To comprehensively determine the effect of dance activities on the cognitive functions and its sub-domains of older adults with mild cognitive impairment (MCI).We obtained data from PubMed, Web of Science, EBSCO, China national knowledge infrastructure, Wanfang data, and VIP databases from 2017/01/01 to 2022/03/01. We included trials of older adults with MCI that underwent dance activity intervention and fulfilled the inclusion criteria. Two researchers independently assessed the quality of the study using the Cochrane risk of the bias assessment tool. Meta-analysis was performed when data were available, with further subgroup analysis, using Review Manager 5.4, and sensitivity analysis was performed using Stata software 15.1.MMSE = 0.65, 95% CIMMSE , pMMSE = 0.004; SMDMoCA = 0.87, 95% CIMoCA , pMoCA < 0.0001], memory , visuospatial function , cognitive flexibility , attention , and balance . Further subgroup analysis showed that open-skill dance activity (OSDA) was more effective in promoting global cognition in older adults with MCI than closed-skill dance activity (CSDA) because of the different stimulation provided by the two types of dance activities in the brain regions of the older adults (p = 0.0002). It could be speculated that dance activity improved cognitive function mainly by affecting the microstructure and function of the cingulate tract, hippocampus, cardiovascular function, and other brain areas of older adults with MCI.Search terms yielded 183 articles, of which 12 fulfilled the inclusion criteria. This included 7 high-quality studies and 5 medium-quality studies. A total of 820 older adults were analyzed. Results showed that dance activity had beneficial effects for global cognition [SMDDance activities can significantly improve global cognition, memory, visuospatial function, cognitive flexibility, attention, and balance in older adults with MCI. However, more trials with rigorous study designs are necessary to provide more concrete evidence in the future. The rapid aging of the global population entails an increase in the prevalence of cognitive impairment in the older generation. A previous study reported that in the past decade, the prevalence of mild cognitive impairment (MCI) in the elderly population of China was 19%, which was higher than that of Japan during the same period  statement  AND ].We performed a comprehensive search in the following six databases: PubMed, Web of Science, EBSCO, China National Knowledge Infrastructure, WanfangData, and VIP Data. We searched the databases from January 1, 2017, to March 1, 2022. We used the PICOS framework to identify the keywords and also used the Boolean search method. Taking Web of Science as an example, the search formula was as follows: , with high and significant heterogeneity (I2 = 83% and Chi2p < 0.00001)  to determine the effects of dance activities on global cognition. The score of MoCA shows a positive correlation with the cognitive functions of the subjects, and the weight of each study was determined . The met0.00001) .The results of the above indicate that dance activity could enhance the global cognition of adult older adults with MCI.Apart from the effects on global cognition, a majority of studies also determined the effects of dance activity on specific cognitive sub-domains such as memory, visuospatial function, cognitive flexibility, attention, and balance. Some subdomains of cognitive function were reported with multiple measures. In these circumstances, when calculating the mean effect size estimate, we averaged the effect sizes across the measures and components.p < 0.00001], with low heterogeneity (I2 = 4% and Chi2p = 0.39), which indicates dance activity positively affects the memorial function of older adults with MCI.A total of 5 studies determined the effects of dance activities on memory, of which 2 studies used the digit span test (DST), and 3 studies used logical memory (LM). The scores of both DST and LM were positively correlated with the memorial functions of the subjects. The meta-analysis showed significant differences between groups in memory , with moderate heterogeneity (I2 = 50% and Chi2p = 0.08), which indicates that the visuospatial function was improved after dance intervention.A total of 6 studies conducted the trail-making test-A (TMT-A). The score of the TMT-A test was negatively correlated with the visuospatial functions of the subjects. The meta-analysis showed significant differences between groups in visuospatial function , with homogeneity , which indicates that dance activity intervention improved participants' cognitive function.yyA total of 6 studies examined the results of the trail-making test-B (TMT-B). The score of the TMT-B test was negatively correlated with the cognitive flexibility of the subjects. The meta-analysis showed significant differences between the groups in terms of cognitive flexibility , with homogeneity (I2 = 0% and Chi2p = 0.95), which indicates that participants' attention could be enhanced by dance activity intervention.A total of 3 studies examined the effects of dance activities on attention, of which 1 study used the test of everyday attention (TEA), and 2 studies used the symbol digit modalities test (SDMT). The scores of both TEA and SDMT were positively correlated with the attention of the subjects. The meta-analysis showed significant differences between groups in attention , with high and significant heterogeneity , which indicates that the balance of participants was enhanced after dance intervention  test was positively correlated with the balance of the subjects. The meta-analysis showed significant differences between groups in cognitive flexibility , with high heterogeneity (I2 = 67% and Chi2p = 0.010), whereas a large, significant effect was found in OSDA , with homogeneity (I2 = 0% and Chi2p = 0.36).p = 0.002] and the intervention of 12 weeks or fewer than 12 weeks  (p = 0.17). In terms of frequency, the result showed a significant effect on both 1–2 times per week  and 3 times per week , and the difference between two groups was significant (p = 0.03).MMSE1 = 0.56, 95% CI , p < 0.0001; SMDMMSE2 = 0.30, 95% CI , p = 0.03; SMDMoCA1 = 0.78, 95% CI , p = 0.0001; SMDMoCA2 = 0.71, 95% CI , p < 0.00001]. There was no significant difference between the two age groups .The effects of dance intervention on global cognition of different age groups are shown in A sensitivity analysis was performed, which excluded 5 poor-quality studies, for global cognition, with the effect of MMSE and MoCA both slightly decreased . The result indicated the potential publication bias in the excluded studies , 8.MMSE were 0.44, 0.66, and 0.96, SMDMoCA were 0.66, 0.87, and 1.69, respectively).We conducted a sensitivity analysis examining a correlation of 0 or 0.9. The results showed that both effects of MMSE and MoCA remained significant  and 0.818 (MoCA), implying no significant publication bias in this meta-analysis.We used Egger's test to assess the publication bias of the studies. The In the present meta-analysis study, we determined the effects of dance activities on the cognitive functions of older adults with MCI and further explored the variations when the intervention characteristics were different through the trials published in the last 5 years, which indicates the novelty of the data and the conclusion. Overall, there was a clear trend that dance intervention positively impacted global cognition and its sub-domains, including memory, visuospatial function, cognitive flexibility, attention, and balance. Our findings were in accordance with those of a recent meta-analysis  value of the left fibrous circuit in older adults with MCI was lower than that of normal people .Through the intervention implementation content reported in the original studies, studies were divided into OSDA and CSDA. CSDA had strong predictability and was characterized by less varied movements and a relatively single and stable form, whereas OSDA had relatively strong unpredictability and uncertainty and was flexible, irregular, and more diverse. The results of this study showed that even though the effects of both dance modalities were positive and significant, the effects of OSDA were significantly better than that of CSDA  using MMSE or MoCA, the effects in group 1 were greater than those in group 2 , indicatWhen estimating effect size, high heterogeneity was discovered, which could be attributed to differences in design between the included studies. As previously stated, the characteristics of the included studies differ. Ten RCTs and two CTs were included in our study. The use of randomization may aid in providing stronger evidence. There are also various intervention types, such as OSDA  and CSDA (square dance and aerobic dance). Different types of interventions stimulate individuals' brains in different ways. The time, frequency, and length of the interventions in the trials were clearly different, which may be one of the most important reasons for the heterogeneity. Because the best dance intervention dose is still unknown, determining appropriate intervention doses for older adults with MCI is difficult. Because the study designs of the included trails are based on a thorough consideration of the subjects' actual situation and physical condition, there are some differences in the effect.The findings above should be interpreted with caution. As in the above results, while a high degree of heterogeneity could be seen in MMSE, MoCA, balance, and CDSA, Egger's asymmetry test indicates a symmetrical distribution of effect sizes and a low risk of publication bias.First, to ensure the quality of the included studies, all the included studies were written in Chinese or English and published in the core journals of China and abroad. Papers, conference papers, gray literature, unpublished studies, and studies written in other languages were not included in this meta-analysis, which can lead to publication bias and introduce language bias, as it may not cover all potential studies. Second, using MMSE or MoCA alone to evaluate global cognition should not be regarded as sufficient as a screening tool as they cannot substitute for neuropsychological testing. Third, some heterogeneity was found among the studies, and subgroup analysis did not reduce the heterogeneity. Many methodological weaknesses, such as incomplete reports of participants' gender and the use of blinding, were identified, which can question the validity of the results. Older adults who were identified as MCI patients in the original study were eligible to be included in this meta-analysis. Therefore, the conditions of the subjects, the research design, and the implementation can all be sources of heterogeneity, and certain interactive effects can be found among the above factors. Furthermore, regarding missing data, three studies used an intention-to-treat analysis (Zhu et al., First, at present, in the dance activity intervention for older adults with MCI, the specific dance types, frequency and length of intervention, and measurements of outcome indicators were many, which can affect the authenticity and reliability of the research results to a certain extent. Therefore, to improve the methodological quality, more randomized controlled trials with rigorous study designs and larger sample sizes are required to strengthen the control of bias from the aspects of the use of blinding and allocation concealment. Second, the effects of different types of dance activities and the different types and doses of intervention should be compared to determine better and more reasonable content and extent of dance activity intervention. Third, to further improve the in-depth discussion of dance activity intervention, future research should involve the analysis of brain structure, function, cardiovascular function, and their underlying mechanisms. Furthermore, an intention-to-treat analysis is suggested when dealing with missing data, as it is considered better to avoid bias.Dance activities have a positive effect on the cognitive function, memory, visuospatial function, cognitive flexibility, attention, and balance of older adults with MCI. However, because of the evidence base, the results should be interpreted with caution. Nevertheless, dance activity can play an important role in improving the cognitive function of elderly people as a basis for a physically active lifestyle, and they can get a variety of physiological, social, and cognitive health benefits. Both body movement and music elements in dance could be presumed reasonably to promote the cognition of older adults with MCI. Future high-quality research is required to establish certainty in the effectiveness of dance activity in older adults with MCI by searching for optimal programs, dose-response relations, and long-term sustainability.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.YY and XL contributed to the conception of the study. YY and WL contributed significantly to the literature search. YY performed the data analysis and wrote the manuscript. XL helped perform the analysis with constructive discussions. All authors read and approved the final manuscript.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.


