Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls . Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex , hypertension , and diabetes  were associated with a lower effect size. Conclusions. Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.Background. Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. Methods. A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. Results. The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665–0.912;  Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that exhibits an autosomal codominant inheritance pattern, causing reduced levels of alpha-1 antitrypsin (AAT) in the bloodstream . Based oRegardless of severity, the fundamental pathological mechanism in individuals with AATD is an imbalance between proteases and antiproteases , along wGiven the uninhibited elastase activity on the elastic tissue of the arterial wall , AATD maGiven the information provided, we planned to conduct a systematic review with meta-analysis of all studies evaluating the prevalence of ischemic heart disease in individuals with AATD and non-AATD controls. Furthermore, we intended to include meta-regression analyses to examine the influence of various genotypes, as well as important clinical and demographic variables, on the observed results.We created a protocol with defined objectives and inclusion criteria to conduct a detailed literature research. The protocol predetermined the outcomes, statistical analyses, and methods for evaluating study quality, and it was registered on PROSPERO under the identification number CRD42023429756.Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive literature search in the primary scientific databases, including PubMed, Web of Science, Scopus, and EMBASE . We usedFollowing a pre-specified protocol, all studies evaluating the prevalence of ischemic heart disease in individuals with AATD and non-AATD controls were considered. Abstracts and posters from scientific conferences were also evaluated, while case series without a control group, case reports, animal studies, and reviews were excluded. The main outcome measure was defined as the presence of any acute, subacute, and/or chronic heart disease of ischemic etiology, including stable or unstable angina pectoris, coronary atherosclerosis, coronary thrombosis, and acute myocardial infarction with its concurrent or subsequent complications . Where possible, data on sample size and AATD genotype, as well as key demographic and clinical variables related to comorbidities and lung function, were extracted in all included studies.To assess the methodological quality of the non-randomized observational studies, we employed the Newcastle–Ottawa Scale (NOS). This scale provided a standardized framework for evaluating the quality of the articles . In summStatistical analyses were carried out with Comprehensive Meta-analysis Version 3  and Review Manager Version 5.4.1 . In each group, the absolute risk in cases and controls was calculated as [(number of events)/] × 100. The attributable risk, namely the percentage of disease in the exposed group that can be attributed to the exposure, was defined as [(number of events in cases—number of events in controls)/(number of events in cases)] × 100. In case of a negative attributable risk, the prevented fraction of disease was calculated as [(incidence rate in controls—incidence rate in cases)/(incidence rate in controls)] × 100, thus expressing the proportion of cases of the disease that have been prevented by the exposure . To analp-value ≤ 0.05. In order to account for statistical heterogeneity among the studies, we conducted the chi-square Cochran’s Q test and calculated the I2 index. The I2 index quantifies the inconsistency among the study results and represents the proportion of total variation in estimates that can be attributed to heterogeneity rather than sampling error. A brief interpretation of the I2 values is as follows: 0% indicates the absence of heterogeneity, values below 25% suggest low heterogeneity, values from 25% to 50% indicate moderate heterogeneity, and values greater than 50% indicate high heterogeneity [The overall effect was assessed using Z-scores, with statistical significance set at a ogeneity .p-value <0.10 was considered statistically significant for these tests [To investigate potential sources of heterogeneity, we performed additional analyses by excluding one study at a time. We also visually examined funnel plots, which display the relationship between effect size and precision (1/standard error of the log odds ratio), to identify any asymmetry and assess for potential small-study effects. Furthermore, we conducted the Egger’s regression test and the Begg and Mazumdar rank correlation test to quantitatively evaluate publication bias, in addition to subjective assessment. A se tests . Finallyse tests .In order to investigate potential sources of heterogeneity, we planned to repeat the analyses by including only “better quality” studies according to NOS . Additionally, another sensitivity analysis was performed after excluding the studies enrolling individuals with AATD primarily or exclusively on the basis of serum AAT levels or medical history. To ensure no data overlap, we also decided to conduct an additional analysis by excluding the studies where the participants could potentially be a subset of those enrolled in other studies conducted within the same region or country, but with a larger sample size.Finally, we planned to separately analyze the included studies according to their prospective or retrospective design.1), forced vital capacity (FVC), and FEV1/FVC), and exercise capacity ). Similarly, we considered the possibility that the difference between cases and controls may be affected by disease severity and, therefore, by specific AATD genotypes  and/or augmentation therapies. Finally, we explored the hypothesis that the rate of patients diagnosed with COPD among cases and controls could somehow influence our results. In order to test the possible effect of the above variables in explaining the results observed across studies, we planned to perform meta-regression analyses after implementing regression models with the differences in the prevalence of cardiovascular disease as dependent variables (y) and the above covariates as independent ones (x). For multivariable meta-regressions, we planned to evaluate multicollinearity using the variance inflation factor (VIF). VIF values exceeding 2.5 would indicate the presence of collinearity that could potentially compromise the reliability of the regression model [We also speculated that our results on ischemic risk in AATD may be influenced by the differences between cases and controls in major demographic  and clinical variables related to cardiovascular risk ), pulmonary function . However, after excluding the study by Fähndrich et al. [2: 43.6%, p = 0.100). Conducting additional analyses by excluding one study at a time did not yield relevant changes in the overall results on ischemic heart disease.Computing the prediction interval, we calculated that the true effect size in 95% of future comparable populations would fall between 0.49 and 1.24, thus largely on the left side of the null effect line A. The heh et al. , all resp = 0.241) and the Begg and Mazumdar rank correlation test (p = 0.386). Accordingly, the Duval and Tweedie’s trim and fill analysis showed that, after adding one imputed unpublished study, all results were substantially verified  for studies evaluating ischemic heart disease in order to identify asymmetry B. Being verified .p = 0.049, 2: 67.3%, p = 0.027), while the Egger’s test did not show statistical significance (p = 0.248). No other tests for assessing publication bias were conducted due to the limited number of datasets available for this outcome.The analysis of four studies ,27,28,31p < 0.001, 2: 40.6%, p = 0.135). Similar results with no significant heterogeneity were also obtained after excluding two studies [Given the median value of the NOS quality assessment of 6 , we repe studies ,28 ident studies , which p studies , was alsp = 0.039, p < 0.001, 2 = 0%; p = 0.430). Due to the limited number of datasets, no subgroup analysis was planned for myocardial infarction.Considering the differences in study design, we planned to separately analyze prospective and retrospective studies. Interestingly, in the subgroup analysis of prospective studies ,26,27,28p < 0.001, p < 0.001, p = 0.021, p < 0.001, Meta-regression analyses showed that the findings of our study on ischemic heart disease remained unaffected by any of the considered AATD genotypes  nor by the disparity in COPD prevalence between individuals with AATD and the control group. On the other hand, higher differences in the prevalence of male sex  and hypertension  were confirmed as independent predictors of the effect size, with multicollinearity being substantially excluded as a high VIF  was not detected. No other multiple regression model could be implemented due to the lack of complete information on all predictors in included studies and to the limited number of datasets. For the same reason, no univariate or multivariable regression model was implemented for myocardial infarction.In multivariable regression models, assuming that the difference between cases and controls in COPD prevalence was held constant, we found that the differences in the prevalence of males (Z-score: 3.43; Supported by a number of sensitivity and subgroup analyses, this meta-analysis indicates that AATD may have an impact on atherosclerosis progression and global vascular health, with a reduced risk of ischemic heart disease and acute myocardial infarction. Additionally, our meta-regression models suggest that these findings are not influenced by different AATD genotypes or COPD prevalence. On the other hand, it is important to highlight that male