test  had FSGS, 9 (15%) had MCD and 6 (10%) had IgAN; 4 of the 6 patients with IgAN had FSGS changes in renal pathologic findings. The baseline characteristics of patients with SRNS and FSGS enrolled are shown in There were 21 studies investigating the association between p.R229Q and SRNS/FSGS, including the present study. A flow chart shows the literature search for relevant studies on the association between p.R229Q and SRNS/FSGS . The stuP < 0.001, P = 0.004, P < 0.001, The minor allele frequency (MAF)  of p.R229Q was.06 in the patients with SRNS/FSGS and.03 in the healthy controls. An increased risk for p.R229Q in SRNS/FSGS was confirmed by the allelic model . However, no association was found in the African and Asian populations. In the subgroups stratified by onset age, the p.R229Q variant increased the risk of SRNS among the early-onset patients in the allelic , and dominant  models, while no significant association was found in all the three genetic models among the late-onset patients.A subgroup analysis was performed based on disease phenotype: SRNS or FSGS. A significant increased risk of SRNS and FSGS in patients with R229Q was determined based on the allelic model  was observed in the included dominant model, so a sensitivity analysis performed. The combined ORs were similar with one another, with a narrow range from 1.72 (95% CI: 1.32-2.26) to 2.08 (95%CI: 1.49-2.91)  . It indiP = 0.15). It indicated that there was no significant publication bias in our meta-analysis  were identified. However, the distribution of genotypes among our patients and the controls were similar, which suggested that the SNPs did not increase the risk of SRNS or FSGS. We did not find non-synonymous variations in NPHS2, and no p.R229Q was observed in patients with either SRNS or FSGS. It suggested that adult-onset NPHS2 mutation was rare in Chinese patients, and that p.R229Q had no effect on the patients, at least in our population.s of age , 27, whis of age , 29. A sP = 0.024) or FSGS . As FSGS was a common cause of SRNS in both children and adults, we could hypothesize that p.R229Q plays a pathogenic role in FSGS and SRNS. These findings were consistent with previous studies, suggesting that the p.R229Q allele may be a disease-causing variant, which could enhance the susceptibility of FSGS, and FSGS patients with podocin mutations were more likely to be p.R229Q in heterozygous state with one pathogenic mutation , dominant , and recessive  models. Furthermore, it was significant in the subgroups of either SRNS , dominant (GA + AA vs. GG), and recessive (AA vs. GG + GA) models, to explain the allele frequency and genotype-phenotype correlation of p.R229Q in these studies. We concluded that p.R229Q might play a pathogenic role in developing SRNS/FSGS in the state of compound heterozygotes (The results from our meta-analysis were different from Lu Lu’s study , which rozygotes .Additionally, we found that the frequency of p.R229Q was various throughout different populations. The frequency was higher in Caucasians than in Asians and Africans . For theEven though many studies and meta-analyses had been conducted on the genetic role of the p.R229Q variant in the previous years, most of them were performed on Caucasians. Limited studies were available on African and Asian populations. This limited our ability to reach a strong conclusion and investigate a potential function on the basis of race. Moreover, p.R229Q was recently discovered pathogenic only when trans-associated to specific mutations, and this could not be analyzed by the current meta-analysis , 39.NPHS2 mutations were rare in Asian patients with sporadic adult-onset FSGS/SRNS and p.R229Q was undetectable in our cohort. NPHS2 p.R229Q may play an important role in enhancing susceptibility to FSGS/SRNS, especially in Caucasian and early-onset patients. Further studies and international multi-ethnicity approaches are needed to distinguish a pathogenic and benign p.R229Q genotype-phenotype correlation for clinical assessment.In conclusion, our study indicated that ON470453 - ON470576.The original contributions presented in this study are publicly available. This data can be found here: GenBank, accessions The studies involving human participants were reviewed and approved by Ruijin Hospital Human Research Ethics Committees. The patients/participants provided their written informed consent to participate in this study.QZ and XZ completed the screening test and extracted all the data that were needed for the meta-analysis. QZ and QW drafted the original manuscript. YL, JT, and XH helped in polishing the manuscript and were responsible for the figures. JX and NC created the overall design of this study. HS, PS, and HR revised the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer FL declared a shared parent affiliation with the authors JX, QW, JT, XH, HS, XZ, YL, PS, HR, and NC to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bowel resection is often required to obtain complete removal of ovarian cancer. A major complication of this operation is anastomotic leakage, which has been shown to increase morbidity and mortality in this population. Numerous original research studies have assessed the risk factors for anastomotic leaks. We aimed to conduct a systematic review and meta-analysis to identify statistically significant risk factors. This meta-analysis identified multiple bowel resections as the only significant risk factor. With further research to identify additional risk factors, new management guidelines could be implemented to minimize the risk of anastomotic leaks and improve patient outcomes.Introduction: Anastomotic leaks (AL) following ovarian cytoreduction surgery could be detrimental, leading to significant delays in commencing adjuvant chemotherapy, prolonged hospital stays and increased morbidity. The aim of this study was to investigate risk factors associated with anastomotic leaks after ovarian cytoreduction surgery. Material and methods: The MEDLINE (via PubMed), Cochrane Library, EMBASE and Scopus bibliographical databases were searched. Original clinical studies investigating risk factors for AL in ovarian cytoreduction surgery were included. Results: Eighteen studies with non-overlapping populations reporting on patients undergoing cytoreduction surgery for ovarian cancer  were included in our analysis. Patients undergoing ovarian cytoreduction surgery complicated by AL had a significantly higher rate of 30-day mortality but no difference in 60-day mortality. Multiple bowel resections were associated with an increased risk of postoperative AL, while no association was observed with body mass index (BMI), American Society of Anesthesiologists (ASA) score, age, smoking, operative approach , neoadjuvant chemotherapy and use of hyperthermic intraperitoneal chemotherapy (HIPEC). Discussion: Multiple bowel resections were the only clinical risk factor associated with increased risk for AL after bowel surgery in the ovarian cancer population. The increased 30-day mortality rate in patients undergoing ovarian cytoreduction complicated by AL highlights the need to minimize the number of bowel resections in this population. Further studies are required to clarify any association between neoadjuvant chemotherapy and decreased AL rates. Ovarian cancer remains the most lethal gynecological malignancy, with a five-year survival of 43% in the United Kingdom . OptimalBowel resection is frequently required to achieve optimal cytoreduction, particularly in advanced ovarian cancer . The mosGiven the detrimental effects of AL on patient outcomes, the identification of risk factors for AL is of utmost importance to improve