Statins have been reported to reduce the risk of gallstone disease. However, the impacts of different durations of statin use on gallstone disease have not been clarified. The aim of this study is toperform a systematic review with meta-analysis to update and to elucidate the association between statin use and the risk of gallstone disease and cholecystectomy.Medline, Embase and Cochrane Library were searched from the inception until August 2022 for relevant articles investigating the difference in the risk of gallstone disease between statin users and non-users . Meta-analyses were conducted using odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to compare the risk of gallstone disease and cholecystectomy between statin user and nonusers.Eight studies enrolling 590,086 patients were included. Overall, the use of statins was associated with a marginally significant lower risk of gallstone disease than nonusers . Further subgroup analysis showed that short-term users, medium-term users, and long-term users were associated with a significantly higher risk , comparable risk , and significantly lower risk of gallstone diseases  respectively, compared to nonusers.Patients with medium-term or long-term use of statins without discontinuation are at a lower risk of gallstone disease or cholecystectomy. Gallstone is one of the most common indications for hospitalization in developed countries . The preWe conducted the present systematic review and meta-analysis following Cochrane Handbook for Systematic Reviews and Interventions  and repoArticles with the following criteria were included: (1) Randomized controlled trials, prospective studies, retrospective studies and case-control studies; (2) studies involving human adults without history of gallstone disease or cholecystectomy as participants; (3) studies reporting clinical outcome as with/without diagnosis of gallstone disease or record of cholecystectomy. Studies not investigating the use of statins were excluded. In case of duplicate studies with an accumulated number of patients or increased durations of follow-up, only the most complete reports were included.Two investigators (Y.C and K.Y.C) independently extracted relevant information from tables or results of eligible articles. Extracted data included first author name, publication year, country where the study was conducted, follow-up durations, number of participants, sex, age range, underlying diseases, and method used to identify cases. Additionally, we obtained adjusted odds ratio (OR) and standard error (SE) from each study. For studies that reported outcomes by relative risk (RR), since the extracted RR and SE were adjusted, the formula  for the Two investigators (Y.C and H.M.L) independently completed a critical appraisal of included literature by using the Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I) tool  for retrP values <0.05 were considered statistically significant. Heterogeneity was assessed using I2 statistics proposed by Higgins and Thompson  and current or former statin users.Meta-analysis was conducted using R software with the “metafor” package  Supplem. RegardiThompson , with esn = 49) and irrelevant references (n = 942) and retrieved 16 full texts for further review. Eventually, six case-control studies  and former users . Medium-term current statin user had significant lower risk of gallstone disease compared to nonusers  and former users had comparable risk of gallstone disease compared to nonusers . Long-term use of statin significantly reduced the risk of gallstone disease in current users  but former users had comparable risk of gallstone disease compared to nonusers .To explore the source of heterogeneity, we performed subgroup analysis according to the durations of statin use in three studies  that exc2 = 4%; Additionally, the pooled analysis of four studies  involvin2 = 71%).Statins are one of the most common prescribed regimens in the treatment and prevention of cardiovascular disease . In addiOne of the sources of heterogeneity would arise from the differences in demographics among included studies. For example, there were wide variation in prevalence of diabetes, ischemic heart diseases, and cerebrovascular diseases among included studies. Moreover, baseline characteristics that may be associated with gallstone disease such as hyperlipidemia, estrogen exposure or hormone therapy were only reported in two studies. On the other hand, we acquired adjusted ORs from included studies and pooled in meta-analysis, however, the variables adjusted for were not consistent in each study, which would contribute to the statistical heterogeneity.Most of the included studies defined case as “cholecystectomy required”. The use of statin may not only impact the formation of gallstone but the symptom severity of gallstone disease. For instance, Our results demonstrated that there was a marginally significant reduction in the risk of developing gallstone disease among statin-ever users. The subgroup analysis showed a dose–response relationship between the number of prescription and the risk of gallstone diseases, and, of note, the protective effect of stain was only observed in medium and long-term current users. However, this result had to be interpreted with caution since the durations of statin use was solely based on the prescription of medication in medical records. Paucity of detailed dosage of statin prescription and information for drug compliance may hindered the accuracy of statin exposure. Moreover, the cut-off time selected for the definition of current and former users varied from 90 days to 180 days representing an obvious source of conceptual heterogeneity.As a matter of fact, long-term statin users only accounted for 15% of all statin users in our analysis. We postulated that the underlying reason for such small proportion may be associated with either discontinuation of statins or low adherence to medications. Although statins are one of the most effective medications for the secondary prevention of cardiovascular diseases, non-compliance and discontinuation with this medication are common problems . AlthougConsequently, we propose that the recurrence of dyslipidemia may be responsible for neutral and detrimental effects on gallstone formation in medium- and short-term users, respectively.In our study, we included three more studies  comparedThe findings of our meta-analysis must be interpreted within the context of the study limitations. First, we included case-control studies and retrospective cohort studies, which induced a potential bias due to the confounding that was generally not well-controlled. Second, we investigated the protective effect of statin on gallstone development; however, the definition of statin use, and gallstone disease were not consistent in each study. Third, baseline characteristics that may be associated with gallstone formation such as hyperlipidemia, estrogen exposure or hormone therapy were not reported in several studies, which hindered the accuracy of our findings. Last but not least, healthy user and adherer effect are two easily overlooked sources of bias, especially in observational studies . PatientBased on our meta-analysis, long-term and medium-term use of statins without discontinuation lower the risk of gallstone disease or cholecystectomy. Nonetheless, given the observational nature of the included studies, we propose that further prospective studies should be undertaken to overcome the aforementioned limitations.10.7717/peerj.15149/supp-1Supplemental Information 1MOOSE checklist, Search Strategy, and Data extraction and data synthesisClick here for additional data file.