sex, hypertension, and diabetes, all recognized as cardiovascular risk factors, tend to diminish such a beneficial cardiovascular effect in this clinical setting. Collectively, these findings support the hypothesis that individuals with AATD, especially those without a low concurrent metabolic risk, could exhibit a decreased burden of cardiovascular disease, even in the presence of only mild deficiency of the serine protease inhibitor.Our findings align with a clinical and scientific context that has been increasingly focusing on the multitude of manifestations of AATD , also coA series of clinical studies and animal models have attempted to explore the role of AAT and its deficiency in the progression of atherosclerosis and, more broadly, on the cardiovascular system. All these studies seem to converge on the hypothesis that AAT is somehow crucial in maintaining the stability and integrity of the vascular wall, but how this translates into clinical terms remains to be clarified . In 2001Based on the information provided so far, it appears challenging to provide a full pathophysiological explanation and univocal interpretation for our results, which are however substantiated by large and high-quality epidemiological data, as our pooled analysis encompassed over 24,000 individuals with AATD and over half a million controls without. Additionally, while meta-regressions indicate that our results are not affected by AATD genotypes, it is worth noting in our analyses a larger effect size associated with the increase in patients requiring augmentation therapy. Overall, this may suggest the possibility of an even lower cardiovascular risk in more severe forms of AATD. The fact that the prevalence of COPD, which is itself an independent risk factor for cardiovascular disease , did notDahl et al. , who werOverall, the available evidence seems to suggest that the imbalance between elastase and protease in large elastic arteries of individuals with AATD may compromise the integrity of the arterial wall, leading to reduced elasticity and progressive enlargement . This, iCollectively, irrespective of speculations on this matter, our meta-analysis results emphasize the urgent need for clinical and preclinical studies to better understand the whole spectrum of comorbidities associated with this often underrecognized and disabling condition, thus facilitating the identification of more personalized pharmacological and rehabilitation strategies ,62,63,64It is important to recognize some limitations in our study. Firstly, as meta-analyses depend on pooled data, the observation of a high degree of heterogeneity is the greatest problem. As a matter of fact, AATD is a condition with a highly variable clinical spectrum, influenced by genotype and environmental factors, especially cigarette smoking. Considering that AAT levels are lower by 84% in PiZZ, 49% in PiSZ, 17% in PiMZ, and only 7% in PiSS individuals , the subAdditionally, it should be considered that the majority of participants included in our meta-analysis are from a few large population studies, with Nakanishi et al.  accountiAnother significant limitation pertains to the design of the studies included in our pooled analyses, as only half were prospectively designed to specifically investigate cardiovascular comorbidities in this clinical context. Nevertheless, it is noteworthy that our results remained consistent when analyzing these prospective studies separately, with an even greater effect size observed.In summary, individuals with AATD, especially those without a low concurrent metabolic risk, may exhibit a reduced risk of ischemic heart disease and myocardial infarction, even in the presence of mild deficiency of the serine protease inhibitor. While caution is warranted due to the observational nature of the data and the relevant limitations of our meta-analysis, these findings align with a substantial body of epidemiological evidence indicating that the frequency of ischemic cardiac complications is lower in this patient population, whereas that of dissection and aneurysm may be higher. Consequently, additional studies are needed to validate these findings and comprehensively characterize the range of comorbidities in this clinical context. This will facilitate effective disease management, identification of pharmacological and rehabilitation strategies, and the implementation of primary and secondary prevention protocols.


Plasmodium infection and investigation of the Rh blood group were searched in five databases . Strengthening the Reporting of Observational Studies in Epidemiology was used to assess the reporting quality in the included studies. A random-effects model was used to calculate the pooled log OR and 95% confidence intervals (CIs). Database searches yielded a total of 879 articles, of which 36 were eligible for inclusion in the systematic review. The majority of the included studies (44.4%) revealed that Rh+ individuals had a lower proportion of malaria than Rh− individuals; however, the remaining studies revealed a higher or no difference in the proportion of malaria between Rh+ and Rh− individuals. Overall, with moderate heterogeneity, the pooled results showed no difference in malaria risk between patients with Rh+ and Rh− . The current study found no link between the Rh blood group and malaria, even though there was a moderate amount of heterogeneity. Further studies using prospective designs and a definitive method for Plasmodium identification are needed to investigate the risk of Plasmodium infection in Rh+ individuals and increase the reliability and quality of these studies.In the literature, there was inconsistency in the risk of malaria between individuals with Rhesus blood group positive (Rh+) and negative (Rh−). The systematic review aimed to investigate the risk of malaria among participants with different Rh blood types. All observational studies that reported the occurrence of  The Rh blood group system is a blood group with a high diversity of antigens. At present, more than 50 antigens have been identified in the Rh system, with the main antigens being C, c, D, E, and e. Rh-positive (Rh+) and Rh-negative (Rh−) blood groups refer to the presence and absence of D antigen expression on the red blood cell surface, respectively . FurtherThere have been few studies on the relationship between the Rh blood group system and infectious diseases. Even though previous studies have reported the relationship of the Rh blood group with the novel coronavirus disease (COVID-19), parvovirus infection, leptospirosis, HIV, and hepatitis B ,5,6,7,8.Plasmodium falciparum, Plasmodium ovale curtisi, Plasmodium ovale wallikeri, Plasmodium malariae, Plasmodium vivax, and Plasmodium knowlesi are six species of Plasmodium that can infect humans and cause malaria   were explored to access articles . A metholudism)] . This sePlasmodium infection using microscopic, serological, or molecular methods for the identification of Plasmodium species were eligible for this review. Furthermore, the Rh blood group of participants with and not without Plasmodium infection must be reported in the eligible studies. The Rh blood group could be determined by a slide or tube agglutination method. Articles with no clear evidence on the Rh blood group or Plasmodium spp. were excluded from the review. Furthermore, the following articles were excluded: malaria cases without Rh blood group assessment; full texts were unavailable or could not be accessed; reviews; data of the Rh blood group or Plasmodium infection could not be extracted; no data of an association between malaria and the Rh blood group; a poster; a letter to the editor; a case report; a book; and a book chapter. All observational studies that reported the occurrence of Plasmodium infection, Plasmodium spp., the clinical status of malaria , number of participants with malaria (and Rh+), number of participants without malaria (and Rh+), and number of participants without malaria (and Rh−). The selection of eligible studies and extraction of data files were independently performed by the three authors  and were further evaluated for discrepancies by another author (AM).A standard extraction from a Microsoft Excel  spreadsheet was used to import the data of the first author, publication year, time period for the study, continent, country, study design, type and number of participants, age group of participants, a diagnostic method for Strengthening the Reporting of Observational Studies in Epidemiology was used to assess the reporting quality of observational studies, including cross-sectional studies, cohort studies, and case-control studies . The cri2) of 25%, 50%, and 75% indicating small, moderate, and high degrees of heterogeneity, respectively [p < 0.05), subsequently subgroup analysis was carried out. Factors for metaregression and subgroup analysis were publication year, design of the study, location, subjects, age range, Plasmodium spp., clinical status, the technique of Plasmodium detection, and publication quality. The fixed effect model was utilized in the sensitivity analysis to calculate the combined log OR and 95% CIs in the absence of heterogeneity. The leave-one-out meta-analysis was performed to investigate whether the result of an individual would affect the pooled estimate. Egger’s test was used to identify the effects of small studies once publication bias was detected through thorough observation of a funnel plot’s asymmetry. All statistical tests were carried out using Stata 17.0 software , and statistically significant was defined as a p value less than 0.05.A random-effects model has been employed to compute the combined log odds ratio (OR) and 95% confidence intervals (CIs) . Under tectively . CandidaA total of 879 articles were yielded from database searching, including Scopus (n = 103), EMBASE n = 129), MEDLINE (n = 73), PubMed n = 138), and Ovid n = 436). In addition, 997 articles were retrieved from searching Google Scholar. After the selection of studies, 36 studies were eligible for inclusion in the systematic review [, MEDLINE. In addi, and OviP. falciparum, while 66.7% (24) were asymptomatic Plasmodium-infected patients. The most common diagnostic test was microscopy  followed by RDT   .Based on the STROBE criteria, two-thirds of studies (75%) were of moderate quality ,53,54,55For qualitative synthesis, 13 studies 36.1%) showed a higher proportion of malaria in Rh+ individuals than in Rh− individuals ,53,54,56.1% showep = 0.85, pooled log OR: 0.02, 95% CI: −0.20–0.25, I2: 65.12%, 32 studies, Thirty-two studies with a study population of 1,007,763 reported the quantitative number of participants with malaria infection and Rh blood groups, which were included in the meta-analysis of the pooled log OR ,54,55,56Plasmodium spp., clinical status, the technique of Plasmodium detection, and publication quality showed no significance of these covariates on the pooled log OR , indicating some studies were missing from the meta-analysis and causing funnel plot asymmetry. The trim and fill method showed a significant association between Rh blood groups and malaria .The funnel plot was asymmetric , and thePlasmodium infections between individuals with Rh+ and Rh−, the meta-analysis demonstrated no difference in the risk of Plasmodium infections among the two blood groups. It was true that most of the studies (44.4%) reporting an association between the Rh blood group and malaria showed a lower proportion of malaria in Rh+ individuals than in Rh− individuals, but only a few studies investigated the association using statistical analysis. In addition, several studies investigated the association between the risk of Plasmodium infections among individuals with Rh+ and Rh− in a small number of participants. Therefore, the variation in sample size between studies might affect the conclusion made by the random effects model, as smaller studies had more influence on the conclusion of the meta-analysis finding. Although the largest study by Altayar et al. [Plasmodium infection, the weight of the study was 7.85% since large studies lose influence and small studies gained influence in the random-effects model [Plasmodium infection, thereby limiting the reliability and quality of the results presented in their study. There were different results of meta-analysis between the random effects model and the fixed effects model. The random effects model revealed no association between the Rh blood group and Plasmodium infection. However, the fixed effects model by combining the effect estimates in the sensitivity analysis showed a significant association between Rh+ and Plasmodium infection. Since each study included in the meta-analysis provided different effect sizes  and there was heterogeneity between studies, the random-effects model rather than the fixed-effect model was the more appropriate statistical model for combining effect estimates [Although there was inconsistency in the risk of r et al. , with a ts model . Notablyts model  used thestimates .Plasmodium infection. In other well-studied associations between malaria and blood group, such as the ABO blood group, individuals with blood group O had less rosetting than those with the A, B, and AB blood groups, which reduced the risk of malaria infection and/or severity due to rosetting was associated with malaria severity [FY*1 and FY*2 are codominant alleles encoding the Duffy blood group antigens Fya and Fyb. These antigens give rise to four major Duffy phenotypes: Fy(a+b+), Fy(a+b−), Fy(a−b+), and Fy(a−b−) [DARC gene [P. vivax parasites. Mutations in the coding region of the FY alleles (Duffy null phenotype) result in the absence of the receptor from RBCs and resistance to P. vivax infection. MN blood group antigens carried on glycophorin A (GPA), act as receptors for pathological P. falciparum [P. falciparum than other blood groups. The pathogenesis is mainly dependent on the adherence of P. falciparum parasitized erythrocytes to the endothelium of blood vessels [a/Knb (KN1/KN2), McCa/McCb (KN3/KN6), Sl1/Sl2 (KN4/KN7), Yka (KN5), Sl3 (KN8), and KCAM (KN9) antigens [The mechanism by which the Rh blood group could serve as a protective or risk factor for malaria is unknown. The Rh blood group might alter the adhesion properties of the parasites to the RBC’s membrane and sequester itself in less desirable locations for severity ,57,58. BFy(a−b−) . Fy(a−b−ARC gene . Duffy-glciparum . The O b vessels . The A a vessels . Cytoadh vessels . The O b vessels . The Knoantigens ,66. Thesantigens . Helgesoantigens .The current study contained several limitations. First, the moderate heterogeneity in the meta-analysis results may have an impact on the study’s conclusion. Second, the meta-regression analysis was used to investigate the source of the outcome’s heterogeneity. However, no probable source of heterogeneity was discovered. Third, there was a publication bias among the studies included in the meta-analysis, as visualized in the funnel plot and the results of Egger’s test, which might affect the conclusion made by this study. Fourth, the majority of the studies included in the systematic review were of moderate reporting quality, so the meta-analysis results were based on quality levels. There was no significant effect of study quality on the pooled effect estimate when study quality was included in the meta-regression analysis.Plasmodium identification are needed to investigate the risk of Plasmodium infection in Rh+ individuals and increase the reliability and quality of these studies.The current study found no link between the Rh blood group and malaria, even though there was a moderate amount of heterogeneity. Further studies using prospective designs and a definitive method for


To systematically evaluate the risk factors for perimenopausal depression in Chinese women and to provide a basis for screening perimenopausal women at high-risk for depression.A computer search of seven databases, including SinoMed, PubMed, Web of Science, and so on, and two clinical trial registries on the risk factors for depression in Chinese women during perimenopause was conducted for meta-analysis. The search time limit was from the establishment of the database to December 2022. The included case–control and cross-sectional studies were evaluated using the Newcastle–Ottawa scale (NOS) and criteria developed by the Agency for Healthcare Research and Quality (AHRQ).p < 0.05].A total of 15 papers with 12,168 patients and 18 risk factors were included. Meta-analysis results showed that the risk factors for depression in perimenopausal women were relationship quality , marital status , family income [OR = 1.48 95% CI ], comorbid chronic diseases , exercise status , perimenopausal syndrome , age , and stressful events , and social support was a protective factor [OR = 0.76, 95% CI , Based on the exploration of risk factors for perimenopausal depression in Chinese women, we aimed to provide guidance for the screening of risk factors for depression in perimenopausal women and thereby reduce the incidence of depression.https://www.crd.york.ac.uk/PROSPERO/#myprospero, CRD42023403972. It is estimated that the number of perimenopausal women will reach 1.2 billion worldwide in 2030, including more than 280 million perimenopausal women in China  and resuCurrently, most of the studies on risk factors for depression in Chinese perimenopausal women are single studies that are influenced by sample size, study population, and study site, and the results regarding perimenopausal depression risk factors are still controversial. Therefore, this study systematically evaluated the literature on risk factors for perimenopausal depression in Chinese women based on clinical questions with the aim of providing evidence-based guidance for the screening of risk factors for depression in perimenopausal women worldwide, thus providing a basis for early identification and prevention of depression in perimenopausal women.2.2.1.This study has been registered on the PROSPERO platform as required under registration number CRD42023403972.2.2.ClinicalTrials.gov and Chinese Clinical Trail Registry) about studies on risk factors for perimenopausal depression in Chinese women. The search time limit was from the establishment of the database to December 2022. The final search strategy was determined after an initial search by 2 researchers (first and third author) using an advanced search strategy; the search terms included 3 main core elements: (a) menopause ; (b) depression ; and (c) risk factors . Detailed retrieval strategies are available as The literature search and pooled analysis were performed according to the latest version of the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) statement . Compute2.3.Inclusion criteria were as follows: (a) the study population was perimenopausal Chinese women ; (b) the study was an epidemiological study of risk factors for perimenopausal depression in Chinese women; (c) the outcome indicators were perimenopausal Chinese women who presented with depression, and OR values and 95% CI or convertible data were provided; and (d) the type of study was either a cross-sectional study or a case–control study.Exclusion criteria were as follows: (a) duplicate publications; (b) reviews, systematic evaluations, and conference papers; (c) literature for which valid data could not be extracted; and (d) literature of low quality.2.4.Two investigators (first and second author) imported the included studies into EndNote literature management software, used the EndNote automatic check function and manually removed duplicate literature, read the titles and abstracts of the literature for initial screening, excluded literature with inconsistent study content and study design, and read the full text