prognosis in the ovarian cancer population. The risk factors associated with AL in patients undergoing colorectal surgery have been well described in the literature and include a prolonged operating time, the use of neoadjuvant chemotherapy, anastomotic level  and pre-operative hypoalbuminemia ,11,12. HThis systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and in line with the protocol developed and agreed a priori by all authors. Studies investigating risk factors for anastomotic leaks in patients undergoing ovarian cytoreduction surgery were deemed eligible for analysis. Exclusion criteria were: (i) articles published in languages other than English, (ii) narrative or systematic reviews and meta-analyses, (iii) case reports, errata, comments, perspectives, letters to the editor and editorials that did not provide any extractable data, (iv) published abstracts with no available full text and (v) non-comparative studies (single-arm studies). No publication date, sample size restrictions or any other search filters were applied. This study is registered with PROSPERO, number CRD42022364076.Eligible studies were identified by searching through the MEDLINE (via PubMed), Cochrane Library, Embase and Scopus databases (end-of-search date: 28 November 2021) by two independent researchers. The search strategies used are described in more detail in A standardized, pre-piloted form was used for data tabulation and extraction. Two reviewers extracted the data independently, and any disagreements were identified and resolved by a third reviewer. We extracted the following data from the included studies: (i) study characteristics , (ii) patient characteristics  physical status classification), (iii) operation , (iv) intraoperative outcomes , (v) mortality outcomes and (vi) chemotherapy administration .We assessed the risk of bias using the Risk of Bias tool of the National Heart, Lung and Blood Institute (NHLBI). The tool examines eight domains as possible sources of bias: (i) study objectives, (ii) study population, (iii) consecutiveness of the population, (iv) comparability of the subjects, (v) intervention, (vi) measurement of outcomes, (vii) follow-up and (viii) statistical analysis results. For each domain, questions are answered with “yes” or “no”. Based on these answers, an overall risk of bias assessment was calculated for each included study .p < 0.05 and I2 ≥ 50%. The random-effects model was used to calculate the pooled effect when heterogeneity was high, while the fixed-effects model was used when low heterogeneity was encountered. All statistical analyses and forest plots were performed with the use of Reviewer Manager 5.4.1 software (Review Manager (RevMan) [Computer Program]. Version 5.4.1, Copenhagen: The Nordic Cochrane Centre, Denmark, The Cochrane Collaboration, 2020).Available data were handled according to the principles stated in the Cochrane Handbook . Data onThrough our systematic search, 125 unique articles were retrieved, 68 of which underwent full-text evaluation for eligibility (57 studies excluded based on title and abstract screening). Ultimately, 18 studies reporting on 4622 patients undergoing cytoreduction surgery for ovarian cancer (4278 non-AL and 344 AL patients) fulfilled the inclusion criteria and were included in our quantitative data synthesis ,29,30,31p = 0.38, I2 = 0%) and current smoking status  were not associated with a significantly increased risk of AL, as reported by two and three studies, respectively [p = 0.5, I2 = 40%)  nor the ASA III-IV classification  were significantly associated with AL  . Neither with AL .p = 0.06, I2 = 44%). Similarly, in subgroup analysis, there was no difference in AL rate with the use of bevacizumab . The use of HIPEC was also not linked to a statistically significant increase in AL rates  when combined with surgical management  was associated with an increase in AL. The type of anastomosis, including hand-sewn  or stapled  was not associated with a significant increase in AL  as well as primary  versus secondary cytoreductive or recurrent disease were not associated with a significantly altered risk of AL  but not with 60-day mortality   .The mean score of the NHLBI scale was 7.7 ± 1.1. These results highlight that the included studies were, on average, of good quality. This is outlined in This systematic review and meta-analysis of 18 retrospective studies showed that multiple bowel resections increased the risk of AL following ovarian cytoreduction surgery. In addition, the presence of AL in ovarian cytoreduction surgery significantly increased the risk of 30-day mortality. These findings indicate that multiple bowel resections may be a major contributor to poor outcomes, including 30-day mortality, in patients with ovarian cancer who require bowel anastomosis. Historically, AL was thought to only impact 30-day mortality ,34, giveOur analysis revealed that the use of neoadjuvant chemotherapy was associated with a clinically significant decrease in the rate of AL that marginally failed to attain statistical significance. In the neoadjuvant setting, a typical regimen consists of two or three courses administered prior to interval cytoreductive surgery, followed by up to six courses of chemotherapy postoperatively . This reOur analysis further confirmed that there is no significant difference in AL rates in patients receiving HIPEC. HIPEC consists of circulating warmed chemotherapeutic agents around the peritoneal cavity intraoperatively, following resection and prior to anastomosis or stoma formation, and aims to eliminate any remaining neoplastic cells. A recent phase III trial, randomizing patients with advanced ovarian cancer to either HIPEC or no HIPEC during cytoreductive surgery, demonstrated that HIPEC increases recurrence-free survival and overall survival . MoreoveProtective stoma formation describes the process of creating a temporary diverting proximal stoma in patients at higher risk of complications, such as AL, to prevent postoperative morbidity . Our anaSecondary debulking describes cytoreduction surgery in the setting of recurrence in patients that underwent primary surgery to remove the tumor found in the first place. Our analysis found no significant difference in AL rates between individuals undergoing primary or secondary recurrent disease cytoreduction procedures. However, in the literature, the eligibility criteria for secondary cytoreductive surgery seem to be more selective than for primary cytoreductive surgery ,50. TherThe limitations of this study include the use of observational studies as opposed to randomized controlled trials. Other limitations include the small number of patients, with few studies primarily designed to investigate AL-associated risk factors, and many of these only consider AL in subgroup analysis. Furthermore, additional relevant factors, including the surgeon’s experience, blood loss and the need for transfusion, were not amenable to analysis due to limited available data. The role of preoperative hypoalbuminemia  was not examined in this study as it is a well-established independent preoperative risk factor for AL after colorectal surgery ,53,54,55In conclusion, our study suggests that AL is associated with a significantly increased 30-day mortality rate in the ovarian cancer population undergoing a cytoreduction operation. Multiple bowel resections were a risk factor for AL in this patient population. However, larger prospectively-designed studies are required to increase the statistical power of any future analyses and more accurately assess a wider range of risk factors for an anastomotic leak in ovarian cytoreduction, similar to bowel cancer studies.