To compare the burden of age-related eye diseases among adults exposed to higher versus lower levels of ambient air pollutants.3], particulate matter [PM] less than 2.5 µm in diameter [PM2.5], and PM less than 10 µm in diameter [PM10]) and the age-related eye disease outcomes of glaucoma, age-related macular degeneration (AMD), or cataract. Pooled odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated using a random-effects meta-analysis model. PROSPERO registration ID: CRD42021250078.MEDLINE, EMBASE, and Scopus were searched for relevant articles until September 30, 2021. Inclusion criteria included studies of adults, aged 40+ years, that provided measures of association between the air pollutants . Consistent evidence was also found for O3 and cataract, with three of three studies reporting an inverse association. Two of two studies reported a null association between PM2.5 and cataract, while one of one studies reported a positive association between PM10 and cataract. One of one studies reported a positive relationship between CO and AMD. Other relationships were less consistent between studies.A total of eight studies were included in the review. Consistent evidence for an association was found between PMCurrent evidence suggests there may be an association between some air pollutants and cataract, AMD, and glaucoma. Research from the developing world has been done that reports that household air pollutants are associated with eye diseases like cataract.2, SO2, O3, PM2.5, PM10) and age-related eye disease .The purpose of this study was therefore to synthesize the existing evidence on the global associations of ambient air pollutants , hazard ratio (HR), or linear regression coefficient (β) and the respective 95% confidence interval (CI). Only English peer-reviewed studies published prior to September 2021 that used cross-sectional, prospective or retrospective cohort, and case-control study designs were considered eligible for the systematic review. Studies examining the same air pollutant and eye disease that used the same type of regression procedure were considered eligible for inclusion in the meta-analysis.Eligible studies were those of middle- and older-aged adults, aged 40+ years, that studied the association between air pollutants such as CO, NO2, SO2, O3, PM2.5, PM10) with the outcomes of age-related eye disease  in middle- and older-aged adult populations using the keywords “glaucoma,” “cataract,” “macular degeneration,” “air pollution,” “particulate matter,” “carbon monoxide,” “sulfur dioxide,” “nitrogen dioxide,” and “ozone,” with the appropriate MESH terms until September 30, 2021. A search of the reference lists of included studies and other relevant reviews was also conducted in an attempt to retrieve additional relevant articles.MEDLINE, EMBASE, and Scopus were searched for articles that compared higher versus lower levels of environmental air pollutants  independently screened the titles and abstracts of the identified studies for inclusion and graded them as eligible, ineligible, or potentially eligible based on the prespecified inclusion criteria. The full text of studies deemed potentially eligible based on the title and abstract were then independently reviewed and graded as eligible or ineligible. Conflicts that arose during title and abstract screening were resolved through a full-text review and discussed by the two independent reviewers until a final decision was agreed upon. Full texts from the articles deemed eligible in the title and abstract screening were independently reviewed by the two researchers and graded as eligible or ineligible; any conflicts that arose were resolved through a discussion between the two reviewers until an agreed final decision was reached. A study was included in the systematic review only when both reviewers independently assessed it as satisfying the inclusion criteria based on the full-text review.Using a standardized data extraction form, the two reviewers (AG/GL) independently extracted data from the included articles. The two reviewers met to discuss any identified discrepancies in the extracted data; disagreements between reviewers were discussed until a consensus had been reached. AG may be contacted to request either raw data or additional data to those reported.Data abstracted included the following summary data: sample characteristics , study design, publication details, air pollutant(s) reported including how they were measured, health outcome(s) reported  including how they were measured, the reported associations of the air pollutants with age-related eye disease, and adjustment variables.,At the study level, risk of bias and applicability was independently assessed by the two reviewers (AG/GL) using the Newcastle–Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses.The principal outcome of interest is the association between air pollutants and the health outcomes of glaucoma, AMD, or cataract. Quantitative effect estimates, including both ORs and HRs and the respective 95% CIs, were assessed.3 increase in air pollutant exposure). Pooled OR estimates and 95% CIs were calculated using a random-effects meta-analysis model in which study weights were inversely related to the total variance, and between-study variability was estimated using restricted maximum likelihood. To account for heterogeneity, we performed sensitivity analyses in which the meta-analysis was stratified by study design and by glaucoma assessment method . In the meta-analyses, the percentage of variance due to heterogeneity was estimated by the I2 statistic. Analyses were conducted using Stata SE Version 16 .Data were converted to a tabulated form in order to allow for analysis of results. Studies were grouped by the age-related eye disease reported. For studies grouped by the measured air pollutant and the age-related eye disease that used the same type of regression, effect estimates were converted to the same unit increase  using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to determine the magnitude of effect and quality of evidence.N = 467,566) were included in the review.–,–A study flow diagram, which details search and inclusion criteria, is presented in ,The characteristics of the included studies are presented in ,,,,–,,Risk of bias assessments are presented in ,,2 . There was no increased risk for the second or third quartiles, indicating a threshold rather than a dose–response effect. Chang et al.2.5 . However, they did not find any significant association between exposure to PM10 or NO2 with AMD. Chua et al.2.5 levels were more likely to have visually impairing AMD  in a single–pollutant model. However, in a multipollutant model, they found a borderline association between exposure to PM2.5 and visually impairing AMD . NO2, SO2, and O3 were not related to AMD in the multipollutant model.Three studies reported on the outcome of AMD.,,10, NO2, or SO2 exposure and any cataract in single- or multipollutant models. However, the results for NO2 differed by cataract subtype. NO2 (per 0.003-ppm increase) showed a protective association with anterior subcapsular cataracts  in the multipollutant model only and a protective association with nuclear cataracts in the single-pollutant  and multipollutant models . Choi et al.3 exposure (per 0.003-ppm increase) and any cataract that was consistent across single-pollutant  and multipollutant  models. When assessing by cataract subtype, there was a statistically significant relationship between O3 exposure with nuclear cataract in both single-pollutant  and multipollutant  models but not for anterior subcapsular, posterior subcapsular, or cortical cataracts.2  was associated with an increased risk of cataract. They also found that PM10 was associated with an increased risk of cataract . Also in contrast to Choi et al.,2 exposure had a higher cataract incidence, with HRs of 1.07  for the second quartile and 1.05  for the third quartile. The fourth quartile did not have a higher incidence . Shin et al.3 and cataract . There was no increased risk of cataract reported for those with greater exposure to PM2.5. Finally, Grant et al.2.5 and cataract  in a single-pollutant model. However, they did not find an increased odds of cataract among those with greater exposure levels to PM2.5  in the multipollutant model. Further, higher O3 levels were reported to be inversely associated with cataract in a multipollutant model .2 or SO2 with cataract in a multipollutant model.Three studies reported on the outcome of cataracts.,–2.5 exposure was associated with a higher odds of glaucoma in a single-pollutant model . Second, Sun et al.2.5 was associated with primary open-angle glaucoma in a single-pollutant model. These findings were statistically significant per increase in WHO exposure level of PM2.5  and comparing the highest exposure category to the reference level . Grant et al.2.5 level (per IQR) was significantly associated with glaucoma in both the single-pollutant  and multipollutant  models. NO2, SO2, and O3 were not associated with glaucoma in a multipollutant model. Finally, Yang et al.3 increment in PM2.5 exposure was associated with a higher odds of glaucoma in a single-pollutant model .Finally, four studies reported on the outcome of glaucoma.2.5 exposure using the same type of regression and were therefore eligible for inclusion in the meta-analysis. The forest plot of the studies included in the meta-analysis is presented in 3 increase of PM2.5 on glaucoma was 1.18 . The I2 value was 96%, indicating high heterogeneity. In our meta-analysis stratified by study design, the pooled OR for each 10-µg/m3 increase of PM2.5 on glaucoma in cross-sectional studies was 1.33  and the I2 value reduced to 67%  for self-reported glaucoma and 1.02  for glaucoma determined by an ophthalmologic exam or health administrative records. In both models, the I2 value reduced substantially  inflammasome-mediated pyroptosis in trabecular meshwork cells. Only Grant et al.2, SO2, and O3 and glaucoma in the multipollutant model. Adjusting for these other pollutants strengthened the relationship between PM2.5 and glaucoma. When study results were pooled in the meta-analysis, however, the