of the remaining literature to determine the final included literature. Two investigators extracted the basic information of the included literature, including first author, year of publication, study type, region, sample size, risk factors, OR values, and 95% CI. If there were differences at any point throughout the entire process of document selection and data extraction, the two researchers discussed the difference and negotiated, and if there was any disagreement, the corresponding author was consulted.2.5.The appropriate literature quality evaluation tools were used according to the different types of literature, and the quality of the included case–control studies was evaluated using the Newcastle–Ottawa scale (NOS) , and tho2.6.Q test and I2, and when p > 0.1 and I2 ≤ 50%, the heterogeneity was small, and the fixed-effects model was used for data analysis; when p < 0.1 or I2 > 50%, statistical heterogeneity existed, and the random-effects model was used for data analysis. The stability of the meta-analysis results was tested by sensitivity analysis through a piecewise exclusion method and differences in the combined effect sizes of the two effect models; funnel plots and Egger′s test were used to determine whether the included studies had publication bias .Data analysis was performed using Reviewer Manager 5.4 software. The heterogeneity of the included studies was determined by the 3.3.1.A total of 1,057 studies were retrieved, including 770 Chinese studies and 287 English studies; 324 duplicate studies were excluded, 718 studies that did not meet the inclusion criteria were excluded, and 15 studies were finally included . The spe3.2.A total of 15  studies 3.3.Eleven cross-sectional studies , 22, 25 3.4.p < 0.05). The results of the specific analysis are shown in The number of studies including the education level, relationship with neighbors, BMI, place of residence, insomnia status, and FSH level in this study was limited, so they were not combined for analysis. The results of the meta-analysis showed that relationship quality, marital status (mainly divided into two situations: married and divorced/without spouse), family income, comorbid chronic diseases, social support, exercise status, perimenopausal syndrome, age, and stressful events were associated with perimenopausal depression in Chinese women , and statistical heterogeneity existed among the studies. Sensitivity analysis revealed that the study by Zhao et al. . A fixed-effects model was selected for the combined analysis, and the results showed a statistically significant difference . A total of five studies . There was no statistical heterogeneity across studies, and the fixed-effects model was selected for the combined analysis, which showed statistically significant differences . A total of four studies . There was no statistical heterogeneity among the studies, and the results of the combined analysis with a fixed-effects model showed a statistically significant difference . A total of five studies . Sensitivity analysis was performed and found that the study by Chen et al. . A fixed-effects model for combined analysis showed statistically significant differences . The specific analysis is shown in A total of four factors were included in the analysis, and the results showed that relationship quality, marital status, social support, and age were strongly associated with depression in perimenopausal women. A total of seven studies , 21, 23 o et al.  induced  studies , 20, 24  studies , 18, 21  studies  analyzedn et al.  induced 3.4.2.p = 0.98, I2 = 0%). There was no statistical heterogeneity among the studies, and the fixed-effects model was selected for the combined analysis, which showed a statistically significant difference . The specific analysis is shown in A total of four studies , 21, 23 3.4.3.p < 0.001, I2 = 99%); statistical heterogeneity existed across studies, and sensitivity analysis revealed that the results of each study were stable, so a random-effects model was chosen for the combined analysis, which showed statistically significant differences . A total of four studies . Sensitivity analysis revealed that the study by Li et al. . A fixed-effects model was selected for the combined analysis, and the results showed a statistically significant difference . The specific analysis is shown in A total of 2 risk factors were included for analysis, and the results showed that comorbid chronic diseases and perimenopausal syndrome were risk factors for the development of depression in perimenopausal women. A total of nine studies , 20, 22  studies , 21, 23 3.4.4.p = 0.004, I2 = 71%). Sensitivity analysis revealed large heterogeneity associated with the studies of Ye et al. (p = 0.47. I2 = 0%); a fixed-effects model was selected for the combined analysis, which showed a statistically significant difference . A total of four studies . Sensitivity analysis revealed large heterogeneity in the study by Liu et al. . A fixed-effects model was used for the combined analysis, and the results were statistically significant . Three studies  are the risk factors for perimenopausal women’s depression, to increase awareness of prevention among perimenopausal women and to reduce the global incidence of depression in perimenopausal women.5.In this study, we systematically searched for studies related to perimenopausal depression in Chinese women and strictly followed the meta-analysis production process to summarize and analyze their influencing factors. It was concluded that poor marital relationships, no spouse, low family income, comorbid chronic diseases, lack of exercise, perimenopausal syndrome, late perimenopausal period, and stressful events were risk factors for depression in perimenopausal women, while social support was a protective factor against depression in perimenopausal women; this provides a reference basis for global preventive health care for the occurrence of depression in perimenopausal women. However, the subjects included in this study were mostly from China, which may affect the comprehensiveness of the results. In the future, more high-quality global studies on risk factors for depression in perimenopausal women should be included to obtain more comprehensive results.The original contributions presented in the study are included in the article/QG: conceptualization, study design, literature search, quality evaluation, writing the manuscript. RY: study design, literature search, quality evaluation. ZL: data extraction, methodological guidance, proofreading of data. LW: data extraction, data proofreading. YL: organizing data, proofreading data. YY: organizing data, proofreading data. LZ: supervision, financial support, revision of manuscripts. All authors contributed to the article and approved the submitted version.


The aims of the review were to identify and quantify risk factors for MESCC and analysis location of SPC in postoperative patients with EC; to predict incidence of MESCC over follow-up time.an electronic search of studies reporting potential risk factors, the incidence of MESCC, and the location of SPC were performed on PubMed, Web of Science, Cochrane Library, Embase, and Scopus from inception to 10 November 2022. The Newcastle-Ottawa scale was used to assess the study quality, and the qualitative strength of evidence rating of all items was provided. The meta-regression model was used to predict the incidence of MESCC over follow-up time, the location distribution of SPC was presented using clustered column chart, while the publication bias was assessed using funnel plots and Egger’s test.smoking, age, history of multiple other cancer, and Lugol-voiding lesions (LVLs) were determined to be the risk factors of MESCC. LVLs were qualitatively determined as “definite” and the history of multiple other cancer as “likely.” The overall pooled MESCC incidence was 20.3% (95% CI: 13.8% to 26.8%), with an increase of 0.20% for each additional year of follow-up. The head and neck were the most common locations for SPC, followed by the esophagus.timely investigating the age of patients, previous history of cancer and monitoring the number of LVLs in the first 5 years after operation are of great significance to identify high-risk populations of MESCC for timely medical care. Education and behavior correction about smoking are advocated. Tumor markers should be regularly detected in the head and neck, esophagus, and stomach. Endoscopic resection was associated with a higher incidence of MESCC, which provided a reference for doctors to choose the removal method.https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022377030. The 5-year survival rate range from 15-25%; thus, it is the sixth most common cause of cancer-related deaths in the world . HoweverStudies have shown varying incidences of MESCC after treatment. A study by Uno et al. reported an incidence of 14.9% in 40.5 months after endoscopic submucosal dissection . FurtherThis study explored the risk factors for the development of MESCC, evaluated the incidence of MESCC, and ranked the locations of the SPC. The outcome of this analysis will guide clinical practices and effectively identify high-risk populations, optimizing the outcome of patient prognosis.22.1The protocol was registered according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) guidelines , 15 in t2.2With the assistance of an evidence-based medicine specialist, the following search terms of interest were considered to construct a strategy: (1) the esophagus, (2) the method of removing carcinoma, (3) carcinoma occurrence after removal, and (4) risk factors. The online databases of PubMed, Web of Science, Cochrane Library, Embase, and Scopus were searched from inception to 10 November 2022. The search terms were performed separately in all databases and combined with free words. Furthermore, the reference lists of all included articles