Preliminary studies indicated that enhanced plasma levels of lipoprotein(a) [lp(a)] might link with the risk of calcific aortic valve disease (CAVD), but the clinical association between them remained inconclusive. This systematic review and meta-analysis were aimed to determine this association.We comprehensively searched PubMed, Embase, Web of Science, and Scopus databases for studies reporting the incidence of CAVD and their plasma lp(a) concentrations. Pooled risk ratio (RR) and 95% confidence interval (95% CI) were calculated to evaluate the effect of lp(a) on CAVD using the random-effects model. Subgroup analyses by study types, countries, and the level of adjustment were also conducted. Funnel plots, Egger's test and Begg's test were conducted to evaluate the publication bias.Eight eligible studies with 52,931 participants were included in this systematic review and meta-analysis. Of these, four were cohort studies and four were case-control studies. Five studies were rated as high quality, three as moderate quality. The pooled results showed that plasma lp(a) levels ≥50 mg/dL were associated with a 1.76-fold increased risk of CAVD , but lp(a) levels ≥30 mg/dL were not observed to be significantly related with CAVD . We performed subgroup analyses by study type, the RRs of cohort studies revealed lp(a) levels ≥50 mg/dL and lp(a) levels ≥30 mg/dL have positive association with CAVD .High plasma lp(a) levels (≥50 mg/dL) are significantly associated with increased risk of CAVD. Calcific aortic valve disease (CAVD) is one of the most common valve disorders . CAVD isLPA genotype, which could mediate the levels of lp(a), had a strong relationship with CAVD  levels, was independently related to an augmented risk of CAVD  levels ≥50 mg/dl . Previouith CAVD . Multipl of CAVD , 16. How of CAVD , 18, whi of CAVD . In respThe systematic review and meta-analysis were performed following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)  and MetaTwo authors (Liu QY and Yu YQ) systematically searched the electronic databases, including PubMed (MEDLINE), Embase, Web of Science, and Scopus, up to 31 August 2021. Searching terms included [“lipoprotein(a)” or “lp (a)” or “lipoprotein”] and  without language or sample size restrictions. The reference lists of relevant reviews, original reports were also searched for potential eligible records. The initial screening of eligible studies was based on the titles and abstracts.All cohort studies and case-control studies that had investigated the association between lp(a) and the risk of CAVD were eligible for inclusion. 2016 ESC/EAS Guidelines suggested that lp(a) ≥50 mg/dL had a significant risk of CVD . EuropeaData extraction was completed by two reviewers (Liu QY and Lai RM) independently. If there were disagreements, a third reviewer would be consulted (Ju JQ). Information extracted from each included study comprised first author's name, publication year, country or region where it was performed, study design, and follow-up duration. Demographic data included the number of participants and primary characteristics were obtained.Both cohort studies and case-control studies were estimated the risk of bias according to the Newcastle–Ottawa quality assessment scale (NOS), with a maximum score of 9 . The sumThe pooled CAVD prevalence was compared between individuals with lp(a) levels <50 vs. ≥50 mg/dL and with lp(a) levels <30 vs. ≥30 mg/dL, respectively. Adjusted risk estimates of CAVD reported directly in the included studies were extracted, including odds ratios (ORs), hazard ratio (HRs), and risk ratios (RRs). Adjusted factors were currently identified risk factors related to the occurrence and development of CAVD, including age, sex, hypertension, smoking, dyslipidemia, BNP, diabetes, and obesity, and at least one of them was required to be adjusted in advance . StudiesZ-test, and a two-tailed P < 0.05 was deemed statistically significant. Chi-square Cochran's Q-test and I square statistics were used to assess potential heterogeneity among studies. In detail, I square >50% was defined as high statistical heterogeneity, I square of 0–50% indicates low heterogeneity, I square = 0% indicates no heterogeneity, respectively . Potential publication and small sample bias were evaluated by Egger's and Begg's test . The funA total of 2,032 articles were identified in four databases. After the final full-text screening, eight eligible studies were included for systematic review and meta-analysis , 36–41. Of the eight included studies, four were cohort studies, and four were case-control studies. Three included studies originated from America, four from Europe, and the remaining one study was unknown. The age of participants ranged from 51 to 75 years. The proportion of females was 35–57%. Five studies evaluated the association between AVS and lp(a), three estimated associations between aortic valve calcification (AVC) and lp(a). In the four included cohort studies, outcome events occurred in 1,383 of 52,134 participants during follow-up. The case-control studies comprised 425 cases and 372 controls. Characteristics of the included studies are displayed in The NOS quality assessment scores ranged from 5 to 8 in cohort studies and 6 to 7 in case-control studies. Two out of four cohort studies were identified as high quality, two as moderate quality. Three out of four case-control studies were identified as high quality, one as moderate quality. Scoring details are provided in Lp(a) 50 mg/dL group analysis We extracted all the effect estimates of CAVD from seven studies grouped with 50 mg/dL of lp(a) level. One study used the Cox regression to calculate the HR. The rest of the studies used logistic regression and reported ORs and RRs.P < 0.001). And lp(a) ≥50 mg/dL might be a risk indicator for CAVD. However, the included studies had substantial statistical heterogeneity (I square = 59.2%), which needed further analysis. The association between lp(a) ≥50 mg/dL and CAVD were significant in both cohort studies  and case-control studies  , which suggested elevated lp(a) level might increase the risk of CAVD by 76% (41–5.28) .P = 0.072; Lp(a) 30 mg/dL group analysis Five studies, which consisted of two cohort studies and three case-control studies, examined the association between lp(a) ≥30 mg/dL and CAVD. The pooled RR was 1.28 , which indicated lp(a) concentration of 30 mg/dL or higher was not significantly associated with CAVD  and AVC or AVS. AVC and AVS are the preclinical and post-clinical phases of CAVD, regarded as the representative of CAVD. So we analyzed the associations of lp(a) with these two outcomes, respectively. In the lp(a) 50 mg/dL group, four studies reported the association with AVS, three reported the association with AVC. The separate meta-analysis indicated that lp(a) ≥50 mg/dL was significantly correlated with AVC  and AVS . In the lp(a) 30 mg/dL group, two studies reported the association with AVS, three reported the association with AVC. And the relationship of lp(a) ≥30 mg/dL with AVC  is stronger than with AVS . As shown in Subgroup analyses stratified according to study types, countries, and level of adjustment, the statistically significant association between lp(a) ≥50 mg/dL and CAVD risk was observed in all subgroups. When the subgroup analysis was conducted considering the study types in lp(a) 30 mg/dL group, a significant positive effect of lp(a) ≥30 mg/dL on CAVD was noted in the cohort studies , while the result of case-control studies had a positive trend without statistical significance . A subgroup analysis stratified by different countries, lp(a) ≥30 mg/dL was associated with a higher risk of CAVD in Europe , but not in America . In a subgroup analysis by the level of adjustment , the pooled RR in studies adjusted for six or more covariates  was more marked than in the less than six covariates group . The details are shown in P = 0.230; Egger's test, P = 0.499; lp(a) 30 mg/dL group: Begg's test, P > 0.99; Egger's test, P > 0.99].Publication bias assessment of the above two groups was performed using funnel plots at first. There might be asymmetry in the two diagrams figure . TherefoWe evaluated the relationship between elevated plasma lp(a) level and CAVD. The major findings were as follows: (1) The incidence of CAVD was higher in the high lp(a) level group than in the low-level group, as reported by most of the original studies. 