association between exposure to PM2.5 and glaucoma no longer reached statistical significance, and significant heterogeneity was measured. As these studies used different methodologies, analysis methods, and adjustment of confounding variables, the accuracy of the estimate derived in the meta-analysis is unclear. Stratifying the meta-analysis by study design resulted in an increased OR estimate of the association between PM2.5 and glaucoma to borderline significance for cross-sectional studies, but moderate heterogeneity was still measured. Stratifying the meta-analysis by glaucoma assessment method resulted in an increased OR estimate of the association between PM2.5 and International Classification of Diseases (ICD)-coded or ophthalmologist-evaluated glaucoma to borderline significance, as well as in a statistically significant OR estimate of the association between PM2.5 and self-reported glaucoma and reduced heterogeneity measures to 0%. Therefore, the difference in glaucoma assessment methods appears to be the factor contributing most significantly to heterogeneity in this study.Finally, the four studies that examined glaucoma in this review all reported higher burdens of glaucoma among those with higher exposure levels to PM,,–,,,–,,,,,,,,,,,,,–,,,Strengths of the current study include the use of recent evidence, in which large sample sizes were utilized. Due to the scarcity of the data on this topic and the significant heterogeneity among the included studies, we were unable to pool most study results into a meta-analysis. Limitations were also significant among the included studies. The major limitation impacting the robustness of our study findings is that six2.5. There appears to be a protective association of O3 exposure and cataract. Increased PM2.5 exposure was also found to be associated with glaucoma. These associations as well as those of NO2, PM10, and SO2 with age-related eye disease should be confirmed using longitudinal data and potential mechanisms should be explored by investigating interactions with genetic factors or inflammatory markers that may be involved in the causal pathway.To conclude, an increased risk of AMD was reported among individuals exposed to higher levels of CO and perhaps PM


ACE) gene has yielded controversial results on whether different ACE polymorphisms are linked with human longevity. ACE polymorphisms are a risk factor for Alzheimer’s disease and age-onset diseases that may contribute to the mortality of older people. Our goal is to consolidate existing studies, using artificial intelligence-assisted software to come to a more precise understanding of the role of the ACE gene in human longevity. The I (insertion) and D (deletion) polymorphisms in the intron are correlated with the levels of circulating ACE; homozygous D (DD) is high, and homozygous I (II) is low. Here, we performed a detailed meta-analysis of the I and D polymorphisms using centenarians (100+ years old), long-lived subjects (85+ years old), and control groups. ACE genotype distribution was analyzed across a total of 2054 centenarians and 12,074 controls, as well as 1367 long-lived subjects between the ages of 85–99, using the inverse variance and random effects methods. The ACE DD genotype was found to be favored in centenarians (OR: 1.41 (95% CI: 1.19–1.67), p < 0.0001) with a heterogeneity of 32%, and the II genotype slightly favored the control groups (OR: 0.81 (95% CI: 0.66–0.98), p = 0.03) with a heterogeneity of 28%, corroborating results from previous meta-analyses. Novel to our meta-analysis, the ID genotype was found to be favored in control groups (OR: 0.86 (95% CI: 0.76–0.97), p = 0.01) with a heterogeneity of 0%. The long-lived group showed a similar positive association between the DD genotype and longevity (OR: 1.34 (95% CI: 1.21–1.48), p < 0.0001) and a negative association between the II genotype and longevity (OR: 0.79 (95% CI: 0.70–0.88), p < 0.0001). The long-lived ID genotype did not show significant findings (OR: 0.93 (95% CI: 0.84–1.02), p = 0.79). In conclusion, the results suggest a significant positive association of the DD genotype with human longevity. However, despite the previous study, the results do not confirm a positive association of the ID genotype with human longevity. We suggest a few important paradoxical implications: (1) inhibition of ACE can increase longevity in model systems from nematodes to mammals, seemingly opposite to the finding in humans; (2) exceptional longevity associated with homozygous DD is also associated with age-related diseases with higher mortality risks in homozygous DD. We discuss ACE, longevity, and age-related diseases.Current research on the angiotensin-converting-enzyme ( SIRT1, APOE, FOXO3A, ACE, ATM, NOS1, NOS2, KLOTHO, and IL6 [ACE encodes an angiotensin-converting enzyme, which has two functions with opposing effects on health [ACE, when altered, is a risk factor gene in Alzheimer’s disease [ACE alterations are associated with Alzheimer’s disease [ACE on longevity may differ depending on the health conditions of advanced aging [Human life expectancy has increased in the past millennia since the studies of longevity in ancient Greek and Roman populations ,2,3. The and IL6 ,6. Of thn health ,8. First disease ,10. ACE ACE gene is located on chromosome 17q23. The ACE I/D polymorphisms were first identified in 1990; they are characterized by the presence  or absence  of a 287-bp (base pair) Alu repeat sequence in intron 16 [ACE; the D-allele is higher, and the I-allele is lower [The ntron 16 . The I/Dis lower . DD indiis lower ,13. Otheis lower , ischemiis lower , coronaris lower . In addiACE D allele is associated with the risk of cardiovascular disease (CVD), hypertension, Alzheimer’s disease, and other common causes of death in older people, a previous study noted an increased frequency of the DD genotype among a group of centenarians from France [Paradoxically, though the m France . Since tm France , whereasm France ,23. In tWe tested the following AI-assisted programs for meta-analysis: ASReview, Colandr, Parsifal, and Rayyan. Of the programs, Colandr was selected for its accessibility and intuitive user interface. It is assisted by machine learning and natural language processing, which provide an integrated data extraction function and seven additional functions  . It usesOur literature search is summarized in ACE on longevity. The previous meta-analysis compared the frequencies of various combinations of I and D  [The major differences from the previous meta-analysis were as follows. First, we used different age groups for a more precise understanding of the effect of ID + II)  and lackID + II)  that wasID + II)  for the p < 0.0001) with mild heterogeneity (32%), indicating a significant positive association between the DD genotype and longevity.As shown in p = 0.01) with no evidence of heterogeneity (0%), indicating a significant negative association between the ID genotype and longevity.As shown in p = 0.03) with mild heterogeneity (28%), indicating a significant negative association between the II genotype and longevity.As shown in p < 0.00001) with mild heterogeneity (30%), indicating a significant positive association between the DD genotype and longevity.The association between the DD genotype and exceptional longevity was analyzed in 18 studies ,39,40,41As shown in p = 0.11) with no evidence of heterogeneity (0%). There was no significant difference in the frequency of the ID genotype between the long-lived (85+ years old) and control groups.The ID genotype was found to have an OR of 0.92  with mild heterogeneity (30%), indicating a significant negative association between the II genotype and longevity. The risk of bias of the studies was assessed using ROBINS-1 (method). As shown in As shown in ACE genotype and longevity. In addition, the use of AI and machine-learning software has aided in the search and screening process to compile even more studies and process the associated data. Our meta-analysis suggests, with increased confidence, that there is a significant positive association of the DD genotype with exceptional longevity across populations of different ethnicities. It has been reported that serum ACE levels correlate in the order of DD > ID > II, in which DD is the highest [Centenarians are the fastest-growing demographic group of the world’s population, having roughly doubled every decade since 1950 . It has  highest ,12,13. TACE paradox, as Alzheimer’s disease is only one of many diseases that affect older people. As the full role of ACE in the human body has not been determined, the D-allele may have some neuroendocrine or immunomodulatory functions that have yet to be discovered [ACE’s role in longevity. This raises an unanswered key question as to how exceptional longevity is associated with positive risks of age-onset diseases that may increase the risk of mortality. Interestingly, the study of two traits (IP6K3 and IPMK) suggests that gene–gene interactions may be more meaningful than single polymorphisms [The results present a couple of paradoxes in which the D-allele has been reported as a risk factor for hypertension , CVD 1616, pneumscovered  that mayorphisms . Thus, sorphisms .Another paradox is that the inhibition of ACE by mutations or drugs can extend lifespans in model systems from nematodes, fruit flies, and mammals ,52. ThisACE centenarian studies in the databases searched. The results corroborated the positive association between the DD genotype and exceptional longevity and the negative association between the II genotype and exceptional longevity that have been noted in previous meta-analyses. A novel finding was that the ID genotype, which had previously shown no significant associations with longevity, was found to have a significant negative association with longevity in the centenarian-only analysis.Our meta-analysis includes a comprehensive review of studies performed on centenarians, from Schachter’s initial study in 1994 up to the present, for a total of 2054 centenarians. We did not limit the literature search to only studies written in English, thus our data represent all of the current ACE on health may differ among different age