Despite that several original researchers have investigated the association between neck circumference (NC) and the risk of diabetes mellitus (DM), their results remain controversial. This review aimed to quantitatively determine the risk of DM in relation to the NC.We conducted a literature search of PubMed, Embase, and the Web of Science from these databases’ inception through September 2022 to identify observational studies that examined the association between NC and the risk of DM. A meta-analysis of the random-effects model was applied to combine the results of the enrolled studies.Sixteen observational studies involving 4,764 patients with DM and 26,159 participants were assessed. The pooled results revealed that NC was significantly associated with the risk of type 2 DM (T2DM)  and gestational DM (GDM) . Subgroup analysis revealed that after controlling for BMI, the relationship between the NC and T2DM remained statistically significant . Moreover, the pooled OR of T2DM was found to be 1.16 (95% CI: 1.07–1.27) for an increment per each centimeter in the NC.Integrated epidemiological evidence supports the hypothesis that a greater NC is associated with an increased risk of T2DM and GDM.The online version contains supplementary material available at 10.1186/s13098-023-01111-z. The incidence of diabetes mellitus (DM) has increased substantially in recent decades , which hObesity is a well-established risk factor for DM . SeveralOver the past decades, numerous studies have assessed the relationship between NC and DM, but the results remain inconsistent. Some investigations have reported that NC has a direct relationship with DM –11, wherThe present systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement . PubMed,The studies were included in the meta-analysis if they met the following inclusion criteria: (i) the study design was cross-sectional, cohort or case-control, (ii) the odds ratio (OR) or relative risk (RR) with 95% confidence interval (CI) of DM incidence related to the NC were reported or could be calculated from the provided data. Abstracts, non-original papers , gray literature, unpublished studies, and studies providing data on the relationship between the NC and diabetes-led mortality or complications were excluded. If there was more than one report from the same study, we only included the report with the most detailed information for both NC and the outcome.Two authors (D.L. and Y.Z.) independently extracted the following information from the included studies: first author, publication year, country or region, study design, age, sample size, the number of men and women, the cutoff point for NC, adjusted OR/RR with 95% CI, and the adjusted factors. The differences in data extraction between the two investigators were resolved via discussion with the third investigator (S.C.).We assessed the methodological quality of cohort and case-control studies with reference to the Newcastle–Ottawa Scale, which awards a score of 0–9 based on the selection of participants, comparability of the groups, and exposure/outcome assessment . StudiesThe assessment tool involving 11 items, as recommended by the Agency for Healthcare Research and Quality, was applied for cross-sectional studies . The quaEach study was rated independently by two authors (D.L. and Y.Z.). Any disagreements were resolved via discussion with a third investigator (S.C.).Q statistic with a significance level of < 0.10 and I2 statistic were applied to test the heterogeneity. The I2 statistic measures the percentage of total variation across studies because of heterogeneity rather than because of chance. It was calculated according to the formula by Higgins [I2 value of at least 50%. Sensitivity analyses and subgroup analyses were conducted to evaluate the influences of the study design and population characteristics on our results. All statistical analyses were conducted by using STATA statistical software version 13.0 . P values were two-sided with a significance level of 0.05.We considered OR as the common measure of association between the NC and the risk for DM. The reported RR was considered approximately as the OR. We calculated an overall pooled OR by using a random-effects model for the main analysis . If stud Higgins . SubstanThe results of the literature research and selection are illustrated in Fig. The main characteristics of the 16 studies are summarized in Table I2 = 82.6%, P = 0.001).The results from the random-effects model combining the ORs for the relationship of T2DM with NC are shown in Fig. I2 = 83.9%, P < 0.001)  to 2.71 (95% CI: 1.43–5.14) Fig. .P = 0.003). Subgroup analysis by controlling for age also indicated a statistically significant difference in results (P = 0.001). No significant difference was detected between the groups in terms of other variables. Notably, subgroup analyses by controlling for BMI indicated that the heterogeneity mainly arose from studies with unadjusted BMI (I2 = 93.2% for studies with unadjusted BMI and I2 = 0% for studies with adjusted BMI).Table I2 = 34.6%, P = 0.164).The results from the random-effects model combining the ORs for the relationship between GDM and NC are depicted in Fig. The sensitivity analysis indicated that the results were unaffected by any single study, with the pooled OR ranging from 1.25 (95% CI: 1.16–1.40) to 1.36 (95% CI: 1.15–1.61) Fig. .Table NC, a novel anthropometric index, is considered a marker of subcutaneous fat distribution in the upper body and an independent predictor of metabolic disorders, such as glucose intolerance, hypertension, and fatty liver disease –31. ThisSeveral potential mechanisms have so far been proposed to describe the relationship between NC and DM. First, NC is correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels, both of which are robust markers for decreased insulin sensitivity , 32. AddOwing to the substantial heterogeneity in studies exploring the association between NC and the risk of T2DM, subgroup analyses were conducted based on various factors. The findings showed that the association between NC and T2DM risk remained significant in most subgroups. The percentage and distribution of body fat for the same BMI varies across different populations . TherefoNC exhibits several advantages against previously used indices, such as BMI and WC. Although BMI is the most widely used index for defining overweight and obesity, it cannot assess body fat distribution. Likewise, although WC is a commonly used index for evaluating abdominal obesity, it fluctuates greatly and can be easily affected by conditions and time . NC is sOur study has several strengths. First, in this systematic review and meta-analysis, the relationship