2) The pooled results of lp(a) 50 mg/dL group supported that plasma lp(a) ≥50 mg/dL might be a risk factor for CAVD. Whereas, there was insufficient evidence for the association between plasma lp(a) ≥30 mg/dL and CAVD. Also, substantial heterogeneity between studies was not well-explained by subgroup analysis with a 30 mg/dL lp(a) cut-off value, which called for caution when interpreting the result. (3) Patients with plasma lp(a) ≥50 mg/dL might have a higher risk of CAVD than those with lp(a) ≥30 mg/dL. Therefore, we speculated that the magnitude of lp(a) concentration might have a dose-response relationship with CAVD. (4) The progression of CAVD has multiple stages, including calcification and stenosis, etc. AVC, an independent predictor of cardiovascular events , not onl The poolBesides other conventional risk factors like age, sex, hypertension, and smoking, dyslipidemia played a vital role in calcific aortic valve disease . Lipids Several plausible mechanisms may account for the underlying pathophysiology of lp(a)-mediated CAVD. Lp(a) is a low-density lipoprotein-like structure, which mainly contains apolipoprotein B (apo B) covalently bound to apolipoprotein(a) [apo(a)] , 56, traWelsh et al. revealed reducing the baseline lp(a) levels by 80%, patients with lp(a)≥175 nmol/l and baseline CVD could decrease the risk of CVD by 20% . And theThere are several strengths of our meta-analysis. Firstly, this is the first meta-analysis assessing the association between lp(a) and CAVD. Secondly, our analysis included a comprehensive search strategy, a considerable number of participants, a subgroup analysis for heterogeneity. And we integrated all relevant cross-sectional and case-control studies, allowing us to determine whether there was a significant relationship between lp(a) and CAVD. Thirdly, most of the included studies have controlled the confounders, which ensured the reliability of the outcomes. Finally, we investigated the relationship between high lp(a) levels (≥50 and ≥30 mg/dL) and the incidence of CAVD, respectively, which provided some guidance for patients with elevated plasma lp(a) levels to assess their risk of CAVD. However, heterogeneity was observed in our meta-analysis, even though most of studies had adjusted multiple potential confounders. Therefore, the results of the present analyses should be interpreted with caution.Based on the current cohort studies and case-control studies, we could conclude that patients with lp(a) ≥50 mg/dL were at a significantly high risk of CAVD. However, further large-scale prospective cohort studies with high quality and adequate control for confounders are necessary to draw a firm conclusion on the causality between plasma lp(a) and CAVD.The original contributions presented in the study are included in the article/QL and JJ conceived the study. QL and YY searched the studies, screened the studies, analyzed the data, and wrote the manuscript. QL and RL extracted the data. TW, YF, and RX assessed the risk of bias. JL, JJ, and HX reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.This research was supported by grant CI2021A00917 from the China Academy of Chinese Medical Sciences Innovation Fund, grant ZYYCXTD-C-202007 from the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine, and grant ZZ13-YQ-017 from the Central Public Welfare Research Institutes of China Academy of Chinese Medical Sciences.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Epidemiological studies of citrus consumption in relation to melanoma risk have yielded conflicting results. This meta-analysis was performed to investigate the dose-response association between citrus consumption and risk of melanoma.Relevant prospective cohort studies were identified by searching PubMed, Embase, Scopus, and Web of Science databases up to February 28th, 2022. Results from individual studies were pooled using a random-effects model.Five prospective studies, with 8,836 melanoma cases and 977,558 participants, were included in the meta-analysis. A significantly increased risk of melanoma was associated with the highest categories of either total citrus products  or citrus fruit consumption , but consumption of citrus juice was not associated with melanoma risk . The dose-response analyses revealed that for per 1 serving/day increase in total citrus or citrus fruit consumption, the risk of melanoma increased by 9 and 12%, respectively. An inverted U-shaped curvilinear relationship, but not linear association, was observed between citrus juice consumption and melanoma risk.Citrus consumption was generally associated with a greater risk of malignant melanoma. Our findings may have important public health implications with respect to preventing melanoma. The global incidence of malignant melanoma has increased steadily over the past several decades . CurrentHigh exposure to solar ultraviolet (UV) is thought to play a fundamentally important role in the development of malignant melanoma . Such phUnderstanding the exact influence of high citrus consumption on melanoma risk have important public health implications with respect to establishing clear dietary guidelines to prevent melanoma. Therefore, we conducted the current meta-analysis of all available prospective cohort studies to quantify the dose-response relationships between dietary consumption of citrus products, including total citrus, citrus fruits, and citrus juice, and melanoma risk.This meta-analysis was designed, implemented, analyzed, and reported in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol .We systematically searched papers that published until February 28th, 2022 in the databases PubMed, Embase, Scopus, and Web of Science. The following keywords were used in the systematic search: (citrus OR “citrus aurantifolia” OR “citrus sinensis” OR “citrus paradisi” OR “citrus juice” OR lemon OR grapefruit OR orange) AND (melanoma OR “melanotic freckle” OR “skin cancer”). Our search was restricted to observational studies conducted in humans, and no restriction was applied on language of the publications. Additional articles were also identified by reviewing the references cited within the retrieved relevant studies. The literature search was conducted by two investigators independently.Studies were considered eligible if they satisfied the following four criteria: (1) prospective study design of adults (aged > 18 y); (2) the exposure of interest was dietary intake of citrus, including citrus fruit and citrus juice; (3) the outcome was melanoma; and (4) the authors reported risk estimates with 95% confidence intervals (95% CI). Retrospective studies, animal studies, commentaries, reviews, and meta-analyses were excluded, as well as studies that focused on other skin malignancies. To ensure the correct identification of eligible studies, a two-step selection process was performed. Two investigators conducted an initial screening of all titles and/or abstracts independently; the full text of each potentially relevant paper was then evaluated. Any discrepancies were solved by consensus or by a third senior reviewer.Data were extracted using a standardized data collection form. We extracted the following information from every included study: first author and year of publication, the study's location, the study's name (where applicable), the duration of follow-up, gender distribution, sample size (the number of cases and participants), the method used to assess dietary intake , the dietary categories of citrus consumption, and the corresponding risk estimates with 95% CI. We extracted the risk estimates from only the fully adjusted models.The quality of these included studies was evaluated according to the Newcastle-Ottawa scale for non-randomized studies . This scRelative risks (RRs) or odds ratios (ORs) with 95% CIs were used as the common measure of association across studies. We calculated the summarized RRs and their corresponding 95% CIs using a random-effects model, which incorporates both within- and between-study variability . When stDue to the relatively wide range of definitions for the exposure categories in the included articles, we performed a dose-response analysis based on a 1 serving/day increase in consumption of total citrus, citrus fruit, and citrus juice, in addition to the comparison between the highest and lowest categories. When the consumption was expressed in grams, we converted the amount by considering the average weight: 100 g for a serving of total citrus or citrus fruit, and 50 g for a serving of citrus juice. The method of dose-response meta-analysis was proposed by Greenland and Longnecker and the publicly available code written by Greenland and Longnecker  and OrsiI2 statistic, with values of 25, 50, and 75% representing low, moderate, and high degrees of heterogeneity, respectively  but not publication bias . Interestingly, when stratified by gender, the correlation remained statistically significant only among women  with attenuated heterogeneity (I2 = 20.1%).The multivariable-adjusted RRs of melanoma risk for the highest vs. the lowest category of total citrus consumption in each study, and for all studies combined, are shown in I2 = 37.4%) . Among individual citrus fruits, grapefruit showed a more apparent association with melanoma risk . Consumption of oranges was not significantly associated with a higher risk of melanoma .In the fully adjusted models, participants in the highest category of citrus fruit consumption had a significantly increased risk of melanoma , with moderate heterogeneity (= 37.4%) . NeitherI2 = 53.0%), without evidence of publication bias  (I2 = 0.0%), comparing the highest category with the lowest. However, significant association was seen between orange juice consumption and melanoma risk; the pooled RR comparing the highest with the lowest levels of orange juice consumption was 1.32 .The effect of citrus juice consumption on melanoma risk was also analyzed. However, we did not observe consistent significant association between consumption of citrus juice and melanoma risk  .Two stud's test) , 21. ForI2 = 66.6%) (P < 0.01 for non-linearity) (I2 = 42.0%) (P = 0.06 for non-linearity) (I2 = 60.9%) (P < 0.05 for non-linearity), with the highest risk at ~0.5–1 serving per day  . In addinearity) . When we= 42.0%) . Howevernearity) . The ass= 60.9%) , but in  per day .In this meta-analysis of prospective cohort studies, we observed a positive association with increased melanoma risk for higher consumption of citrus, especially of citrus