groups [ACE DD and II genotypes were consistent across both age groups, with strong associations in the DD genotype with exceptional longevity and with negative associations in the II genotype. Interestingly, the ID genotype had a significant negative association among centenarians but did not show a significant association among long-lived groups. The straightforward interpretations are as follows: (1) The DD genotype is associated with centenarians and the long-lived groups, and the D alleles follow the inheritance pattern of autosomal recessive. (2) The II genotype is negatively associated with longevity in both age groups. (3) The ID genotype shows a weakly negative association with centenarians, but the trend was not significant in the long-lived control. Thus, more detailed studies with a series of ages will be needed.It is implicated that the effect of e groups . Thus, wACE. Thus, we were not able to have a series of ages to define age-dependent enrichment of the ACE D and I alleles. Third, another limitation is that the vast majority of the centenarian studies on ACE used Caucasian populations. Selectively analyzing the studies of Caucasian populations gives the same results as the pooled data, indicating that there were no major differences in associations across ethnicities within this present review. However, there were not enough Asian studies to sufficiently analyze the strength of association within Asian populations only. We also did not find any studies on ACE polymorphisms in Hispanic/Latino or Black centenarian cohorts in our literature search. For future meta-analyses, a greater diversity of such studies should be taken to better illuminate the role of ACE in aging populations across all different environmental or lifestyle risk factors.The limitations of this study are as follows. First, one issue can be summarized as a general limitation of the meta-analysis method. Each search engine lists the papers that are indexed by their criteria, which may mean missing relevant studies. We included three search engines to reduce this risk of missing studies. Second, related to the first limitation is that the criteria to analyze the data rely on the criteria used in each study. For example, control groups of the past studies ranged broadly and were diverse (18–85 years old). There was a lack of detailed age groups to compare the effect of ACE I/D polymorphisms in centenarians published before 25 May 2022. A total of 80 studies were obtained from the Human Genomic Aging Resource’s Longevity Map database, Scopus, PubMed, and Google Scholar using the keywords “ACE” OR “angiotensin-converting enzyme” AND “longevity” OR “centenarian” OR “nonagenarian” (subjects 90+ years). Studies of all languages were included. The titles and abstracts of each article were imported to Colandr [Due to nomenclature inconsistency among studies, we used I (insertion) and D (deletion) alleles as follows: The genotypes were referred to as homozygous insertion (II), heterozygous insertion/deletion (ID), and homozygous deletion (DD). The I and D polymorphisms were referred to as I/D. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  and perf Colandr , which uACE I/D polymorphisms and longevity; (2) case-control study design; (3) study provides sample size, genotype data, odds ratio (OR), and 95% confidence interval (CI) or the data necessary to calculate the results. The exclusion criteria of the studies were as follows: (1) not relevant to ACE I/D polymorphisms or longevity; (2) review or meta-analysis; (3) minimum long-lived population age <85 years or unspecified; (4) no control group or maximum control group age >85 years. Data were then separated into centenarian-only and long-lived (85+ years old) sections. Studies were included in the centenarian-only section if the mean population age was >100. In total, we obtained 13 papers that met all our inclusion criteria for centenarians and 19 papers for the long-lived group.Studies were included if they met all of the following conditions: (1) evaluation of the Data were extracted independently by the author and an assistant, and any discrepancies were settled by consensus. The data extracted included the author’s name, year of publication, ethnicity of the study population, sample size, and genotype numbers in long-lived and control groups. Allele frequencies were calculated if not directly reported. If the study had multiple control groups of varying age ranges, the control group was defined as all individuals ≤85 years of age, and data were extracted accordingly.ACE genotype and longevity, the odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated for each genotype . All statistical analyses were performed using The Cochrane Collaboration’s Review Manager (RevMan) Version 5.4 using the random effects statistical model and inverse variance methods to determine the odds ratio, p-value, and heterogeneity I2, among others, as described previously [p-value < 0.05 to judge statistical significance. The risk of bias in the studies was evaluated as described previously [To determine the association between eviously . We usedeviously . The reseviously ,57. BiasACE DD genotype and centenarians and long-lived groups. Although ACE polymorphisms are a risk factor for Alzheimer’s disease and age-onset diseases that may contribute to mortality, the ACE DD genotype but not the ID genotype was in favor of exceptional longevity over the mortality expected in older people. The DD genotype is associated with a reduced risk of Alzheimer’s disease and increased longevity. It is consistent with an ACE function as an amyloid degradation enzyme, which may be important in exceptional longevity in humans. Additionally, the DD genotype causes a high circulating ACE. In contrast, the DD genotype is also associated with an increased risk of various other diseases. These include hypertension [ACE as a longevity gene.Our meta-analysis suggests a significant positive association between the rtension , ischemirtension , coronarrtension , left vertension , and pnertension . Some ofrtension . The DD rtension . This ma


There is always one moment in childhood when the door opens and lets the future in‐Graham GreeneThe search for nemesis of inflammatory bowel disease (IBD) has intensified in the recent decade and the immunological hubs are being throttled at multiple sites with the fond optimism that one of these countless hubs may be the holy grail. Despite this, the desultory of the disease is such that the treating physician would want to strike at the primary preventive level. Numerous studies and meta‐analysis have explored the possible factors that may trigger disease causation.et al.—the stage of compounding prevalence in developed nations, and the stage of emergence or accelerating incidence in the developing world.The epidemiology of IBD in developed and developing nations is expected to course through various stages of evolution as proposed by Kaplan et al. have made a welcome addition to the existing, and should be congratulated for their efforts.Considerable efforts have been made globally in this direction, although there have been very few consistent and many more heterogeneous associations, which till date have precluded the development of any definite recommendation for prevention of IBD in high‐risk populations.vs questionnaire), recall bias, sample size of included studies, and the possibility of antibiotic use being a surrogate of recurrent childhood infections, which in consonance with the hygiene hypothesisPrevious studies have identified an East–West divide in the association between antibiotic use and the risk of IBD, with a positive association in the West and negative association in studies from the East. In a previous prospective inception cohort study from the same authors, antibiotic use in childhood, breastfeeding, and pet exposure in childhood protected against CD in Asians, in comparison to asymptomatic controls .vs East), discrepant effect has also been demonstrated within populations with respect to most of the early life risk factors. In a recent meta‐analysis of early life exposure and risk of IBD, the only protective factor was breastfeeding, and the harmful factors were passive smoking during antenatal period and otitis media in early childhood. Antibiotic exposure had a trend toward positive association and other factors such as mode of delivery, socioeconomic factors, hygiene‐related factors, child health, physical activity, and vaccination had uncertain significance.Like antibiotics, there are other factors that have a divergent association with CD risk in East and West, as demonstrated in the Asian prospective cohort study, Middle East migration study, the meta‐analysis comparing East and West, and a recent umbrella review of meta‐analysesThe lack of family history as a risk factor for IBD in Asians, although was surprising, was in agreement with a low family history of IBD as reported in cohort studies from Asia.versus West, urban versus rural, children versus adults, migrant versus native, Caucasians versus non‐Caucasians, and due to differences in the included controls‐related versus unrelated, healthy versus diseased, same, or different geographical area, matched versus unmatched. Methodological discrepancies could be due to differences in study design (cohort vs case–control), timing of assessment , unmeasured confounders that arise due to lack of randomization at baseline, issue with reverse causality (when the risk factors are measured close to disease onset), and the method of measurement. Environmental risk factors or the exposome are difficult to measure or quantify, because of recall bias, missing data, interviewer bias, and lack of uniform definitions. Dose–response relationship if present (like with breastfeeding or antibiotic) could add strength to the association, in the absence of which the association remains plausible.So, what do we infer from these observations? Does the present evidence assist us to formulate preventive strategies against the accelerating incidence/compounding prevalence of IBD? As with the heterogeneity associated with IBD phenotype, natural history, disease course, and treatment response, there is substantial heterogeneity in the observed associations between environment and IBD. The possible reasons could be biological or methodological. Biological differences could arise due to inherent differences between the populations assessed—East We again commend the authors for their well‐conducted study, which adds to the existing evidence and raises further questions related to this exciting and intriguing concept. However, we are still very distant from the conclusion and need global multicenter efforts with large, well‐designed, prospective cohort studies, which take care of the possible biological and methodological biases that have been identified within the current evidence. Undoubtedly, one would agree with Fredrick Douglass that “It is easier to build stronger children rather than repair broken men.”Indian Council of Medial Research: Center for Advanced Research and Excellence in intestinal diseases 55/4/11/CARE‐ID/2018‐NCD‐II