between NC and T2DM was evaluated for the first time. Although Rahnemaei FA et al.’s study involved NC and DM, the researchers concentrated on the relationship between various anthropometric indicators and GDM . Second,However, there are some limitations, which are of concern. First, adjusted confounders varied among the included studies. Some probably important residual confounders, such as BMI, sex, and age, were not adjusted in certain studies. Second, different cutoff points for NC size were defined across studies, which might have introduced heterogeneity in the obtained results. Third, publication bias was not evaluated owing to the small number of studies on T2DM risk and GDM risk that were included in the meta-analysis in relation to the NC.The findings from this meta-analysis suggests that the risk of T2DM is elevated in individuals with a high NC. Moreover, pregnant women with high NC values have higher odds of GDM than those with low values. Nonetheless, the number of included studies was limited, and some possibly important residual confounders, such as BMI, were not adjusted in certain studies. Thus, more high-quality studies are required to confirm the predictive potential of NC for DM.Below is the link to the electronic supplementary material.Supplementary Material 1


The oxidative balance score (OBS) has been utilized to assess the overall pro- and antioxidant exposure status in various chronic diseases. The current meta-analysis was carried out to pool the association between OBS and the risk of cancer.2. A random-effects model meta-analysis was conducted to estimate the pooled effect sizes. Possible sources of heterogeneity were explored by subgroup and meta-regression analysis.We systematically searched the Web of Science, PubMed, Scopus, Embase, and Google Scholar up to August 2023. All observational studies which evaluated the association of OBS with the risk of cancers were included. There was no time of publication or language restrictions. Heterogeneity between studies was assessed using the Chi-square-based Q-test and the ITotally, 15 studies (9 case–control and 6 cohorts) were eligible for meta-analysis. Random effect model meta-analysis of case–control studies showed that higher OBS significantly decreases the odds of cancers . In the cohort studies, the association of OBS with the risk of cancers was not significant . The subgroup analysis showed that cancer type and gender were the potential sources of heterogeneity.Our results show an inverse and significant association between higher OBS and odds of colorectal cancers in case–control and cohort studies. In the case of prostate cancer in cohort studies, our results did not align with the hypothesis. Considering the importance of diet and antioxidant balance in the conditions of malignancy, it is suggested to conduct more comprehensive studies with standard measurement methods to obtain conclusive results. Cancer has emerged as a prominent global illness, posing a significant hazard to the well-being of humanity . AnnuallThe development of pathophysiological conditions like cancer is widely attributed to excessive cellular oxidative stress. Healthy cells utilize various mechanisms to maintain intracellular levels of reactive oxygen species (ROS) and overall redox homeostasis, thus preventing damage to DNA, proteins, and lipids . The disOverall, due to the existence of inconsistent findings, there is a need for a meta-analysis that will summarize all of the available studies in this field. So, the current meta-analysis was carried out to pool the association between oxidative balance score and cancer.This systematic review and meta-analysis was designed and implemented to assess the association of oxidative balance score and cancer morbidity in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .We conducted a systematic review through which all related documents were searched in databases, including Web of Science, Embase, PubMed, Scopus, and Google Scholar until August 2023. The main routes for keyword combination extracted from  AND ) and all related terms. Also, to identify additional studies, the references cited within the relevant articles were reviewed. Two of the authors searched mentioned databases to identify eligible studies independently, and all articles obtained from a comprehensive search were managed by EndNote X9 software .Studies were eligible for inclusion criteria in this review that assessed the relationship(s) of oxidative balance score with cancers in human with no limitation for the time of publications or researches, the language of papers, or gender. PECO was defined as a structured question describing the Population , Exposure , Comparison (control group), and Outcome (incidence of cancer). Data from the searched papers were transferred to the Endnote software libraries. Duplicate records were excluded. To assess the eligibility and relevancy of included articles, in a three-step process, titles, abstracts, and full-text screening were conducted by two expert researchers independently.Articles that had any of the following criteria were excluded from the meta-analysis: 1) trials; 2) studies which conducted in animals or labs; 3) other outcomes except cancer morbidity was reported such as mortality rate; 4) Studies that did not calculate and report the score related to oxidative balance; 5) review articles, editorials, letter to editors and case report studies.The results of searches were evaluated by two of the authors based on mentioned the inclusion and exclusion criteria and extracted data from the studies independently. In extraction step, a checklist was used that included general, methodological and exposure and outcome related characteristics such as the first author, study country, study design, publication year, sample size, type of FFQ questionnaire, age and gender of participants, score of oxidative balance, exposure levels, type of cancer, detection methods and effect size. If a study had reported results for different cancer type (even both gender separately or in a specific gender), the reported effect sizes (EFs) were considered as a different study in meta-analysis. In some of the included studies, based on the stage of cancer progression, the participants were divided into two groups, non-advanced and advanced, and we reported the results in the same way. While, if there was no report on the stage of disease progression in the studies, we reported them as typical cases.The quality of the included documents were assessed by using the Newcastle–Ottawa Quality Assessment scale . Concern2, and the result of the Q-test was considered to be statistically significant at P < 0.1. According to the value of