fruits. Significantly higher risks of 9 and 12% were seen for melanoma with every additional 1 serving/day of total citrus and citrus fruits consumed, respectively. Although no significant trend for citrus juice consumption in linear dose-response analysis, an inverted U-shaped curvilinear association was shown. To the best of our knowledge, this is the first meta-analysis providing a comprehensive insight into the quantitative association between consumption of citrus products and melanoma risk.Citrus products are widely popular foods, but are also rich sources of psoralen, a naturally occurring furocoumarin used to kill foreign pathogens . In the Since 2015, five large-scale prospective cohort studies have investigated the hypothesis, but yielded mixed results. Data from the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) showed a significantly positive association between citrus consumption and risk of malignant melanoma . ConversIn general, our findings agree with a carcinogenic role of citrus products in the development of melanoma, support to guide safe sun exposure behaviors among those with high consumption of citrus products. In addition, we indicated the inconsistent influence of citrus consumption on melanoma risk among women and men for the first time. However, the potential mechanisms underlying the sex differences remain to be further explored. More investigation is needed to confirm this finding.Grapefruit and oranges are two of the most commonly consumed citrus fruits, accounting for more than 90% of citrus market share. Interestingly, grapefruit showed a stronger association with melanoma, which might be explained by its higher content of psoralen when comparing to oranges . IndustrStrengths of our study include comprehensive literature search and large number of participants and cases included. Because we included only prospective cohort studies, the influence of reverse causation and selection bias was minimized. Additionally, either linear or non-linear dose-response analysis between citrus consumption and risk of melanoma was conducted, allowing us to evaluate the shape of the potential association.Some limitations are worth noting. First, although we identified a few potential sources of heterogeneity, most of the observed high variation among different populations remained unexplained due to limited numbers of studies. Second, the limited original data also resulted in difficulty to the generalizability of our findings. Third, measurement errors in dietary assessment are inevitable and statistical approximation used in out dose-response analyses might also involve errors. Lastly, since our analyses were based on observational studies, residual confounding cannot be completely ruled out.In conclusion, our dose-response meta-analysis of prospective studies found that higher consumption of total citrus or citrus fruit was associated with an increased risk of melanoma. We also showed an inverted U-shaped relationship between citrus fruit consumption and melanoma risk. These findings have important public health implications with respect to improving melanoma prevention strategies. But extrapolating these conclusions to the global population should be done cautiously, because all results analyzed in the study were reported from Western countries. Thus, further studies are required to strengthen the evidence and to uncover the underlying mechanisms.The original contributions presented in the study are included in the article/XF and FL contributed to conception and design. XF and DH searched the databases and checked them according to the eligible criteria and exclusion criteria. JY helped conduct quality assessment of including studies. XF analyzed the data and wrote the draft of the article. Final version was edited and approved by all authors.This study was supported by research grants from the National Natural Science Foundation of China , the Natural Science Foundation of Zhejiang Province (Y22C115257 to XF), and the Program of Shanghai Academic Research Leader (20XD1423600 to FL).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P < 0.001; I2 = 37.0%), but these associations were not observed with intakes of low or high-fat dairy, cheese or milk. Increased risk of endometriosis was associated with higher consumption of red meat , trans fatty acids (TFA) , and saturated fatty acids (SFA) . The results of this meta-analysis suggest that there may be differing associations between dietary intake of dairy foods, red meat, SFAs, and TFAs and the risk of endometriosis. It may be useful to extend the analysis to other types of food groups and dietary patterns to obtain a complete picture. Additionally, further investigations are needed to clarify the role of diet in the incidence and progression of endometriosis.Dietary factors may play a role in the etiology of endometriosis and dietary intake of some food groups and nutrients could be associated with endometriosis risk. This systematic review and meta-analysis of observational studies was conducted to summarize the findings on the association between dietary intakes of selected food groups and nutrients , and the risk of endometriosis among adult women. PubMed, Scopus, and ISI Web of Science were systematically searched up to September 2022. The inverse variance-weighted fixed-effect method was used to estimate the effect size and corresponding 95% CI. A total of 8 publications (4 studies) including 5 cohorts and 3 case-control with a sample size ranging from 156 to 116,607 were included in this study. A higher intake of total dairy [all low-fat and high-fat dairy foods] was associated with decreased risk of endometriosis (RR 0.90; 95% CI, 0.85 to 0.95; Trial registration: PROSPERO, CRD42020203939. Endometriosis is a gynecological condition defined as the presence of endometrial glands and stroma-like lesions outside the uterus that can cause infertility and severe debilitating pain . The preDietary factors can be related to endometriosis etiology due to their role in regulating steroid hormone metabolism, the effect on muscle contraction, regulating inflammation, oxidative stress, and the menstrual cycle . For insDietary factors may be associated with the progression and development of endometriosis, but the findings are contradictory due to various issues including different study designs, sample size, and other methodological aspects. For instance, some observational studies did not show any significant association between dairy intake and endometriosis risk , 7 whileAlthough a previous literature review examined the relationship between diet and endometriosis risk, that study searched the literature up to 2011 and also overlooked a meta-analysis on this topic. Therefore, conducting a more comprehensive systematic review and meta-analysis of this issue was necessary. Therefore, the current study was conducted to summarize the findings on the association between dietary food groups and nutrient consumption and the risk of endometriosis using a systematic review and meta-analysis of observational studies among adult women.The present study was designed and conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statements  and alsoPopulation (aged > 18 years old women), Exposure , Comparison , Outcome (risk of endometriosis), and Study design (case-control or cohort studies).The PI(E) COS model was used to determine eligibility criteria, representing To be included in our study, articles investigating the association between dietary food groups and nutrients and the risk of endometriosis had to meet the following criteria: (1) original human observational studies either with case-control or cohort design; (2) published in the English language; (3) which reported at least one of the intended food groups or nutrients including fat, red meat, poultry, fish, total fruits, total vegetables, total dairy, milk, cheese, egg, and legumes as exposure in association with endometriosis risk as an outcome.The exclusion criteria were as follows: (1) pre-clinical studies; (2) females aged < 18 years old; and (3) not original full-length articles including poster abstracts, case reports, review articles, editorials, or without original data or articles with no appropriate outcome measures. Two assessors independently (A.A and E.K) conducted the selection process. Any disagreement was resolved through discussion with a third reviewer (G.A).The following data were extracted: the first author’s name, published year, study location, sample size, participant characteristics [including age and body mass index (BMI)], study design, endometriosis diagnosis method, type of dietary assessment approach, and statistical adjustment.The quality assessment of eligible studies was performed by two reviewers (A.A and E.K) individually using the Newcastle-Ottawa Scale (NOS) star system  , which f2) test and I2 statistic   . The low%, the meA total of 8 publications 4 studies) were included in this systematic review and meta-analysis with a sample size ranging from 156 to 116,607. Participants’ mean age at the baseline of studies ranged from 18 to 41.38 years. The included studies were conducted between 2004 and 2020. Among included publications, six were from the United States  studies , 21, oneP < 0.001, with no evidence of significant heterogeneity  , and was without between-study heterogeneity  , with evidence of significant heterogeneity  , with no evidence of heterogeneity   