were screened manually to capture studies omitted in the initial search. Only literature published in English without regional restrictions was included. The search strategies on all databases are presented in the 2.3MESCC was defined as a non-recurrent squamous cell carcinoma that appeared in the esophagus after the first endoscopic or surgical treatment of EC. SPC was defined as primary carcinoma occurring at any site after endoscopic or surgical treatment of EC, which was pathologically proven not to be the recurrence or metastasis of the first carcinoma. Inclusion criteria were: 1) patients with curative ER  or surgery (esophagectomy) or the above regiments combined with chemoradiotherapy, excluding chemoradiotherapy alone and untreated, 2) intervention: existed a risk factor associated with the occurrence of MESCC, 3) comparison: without the risk factor above, 4) reported at least 1 potential risk factor or incidence of MESCC or distribution of SPC and met the definition, 5) randomized controlled trials, cohort or case-control studies. Exclusion criteria were: 1) studies with duplicate data (choose the study with the most comprehensive data), 2) case reports, reviews, comments, and meeting records, 3) animal studies and 4) publications on other diseases.2.4The screening process was conducted by automatically excluding duplicated studies using EndNote X9 software and manually by a reviewer. Afterward, the titles, abstracts, and full text were reviewed independently by 2 reviewers according to the inclusion and exclusion criteria, and discrepancies were resolved by consensus or by a third independent researcher. All relative studies that addressed complications other than metachronous carcinoma and second carcinomas after EC removal were excluded during the title and abstract review phase. Case reports, case series, and meeting abstracts were excluded. Prospective studies can identify potentially modifiable risk factors because the sequence of items and the development of MESCCs is clear. Conversely, items identified in the retrospective study can only be considered associated modifiable factors because of no temporal relationship.2.5The semi-quantitative principle of star system of the Newcastle-Ottawa Scale (NOS) was used to assess the quality of observational studies. The risk of bias and methodological quality of the included studies was assessed independently by 2 blinded reviewers, and discrepancies were resolved through discussions with a third reviewer. The NOS tool consists of 8 items in 3 domains  used to assess the quality of cohort studies. For each item, a series of response options are provided with a star system such that higher stars indicate higher quality. Based on the full-text review of each study, the researcher must select the most appropriate response option. If responses indicate a low risk of bias, 1 star is assigned, except for the comparability domain, which is assigned 2 stars. Overall, the score ranges from 0 – 9 stars, with 1-4 stars, 5-6 stars, and 7-9 stars indicating low, moderate, and high quality, respectively. Studies were not excluded based on their quality assessment score. Studies with low-quality assessment scores were not excluded. However, their score was used to determine the strength of their evidence qualitatively.2.6Data were collected in a standard pre-designed form and verified independently by reviewers. The data include 1) The baseline characteristics comprising title, first author, publication year, region, study design, study period, sample size, inclusion and exclusion criteria, 2) risk factors: removal method of EC, the definition of MESCC, follow-up period, potential risk factor, the method of factor measurement, measurement values reported, statistical test used, significance level; 3) incidence of MESCC, the definition of SPC, location of SPC; 4) methodological information: all relevant details on selection, comparability, and outcome or exposure. Studies with the same subjects or a part of them were excluded to avoid duplication. Some risk factors that fall into more than 2 categories, such as alcohol consumption, were regrouped into 2, rarely drinking and heavy drinking. However, in the original text, there were four groups: seldom, light, moderate, and heavy drinking. Raw data and hazard ratio were recorded for each risk factor when available. Adjusted effect sizes were preferred, followed by raw data if the above data were present simultaneously.2.72 statistics and Cochran’s Q test with a value of >50% and/or p<0.05, indicating significant heterogeneity. Subgroup analysis was performed to explore potential sources of heterogeneity according to a) removal method, b) type of cohort study (prospective or retrospective), c) follow-up schedule , d) median/mean follow-up time (< or >60 months), and e) data type. Sensitivity analysis was performed by applying the other analysis model or (and) excluding 1study at a time. Risk factors reported by 3 or more studies were quantitatively analyzed to estimate a combined RR. Likewise, the strength of evidence of all items was qualitatively rated to label each risk factor as “definite,” “likely,” “unclear,” or “not a risk factor” based on the number and percentage of studies evaluating the factors and showing a positive association (The risk ratio (RR) at 95% confidence interval (CI) for factors of dichotomous variables was calculated using the Comprehensive Meta-Analysis software (version 3.3.070) and the statistical significance  at <0.05. The pooled effect sizes were computed based on the heterogeneity among studies, with the fixed effects model when it was low and the random effects model when it was high. Heterogeneity was evaluated using Iociation Table 1.33.1The initial 5 database searches yielded a total of 1788 articles. After EndNote X9 software automatically removed duplicates, 1038 articles remained. Upon screening the titles and abstracts of the 1038 articles, only 92 studies were included for full-text review. Following the full-text review, 22 studies were included in this study, among which 13 were analyzed for risk factors, 21 for incidence of MESCC, and 9 studies for the location distribution of SPC. A total of 13 factors, 11 of which were quantitatively analyzed. The 3.2The characteristics of included studies and quality evaluation are displayed in 3.33.1.12 = 40.20% and 38.99%, respectively). The risk of MESCC was positively correlated with the amount of smoking  and had no statistically significant association with gender . The results of fixed effects model and random effects model were statistically consistent. The results of the subgroup analysis based on pre-determined subgroup variables were presented in Smoking and gender were quantitatively analyzed in 10 studies with low heterogeneity . There was no significant association between alcohol consumption and MESCC in the fixed  and random  effect models. Subgroup analysis did not find out a source of heterogeneity. In sensitivity analysis, after excluding of the study of Yuka Azuma . The study participants with a history of multiple other cancer were more likely to develop MESCC . Three studies reported smoking after ER as a potential risk factor for MESCC. However, it was not statistically significant . Also, the 3 studies showed no heterogeneity.The 4 studies that described the history of multiple other cancers as a risk factor had a low heterogeneity (I2 = 90.207%). However, there was no statistical significance and heterogeneity when the study by Satoshi Abiko , irrespective of tumor location  and tumor depth . Based on different cut-off standards, the subgroup analysis of the 4 studies on the macroscopic type of tumor showed a decrease in the source of heterogeneity from 49.5% to 0%. However, the results for both subgroups were not statistically significant, which was consistent with the overall result, as shown in Qualitatively, the studies that reported risk factors were of moderate or high quality. Except for 6 studies on LVLs, none of studies on the tumor location, tumor depth and macroscopic type showed positive results. The above 3 factors were labeled as not a risk factor except for LVLs, whose strength of evidence was qualitatively definite. Two studies identified tumor sizes with a cut-off value of 35mm or 30 mm as a factor; however, there was no significant relationship between tumor size and MESCC. Two studies reported lymphovascular invasion as a factor and were not statistically significant. All qualitative and quantitative results are summarized in 3.4Incidence data were extracted from 21 studies. Heterogeneity was high among the 3 subgroups. The random effect model analysis showed that the pooled cumulative incidence of MESCC was 25.7%  after ER, 1.6%  after surgery, and 5.2%  after surgery or ER. The overall pooled MESCC occurrence was 20.3% , as shown in Among 21 studies, 18 reported the duration of follow-up, of which 13 were presented as median and 5 as mean. The meta-regression analysis showed that the incidence of MESCC increased with an extended follow-up time. For each additional year of follow-up, the incidence increased by 0.20%. Due to the different presentation formats (median and mean) of the follow-up time, subgroup analysis was performed. In the median subgroup, the incidence of MESCC increased by 0.36% while the mean decreased by 0.2% for each additional year of follow-up. The predicted 5-year and 10-year incidence rates of MESCC were 12.65%  and 13.65% , respectively.3.5Twelve studies described the distribution of SPC, of which SPC occurring after ER or surgery was diagnosed in more than 20 organs or systems of patients. The head and neck (31.12%) were the most common locations for the distribution of SPC, followed by the esophagus (20.52%), stomach (19.43%), lung (8.82%), and colorectal (5.65%), as shown in 3.6The Egger test analysis showed no publication