I2, in case of severe heterogeneity (I2 >  ~ 75%), the pooled effect size was estimated conducting a random-effect meta-analysis model (with the Der-Simonian and Laird method). Also, for present the result of meta-analysis schematically, the forest plot was used. To identify the possible source of heterogeneity, subgroup analyses were performed according to the type of cancers, gender, case type, control type, and study design. Also, sensitivity analysis was conducted based on one out remove method  to detect the potential outliers.The effect size for the association of OBS with cancers was considered Odds ratio (OR) with 95% confidence interval (CI), as same as, in cohort studies, the effect size was reported as hazard ratio (HR) with 95%CI.. The statistical heterogeneity between studies was evaluated by the Chi-square-based Q-test and the IP-value < 0.05 was considered statistically significant.Publication bias was evaluated using Egger's test and funnel plots. Therefore, in order to find the source of publication bias, we performed the trim and fill test. All analyses were performed by STATA software vision 17 . A In our initial search, 109 articles were identified. After exclusion of duplicate articles and those that did not meet the inclusion criteria, we identified 51 full-text articles of potentially relevant studies were identified. After full-text review, were excluded an additional 39 studies because their design and population were not interested or did not evaluate the association between OBS and cancers. Finally, by reviewing the full texts for cited references and then qualitative synthesis, fifteen observational studies were eligible for systematic review. A flow diagram of the study selection is shown in Fig. The characteristics of the included studies are provided in Tables I2 = 88%, Q test: 83.49; P < 0.01)  .Based on a random-effects model Sensitivity analyses revealed that excluding any single study from the analysis did not significantly change the pooled effect sizes Fig. . Begg's p = 0.77) and overall sample size (p = 0.75), age (P = 0.27) and follow-up duration (P = 0.71).Meta-regression showed that no significant association between OBS and female ratio   and colorectal cancer groups .Six studies with a total of 152,441 participants were included in the meta-analysis , 27, 29.Subgroup analysis based on gender shows a significant relationship between higher OBS and risk of cancer in female ) while this association in male gender was non-significant ). However, heterogeneity remained high in both groups. Moreover, subgroup analysis according to the stage of cancer, no significant results were found in any of the subgroups, while the heterogeneity reached negligible levels in the advance stage 3 & 4) group (Table  & 4 grouP = 0.46)  Fig. .Fig. 6SeP > 0.05).A random-effect meta-regression analysis indicated no effect of female ratio, total sample size and follow up duration on pooled HR (The quality assessment of included studies was according to the modified Newcastle–Ottawa scale  for the The results of this meta-analysis showed that in case–control studies, higher OBS was associated negatively with odds of various cancers. Also, this relationship was stronger in breast cancer with negligible heterogeneity compared to colorectal and prostate cancer. On the other hand, in cohort studies, the overall relationship between OBS and all types of cancers was not statistically significant, although in the subgroup analysis there was a strong and positive relationship between OBS and prostate cancer, on the contrary, in other cancers such as breast, there was an inverse relationship, but statistically significant levels were not achieved. It is also noteworthy that subgroup analysis based on cancer stage did not significantly change the results and the relationship between OBS and cancer was insignificant in all stages. One of the possible reasons for the lack of discrepancy in the results between case–control and cohort studies is the design of them and actually the long-term follow-up period of the patients. Although the reverse causation should not be ignored. In fact, in case–control studies, because the participants are examined at one point in time, the priority and posterity of the exposure and the outcome are not clear, and it is possible that this score did not lead to cancer, but cancer. It has caused a change in diet and a change in this score. This issue can be the possible reason for non-significant results in cohort studies despite the presence of significant results in case–control studies.The results of current meta-analysis in case–control studies are in line with existing theories about the protective effects of antioxidants against conditions with severe oxidative stress such as cancers. Based on our results, higher OBS is inversely associated with colorectal cancer risk. The consumption of pro-oxidants through diet, such as dietary iron, omega-6 fatty acids, and saturated fat, has been linked to an elevation in oxidative stress and DNA damage in the colon. This can be attributed to the increased production of free radicals in the colorectal region , 36–44. Numerous academic studies have investigated the correlation between an oxidative score, which comprises a comprehensive assessment of pro-oxidant and antioxidant exposure status, and the incidence of several types of cancer, such as colon/rectum, prostate, and lung , 47, 48.In the current systematic review and meta-analysis, we gathered all available evidence about the association between OBS and different cancer types. However, some potential limitation should be addressed. There was a considerable heterogeneity between the included studies which can be due to the small number of available studies and different methodology of studies. Also, due to the presence of reverse causation in case–control studies, it may not be possible to give a definite conclusion about the effect of OBS on cancer. It is suggested that more qualitative longitudinal studies be conducted in this field. One of the strong points of this study can be called the high quality of the studies included in this study, as well as the separate analysis of the studies according to the different effect sizes.The results of our study showed that OBS has an inverse relationship and a protective effect against cancers such as colorectal and breast in case–control and cohort studies. While the results of longitudinal studies indicated that there is a direct and positive relationship between prostate cancer and OBS. Due to the small number of studies on other types of cancers, we did not reach conclusive results, so it is recommended to conduct more studies in this regard.