with significant heterogeneity  , low-fat dairy , cheese  and milk . As there was evidence of publication bias for high-fat dairy , we conducted trim and fill analysis to determine any potentially missed studies, however, no study was added.No evidence of publication bias was observed for total-dairy  with no evidence of significant heterogeneity   without evidence of heterogeneity   Fig. b.P = 0.114) with no evidence of significant heterogeneity   Fig. c.P < 0.001), with evidence of significant heterogeneity  , with significant heterogeneity  , MUFA , PUFA , SFA  or TFA .No evidence of publication bias was observed for total fat . Also, there was evidence of significant heterogeneity between the effect sizes of included studies . Overall, the meta-analysis result was sensitive to Trabert et al. [Quantitative analysis of total fruits intake in four databases , 21, 22 P = 0.256), with evidence of significant heterogeneity . Overall, the meta-analysis result was sensitive to Harris et al. [Similarly, four studies , 21, 22 P = 0.497, Egger’s test: P = 0.610) and vegetables .No evidence of publication bias was observed for fruits (Begg’s test: P = 0.921), with no evidence of significant heterogeneity . Overall, the meta-analysis result was not sensitive to individual studies. No evidence of publication bias was also observed    Fig. a.Fig. 7FP = 0.208), with no evidence of significant heterogeneity   Fig. b.P = 0.104). Also, there was no evidence of heterogeneity between the effect sizes of included studies   Fig. c.P < 0.001), with evidence of significant heterogeneity   Fig. d.P = 0.602, Egger’s test: P = 0.884), fish , poultry , and red meat .No evidence of publication bias was observed for studies reporting dietary intake of egg (Begg’s test: The results of the sensitivity analysis for fish, poultry, and meat showed that the omission of each study did not affect the overall outcome and that the overall findings were not influenced by a particular study. On the other hand, the meta-analysis result for the egg was sensitive to Trabert et al.  (RR 0.87This systematic review and meta-analysis was conducted to summarize the findings on the association between dietary intakes of selected food groups and nutrients and the risk of endometriosis. Our findings suggest that a high intake of total dairy may be associated with decreased risk of endometriosis. Furthermore, high consumption of red meat, SFA, and TFA was associated with an increased risk of endometriosis. These findings suggest that dietary factors may play a role in the risk of endometriosis.The findings on the relationship between total dairy intake and the risk of endometriosis were in agreement with previous reports , 23, howOur analysis also showed no association between total fat, MUFA, and PUFA intake and an increased risk of endometriosis associated with dietary intake of SFA and TFA. Missmer et al.  in a proIn vitro studies on the survival of endometrial cells in women with and without endometriosis have reported that these cells may be influenced by the fatty acid content of the culture media . ConsumpWe also found no significant association between total fruits and total vegetable consumption and the risk of endometriosis, although the results of the analysis show a declining trend. In a previous report by Youseflu et al. , increasAnalysis of the results of the three studies , 21, 23 Similar to other findings, no association was found between the intake of eggs, fish, and poultry and the risk of endometriosis, whereas eating red meat was associated with an increased risk of endometriosis by approximately 17%, with evidence of significant heterogeneity. Likewise, a prospective cohort study reported that women consuming > 2 servings/day of red meat had a 56% higher risk of endometriosis compared to those consuming ≤1 serving/week . AccordiEnergy adjustment is one of the most important modifications in the context of the association between diet and various health issues . In thisThere was significant heterogeneity between included studies that may have affected the results and lessened the generalizability of the findings. The probable sources of heterogeneity might be differences in age, BMI, study design, geographical variation, and the quality of the studies. Also, not all studies ensure representative samples of the population and the findings should be interpreted with caution. Patients’ food intake was assessed through an FFQ, which is a subjective estimate of a person’s past intake rather than an assessment of absolute intakes. Furthermore, dietary intakes of participants were reported in different manners, including serving/day or gram/day which could be a source of heterogeneity; however, the lowest values were compared to the highest values to diminish the effects of this issue on the outcomes.In conclusion, an optimal intake of total dairy, as well as reduced consumption of red meat, TFA, and SFA may be associated with decreased risk of endometriosis. It may be useful to extend the analysis to other types of food groups and dietary patterns to obtain a complete picture. Additionally, further investigations are needed to clarify the role of diet in the incidence and progression of endometriosis. Cohort studies may be better able to capture long-term intake, especially those that used FFQs administered at multiple time points which need to be done on this topic if future studies.


Diets containing red or processed meat are associated with a growing risk of digestive system cancers. Whether a plant-based diet is protective against cancer needs a high level of statistical evidence.2) and τ2 (Tau2) index were used to quantify the magnitude of heterogeneity derived from the random-effects Mantel-Haenszel model.We performed a meta-analysis of five English databases, including PubMed, Medline, Embase, Web of Science databases, and Scopus, on October 24, 2021 to identify published papers. Cohort studies or case-control studies that reported a relationship between plant-based diets and cancers of the digestive system were included. Summary effect-size estimates are expressed as Risk ratios (RRs) or Odds ratios (ORs) with 95% confidence intervals and were evaluated using random-effect models. The inconsistency index  and case-control  studies. The overall analysis concluded that plant-based diets played a protective role in the risk of digestive system neoplasms. Subgroup analyses demonstrated that the plant-based diets reduced the risk of cancers, especially pancreatic , colorectal , rectal  and colon  cancers, in cohort studies. The correlation between vegan and other plant-based diets was compared using Z-tests, and the results showed no difference.The same results were found in cohort (adjusted RR = 0.82, 95% CI: 0.78–0.86, Plant-based diets were protective against cancers of the digestive system, with no significant differences between different types of cancer.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022322276, Identifier: CRD42022322276. Common digestive system cancers include liver, esophageal, gastric, and colorectal tumors, which are among the 10 most significant healthcare issues worldwide , and theDiet is an inseparable part of people's daily lives, and it has attracted much attention. High quality evidence investigated that red meat, especially the consumption of processed meat, was associated with a growing risk of digestive system cancers , 6. IncrSeveral styles of vegetarian diets are defined based on the specific animal products consumed . VegetarOther classified dietary patterns, such as the Mediterranean diet , prudentWith these complicated classifications, the dietary patterns and subtypes of cancer require further detailed grouping. Therefore, we did this meta-analysis to better assess the association between plant-based diets and gastrointestinal cancers to provide evidence for dietary guidance.The performance of the meta-analysis adhered to the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement  and MetaA literature search was performed in the PubMed, Medline, Embase, Web of Science and Scopus databases before October 24, 2021. The PICOS tool was used to guide the search strategy: (P) Population: patient with digestive system cancers; (I) Intervention: plant-based diet; (C) Comparator: other diet patterns; (O) Outcomes: gastrointestinal system cancers; (S) Study type: case-control and cohort studies. A complete list of the search terms is available in the additional materials section .Our analysis was restricted to articles that met the following criteria: (1) study participants: population with plant-based diets; (2) endpoints: all kinds of digestive system cancers; (3) study type: cohort studies or case-control studies; (4) follow-up rate: at least 70%; and (5) the dietary patterns in the articles included specific food components. Case reports or case series, editorials, narrative reviews, non-English articles,and literature with unqualified data and not available were excluded.Endnote 20 literature management software was used to manage the literature search records. The selection process covered three sections. Two reviewers (Y.Z. and Y.W.) independently reviewed articles based on their titles, and duplicates were removed. Articles with questionable titles were included in the abstract review phase. The same two independent reviewers screened and evaluated the abstracts of all articles selected from the first section for