bias for the following risk factors, including smoking (p=0.38), gender (p=0.28), age (p=0.41), history of multiple other cancer (p=0.35), smoking after ER (p=0.46), alcohol consumption after ER (p=0.37), tumor location (p=0.28), tumor depth (p=0.43) and macroscopic type (p=0.073). Conversely, alcohol consumption (p=0.025) and LVLs (p=0.014) showed publication bias. Also, the incidence of MESCC had publication bias (p=0.012). The funnel plots are summarized in 4This study involves 3 parts, risk factors for MESCC, incidence of MESCC and distribution of SPC. To our knowledge, this study is the first to examine the risk factors and incidence for MESCC after endoscopic or surgical resection of EC.In terms of risk factors, 13 potential risk factors for MESCC were analyzed, among which 7 risk factors including smoking, gender, age, alcohol consumption, history of multiple other cancer, smoking after ER, and alcohol consumption after ER were categorized as demographic, individual factors. In contrast, LVLs, tumor location, macroscopic type, tumor depth, tumor size and lymphovascular invasion were categorized as endoscopic and histological factors. All factors except tumor size and lymphovascular invasion were quantitatively analyzed and the heterogeneity of smoking, gender, alcohol consumption, alcohol consumption after ER and macroscopic type were higher than 30%. After sensitivity analysis and subgroup analysis, factors of smoking, age, and history of multiple other cancer in demographic, individual category and the factor of LVLs in endoscopic and histological category were quantitatively determined to be associated with the development of MESCC. Smoking increases cancer risk by damaging DNA, producing carcinogens, and affecting immune function. The articles suggested that smoking may affect the prognosis and risk of SPC in patients with EC , 33, whiBased on the identified risk factors including smoking, age, history of multiple other cancer and LVLs, high-risk populations are found timely and strictly monitored and followed up to prevent patients from ending dangerous outcomes. Age, history of multiple other cancer, LVLs are unchangeable health risk factors, and smoking is changeable health risk factor. For unchangeable risk factors, routine investigation and surveillance are necessary. Once risk factors are found, attention should be paid to this population. People with young age, history of multiple other cancer, or detected LVLs were identified as high-risk populations. Timely investigating the age of patients, previous history of cancer and monitoring the number of LVLs are of great significance for individuals who will develop MESCC after removal of EC. Detected LVLs are explicitly correlated with the incidence of MESCC. Immediate monitoring of MESCC when LVLs occur facilitates timely physician treatment and patient recovery. For changeable risk factors, education and behavior correction are important. Smoking less or even no smoking should be actively advocated. Although this study showed that the postoperative smoking of the patient had nothing to do with the incidence of MESCC, which may be related to the lack of included studies, there is absolutely no harm in stopping smoking.In terms of the incidence of MESCC, the overall pooled MESCC occurrence was 20.3%. The MESCC occurrence after ER, surgery and surgery or ER was 25.7%, 1.6% and 5.2%, respectively. None of the previously identified variables for subgroup analysis reasonably explained the sources of heterogeneity. Surgery has a lower incidence of MESCC suggested that the method of removal could affect the incidence of MESCC, which provided a reference for doctors to choose the removal method. This is consistent to some extent with the findings of Bestetti et al. on early gastric cancer, where ER was associated with higher risk of recurrence compared with surgery . The lowIn terms of distribution of SPC, this review identified the most common location of SPC of the EC after ER or surgery was head and neck, followed by the esophagus. Therefore, in clinical practice, physicians should be concerned about the occurrence of MESCC and the emergence of head and neck carcinoma, EC, gastric carcinoma, and lung carcinoma in EC patients after operation, which requires physicians to enhance the detection of tumor markers at these sites.Governments should not only invest more in primary health services to enable faster diagnosis and timely treatment, such as screening and follow-up of high-risk populations, but also invest more in scientific research to enable science to guide clinical practice more accurately. Clarifying the responsibilities of primary medical staff, actively carrying out community population education, and consolidating the important position of primary medical institutions in the entire medical system are of great significance for education, supervision, monitoring. Once suspected signs of MESCC or SPC are found, they will be referred to a higher-level hospital immediately.Policy makers need to develop a comprehensive evaluation system for doctors which abandons the principle of “leaving the hospital is over” and values the lifelong management of the patients. The monitoring and long-term follow-up of patients should be included in the evaluation system of doctors, including the monitoring of risk factors and SPC, especially in the first 5 years after operation. Hospital staff should be assigned to monitor clinicians’ prescriptions, such as whether clinicians regularly detect LVLs of patients. The cost of diagnosis and treatment of EC should be covered by medical insurance to increase the compliance of patients.Researchers should focus on both clinical research and basic theoretical research. Designing large, rigorously designed cohort studies to verify and validate the risk factors of MESCC and the increased incidence of MESCC per additional year. Research on the relationship between postoperative factors of EC and MESCC is encouraged and expected. It is the most direct and effective to determine the basic molecular biology causes of MESCC after operation of EC, but it is also the most arduous and painstaking.Some limitations exist in the review. Firstly, the number of studies and sample size included limited the reliability and outreach of the results. In particular, there was a lack of monitoring of postoperative behavior of EC patients. Secondly, although subgroup analysis was performed in predicting annual increases in incidence, differences in the follow-up schedule and time led to bias in the results. Thirdly, even if subgroup analysis was performed in risk factor analysis, different data types would inevitably affect the results. Fourthly, most of the data came from male. It is well known that male and female have distinct differences in physical states, lifestyle habits, susceptibility genes and other aspects, even though the results of this study indicated that gender had nothing to do with the occurrence of MESCC. What is more, all of studies were from Asia, which lack of data support from Western research. Last but not least, due to the nature of the review articles, it is not possible to determine whether the risk factors identified in this study are independent risk factors.The original contributions presented in the study are included in the article/JD, ZB, and XW contributed to the conception and design of the study. JD and ZB organized the database. JD and TL performed the statistical analysis. JD and ZB wrote the first draft of the manuscript. JD, ZB, HZ, JZ, and RX wrote sections of the manuscript. All authors read, reviewed, and approved the final version.


To evaluate the effects of glutamine on the plasma protein and inflammatory responses in colorectal cancer (CRC) patients following radical surgery.We thoroughly retrieved online databases  and selected the randomized controlled trials (RCTs) with glutamine vs. conventional nutrition or blank treatment up until March 2023. The plasma protein associated markers indicators , prealbumin (PA), nitrogen balance (NB), total protein (TP)), inflammatory indicators ), and matching 95% confidence intervals (CIs) were evaluated utilizing the pooled analysis. Subsequently, meta-regression analysis, contour-enhanced funnel plot, Egger’s test, and sensitivity analysis were carried out.[random-effect] = 0.79, 95% CI: 0.55 to 1.03, I2 = 79.4%], PA [SMD[random-effect] = 0.94, 95% CI: 0.69 to 1.20, I2 = 75.1%], NB [SMD[random-effect] = 1.11, 95% CI: 0.46 to 1.75, I2 = 86.9%). However, the content of TP was subjected to comparison across the 2 groups, and no statistical significance was found . Meanwhile, the inflammatory indicators  were decreased significantly followed by the treatment of glutamine.We discovered 26 RCTs, included an aggregate of 1678 patients, out of which 844 were classified into the glutamine group whereas 834 were classified into the control group. The findings recorded from pooled analysis illustrated that glutamine substantially enhanced the plasma protein markers (ALB [SMDThe current study’s findings illustrated that glutamine was an effective pharmaco-nutrient agent in treating CRC patients following a radical surgical operation.PROSPERO registration number: CRD42021243327.The online version contains supplementary material available at 10.1007/s00384-023-04504-8. Colorectal cancer (CRC) is a common malignancy that most predominantly affects the gastrointestinal tract and has become a serious health concern. Data worldwide illustrated that 1,880,725 newly increased CRC patients in 2020, and the CRC mortality rate was expected to be about 9.4% .Radical surgery is the most effective and irreplaceable treatment for nonmetastatic or resectable CRC in the clinic . NeverthGlutamine, an integral constituent of immunological nutrition, is an important source of energy for the digestive system and may help to enhance