Subgroup analysis showed that OC use increased the risk of SCC , whereas no significant association was shown between HRT use and risk of SCC . Additionally, OC and HRT use were linked to an increased risk of basal cell carcinoma (BCC) . Further subgroup analysis suggested both OC and HRT use were associated with an increased risk of BCC . In conclusion, our findings support the hypothesis that the risk of KC among women may be affected by the use of exogenous hormones.Previous studies reported inconsistent results regarding the association between keratinocyte carcinoma (KC) and exogenous hormone therapy. This study aimed to investigate the association between the use of exogenous sex hormones and the risk of KC among women. The databases of PubMed, Ovid Medline, Cochrane, and Web of Science were searched until May 2023. A total of 5293 patients with KC and 106,424 controls were included for analysis. The meta-analysis indicated that oral contraceptives (OC) and hormonal replacement therapy (HRT) use were associated with an increased risk of squamous cell carcinoma (SCC) (OR/RR = 1.25, 95% CI 1.10 to 1.43, IThe online version contains supplementary material available at 10.1186/s12885-023-11459-0. Keratinocyte carcinoma (KC) is regarded as the most frequently diagnosed malignant disease among fair skin populations . KC refeBCC is the most common subtype of KC, accounting for almost 80% of KC , and theIn addition to those risk factor mentioned, the role of hormone exposure was controversial in the development of KC. The use of exogenous hormones has been proved as a high-risk factor of breast cancer and cancers of the female reproductive tract , 19. SevThe present study was conducted on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .We reviewed published articles from PubMed, Ovid Medline database, Cochrane and Web of Science. These studies were published before May, 2023. The following keywords and/or MESH terms were used:  AND . Additional studies were also identified through reference lists of the retrieved articles.We evaluate the article with the following selection criteria: (1) the investigator evaluated the relationship between non-melanoma skin cancer and exogenous hormones such as oral contraceptives (OC) or hormonal replacement therapy (HRT); (2) with eligible statistical parameters to estimate outcomes (odds ratio (OR), relative risk (RR)); (3) the study design was case-control or prospective cohort; (4) review papers, case reports or letters without adequate information to calculate estimated outcomes were excluded from the present study; (5) when the results reported in several models and studies presented in multiple results, we used results with higher follow-up duration.Data were extracted and verified independently by two researchers. The divergence was resolved by another investigator. We collected the following information from the published paper: first author and published year, type of study design, country, type of non-melanoma skin cancer, and adjusted variables. Notably, we extracted risk estimates as they were reported, either as odds ratio (OR) or relative risk (RR).2 statistic were used to evaluated heterogeneity between the enrolled researches. If the p value of Q test was < 0.05 or I2 was > 60%, we applied the random effects model for analysis; otherwise, data were pooled with fixed effects model and corresponding 95% CIs. Subgroup analysis (different study types and OC or HRT) was applied to explore the source of heterogeneity. In addition, sensitivity was imitated by removing one study at a time. The publication bias was evaluated by Begg’s test, Egger’s test and simulating the asymmetry of funnel plot.Stata 12.0 software was employed to statistical analyses. For our meta-analysis, we primarily used the OR as the effect measure. In cases where only the RR was provided in the original studies, we treated it as an approximation of OR, particularly for events with low incidence. Accordingly, the pooled ORs (or approximated ORs from RRs) were estimated using inverse variance methods and the effects were assessed with 95% confidence intervals (CIs). What’s more, Q test and ITitles and abstracts were reviewed by two individuals. After removing duplicates, we found 195 English articles. After reading the abstract and titles, 144 records were excluded because of irrelevant information. Due to the research did not report the statistical parameters to estimate outcomes and other relevant information interested, 15 studies were excluded. As we failed to obtain the original data, 28 studies were discarded. Finally, 8 studies –26, 28 w2 = 35.5%, p = 0.063; Fig. p = 0.345; Egger’s test: p = 0.878; Supplementary Fig. Four cohort studies , 23, 28 2 = 41.6%, p = 0.080; Fig. p = 0.929; Egger’s test: p = 0.336; Supplementary Fig. Two cohort studies , 23 . The results showed that the use of exogenous sex hormone may increase the risk of KC among females.The potential impact of sex hormone in the development of KC may be supported by some epidemiological and laboratory studies. Estrogen receptors on the surface of keratinocytes can be activated to induce cell proliferation, further change the capacity of DNA repair , 30. CavCaini et al.'s  study emIn our study, we reported that sex hormones may act as a potential risk factor for KC. Given the widely use of OC globally, our findings should be verified by more powerful evidence and the impact on the risk of KC cannot be ignored. Of note, there were some limitations in our study. Fist, most of included studies were Caucasians, data from non-white women was few. Our findings may be not applicable for those women. Second, we cannot get more detail information about the use of OC and HRT, such as the first and last use, duration, type of hormones and time since drug discontinuation, etc. and aspects of patients from original literatures, such as residential history, personal sun sensitivity characteristics, body mass index, smoking habits, reproductive history, etc. These factors may influence the bias of results. Third, there were several retrospective studies included in this meta-analysis, thus recalling bias cannot be avoided. Collected information from those studies was totally based on subject recollection. The last one point worth noting, with the development of modern pharmacy, OC and/or HRT formulation that used in included studies may be different from current drug. Modern OC formulations have greatly reduced levels of estrogen .Our findings supported for the hypothesis that the risk of KC among women may be affected by use of exogenous hormones.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3Supplementary Material 4Supplementary Material 5Supplementary Material 6Supplementary Material 7Supplementary Material 8Supplementary Material 9Supplementary Material 10