eligibility. Meanwhile, they assessed full-text articles that warranted further investigation using the eligibility criteria. Disagreements in each phase were resolved by a third independent reviewer (D.W.) from our group.Two investigators (Y.Z. and Y.W.) independently extracted data from each qualified article, including the first author, year of publication, country where study was performed, sex, sample size, study type, follow-up years, the age of study subjects, cancer type, definition of the vegetarian dietary pattern, menstrual status and other confounding risk factors, when available. The divergence was resolved via joint re-evaluations of original articles, and by a third author (D.W.) when necessary.Two authors (Y.Z. and Y.W.) independently assessed the risk of bias of all eligible studies using the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) assessment tool . The fol*ln (1–r))/r. Pooled effect-size estimates were derived under the random-effects model, regardless of the magnitude of between-study heterogeneity. Differences between two estimates were tested using the Z-test proposed by Altman and Bland . Effect size was estimated as risk ratios (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs) in cohort studies and as odds ratios (ORs) with 95% CIs in case-control studies. To make the statistical results more accurate, we transformed the HRs into RRs using the formula RR = (1–expHRnd Bland .2) statistic, which represents the percent of diversity due to heterogeneity rather than chance, was used to quantify the magnitude of heterogeneity derived from the random-effects Mantel-Haenszel model. An I2 > 50% indicated the presence of significant heterogeneity, and a higher percent corresponded to a higher degree of heterogeneity. Another index, τ2 (Tau2), was used to examine the sensitivity of the results to different levels of between-study heterogeneity. To account for possible sources of between-study heterogeneity from clinical and methodological aspects, a large number of pre-specified subgroup analyses were performed according to geographic region, study design, age, sex, cancer type, definition of plant-based dietary pattern, and follow-up interval. To avoid giving large weight to relatively small studies, we fitted the fixed effect models using sensitivity analyses.The inconsistency index  and case-control studies .After summarizing the results of all qualified cohort and case-control studies, the pattern of plant-based diets was statistically associated with the risk of digestive system cancer. The results suggested that a plant-based diet pattern played a protective factor for the risk of digestive system cancer in the cohort studies , colorectal cancer , colon cancer , rectal cancer , gastric cancer , liver cancer , and esophageal cancer  in the cohort studies, and equivalent connections were found in case-control studies for pancreatic cancer , colorectal cancer , gastric cancer , pharyngolaryngeal cancer  and liver cancer . No statistically significant relationship was found between plant-based diets and colon cancer  or rectal cancer   .Cumulative analysis of the included studies obtained completely similar conclusions, and the trend tended to be stable. Sensitivity analyses revealed no significant impact on any single study on overall effect-size estimates.P = 0.000) and case-control studies . The “trim and fill” method was used and no correction was made to the original estimates.Because of between-study heterogeneity, we performed a series of pre-specified analyses to further explore the relationship between plant-based diets and digestive system cancer risk. Notably, the protective effect of plant-based diet patterns was accordant in all subgroup analyses . We did P < 0.001, I2 = 46.4%, Tau2 = 0.017) and females  in the cohort studies (two-sample Z-test P = 0.128).Plant-based diets were statistically associated with digestive system cancer risk in males , Asia  or North America . In the case-control studies, subgroup analysis proved statistical significance of plant-based dietary patterns for digestive cancers in Europe , Asia  or North America .The included cohort and case-control studies were divided into North America, Europe, and Asia. In the cohort studies, subgroup analysis demonstrated statistical significance of plant-based dietary patterns for digestive cancers in Europe  and digestive system cancers in the cohort studies, and this relationship also existed in the prudent dietary pattern , semi vegetarian pattern , and Mediterranean pattern . However, there were no significant difference between pesco-vegetarians  and lacto-ovo-vegetarians . Vegan , prudent , Mediterranean , pesco-laco-ovo-vegetarian  and lacto-vegetarian  diets had robust correlations with digestive tract cancers in case-control studies, but not semi-vegetarian  or DASH diets .We found a significant difference between the vegan pattern  or case-control studies (two-sample Z-test P = 0.158).We combined plant-based diets other than the vegan pattern into the non-vegan diet and found that vegan and non-vegan diets were statistically significant for digestive cancers, but no significant difference was found between the two diets in cohort studies  and normal populations  in cohort studies.Prominent differences were found in people of the Adventists faith .For the median value (10 years) of the follow-up period, the protective effect of plant-based diets for digestive cancers was consistent and significant regardless of the length of follow-up in cohort studies  are primary sources of fiber and other bioactive compounds in the diet , 74. A wEvidences suggests that the effect of a plant-based diet on intestinal flora is inextricably linked to digestive tract tumors. Daily consumption of nuts reduces the risk of cancers of the digestive system. High levels of dietary fiber, polyphenols and unsaturated fats are rich nutrients in nuts, and dietary fiber increases anaerobic fermentation and reduces intestinal transit time, which may reduce the exposure of colorectal mucosa to carcinogens . PolypheDue to the protective effect of vegetarian dietary patterns on tumors, we examined whether people needed to ensure a pure vegan diet. For further research, we divided the plant-based dietary patterns into two categories, including a pure vegan diet and other types of primarily vegetarian diets and found that these two diet types produced equivalent protective roles against digestive system cancers. This conclusion means people do not need to adopt a pure plant-based diet. These results provide a more robust understanding of healthy eating guidance. According to WCRF dietary recommendations, people do not need to completely avoid eating meat but should limit consumption to no more than approximately three portions per week. People should consume a diet that provides at least 30 g per day of fiber and five portions or servings  of a variety of non-starchy vegetables and fruit every day  were included, which provided the power to detect a statistically significant relationship between plant-based diets and digestive cancers. However, the possible limitations of our meta-analysis must be considered. First, the present meta-analysis involved sufficient sample sizes for overall analyses, but the number of qualified studies in some subgroups was very limited. For example, the number of original articles involving pesco-vegetarian, lacto-vegetarian, and lacto-ovo-vegetarian diets was too small, which results in bias in the results to some extent. Second, although all studies used validated questionnaires to collect dietary data, most studies did not provide repeated measurements during the follow-up periods and did not register possible change in diet over time. Third, several of the analyses involved comparing the highest vs. lowest exposure categories, which may exaggerate associations by focusing on the extremes of the distribution. However, with the relative paucity of studies referring to different exposure levels of plant-based diets, we were not able to perform a dose-response analysis to obtain more detailed guideline results. Although all the selected original articles were detailed in their investigation of food, they differentiated between meat from common poultry and red meat and foods with higher fat content and assessed the definition of plant-based diets using specialized scales. However, we cannot completely exclude the consumption of a mixture of red meat and other meats. The World Health Organization classified processed meat as a Class 1 carcinogen and red meat as a Class 2A carcinogen : 2018–35).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