The sensitivity analysis confirmed the robustness of the results, and no significant publication bias was identified. Conclusion: The present meta-analysis suggests that the RLP-C was associated with an increased risk of long-term MACEs in patients with CAD at baseline. It is necessary to conduct randomized controlled trials to explore whether reducing the RLP-C level is conducive to reducing residual cardiovascular risk, even coronary plaque regression.Background: The remnant-like particle cholesterol (RLP-C) has been demonstrated to be associated with residual cardiovascular risk. The meta-analysis aimed to evaluate the impact of baseline RLP-C on the incidence of major cardiovascular adverse events (MACEs) in patients with coronary artery disease (CAD). Methods: A systematic literature search was performed in PubMed and Embase electronic databases from the inception of the databases through 1 October 2022. Studies evaluating the association between baseline RLP-C and the risk of MACEs in patients with CAD were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled by a random-effect method  and a fixed-effects model . Results: Ten studies including 18,053 subjects were finally included in this meta-analysis. In our pooled analysis, compared to CAD patients with the lowest RLP-C category, the CAD patients with the highest RLP-C category had a significantly higher risk of future MACEs during follow-up (HR 1.79, 95% CI, 1.42–2.26, I Coronary artery disease (CAD) is the most common cause of death all over the world, resulting in a huge economic and medical burden ,2. The rIn recent years, triglyceride-rich lipoproteins (TRLs) including chylomicron remnant, intermediate-density lipoprotein (IDL), and very low-density lipoprotein (VLDL), have been regarded as potential cardiovascular risk factors besides LDL-C, especially for patients with metabolic disorders ,13. MostWe searched published studies in PubMed and Embase electronic databases from the inception of these databases to 1 October 2022, using the following retrieval methods described in Inclusion criteria: (1) cohort, or nest case-control study evaluating the association between RLP-C and the risk of MACEs in CAD patients, (2) RLP-C was measured at baseline, (3) the endpoints of studies included MACEs, (4) studies reported hazard ratio (HR), relative risk (RR), or Odds ratio (OR) with 95% confidence intervals (CI) after adjustment of confounding factors, (5) the median follow-up time was over six months.Exclusion criteria: (1) not all participants were diagnosed with CAD at baseline, (2) cross-sectional studies, and (3) conference abstract without full text. The screening of eligible studies was conducted by Yang and Wang, and disagreements were judged by a third reviewer (Y.-D.T.)RLP-C was defined as the cholesterol content of a subset of TRLs, i.e., chylomicron remnants, VLDL, and IDL in the non-fasting state, and VLDL and IDL in the fasting state; calculated by the formula: TC minus HDL-C minus LDL-C. Non-HDL-C was calculated by the formula: TC minus HDL-C. The definition of MACEs was in accordance with the criteria of the original research. The MACEs were typically defined as a composite endpoint including cardiac death, myocardial infarction, stroke and repeat revascularization. When multiple studies deriving from the same data source were appropriate, we incorporated only the one with the maximum sample size. Moreover, if both the outcomes of calculated RLP-C and measured RLP-C were available, we used the outcomes of calculated RLP-C. We used the Newcastle-Ottawa quality assessment scale to evaluate the quality of cohort and nest case-control studies , where 7Two reviewers (Yang and Wang) extracted detailed data from included studies. The extracted data included the last name of the first author, year of publication, country of origin, study design, sample size, subject characteristics , follow-up time, outcomes reported, and confounding factors adjusted in the multivariate regression analyses.2 statistic and Cochran’s Q test to assess the between-study heterogeneity. When the p value of the Q test was <0.1 and I2 was >50%, we used the random-effects model to calculate the pooled HR and 95% CI, otherwise, we used the fixed-effects model to calculate them. The significance of the pooled HR was assessed by the Z test . Subgroup analysis was performed to explore the potential source of heterogeneity. Moreover, sensitivity analysis (excluding one study at a time) was carried out to assess the robustness of the outcomes. Moreover, we would conduct funnel plots to evaluate potential publication bias.STATA version 17.0 was used to perform statistical analysis. The association of baseline RLP-C with the risk of future MACEs was evaluated by calculating the pooled HR and 95% CI. We extracted the HR and 95% CI of the future MACEs in subjects with the highest RLP-C group compared with those with the lowest RLP-C group, when the studies analyzed RLP-C as a categorical variable. When the studies analyzed RLP-C as a continuous variable, we extracted the HR and 95% CI of future MACEs per 1-SD/1-log unit increment of the RLP-C according to the reporting of the original studies. We used the Galbraith plots, the IThe present meta-analysis finally included 10 studies comprising 18,053 subjects according to our retrieving methods and screen criteria . These sp < 0.01) with moderate heterogeneity between studies    A, which  = 0.14) B. To exp = 0.14) . Moreove = 0.14) . The fun = 0.14) . MoreoveThe present meta-analysis supplied a systematic review of published articles and a quantitative estimation of the association between the RLP-C and the risk of MACEs in patients with CAD. The results suggested that the CAD patients with the higher baseline RLP-C level had a significantly higher risk of future MACEs during follow-up regardless of whether the RLP-C was regarded as a category variable or continuous variable, with low risk of publication bias. Several studies were used twice because they reported results regarding RLP-C as categorical variable and continuous variable, respectively. The outcomes of subgroup analysis indicated that the moderate heterogeneity might result from different sample size and country of origin. Moreover, the result of sensitivity analysis suggested the stability of our primary outcomes. In view of the results above, the RLP-C may be the next therapeutic target for patients with a considerable cardiovascular residual risk.p < 0.001). Fujihara and his colleagues [p < 0.01).To our knowledge, the present study is the first meta-analysis estimating the association between the baseline RLP-C and future MACEs in patients diagnosed with CAD at baseline. As we all know, the LDL-C-lowering therapy is the primary treatment for patients with CAD. Nevertheless, some patients are still under considerable cardiovascular residual risk after effective LDL-C-lowering therapy. In that case, the TRLs may play an important role in the cardiovascular residual risk, especially for patients with metabolic disorders, such as diabetes mellitus, metabolic syndrome, and insulin resistance ,27. In rlleagues  consecutThe potential mechanism of the correlation between elevated RLP-C and the risk of MACEs in patients with CAD may include the following aspects. First, the RLP-C can invade the arterial intima and can be absorbed directly by macrophages, promoting the formation of foam cells and accelerating the progression of atherosclerosis, while the LDL can only be taken up by macrophages after being oxidative modified ,29. SecoUnder the condition that LDL-C lowering therapy was widely used, the inflammation and other lipid indicators, including non-HDL-C, TG, LP (a), RLP-C and Apo B, may play important roles in the residual cardiovascular risk. The cholesterol component of TRLs is regarded as the causal culprit instead of TG, because Chylomicron is unable to enter the endarterium and TG can be disintegrated by most cells . MoreoveThe study has some limitations. First, all studies included in the meta-analysis were from Asia, making it difficult to extrapolate the results to other races. Second, the type of CAD, the definitions of MACEs, follow-up time, and confounding factors adjusted were different across the studies, which may lead to potential heterogeneity. Third, as one of the sources of residual cardiovascular risk, LP(a) was adjusted as a covariate in only two studies, which may obscure the true effect of RLP-C. Fourth, the available studies were limited, and the sample sizes of studies varied greatly. The Begg’s test and the Egger’s test were unable to be conducted because the available studies were not more than ten. The results of subgroup analysis indicated that the sample size might contribute to the moderate heterogeneity. Finally, it remains unclear whether the association between the RLP-C and the risk of MACEs is linear or non-linear.The present meta-analysis suggests that the RLP-C was associated with an increased risk of long-term MACEs in patients with CAD at baseline. It is necessary to conduct randomized controlled trials to explore whether reducing the RLP-C level is conducive to reducing residual cardiovascular risk, even coronary plaque regression.