Vitamin D receptor (VDR) gene polymorphisms probably play a key role by affecting the biological function of vitamin D in some adverse pregnancy outcomes, while the relationship between the VDR gene polymorphisms and the risk of HDP remains controversial in current studies. This systematic review and meta-analysis aimed to comprehensively evaluate the association of the VDR gene polymorphisms with HDP susceptibility.Hypertensive disorders of pregnancy (HDP) are currently one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Recent studies provide evidence that maternal VDR gene polymorphisms with HDP were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for non-randomized studies. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) of the five models  were pooled respectively, and subgroup analysis was performed based on ethnicity.This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and a protocol has been registered in the PROSPERO (ID: CRD42022344383) before commencing this review. PubMed, Web of Science, Embase, and the Cochrane Library databases were searched until January 21, 2023. Case-control and cohort studies that reported the association of the VDR gene ApaI polymorphism was associated with HDP susceptibility in the dominant model  and the heterozygote model . In subgroup analysis, the heterozygote model  of the ApaI polymorphism was associated with HDP in Asians, but not in Caucasians.A total of ten studies were included. The VDR gene ApaI polymorphism may be associated with HDP susceptibility. Insufficient evidence to support the existence of ethnic differences in this association.The  HDP areetc. . In addietc. , includiCE) gene , angioteGT) gene , endotheOS) gene , methyleFR) gene , tumor n-α) gene , catechoMT) gene , which w3 2D3), as the active form of vitamin D, mediates its physiological effects by specific interactions with the vitamin D receptor (VDR). The VDR is a DNA-binding transcription factor that is a member of the steroid receptor family in the cell nucleus. When specifically binds to 1,25-Dihydroxyvitamin D3, VDR generates an active signal transduction complex consisting of a heterodimer of the 1,25-(OH)2D3-liganded VDR and unoccupied retinoid X receptor (RXR). This liganded VDR-RXR heterodimer can recognize vitamin D responsive elements (VDREs) in the DNA sequence of vitamin D-regulated genes , and six untranslated exons (1A-1F) , the BsmI polymorphism (rs1544410), the FokI polymorphism  and the TaqI polymorphism (rs731236). Among the four SNPs, three of them occur in the intron sections , while only the FokI variant changes the codon    . Polymortrations . Four cohe codon    increased the risk of preeclampsia among the Chinese population, while another study conducted in China showed that the association of the FokI polymorphism (A>G) with HDP susceptibility was not statistically significant  , and theactivity , the relnificant . In factA protocol was registered before commencing this review in the International Prospective Register of Systematic Reviews PROSPERO (ID: CRD42022344383). The current meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . The PRIrs2228570” OR “BsmI” OR “rs1544410” OR “ApaI” OR “rs7975232” OR “TaqI” OR “rs731236”) AND (“polymorphisms” OR “SNPs” OR “genotype” OR “variant” OR “mutation”) AND . The search strategies for each database are detailed in Original articles from PubMed, Web of Science, EMBASE, and the Cochrane Library databases were systematically searched from the founding date of each database to January 21, 2023. A combination of the following searching terms was used:  providing sufficient data about the genotype frequencies of the VDR gene polymorphisms for calculating the value of odds ratio (OR) and 95% confidence interval (CI); (4) the distribution of genotypes of controls were in accordance with the Hardy-Weinberg equilibrium (HWE); (5) studies were published or written in English.The studies which met the following explicit criteria were included: (1) case-control or cohort design; (2) the relationship between the in vivo or in vitro experiments; (3) studies containing overlapping or insufficient data; (4) duplicate studies retrieved from various databases.The exclusion criteria were: (1) reviews, case reports, letters, conference abstracts, and comments; (2) VDR gene variants; (2) sample size, age, and genotype distribution in both case and control groups; (3) odds ratios (ORs) and corresponding 95% confidence intervals (CIs); (4) the HWE test results for the control group. All data were extracted independently by two researchers (Yu Zhang and Yicong Guo), and if there were disagreements, questions were discussed and resolved by a third reviewer (Xiangling Tang).The following information from eligible studies was extracted or calculated based on genotype distribution: (1) the first author’s name, publication year, country, ethnicity, genotyping methods, types of HDP, and the The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for non-randomized studies. The NOS is a rating scale in which points are awarded to studies based on selection, comparability, and exposure or outcome, where each study score ranges from 0 to 9 points . A studyVDR gene polymorphisms  and the risk of HDP. The heterogeneity was evaluated by Cochran’s Q-statistic test and I-squared (I2)  were calculated respectively, to evaluate the association between the red (I2) . If I2>5 applied . Subgrou applied  and Begg applied , and a vP < 0.05 was considered statistically significant except for Cochran’s Q test. In our study, all analyses were based on previously published research; thus, no ethical approval or patient consent was required.All statistical analyses were performed using Stata v16.0 . A two-sided n = 2), the VDR gene polymorphisms were not measured (n = 8), and other outcomes (n = 4). We finally selected a total of ten qualified articles    of the ApaI polymorphism was associated with an increased risk of HDP in Asians but not in Caucasians.= 0.014)  and the = 0.006) . SubgrouVDR gene Bmsl polymorphism and the risk of HDP in the overall population in the homozygote model   . BesidesVDR gene FokI polymorphism was only found statistically associated with the risk of HDP in Caucasians based on the recessive model   (The = 0.041) . In the = 0.228) .VDR gene TaqI polymorphism had no significant associations with the risk of HDP in both the overall and Asian populations according to the five models. In addition, in subgroup analysis, only one study investigated this relationship among Caucasians and reported a statistically significant association between the TaqI polymorphism and HDP susceptibility in the allele model .The vs. AA) (vs. AA)  to 1.72 (95% CI [1.18–2.50]) in the dominant model (aa + Aa vs. AA)  and from(vs. AA) , indicat(vs. AA) , and the(vs. AA) –S6.VDR gene polymorphisms and HDP susceptibility, we conducted this systematic review and meta-analysis. As far as we know, this is the first meta-analysis to comprehensively investigate the associations between the four common SNPs of the VDR gene and HDP susceptibility by pooling ORs and the corresponding 95% CIs. Our study contributed to identifying the VDR gene as an additional candidate gene for subsequent Genome-Wide Association Studies (GWAS) for