I2 statistic was used to see the degree of heterogeneity. Based on degree of heterogeneity, fixed or random effects model was used to estimate pooled effect using inverse variance method. Results were expressed as hazard ratios and odds ratios with 95% CIs.  A systematic search was conducted on PubMed, Embase, and the Google scholar for eligible studies through September 2021. The quality of selected articles was assessed using JBI checklist. Higgins and Thompson's  After scrutinizing 18017 articles, data from ten relevant studies (seven prospective and three retrospective) was extracted. DR was significantly associated with DKD progression with a pooled HR of 2.42 (95% CI: 1.70–3.45) and a pooled OR of 2.62 (95% CI: 1.76–3.89). There was also a significant association between the severity of DR and risk of progression of DKD with a pooled OR of 2.13 (95% CI: 1.82–2.50) for nonproliferative DR and 2.56 (95% CI: 2.93–.33) for proliferative DR.  Our study suggests that presence of DR is a strong predictor of risk of kidney disease progression in DKD patients. Furthermore, the risk of DKD progression increases with DR severity. Screening for retinal vascular changes could potentially help in prognostication and risk-stratification of patients with DKD. The global burden of diabetes mellitus (DM) has been steadily rising over the past few decades. The International Diabetes Federation (IDF) predicts an increase in the number of patients with diabetes to 643 million by 2030 and to 784 million by 2045 . An estiDKD is often not recognized in the initial stages due to lack of routine screening for microalbuminuria, especially in low-resource settings. Clinicians are heavily reliant on serum creatinine and urine dipstick, both of which are flawed screening tools, and there is a paucity of validated biomarkers that can help in early detection of chronic kidney disease (CKD) . There iDR is one of the microvascular complications in diabetes and approximately affects about 30% of patients with diabetes . There iClinically, DR is screened with fundoscopy, which is a relatively noninvasive, inexpensive method , 23. It A systematic search of PubMed, Embase, and Google Scholar was performed by two independent reviewers (M.G. and T.C.B.) for articles studying the association between DR and progression of DKD in September 2021. Using MeSH terms as well as the free words, the search strategy included the following: [((diabetic retinopathy stage OR retinopathy stage) AND (risk factor OR prognostic factor OR predict OR etiology) AND (nephropathy stage OR diabetic nephropathy stage OR DKD stage) AND (diabetic nephropathy progression OR nephropathy progression)]. The last search date was September 30, 2021.The inclusion criteria for articles were as follows: (1) longitudinal studies (prospective and retrospective); (2) studies including patients with DM (irrespective of type of DM) and presumed or biopsy-proven DKD; (3) presence of DR defined according to well-validated scales, such as the Early Treatment Diabetic Retinopathy Study severity scale; and (4) studies reporting progression of DKD. Studies with no full text, cross-sectional design, and insufficient data to compute hazards ratio (HR) (or odds ratio) for DKD progression were excluded. The rigorous eligibility criteria were strictly followed by two independent reviewers (M.G. and T.C.B.) to control for publication bias. Any disagreements in the inclusion of a paper were resolved by a third researcher (I.R.R.).Using standardized forms, data on year of publication, first author's name, country where study was undertaken, study setting, follow-up periods, sample size, definitions of the exposure (DR) and outcome (ESKD), baseline demographic data including average age of the participants, duration of diabetes, average blood pressure, HbA1c, average eGFR values, and the reported effect estimates (HR or OR with 95% CIs) were extracted from the eligible studies.The Joanna Briggs Institute (JBI) critical appraisal checklist for cohort studies was used to assess the quality of the selected articles . The tooI2 statistic, with I2 of >75% indicating considerable heterogeneity. Pooled effect estimates for DR and DKD progression, as well as for DR severity and risk of DKD progression, were computed using the inverse variance method. A fixed effects model was used when between-study heterogeneity was low, while a random effects model was used if heterogeneity was high. A sensitivity analysis was performed to ascertain robustness of the obtained results. To ascertain publication bias, a funnel plot was constructed by plotting the standard errors of the studies against the corresponding HR. All analyses were performed using R version 4.1.1.Results were expressed as hazard ratios and odds ratios with 95% CIs. The degree of between-study heterogeneity was estimated using the Higgins and Thompson's A total of 18,275 articles were identified after a rigorous search on PubMed, Embase, and Google Scholar. Out of these 18,275 articles, 258 articles were identified as duplicates. The remaining 18017 articles were screened based on the abstracts and titles, separately, by two independent reviewers. Any disagreements on the inclusion of a paper were resolved by the third researcher. A full-text assessment was conducted and finally 10 articles were included in the meta-analysis. The article selection process has been summarized in The relevant characteristics of the selected publications are summarized in Tables I2 statistic indicated considerable heterogeneity for both HR  and OR , a random effects model was used. The obtained results are presented in the forest plots below , while Yamanouchi et al. reported results as HR and raw data to compute OR was not available , 40, 41.Yamanouchi et al. also reported a similar stepwise increase in DKD progression with increasing DR severity with an HR of 1.35 (0.49–3.76) for mild NPDR, 2.89 (1.42–5.86) for moderate NPDR, 5.00 (2.63–9.52) for severe NPDR, and 5.32 (2.89–9.78) [Sensitivity analysis was performed after excluding (a) studies that did not have biopsy-proven DKD patients and (b) studies that were retrospective. There was no significant change in the obtained results with pooled HR of 2.76 (95% CI: 1.26–6.04) and OR of 1.79 (95% CI: 1.04–3.09), respectively.The funnel plot  demonstrThis systematic review included ten longitudinal studies with a pooled sample size of 14,355. Meta-analysis of data from the included studies found that the presence of DR was significantly associated with DKD progression, with a pooled hazard ratio of 2.42 (95% CI: 1.70–3.45). The obtained results were consistent even when pooled estimates were reported in terms of odds ratio . Sensitivity analysis excluding studies with presumed DKD (rather than biopsy-proven cases) and that excluding retrospective studies also yielded similar results, indicating robustness of our findings. All the included studies in our review found a significant association between DR and ESKD, except the one by Mottl et al. [Furthermore, we found that the severity of DR was also significantly associated with DKD progression. There was an increase in DKD progression risk as severity of DR increased, with a pooled OR of 2.13 (95% CI: 1.82–2.50) for NPDR and 3.56 (95% CI: 2.93–4.33) for PDR. Yamanouchi et al. reported a similar relationship with HR of 1.35 (0.49–3.76) for mild NPDR, 2.89 (1.42–5.86) for moderate NPDR, 5.00 (2.63–9.52) for severe NPDR, and 5.32 (2.89–9.78) [Apart from DR, the association of other retinal vascular signs and kidney disease has also been studied. Studies have found that retinal vascular diameters, derived from fundus photographs, were significantly associated with CKD. Yau et al. reported that retinal arteriolar narrowing was associated with incident CKD, while Yip et al. found that retinal venular widening was a predictor of risk of CKD , 42. LeeWhile the association of DR and presence of DKD is already clearly established, it is unclear whether presence of DR (and its severity) is also associated with DKD progression and our study specifically answers this question. Given the unpredictable natural course of DKD, the ability to identify patients at high risk of progression of DKD using DR findings would be an invaluable clinical tool and could potentially guide the nephrologist to individualize therapies tailored to an individual's future risk of ESKD. Tests to ascertain presence (and severity) of DR are noninvasive and economical, thereby making implementation of routine DR screening practicable.A recent meta-analysis by Guo et al. found an association between DR and incidence of cardiovascular (CV) disease and CV mortality in patients with diabetes . TherefoThis evidence provides strong support to build prediction models that can ascertain an individual's risk of ESKD, based on fundus examination. Over the last few years, there have been major breakthroughs in automated and semiautomated retinal analysis systems using artificial intelligence (AI) . AlthougTo the best of our knowledge, this is the first meta-analysis to formally evaluate this association of DR and DKD progression. Although the consistency of the association across different measures of effect and sensitivity analyses indicates credibility of our findings, our meta-analysis is limited by the small number of relevant studies that were obtained in the systematic review and the considerable heterogeneity between the studies. Most of the included studies were retrospective and thus carry a risk of confounding. Likewise, in most of the studies, diagnosis of DKD was presumptive and not biopsy-proven. A majority of the included studies reported association of DR and DKD progression risk in type 2 DM and so it is unclear whether the findings of this meta-analysis can be extrapolated to patients with type 1 DM.Our meta-analysis found that DR is a strong predictor of determining progression of CKD in patients with DKD. This suggests that screening for retinal vascular changes could potentially help in prognostication and risk-stratification of patients with DKD. The severity of DR also can predict progression of DKD. Well-conducted large prospective studies are needed to confirm the findings of this study.