Subgroup meta-analysis did not evidence significant differences in leptin in the different trimesters of pregnancy. Meta-regression showed a positive significant relationship for HOMA in the GDM group (p = 0.05). According to these results, it seems that high levels of leptin can be used as predictive markers in GDM.Gestational diabetes mellitus (GDM) represents a stage of subclinical inflammation and a risk factor for subsequent future type 2 diabetes and cardiovascular disease development. Leptin has been related with vascular and metabolic changes in GDM with heterogeneous and contradictory results with respect to their possible involvement in maternal, perinatal, and future complications. Our objective is to evaluate current evidence on the role of leptin in maternal and perinatal complications in women with GDM. PubMed, Embase, Web of Science, and Scopus databases were searched. We evaluated the studies’ quality using the Newcastle-Ottawa scale. Meta-analyses were conducted, and heterogeneity and publication bias were examined. Thirty-nine relevant studies were finally included, recruiting 2255 GDM and 3846 control pregnant women. Leptin levels were significantly higher in GDM participants than in controls (SMD = 0.57, 95%CI = 0.19 to 0.94;  Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance that begins, or is first recognized, during pregnancy. It complicates about 1–14% of all pregnancies worldwide . In GDM,It has been established that adipokines play a key role in the regulation of many crucial processes in the human body, such as glucose and lipid metabolism, insulin sensitivity, appetite, immune response, and inflammation, and may be treated as potential targets for novel therapeutic strategies in numerous medical conditions . Leptin The purpose of this systematic review and meta-analysis is to define the current knowledge on maternal circulating leptin levels during pregnancy in GDM, as a biochemical mediator associated with its pathophysiology and their potential use as risk markers for GDM development, and to identify important evidence gaps.Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [Cochrane Collaboration [The present systematic review and meta-analysis was reported complying with (PRISMA) ,10, and boration .www.crd.york.ac.uk/PROSPERO, accessed and registered on 26 July 2020; registration code CRD42020194274 [A study methodological protocol was a priori registered in PROSPERO international prospective register of systematic reviews, publicly available (20194274 ), for th20194274 .We searched MEDLINE/PubMed, Embase, Scopus, and Web of Science databases for studies published before April-2021, with no lower date limit. Searches were conducted by combining thesaurus terms  with free terms , designeInclusion criteria: (1) original research from primary-level studies without publication language or date, follow up periods, geographical area or age restrictions; (2) GDM subjects compared to pregnant women without GDM as control group; (3) leptin levels evaluation from maternal plasma or serum; (4) observational study design, regardless of its cross-sectional/longitudinal study design or prospective/retrospective nature; (5) the name of authors, affiliations, clinical settings and recruitment periods were gathered and analyzed in order to detect potential overlapping populations. In such cases, the most recent studies or those reporting more complete datasets were included.Exclusion criteria: (1) retracted articles, interventional studies, reviews, meta-analyses, case reports, editorials, letters, abstracts of scientific meetings, personal opinions or comments and book chapters; (2) in vitro and animal experimental studies; (3) studies that do not assess the disease of interest , do not study leptin levels, or those without a control group; (4) studies reporting insufficient data to extract or estimate mean ± standard deviation (SD); (5) data from overlapping populations.Primary-level studies were selected in two phases, first screening the titles and abstracts of retrieved papers, and then reading the full text selected articles, excluding those that did not meet our precedent review eligibility criteria. Eligibility criteria were applied by two authors (MMRR and CLT) in an independent manner. Discrepancies were resolved by consensus with a third author (PRG). Two authors (MMRR and CLT) independently extracted data from the selected articles, completing a data collection form in a standardized manner using Excel v. Microsoft Office Professional Plus 2013 . These data were additionally cross-checked in multiples rounds, solving discrepancies by consensus. Data were gathered on the first author, publication year, study country and continent, language, sample size, source of sample , leptin determination—extracting means ± SD, measuring units, technique and proper quantification—in GDM and controls, GDM criteria, control group criteria, family and personal risk of diabetes, gestational age, study design, control of risk factors during pregnancy , glucose, insulin, homeostatic model assessment (HOMA), glycosylated hemoglobin (A1cHb), maternal and fetal outcomes, follow-up period and patient loss assessment.We used the Newcastle-Ottawa quality assessment scale (NOS) to assess the risk of bias . Assessmp < 0.05 was considered significant). Statistical heterogeneity was evaluated applying the χ2-based Cochran’s Q test  and quantified using Higgins I2 statistic , which estimates what proportion of the variance in observed effects reflects variation in true effects, rather than sampling error [p < 0.10 considered significant) [Means ± SD maternal leptin levels were extracted from primary-level studies to compare among GDM patients and controls. Since methodological heterogeneity was expected, mainly due to variations in laboratory determination methods (see protocol), the standardized mean difference (SMD) was chosen as effect size measure, estimated by Cohen’s d method with their corresponding 95% confidence intervals (CI). Data expressed as order statistics  were computed and transformed into means ± SD using the methods proposed by Luo et al.  and Wan ng error ,18. Prepng error . For illificant) ,21. Statificant) .The flow diagram  depicts The qualitative analysis was conducted using the Newcastle–Ottawa Scale, which evaluates potential sources of bias in nine domains :In our revision, we only include studies in which the groups of diabetic patients are adequately selected and matched between conditions with their respective controls. Studies without a non-GDM comparator group were excluded. According to the overall Rob the studies were categorized 33.3% as low risk, 46.2% as moderate risk and 20.5% as high risk of potential bias. All studies showed a representativeness of the GDM and control patients , and 100% of studies displayed properly leptin quantification. The analysis revealed that the most frequent biases could be the inadequate description of maternal or fetal outcomes and failure to report on an appropriate follow-up period. In this regard, the risk of bias, with respect to the follow up and attrition rate, was elevated in 82.1% of the studies. It is worth highlighting the relevance of declare the lost to the follow-up which are essential data to evaluate any differences on obstetric and perinatal outcomes and on the subsequent follow-up and development of complications in both, the child and the mother.Meta-analysis on leptin levels in GDM. Leptin levels were significantly higher in GDM participants than in controls . Significant heterogeneity was observed  (= 97.3%) , Table 3Analysis of subgroups. Several subgroups maintained the precedent significant association , by geographical area , by analysis technique , by sample source , by study design , and by risk of bias  (= 0.001) .Univariable meta-regression analyses. A positive significant relationship was found for the co-variate HOMA in the GDM group (p = 0.05), presenting the higher summary scores those primary-level studies showing higher positive SDMs for leptin levels. Significant differences were not found among the rest of study covariates  (cations) .Small-study effects analysis. The visual inspection analysis of the asymmetry of the funnel plot constructed (Egger = 0.765) confirmed the absence of “small-study” effects on the results of this meta-analysis. Therefore, the presence of biases, singularly publication bias, could be potentially ruled out.structed  and the Sensitivity analysis. The general results were stable, i.e., no substantial variations were observed after the sequential repetition of meta-analyses, omitting one study each time. This suggests that the combined estimations reported do not depend on the influence of a particular primary-level study (el study .p < 0.001). These results are in line with Xu et al. [This meta-analysis which examined 39 studies and 6101 patients, showed that leptin levels were significantly higher in GDM participants than in controls , presenting the higher summary scores those primary-level studies showing higher positive SDMs for leptin levels. Significant differences were not found among the rest of study covariates. However, Xu et al. [In the meta-regression analyses, a significant positive relationship was found for the co-variate HOMA in the GDM group . This fact increases the quality of the evidence of the results reported in our meta-analysis, which could even be underestimated, due to the narrower and less robust differences reported by the studies harboring a higher risk of bias [According to our qualitative evaluation -carried out using the Newcastle-Ottawa Scale (NOS)- all primary-level studies systematically reviewed were not conducted with the same rigor, although in general, most of them harbored low risk of potential bias across several domains. After applying a subgroup meta-analysis with sensitivity analysis purposes -i.e., to assess the influence of subsets of studies with lower risk of bias on the overall results-, we found that the studies presenting lower risk of bias significantly showed higher differences according to leptin levels between GDM subjects and controls , there is a need to discover early predictors of GDM risk that would allow intervention and prevention in high-risk women. It seems that high levels of leptin in the serum/plasma of pregnant women can be used as predictive markers in GDM. Future studies are needed to determine which biomolecules have the most potential to predict GDM and its complications.