predicting HDP. Moreover, since genetic genes are rarely affected by environmental factors, spotting SNP loci associated with HDP provided potential instrumental variables for future Mendelian randomization (MR) design, which can reveal the association between various exposure and HDP while avoiding confounding factors and reverse causality  GT variant was associated with preeclampsia in Iran pregnant women , while another study conducted among the Polish did not found such association in the heterozygous model  (ApaI polymorphism showed significantly lower serum 25-(OH) D3 levels than those with the wild genotypes  (ApaI (C>A) CA variant was not correlated with maternal 25-hydroxyvitamin D3 (25-(OH) D3) levels  for women in Brazil . On the contrary, another study conducted by Karras et al. in Greece suggested that mothers with the FokI F/F polymorphism had a 70% lower risk of vitamin D deficiency compared with f/f ones    . Besides < 0.05) , while an Brazil . Howeveractivity , most st studies , while t studies , e.g., Fociation , the exa = 0.03) , however = 0.09) . Third, VDR gene polymorphisms affect the risk of HDP are still not entirely clear, it is rational in biology. Evidence for the association of the VDR gene polymorphisms with common risk factors for HDP has been reported in previous studies, such as obesity  the BsmI polymorphism; (F) the FokI polymorphism; (T) the TaqI polymorphism.(A) the Click here for additional data file.10.7717/peerj.15181/supp-6Supplemental Information 6ApaI polymorphism; (B) the BsmI polymorphism; (F) the FokI polymorphism; (T) the TaqI polymorphism.(A) the Click here for additional data file.10.7717/peerj.15181/supp-7Supplemental Information 7ApaI polymorphism; (B) the BsmI polymorphism; (F) the FokI polymorphism; (T) the TaqI polymorphism.(A) the Click here for additional data file.10.7717/peerj.15181/supp-8Supplemental Information 8ApaI polymorphism; (B) the BsmI polymorphism; (F) the FokI polymorphism; (T) the TaqI polymorphism.(A) the Click here for additional data file.10.7717/peerj.15181/supp-9Supplemental Information 9ApaI polymorphism; (B) the BsmI polymorphism; (F) the FokI polymorphism; (T) the TaqI polymorphism.(A) the Click here for additional data file.10.7717/peerj.15181/supp-10Supplemental Information 10The contribution this makes to knowledge in light of previously published related reports, including other meta-analyses and systematic reviews.Click here for additional data file.


Pre-eclampsia may be associated with the development of endometrial cancer; however, previous findings have been conflicting.To investigate if pre-eclampsia is associated with an increased risk of endometrial cancer.Two independent reviewers screened titles and abstracts of studies identified in MEDLINE, Embase, and Web of Science databases from inception until March 2022. Studies were included if they investigated pre-eclampsia and subsequent risk of endometrial cancer (or precursor lesions). Random-effects meta-analysis was used to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between pre-eclampsia during pregnancy and endometrial cancer risk.2 = 34.1%). In sensitivity analysis investigating risk of endometrial neoplasia , there was some evidence that pre-eclampsia was associated with an increased risk .There were seven articles identified which investigated endometrial cancer, of which one also investigated endometrial cancer precursors. Overall, the studies include 11,724 endometrial cancer cases. No association was observed between pre-eclampsia and risk of endometrial cancer with moderate heterogeneity observed (pooled HR 1.07, 95% CI 0.79–1.46, IPre-eclampsia was not associated with an increased risk of endometrial cancer. Additional large studies with information on pre-eclampsia sub-type aiming to investigate endometrial cancer precursor conditions are merited.The online version contains supplementary material available at 10.1186/s12905-023-02408-x. The incidence of endometrial cancer has increased rapidly in high-income countries , doublinPregnancy is known to confer long-term protection against endometrial cancer, most likely due to pregnancy-induced hormonal changes , 6. The There is limited understanding about the relationship between pre-eclampsia and the risk of endometrial cancer despite some evidence linking pre-eclampsia with a reduced risk of breast cancer . SimilarFindings from epidemiological studies investigating pre-eclampsia and risk of endometrial cancer have been inconsistent. A large Danish case-control study did not find any association between pre-eclampsia and the risk of endometrial cancer . In contFurther investigation of the long-term impacts of pre-eclampsia may provide insights into understudied biological mechanisms of endometrial carcinogenesis. This study aimed for the first time to systematically review the current evidence on the association between pre-eclampsia diagnosed during pregnancy and risk of endometrial cancer.This systematic review was carried out and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, see supplementary Tables The search was carried out using three online databases; EMBASE , MEDLINE , and Web of Science , from database inception until March 2022. The search strategy contained relevant Medical Subject Heading (MESH) and keywords relating to pre-eclampsia and endometrial cancer , see Table All titles and abstracts were independently screened, and relevant abstracts had their full texts reviewed independently, by at least two reviewers . Articles which met the following pre-set criteria were eligible for inclusion:i.Participants: Women and girls with a confirmed pregnancy.ii.Interventions: Recorded diagnosis of pre-eclampsia at any stage during pregnancy.iii.Comparators: Women and girls with a confirmed pregnancy without a diagnosis of pre-eclampsia during pregnancy.iv.Outcome: Endometrial cancer was the primary outcome and endometrial precursors  was a secondary outcome.v.Study design: Observational studies .Studies were included if they reported a risk estimate and 95% confidence interval (CI) or if there was sufficient information provided to calculate an estimate. Any discrepancies were resolved through discussion. Bibliographies of included studies were also reviewed. However, studies which included younger patients or did not report pregnancy and endometrial cancer or premalignant endometrial lesions, were excluded from this analysis.Relevant information concerning the author, publication year, study location, study design, study population characteristics, information on pre-eclampsia diagnosis, duration of follow-up, confounders, information on endometrial cancer diagnosis, and study results were extracted from the full-text articles. The Newcastle-Ottawa Scale (NOS) was used to derive a quality score for each of the studies included in the review .Risk estimates for the association between pre-eclampsia and endometrial cancer risk, including relative risks (RR), odds ratios (OR), or hazard ratios (HR), and corresponding 95% CIs were extracted