nutritional status , 15. In Owing to the differences in research design, demographic selection, sample sizes, and systematic methodologies used in current clinical investigations, all available evidence was difficult to undergo comparison. Therefore, we applied a meta-analysis for RCTs on glutamine used in CRC patients who received radical resection to clarify such misunderstandings and assess glutamine’s therapeutic value in CRC patients.https://www.crd.york.ac.uk/PROSPERO).This meta-analysis protocol was registered earlier in April 2021 in PROSPERO , Cochrane Library, Embase, MEDLINE, and PubMed. Medical subject headings (MeSH) phrases were combined with the free words below in the search queries:  AND (glutamine / Gln/ nutrition / immune-nutrition) AND  AND (inflammation / infection / TNF-α / CRP) AND . The detailed syntax for PubMed database was provided as Supplement The software of Endnote™, Version X8 (Thompson Reuters) was used to integrate all of the search outcomes. Manual removal of duplicates was performed. The initial screening of original articles was conducted separately by two researchers (Kai Xiong and Yu Zhang). The researchers reviewed the whole text of the literature to assess whether the study meets the eligibility requirements. Disagreements were resolved by dialogue or judged by a third party.By utilizing a standardized form, all data were obtained separately from the primary RCTs by two researchers (Guangsong Li and Kai Xiong). The details below were taken from the data: (1) study ID, which includes the first author’s name and the year of paper was published; (2) study participants , sample sizes, and their ages; (3) the treatment and control subgroups’ therapy regimens, including the intervention time, dosage of drugs and duration of intervention; (4) the primary endpoint—plasma protein indicators , prealbumin (PA), nitrogen balance (NB), total protein (TP)) and the secondary endpoint—inflammatory indicators ) were reported in original studies when the treatment ends. If we identified inadequate data, we contacted the authors for more details. Dialogue and agreement were used to resolve differences between the two researchers.The GRADE of Cochrane Collaboration Network was applied to assess the grades of evidence for this study. Regarding quality assessment, the Cochrane Collaboration’s technique for evaluating the risk of bias was utilized. Iteration, debate, and consensus were used to address any issues that arose during the evaluation.I2 test a Q test. The I2 and Q tests findings were used to determine whether a random or fixed effects model should be used. If I2 was less than 50% and P was greater than 0.1, a fixed-effects model was utilized. If not, a random-effect model was utilized. The variables ALB, PA, TP, NB, TNF-, and CRP had a continuous endpoint, and the pooled analyses of these markers were reported as standardized mean difference (SMD). The IC was a dichotomous variable, and the results of pooled analyses were reported as relative risks (RR). A Z test was utilized to measure the significance of pooled effects; P < 0.05 was established as the criterion for statistical significance. The impact of high-risk research on the entire meta-analysis was investigated utilizing sensitivity analysis. To identify possible publication bias and the specific reasons causing publication bias, the contour-enhanced funnel plot and Egger’s regression asymmetry test were utilized. Meta-regression conducted via a random-effect model was utilized to investigate the likely cause of heterogeneity. In meta-regression, the constrained maximum likelihood estimation approach developed by Harbord et al. [Stata version 14.0 (Stata Corporation) was utilized to conduct analyses of all statistical data. Prior to calculating the pooled effect, the heterogeneity of the studies was examined utilizing an d et al.  was emplIn the end, 587 related articles were acquired from the databases. Two hundred fifty-six of them were records that had previously been reported. The remaining publications were then filtered for conference abstracts, animal studies, reviews, and case reports, which resulted in the exclusion of 270 articles, leaving only 61 studies. By reviewing the abstracts or full texts, 35 papers that did not meet the eligibility criteria were excluded. In the end, this meta-analysis included 26 RCTs that fulfilled the required criteria. The article selection procedure is depicted in Fig. In total, 1678 participants was enrolled in 26 different studies –49. AmonAccordingly, we applied the GRADE system to assess the grades of evidence Fig. . The resFigure I2 test = 79.4% and Q test P = 0.000, Fig. I2 test = 75.1% and Q test P = 0.000, Fig. I2 test = 86.9% and Q test P = 0.000, Fig. I2 test = 89.7% and Q test P = 0.000, Fig. Z = 6.35, P = 0.000; SMD = 0.79, 95% CI: 0.55 to 1.03; Fig. Z = 7.30, P = 0.000; SMD = 0.94, 95% CI: 0.69 to 1.20; Fig. Z = 3.37, P = 0.001; SMD = 1.11, 95% CI: 0.46 to 1.75; Fig. Z = 0.05, P = 0.959; SMD = − 0.02, 95% CI: − 0.60 to 0.57; Fig. Figure I2 test = 56.7% and Q test P = 0.014, Fig. I2 test = 79.9% and Q test P = 0.000, Fig. I2 test = 0.0% and Q test P = 0.996, Fig. Z = 13.71, P = 0.000; SMD = − 1.86, 95% CI: − 2.21 to − 1.59; Fig. Z = 8.21, P = 0.000; SMD = − 1.94, 95% CI: − 2.41 to − 1.48; Fig. Z = 5.90, P = 0.000; RR = 0.31, 95% CI: 0.21 to 0.46; Fig. Before pooled analysis of inflammatory indicators , the articles’ heterogeneity was examined. The findings depicted a slight heterogeneity for TNF-α  with included RCTs ≥ 10. Sensitivity analysis of ALB results indicated that the study exclusion of Cheng XY could afPALB = 0.446 . Contour-enhanced funnel plot of ALB , suggesting that the asymmetry of funnel plot was attributable to undiscovered bias instead of publishing bias. Following that, we retraced the primary RCTs and hypothesized that trials having smaller sample sizes, blinding missing or unpublished negative results in several articles might be attributable to those undiscovered biases. On the contrary, the contour-enhanced funnel plot of ICs , thereby revealing that the asymmetry of the funnel plot was due to publication bias.To reveal the exact causes of bias, a contour-enhanced funnel plot was utilized, which incorporated standard milestones to funnel plots in terms of statistical significance values ; ② tumor type ; ③ size of the sample (≥ 100 or < 100); ④ the dosage of glutamine per day (≥ 0.5 g/kg or < 0.5 g/kg). Succinctly, the univariable analysis illustrated that the covariates of tumor type and sample size  has indicated glutamine administration exhibited a positive dosage-dependent influence on restoring the levels of serum ALB in gastrectomy patients, demonstrating that glutamine enhanced nutritional status following surgical operation and reduced the incidence of stress-related inflammation [CRC radical surgery leads to a high inflammatory burden, which can impair hepatic protein metabolism, leading to malnutrition . A recenammation . Klek etammation . TherefoALB reflects the malnutritional state of the host and triggers tumor progression and malignancy . Plasma The mechanism by which glutamine elevates serum ALB and TP in postoperative CRC patients may be as follows. Liver: During severe illness, the liver is the main consumer of glutamine. GlutamiInadditionly, the findings recorded from pooled analysis depicted that glutamine reduced the level of TNF-α and CRP in postoperative patients of CRC when compared with the conventional nutrition support group. Increasing evidence substantiated that glutamine reduced pro-inflammatory mediators secretion in the mucosa of the human intestine and decreased infectious morbidity , 63. A cHowever, there are some limitations in this article. Firstly, none of the 26 selected RCTs had single or double-blinding designs, thereby increasing detection bias risk and de-escalating the grades of pooled evidence. Secondly, the outcomes of the contour-enhanced funnel plot revealed that trials having smaller sample sizes, missing or unreported negative effects, and blinding might all explain the undiscovered bias. Thirdly, meta-regression via the univariate analysis revealed that tumor type and sample sizes in original RCTs were the potential covariates attributable to the heterogeneity and de-escalating the validity of pooled analysis. Despite we tried to maintain the homogeneity of included studies through strict inclusion and exclusion criteria, the heterogeneity is inevitable among all the studies included in the meta-analysis. The protocol of “PICOS” of each study is different, which leads to the existence of clinical heterogeneity. In addition, the original studies were carried out with different RCT methods, for example, some studies were single- or double-blind and some were open-label design, with large or small sample size, et al., which leads to the methodological heterogeneity. Therefore, we attributed the significant heterogeneity between included studies to the clinical heterogeneity and methodological heterogeneity.This meta-analysis comprising 1678 CRC cases from 26 RCTs confirmed that glutamine supplementation substantially improved nutritional status and reduced inflammatory reactions in CRC patients following surgical interventions. Before affirming the findings of this research, it is important to keep in mind the drawbacks of the methodology. The presence of multiple disciplinary teams (MDTs) in the preoperative or postoperative phases of CRC care is generally acknowledged, as is the requirement for long-term pharmacotherapy. To counterbalance the risk–benefit profile of glutamine in the therapy of CRC surgical intervention, further RCTs with a larger scale and multi-dimensional effectiveness and nutritional status evaluation are needed.Supplementary file1 (DOCX 32 KB)Supplementary file2 (DOCX 13 KB)Below is the link to the electronic supplementary material.