The subgroup analyses showed that the geographical region and the Apnea-Hypopnea-Index (AHI) could be confounding factors in the pooled analysis of plasma/serum adiponectin levels. The sensitivity analysis showed the stability of the results. The radial and L’Abbé plots confirmed evidence of heterogeneity. Trial sequential analysis showed sufficient cases in the meta-analysis. Conclusions: With sufficient cases and stable results, the main finding of the meta-analysis identified significantly reduced plasma/serum levels of adiponectin in OSAS cases compared with the controls. This result suggests a potential role of adiponectin in the pathogenesis of OSAS.Background and objective: A variety of diseases, including obesity, type ‖ diabetes, and cardiovascular diseases are associated with obstructive sleep apnea syndrome (OSAS), and decreased adiponectin levels have been shown to be associated with an increased risk of these diseases. However, the association of blood levels of adiponectin in OSAS patients is a challenging and unknown issue with conflicting results. Therefore, we performed a systematic review and a meta-analysis to evaluate plasma/serum adiponectin levels in adult patients with OSAS. Materials and methods: A comprehensive search in four databases  was performed in literature dated older than 12 March 2022, to retrieve the relevant articles. Effect sizes were calculated to show the standardized mean difference (SMD) along with a 95% confidence interval (CI) of plasma/serum of adiponectin between the OSAS patients and controls. The software RevMan 5.3, NCSS 21.0.2, CMA 2.0, trial sequential analysis (TSA) 0.9.5.10 beta, and GetData Graph Digitizer 2.26 were used for data synthesis in the meta-analysis. Results: A total of 28 articles including 36 studies were entered into the meta-analysis. The results showed that pooled SMD was −0.71 (95% CI: −0.92, 0.50;  Obstructive sleep apnea syndrome (OSAS) is associated with recurrent episodes of upper airway obstruction during sleep ,2 that cThe OSAS is a complex disease that may result from the interaction of several genetic and environmental factors . The preAdiponectin, also known as the 30 kDa fat supplement protein (Acrp30), is a protein hormone and adipokine that has been identified by various independent research groups . This hoRegarding the plasma/serum levels of adiponectin in individuals with OSAS compared to controls, the results have been mixed ,35,36,37The present systematic review and meta-analysis was registered in PROSPERO (ID: CRD42022316318) and is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols . The PECOne author (M.S.) performed a comprehensive search in four databases of PubMed/Medline, Web of Science, Scopus, and Cochrane Library for literature published by 12 March 2022 to retrieve the relevant articles. The search strategy was (“obstructive sleep apnea” or “sleep apnea” or “OSA” or “obstructive sleep apnea syndrome” or “OSAS” or “obstructive sleep apnea-hypopnea syndrome” or “OSAHS”) and (“adiponectin”) and (“plasma” or “blood” or “serum”). Moreover, the citations in the retrieved articles related to the subject were tested to ensure that no study was missed and then the titles and abstracts of the relevant articles were assessed by the same author (M.S.); subsequently, the full texts of the articles following the eligibility criteria were downloaded. Another author (A.N.) re-checked the process of the retrieved articles. A disagreement between two previous authors was resolved by a third author (S.B.).Inclusion criteria were any study that: (1) included individuals with and without OSAS; (2) the participants had age ≥ 18 years old; (3) the individuals with OSAS were completely untreated; (4) reported plasma/serum adiponectin levels in individuals with and without OSAS; (5) the OSAS was diagnosed based on polysomnographic results; (6) the OSAS was defined as AHI ≥ 5 events/h; (7) the individuals with OSAS had no other systemic diseases; (8) the controls had no OSAS or any systemic disease. In contrast, exclusion criteria were: (1) meta-analyses, review articles, studies with incomplete data, studies without a control group or control groups with AHI ≥ 5 events/h; (2) studies including individuals younger than 18 years; (3) studies including individuals with OSAS with further somatic and psychiatric issues; (4) studies including individuals with sleep-disordered breathing; (5) conference papers, book chapters, and comment papers were also removed. Two authors (M.S. and I.M.) separately extracted the data of the articles included in the meta-analysis. Extracted data were the first author, the publication year, the country and ethnicity of participants, adiponectin source, assay approach, quality score, the sample size of individuals with OSAS, the mean levels of plasma/serum of adiponectin in samples with and without OSAS, the mean BMI and age, and the AHI of the samples with and without OSAS. The quality evaluation was performed by one author (M.S.). The quality of the studies was evaluated using the Newcastle-Ottawa Scale (NOS) scale . Nine wap-value (2-sided) less than 0.05 was considered significant. A Pheterogeneity < 0.1 or I2 > 50% showed significant heterogeneity and therefore a random-effects model [The Review Manager software version 5.3  was used to compute the effect sizes mirroring the standardized mean difference (SMD) along with a 95% confidence interval (CI) of plasma/serum of adiponectin between individuals with OSAS and without OSAS. To estimate the pooled SMD significance, the Z-test was used, and a ts model , and if ts model  was utilThe Galbraith  plot shows the z-statistics (the result of division by standard error) on the vertical axis and the weight measurement on the horizontal axis , and theA subgroup analysis (“Are the combined effect sizes in these subgroups significantly different from each other?”) was performed according to nine variables. A random-effects meta-regression analysis (describing a linear correlation between auxiliary variables in the study and effect size) was conducted based on seven variables. p-values of Egger’s and Begg’s tests were extracted and a p-value (2-sided) less than 0.10 recommended the existence of the publication bias. The trim-and-fill method was used to estimate potentially missing studies due to publication bias in the funnel plot and adjusting the overall effect estimate.The degree of diffusion bias was determined using the funnel diagram and Egger’s regression test; Egger’s test is commonly used to evaluate the possible diffusion bias in a meta-analysis through funnel plot asymmetry. Egger’s test assesses a linear regression of the intervention effect estimates on their standard errors weighted by their inverse variance  and BeggTo evaluate the stability/consistency of pooled SMDs, both “one-study-removed” and “cumulative” analyses were used.Publication bias and sensitivity analyses were carried out applying the Comprehensive Meta-Analysis software version 2.0 .2 as 91% for the plasma/serum levels of adiponectin, and the mean difference (MD) and variance were based on empirical assumptions that were autogenerated by the software. If the Z-curve reached the RIS line or monitored the boundary line or futility area, enough cases were included in the studies and the conclusions were reliable. Otherwise, the amount of information was not large enough and there was a requirement for further evidence. To address false-positive or negative conclusions from meta-analyses , TSA wasIn some studies, the data were extracted from a graph using GetData Graph Digitizer software version 2.26.0.20 . All authors examined the final statistical analyses, and any concerns were resolved by a discussion.The search in four databases and by hand in other sources identified 588 records . After rThe characteristics of the subjects in the included studies in the meta-analysis were number of cases and controls and mean levels of adiponectin, age, BMI, and AHI for cases and controls.p < 0.00001; I2 = 79%). A pooled analysis showed that plasma/serum adiponectin levels in the OSAS cases were lower than the controls . The pooA subgroup analysis was performed based on nine variables . Among vA sensitivity analysis based on “one study removed  analysisThe results showed that the cumulative Z-curve (blue line) has successfully crossed the conventional boundary (Z-statistic above 1.96), the trial sequential monitoring boundary (concave red line), and RIS line  for plasma/serum levels of adiponectin . TherefoA random-effects meta-regression of plasma/serum levels of adiponectin for individuals with OSAS versus controls is shown in p < 0.00001; I2 = 4%). Therefore, these outliers can be one of the sources of heterogeneity in the initial analysis.p < 0.001). Therefore, a significant relationship between the mean levels of adiponectin in individuals with and without OSAS appears to be unlikely.p = 0.052) and Begg’s (p = 0.022) tests would reveal a publication bias for the plasma/serum levels of adiponectin in individuals with vs. without OSAS .The present meta-analysis with sufficient cases and stable results suggests that the plasma/serum adiponectin levels in individuals with OSAS were lower than those in age-, sex-, and BMI-matched individuals without OSAS. Though, due to outliers, a high heterogeneity was also observed. Further, the subgroup analysis showed that geographical area and AHI in individuals without OSAS could be a confounding factor in the pooled results. Several studies ,65,66,75Adiponectin is a messenger that binds adipose tissue to other organs and is believed to play a key role in insulin resistance, especially in type 2 diabetes. In one study , low adiThe effect of obesity on adiponectin levels in OSAS patients in the studies led to different results. Masserini et al.  reportedDecreased adiponectin concentrations may both exert a detrimental impact on cardiovascular homeostasis and, may be an independent risk factor for cardiovascular issues ,81,82,83López-Jaramillo et al.  reportedThe meta-regression analysis in a meta-analysis conducted by Lu et al.  on indivDespite the robust pattern of results, the following limitations should be considered: (1) Although we used a comprehensive search strategy, we could not claim that all available studies were extracted, as there may have been studies in different languages and in local databases and sources that we did not have access to. (2) There were some conference abstracts that might have been included, but they did not report available data. (3) A bias and heterogeneity across or among the studies can create confounding factors in the results. (4) There were different designs  among the studies included in the present meta-analysis. (5) Most studies were published prior to 2018, and therefore they may have been included in previous meta-analysis. Therefore, earlier studies will effectively have a greater weighing to our meta-analysis.In contrast, the following strengths are highlighted: there were a sufficient number of studies and samples of individuals with and without OSAS; the results were stable; there were matching age, gender, and BMI between samples of individuals with and without OSAS.The main findings of the meta-analysis with sufficient cases and stable results showed significantly decreased plasma/serum levels of adiponectin in individuals with OSAS, compared to individuals without OSAS. This result suggests a potential role of adiponectin in the pathogenesis and maintenance of OSAS; such decreased adiponectin levels might also explain the high incidence of cardiovascular issues and the metabolic syndrome among individuals with OSAS. Future studies, of course, can be performed with an emphasis on geographical area, race, and severity of OSAS or AHI to further determine the effect of these interfering factors. Further such studies might better explain the pathophysiological process affecting the plasma/serum adiponectin levels in OSAS cases. Last, interventional studies with CPAP devices might give the possibility to investigate, if plasma/serum levels of adiponectin levels might increase, once the CPAP device was well applied and established.