The clinical correlation between adipokines levels in the blood and the incidence of senile osteoporosis (SOP) has not been clearly studied. We conducted this meta-analysis to elucidate the relationship between three common adipokines levels  and the incidence of SOP.We searched databases such as CNKI, CBM, VIP, Wanfang, PubMed, Web of Science, Embase, and the Cochrane Library to collect articles published since the establishment of the database until July 30, 2022.2 = I96%), chemerin levels were significantly higher , and adiponectin levels were not significantly different  in SOP patients compared with healthy older individuals with normal bone mineral density (BMD). In addition, correlation analysis showed that leptin levels were positively correlated with lumbar bone mineral density (LBMD) (r = 0.36) and femoral bone mineral density (FBMD) (r = 0.38), chemerin levels were negatively correlated with LBMD (r = -0.55) and FBMD (r = -0.48), and there were significant positive correlations between leptin and adiponectin levels and body mass index (BMI) (r = 0.91 and 0.97).In total, 11 studies met the selection criteria. Our meta-analysis showed that serum leptin levels were significantly lower (mean difference [MD], -2.53, 95% CI: -3.96 to -1.10, The likelihood of having SOP was higher in older individuals with low levels of leptin and higher levels of chemerin. In addition, BMI was somewhat lower with low levels of leptin and adiponectin.https://www.crd.york.ac.uk/prospero/, identifier CRD42022356469. Its most important pathogenesis is the inactivation of osteoblasts and the activation of osteoclasts, which ultimately leads to a disruption of bone metabolism and a reduction in bone tissue . OsteopoWith the accelerated aging of the global population, the incidence of senile osteoporosis (SOP) has increased significantly. Unlike postmenopausal osteoporosis (PMOP), SOP is caused by advancing age and therefore does not only affect women but is also closely associated with men . In recein vivo, but also have a connection with BMD  differentiate into more adipocytes than osteoblasts, which leads to reduced bone formation and contributes to SOP . Adipokiwith BMD , 7.Furthermore, in addition to adipokines, adipose tissue and body mass index (BMI) play an extremely important role in osteoporosis. It was found that adipose tissue and BMI influence both bone density and bone turnover. Some studies found that adipose tissue has a certain mechanical protective effect on BMD, which can effectively prevent the occurrence of fractures after osteoporosis, and a significant association between BMD and BMI has been reported (r = 0.3 to 0.6) –10.Several previous meta-analyses have examined the effects of adipokines levels on BMD and fracture risk in healthy men and women , the dif2We conducted a meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Network Meta-Analyses (PRISMA) and Cochrane methods, and the completed PRISMA checklist is listed in 2.1“Osteoporosis”, “senile osteoporosis”, “senile bone losses”, “SOP”, “adipokines”, “leptin”, “adiponectin”, and “chemerin” were used as our search terms in databases such as China National Knowledge Infrastructure (CNKI), CBM, VIP information database, Wanfang Data, PubMed, Web of Science, EMBASE, and Cochrane Library to search the articles since their establishment until July 30, 2022. This category was limited to human studies. The detailed search strategies are documented in 2.2Two authors independently evaluated and selected relevant studies based on the following criteria: 1) study type: case-control studies and cohort studies; 2) study subjects: the elderly who meet the WHO diagnostic criteria for OP in the case group and healthy older individuals with normal BMD in the control group; 3) study index: data on leptin, adiponectin, or chemerin in SOP and control groups must be recorded completely; and 4) Newcastle Ottawa Scale (NOS) score ≥5. Exclusion criteria: 1) duplicate publications or overlapping study subjects; 2) the full text was not available; 3) relevant data were not provided in the original text or were incomplete and could not be obtained from the authors; 4) animal studies, case reports, editorials, reviews, expert opinion reports, and conference papers; and 5) study subjects suffered from diseases affecting bone metabolism or adipokines expression or had taken drugs affecting bone metabolism and lipid metabolism within 1 year.2.3From the included articles, two authors independently extracted the following information: 1) study characteristics, including first author, year of publication, and location; 2) basic characteristics of the individuals, including sample size, mean age, and mean BMI; and 3) details of biochemical examinations, including the source of the index and method of analysis. In addition, we extracted correlation coefficients  to furth2.4Studies were evaluated for quality using the NOS score , with tw2.5In this meta-analysis, we labeled the differences in leptin, adiponectin, and chemerin concentrations between individuals with SOP and healthy older individuals as the primary outcome and the relationships between the concentrations of adipokines and BMI, LBMD, and FBMD as secondary outcomes.2.6I2 statistic , standard deviation (SD), and corresponding 95% confidence interval (95% CI). Due to inevitable clinical heterogeneity between studies, the random-effects model was a more appropriate method to calculate summary effect measures. The statistical heterogeneity of individual outcome studies was assessed using the Cochrane Q test  and the tatistic . Subgrou33.1After the initial searching, we found 1829 records, used ENDNOTE X9 and manual weight-checking methods to remove 845, then excluded 925 ineligible studies after carefully screening titles and abstracts, read the full text to remove 48 studies that did not meet the inclusion criteria, and finally identified 11  studies 3.2Finally, a total of 11 studies were included in this meta-analysis, including 777 patients with SOP and 560 healthy older individuals with normal BMD. Of these studies, 10 studies –27 were 3.3P = 0.0005) ; therefore, we performed subgroup analyses based on leptin assay approaches to explore potential influencing factors. As shown in P = 0.005) and the RIA group  were statistically lower than in the control group, and there were no statistically significant differences between the two groups (P = 0.09), but statistical heterogeneity was not significantly reduced in the ELISA group (2 = I98%), while significantly reduced in the RIA group (2 = I0). And we performed a sensitivity analysis in which there was no significant change in the combined results after omitting one study at a time, indicating that it could confirm the robustness of the combined results  Figure 2P = 0.53). Although substantial statistical heterogeneity was detected , subgroup analysis was not performed because serum adiponectin levels were measured using ELISA in all studies. Sensitivity analysis has confirmed the robustness of the combined results . We detected significant statistical heterogeneity , but we did not perform subgroup analyses because serum chemerin levels were measured using ELISA in all studies. Moreover, sensitivity analysis has confirmed the robustness of the combined results , 0.12 , and -0.61 . Thus, the total r values for leptin, adiponectin, and chemerin were 0.36, 0.12, and -0.55, respectively. Analysis of the correlations showed that leptin levels were significantly and positively correlated with LBMD, and chemerin levels were significantly and negatively correlated with LBMD. Meanwhile, as shown in P <0.00001), 0.17 , and -0.52 . Thus, the total r values for leptin, adiponectin, and chemerin were 0.38, 0.17, and -0.48, respectively. Analysis of the correlations showed that leptin levels were significantly and positively correlated with FBMD, and chemerin levels were significantly and negatively correlated with FBMD. Sensitivity analysis confirmed the robustness of the combined leptin and chemerin results , 2.07  and 0.91 . Thus, the pooled r values for leptin, adiponectin, and chemerin were known to be 0.91, 0.97, and 0.72, respectively. The meta-analysis of correlation coefficients revealed significant positive correlations between leptin, adiponectin levels, and BMI, further confirmed by the sensitivity analysis results  states that publication bias studies with funnel plots are not required when there are fewer than 10 studies.We did not assess publication bias for leptin, adiponectin, and chemerin because the Cochrane Handbook of Interventional System Reviews  and AdipoR2 to positively regulate bone formation , on the It was found that chemerin can regulate lipogenesis and osteogenesis in BMSCs, thereby dynamically regulating bone metabolism in the body. One study found that chemerin-deficient mice showed reduced bone mass and bone formation, whereas chemerin-overexpressing mice showed increased osteogenic differentiation and increased bone mass and bone formation . HoweverIn conclusion, the results of our meta-analysis suggest that older individuals with lower levels of leptin and higher levels of chemerin are more likely to have SOP. Interestingly, many studies showed a positive correlation between BMI and BMD, and low BMI is an important risk factor for osteoporosis , 45. Our4.2Our study has unique advantages. First, this study is a cutting-edge analysis of studies designed to assess the clinical relevance of adipokines levels to SOP and explore other biomarkers that can predict and improve SOP. Second, our literature search and findings were comprehensive. Third, although some of the results showed heterogeneity, the quality of the included studies was at an intermediate to a high level of confidence, and we also performed a detailed subgroup analysis based on whether the assay approaches of different adipokines levels in blood influenced the result.Of course, there are several limitations to consider. First, despite our best efforts to conduct subgroup analysis, the heterogeneity of each subgroup remained high, suggesting that there are still several unknown factors that may have contributed to study heterogeneity, such as geography, mean BMI, ethnicity, actual age, and nutritional status of older individuals. Second, our study included only case-control studies and lacked validated longitudinal cohort studies to infer a causal relationship between adipokines levels and the occurrence of SOP. Third, the correlation between adiponectin and SOP is different from some other studies, although some studies indicate that adiponectin predicted the incidence of osteoporotic fractures, our meta-analysis did not detect a significant correlation. Given the limited number of trials and small sample sizes for some outcomes, these findings may not be sufficient to ensure significant differences. Despite these limitations, our meta-analysis adds statistical power by pooling the results of individual studies, which means that the total number of subjects is large enough to support stronger conclusions.4.3Currently, the prediction and diagnosis of osteoporosis and resulting fractures in the elderly are often based on imaging, but the use of imaging is limited to the analysis of only a single skeletal region, which is often not representative of the disease status of the entire skeleton in the elderly. Serum biomarkers may be more effective than imaging in predicting the status of the entire skeleton; moreover, BMD often does not reflect short-term changes in bone status during treatment, and complete reliance on BMD to predict treatment outcome and prognosis would be biased, whereas serum biomarkers can reflect bone metabolism in patients in the short term, which can improve the sensitivity and specificity of osteoporosis detection and monitoring in the continuous metabolism of bone tissue. In conclusion, the meta-analysis showed that the elderly with low leptin levels and high chemerin levels were more likely to have SOP, and BMD was positively correlated with leptin and negatively correlated with chemerin. However, the underlying mechanism of dysregulation of adipokines levels and whether correction of dysregulation of adipokines levels can be used to treat SOP and reduce the risk of osteoporotic fractures remains to be investigated.The original contributions presented in the study are included in the article/JW and SL designed the project. JW and YZ collected and sorted the data. SL and RD reviewed the data. JW completed the first draft. SN revised the draft. SL, YZ, and RD reviewed the full text. and SL provided fund support. All authors contributed to the article and approved the submitted version.