We systematically quantified the currently inconclusive association between Mediterranean diet patterns and the risk of lung cancer.We searched the PubMed, Cochrane, Database of Abstracts of Reviews of Effects (DARE) and Web of Science electronic databases to identify relevant articles published before October 2021. We used the Newcastle–Ottawa scale to assess the quality of the published research and a random-effects model to estimate the aggregate hazard ratios and 95% CIs. As a result of significant heterogeneity, we performed subgroup analysis, meta-regression analysis, and sensitivity analysis. Where data were available, we also performed a dose–response analysis.I2 = 59.9%, P < 0.05). As a result of the significant heterogeneity, we conducted subgroup analysis, meta-regression analysis, and sensitivity analysis and found that the study design was the source of the heterogeneity. Subgroup analysis and sensitivity analysis showed that the final results did not change very much, the sensitivity was low and the results were relatively stable. The dose–response relationship showed that, based on the lowest Mediterranean diet score (0 points), for every three-point increase, the risk of lung cancer was reduced by 9%.Nine articles were included in the meta-analysis. The meta-analysis showed that there was a significant negative correlation between Mediterranean diet patterns and the risk of lung cancer in the general population with a hazard ratio of 0.82, a 95% CI of 0.74–0.92, and a high heterogeneity (The evidence in this meta-analysis shows that there is a significant negative correlation between Mediterranean diet patterns and the risk of lung cancer, suggesting that Mediterranean diets are a protective factor in lung cancer. Lung cancer has become the top malignant tumor in terms of morbidity and mortality . Lung caThe role of dietary nutrients in the prevention and treatment of lung cancer has become a focus of recent research. Vieira et al.  showed tMediterranean diets are sustainable dietary patterns with the following characteristics: (a) a high intake of cereals, vegetables, fruits, beans, and nuts; (b) a moderate intake of poultry, fish, eggs, fresh seafood, and dairy products and a regular, moderate intake of wine; (c) a low intake of red meat, processed meat, and sugary foods; and (d) the use of vegetable oils containing unsaturated fatty acids instead of animal fats containing saturated fatty acids when cooking, especially olive oil . EpidemiGnagnarella et al.  showed tThe relationship between Mediterranean diets and the risk of lung cancer is still controversial. We, therefore, need to conduct a comprehensive meta-analysis to investigate this relationship. This research aimed to systematically study and review observational articles to determine the relationship between Mediterranean diet patterns and lung cancer. Through this meta-analysis, we aim to understand the influence of Mediterranean diet patterns on the health of the general population, improve quality of life, and explore the protective factors of this diet pattern toward lung cancer to provide a theoretical basis for reducing the incidence of this disease.We searched all the studies included in the PubMed, Cochrane, Database of Abstracts of Reviews of Effects (DARE), and Web of Science electronic databases before October 2021. The following search terms were used: (“diet Mediterranean” or “Mediterranean diet” or “diets Mediterranean” or “Mediterranean diets”) and (“lung neoplasms” or “pulmonary neoplasms” or “neoplasms lung” or “lung neoplasm” or “neoplasms pulmonary” or “neoplasm pulmonary” or “pulmonary neoplasm” or “lung cancer” or “cancer lung” or “cancers lung” or “lung cancers” or “pulmonary cancer” or “cancer pulmonary” or “cancers pulmonary” or “pulmonary cancers” or “cancer of the lung” or “cancer of lung”). We also searched the references of related articles to obtain other potential studies.We screened the articles based on their titles and abstracts. We excluded studies that did not include a correlation between the Mediterranean diet and lung cancer. We used the following inclusion criteria: (a) the incidence of lung cancer was used as the outcome; (b) the study design was case–control, cohort, and follow-up studies of randomized clinical trials; and (c) the study provided the odds ratio (OR), risk ratio (RR), hazard ratio (HR) of lung cancer, and the 95% CI, or sufficient data to fully estimate these values. We excluded review articles, studies not published as a full article  and studies lacking sufficient data relevant to lung cancer. For overlapping publications, we selected the most recent data with the longest follow-up time.The data were extracted independently by two investigators (HZD and TRC) from studies that met the inclusion criteria and any ambiguities were resolved by a third investigator. We extracted the following information from each study: first author; year of publication; country; study type; duration of the study; sample size; age; sex; the number of participants in different groups; Mediterranean diet score (MDS) system; components of the MDS; risk estimates; the 95% CIs from the most fully adjusted models for the association between a Mediterranean diet and lung cancer; and adjustment factors.We evaluated the methodological quality of the included studies according to the Newcastle–Ottawa scale (NOS) . The totThe MDS was defined specifically to measure adherence to the Mediterranean diet. In our meta-analysis, a Mediterranean diet alternative score (aMED) was adapted for five studies , 17–19. This meta-analysis aimed to examine the relationship between the Mediterranean diet and the risk of lung cancer in the general population. The associated effects include the OR and HR. Considering that lung cancer is a rare disease with an incidence rate of < 5/1,000, the OR and HR values can be directly combined with the effect size and expressed by the HR value. The most fully adjusted HRs with their 95% CIs from individual studies were extracted and transformed to their logarithms to stabilize the variances and normalize the distributions.I2 and P-values were used to test the heterogeneity of the included studies. P < 0.05 was considered heterogeneous. I2 > 50% indicated high heterogeneity, 25–50% indicated moderate heterogeneity, and I2 < 25% indicated low heterogeneity. A fixed-effects model was used for combined analysis. Otherwise, a random-effects model was used for analysis when no significant heterogeneity (I2 < 50% or P > 0.05) was observed. As a result of the heterogeneity of the results, we conducted subgroup analysis based on several variables, namely, geographical area, study type, and other study characteristics. We also used meta-regression to explore the source of the heterogeneity. We used Begg’s test   .Subgroup analyses on geographic area, study type, number of cases, and adjustments for energy intake, family history, age, ethnicity, and education showed a significant association between Mediterranean diet patterns and the risk of lung cancer. The association was overall consistent in analyses stratified by publication time, MD score system, and adjustments for smoking status .P = 0.016), whereas the publication year and study area did not have a significant impact on the heterogeneity between studies . Subsequently, we included the two covariates of study type and region in the meta-regression model and performed meta-regression analysis of multiple covariates. We found that the variance component between the studies decreased from 0.0195 to 0, indicating that 100% could be explained.To explore the source of heterogeneity, we also established a regression model of effect size on a single covariate using the year of publication, design type, and research area as covariates and performed a single-factor meta-regression analysis. The results of the analysis showed that the type of study design was a covariate with a significant impact on the heterogeneity between studies (P < 0.001). In the real life, based on the lowest MDS (0 points), for every three-point increase, the HR for lung cancer = 0.91 and the 95% CI = 0.89–0.94; that is, for every three-point increase in the MDS, the risk of a person developing lung cancer is reduced by 9%. P non-linearity = 0.469) of (0–8) and 10% of (0–9)  for a three-score increase in adherence to a Mediterranean diet pattern. The relationship was consistent in dose–response analyses stratified by scale range.Given that three of the nine articles did not provide dose grouping and the article by Schulpen et al.  includedP = 0.226) or Begg’s test (P = 0.086) (We used Begg’s regression asymmetry test and Egger’s regression asymmetry test to assess publication bias and found no significant publication bias for either Egger’s test (= 0.086) . We cond= 0.086) . The resThe results of our meta-analysis suggested a significant negative correlation between Mediterranean diet patterns and the risk of lung cancer, thereby showing that Mediterranean diet patterns are a protective factor for lung cancer. Further subgroup analysis showed that the type of study was a possible reason for the heterogeneity of the results. Subsequently, the multivariate meta-regression analysis was performed including the two covariates of study type and region. The results showed that 100% of the sources of heterogeneity could be explained. The results of a meta-analysis of the dose–response relationship showed that based on the lowest MDS (0 points), each three-point increase reduced the risk of lung cancer by 9%. This study is the first meta-analysis to explore the relationship between Mediterranean diet patterns and the risk of lung cancer in the general population. Our findings are of great significance in reducing the incidence of lung cancer.At present, there are several possible mechanisms linking Mediterranean diet patterns and a reduction in the incidence of lung cancer. First, Mediterranean diets are rich in plant-based foods , which provide a large amount of dietary fiber and bioactive compounds . A higher intake of dietary fiber can reduce the risk of lung cancer . Short-cWe found a significant negative correlation between Mediterranean diet patterns and the risk of lung cancer. This finding is consistent with the conclusion of a 2003 case–control study, which reported that some typical foods in Mediterranean diets were related to a reduction in the risk of lung cancer . VardavaThe heterogeneity among studies is a critical issue in meta-analysis and the existence of heterogeneity directly affects the interpretation of the meta-analysis results. We, therefore, focused on exploring the sources of heterogeneity among studies. Although most of the included research results were adjusted for common influencing factors, such as age, sex, race, and smoking status, other factors among the studies may be a source of heterogeneity. We carried out a subgroup analysis and did not find significant differences in effect between Mediterranean diet patterns and the risk of lung cancer. The results of the meta-regression showed that the type of study design had a significant impact on heterogeneity among studies, whereas the year of publication and study area did not. A total of nine articles, including seven cohort studies and two case–control studies, were included in this meta-analysis because the etiology hypothesis of the case–control study was weaker than that of the cohort study, which led to the heterogeneity. Heterogeneity may also be caused by other factors, such as personal behavior and lifestyle, and environmental and genetic factors.P detected by the Begg’s method and the funnel chart was symmetrical. This study, therefore, has no publication bias and the sensitivity analysis results were very stable and reliable.This study has many advantages. First, the studies included were prospective cohort studies and retrospective case–control studies with large sample sizes. Second, the included studies were all published in the last 5 years and were all of the high quality. The dose–response evaluation of the effects of the included studies may be comprehensive and can effectively explore whether Mediterranean diet patterns are a protective factor for lung cancer. Third, no publication bias was observed in the judgment of The results of the meta-analysis have scientific value and significance. We found that there was a significant negative correlation between Mediterranean diet patterns and the risk of lung cancer in the general population, which suggests that Mediterranean diet patterns are a protective factor for lung cancer. These results provide clear information for clinical recommendations and the prevention of lung cancer.This meta-analysis has some limitations. First, most of the included studies were from Europe, with some studies from the United States and Australia. The results may not be universal as a result of the lack of data from Asia and Africa. Second, a stronger association between Mediterranean diet patterns and lung cancer was observed in the case–control study. The inclusion of case–control studies may lead to recall and selection bias. Considering that the retrospective bias in the case–control study and the patient’s early symptoms may cause changes in eating habits, case–control studies may exaggerate the relevance of the merged results in heterogeneity. Third, some studies have pointed out that Mediterranean diet patterns are related to the risk of lung cancer, but data were not reported or the reported data were incomplete and cannot be combined, which may also lead to deviations in the results.This meta-analysis showed a significant negative correlation between the Mediterranean diet pattern and the risk of lung cancer. The dose–response relationship showed that based on the lowest MDS (0 points), every three-point increase reduced the risk of lung cancer by 9%. This study is the first meta-analysis to explore the relationship between Mediterranean diet patterns and the risk of lung cancer in the general population. Our findings are of great significance in reducing the incidence of lung cancer. More epidemiological studies, especially cohort studies, should be encouraged to further understand the mechanism. Future studies should be carried out widely in Asia and Africa.The original contributions presented in the study are included in the article/HD and TC contributed to the conception, design, search, statistical analyses, and manuscript drafting. XL and TZ contributed to the conception, design, and data interpretation. BL contributed to the conception, design, statistical analyses, and data interpretation. ZL supervised the study. All authors approved the final manuscript before submission.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.