from each study. ORs and RRs in this instance should roughly approximate a HR as endometrial cancer is not a common outcome , 28. MulThe risk estimates and associated 95% CIs were converted to log values and a random-effects model  was usedA sub-group analysis was carried out restricting to higher quality (NOS score of ≥ 7) and lower quality (NOS score of < 7) studies. A sub-group analysis was also conducted restricted to studies that adjusted for confounding factors  and maternal age). Additionally, a sensitivity analysis was conducted to include studies that investigated the risk of any endometrial neoplasia, including precursor conditions . Finally, to evaluate their individual effect on the pooled estimate, a sensitivity analysis was conducted whereby each study was systematically removed from the main analysis.A flowchart displaying the study selection process is outlined in Fig. There was some potential overlap in study populations in two of the identified articles , 32 howeThe characteristics of the included studies are detailed in Table All studies included pregnancies complicated by pre-eclampsia, identified through medical records or national birth registries, Table Endometrial cancer diagnoses were ascertained from cancer registries in four studies, , 31–33 h2 = 34.1%).Figure 2 = 50.7%, NOS score < 7: pooled HR 0.90, 95% CI 0.39–2.08, I2 = 0.0%), Table 2 = 38.5%), Table 2 = 0.0%), Table Results were largely similar in sub-group analysis based on study quality;  by the additional inclusion of 3,370 cases which resulted in a significant 34% increased risk in pooled analysis. However, only one study investigated these additional outcomes. Further investigation of endometrial cancer precursor conditions is required to elucidate if pre-eclampsia may influence earlier stages of endometrial carcinogenesis. This is especially relevant given that endometrial atypical hyperplasia carries a high risk of progressing to endometrial cancer .Potential biological mechanisms linking pre-eclampsia and endometrial cancer are currently understudied. Elevated androgen levels are observed in women with pre-eclampsia , possiblIn contrast to the main findings from this review, there is suggestive evidence that pre-eclampsia during pregnancy may be associated with a reduced risk of breast cancer , 50. DurDespite the large number of endometrial cancers cases included in the meta-analysis , only seven studies met the criteria for our systematic review. Most studies in the review identified pre-eclampsia and endometrial cancer from national registers and medical databases which reduced potential recall bias however, misclassification of exposure is still possible and may have attenuated results. Varying definitions for pre-eclampsia were used across the studies which may reflect differences in study time periods. This was notable in the study by Calderon-Margalit et al.  whereby Overall, the findings from this systematic review and meta-analysis suggested no association between pre-eclampsia and subsequent risk of endometrial cancer. There was some weak evidence to suggest that pre-eclampsia was associated with an increased risk of any endometrial neoplasia, but studies were limited. To further elucidate the relationship between pre-eclampsia and endometrial cancer risk, future studies are required and should aim to include large prospective cohorts using validated data to investigate pre-eclampsia onset, as well as endometrial cancer type and precursor conditions.Below is the link to the electronic supplementary material.Additional File Table 1: Meta-analyses Of Observational Studies in Epidemiology (MOOSE) Checklist. Additional File Table 2: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist


There are several approaches to THA, and each has their respective advantages and disadvantages. Previous meta-analysis included non-randomised studies that introduce further heterogeneity and bias to the evidence presented. This meta-analysis aims to present level I evidence by comparing functional outcomes, peri-operative parameters and complications of direct anterior approach (DAA) versus posterior approach (PA) or lateral approach (LA) in THA.A comprehensive multi-database search  was conducted from date of database inception to 1st December 2020. Data from randomised controlled trials comparing outcomes of DAA versus PA or LA in THA were extracted and analysed.. DAA has a longer operative time  but a shorter length of stay compared to PA . There was no difference in operative time or length of stay when comparing DAA versus LA. DAA also had significantly better HHS than PA at 6 weeks  and LA at 12 weeks . There was no significant difference in risk of neurapraxia for DAA versus LA or in risk of dislocations, periprosthetic fractures or VTE between DAA and PA or DAA and LA.Twenty-four studies comprising 2010 patients were included in this meta-analysisThe DAA has better early functional outcomes with shorter mean length of stay but was associated with a longer operative time than PA. There was no difference in risk of dislocations, neurapraxias, periprosthetic fractures or VTE between approaches. Based on our results, choice of THA approach should ultimately be guided by surgeon experience, surgeon preference and patient factors.Meta-analysis of randomised controlled trials. Total hip arthroplasty (THA) is a highly successful treatment for hip osteoarthritis, offering significant pain relief and improved quality of life by restoring function and mobility . THA hasThere are several surgical approaches to THA, including posterior approach (PA), lateral approach (LA) and direct anterior approach (DAA), all of which have their respective advantages and disadvantages. PA involves splitting of gluteus maximus to access the hip joint posteriorly. PA allows for excellent exposure of both acetabulum and femur and avoids disruption of the hip abductors . HoweverThere is ongoing debate with no clear consensus on the most optimal THA approach. Although several meta-analyses on this subject have previously been published, these meta-analyses had included non-randomised controlled trials (RCT) , 14–17 wThis meta-analysis aims to present level I evidence by evaluating and comparing 1. functional outcomes, 2. peri-operative parameters and 3. complications of DAA versus LA or PA in THA.This meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria. A comprehensive multi-database search  was conducted from date of database inception to 1st December 2020. The Medical Subject Headings and Boolean operators utilized were: [ AND (Approach)]. Results were subsequently filtered for RCTs. Identified articles and their corresponding references were reviewed and considered for inclusion according to the selection criteria.All RCTs directly comparing outcomes of DAA versus LA or PA in THA were considered for inclusion. Non-English language studies, non-peer-reviewed studies, conference abstracts, unpublished manuscripts and studies not directly comparing outcomes between THA approaches were excluded. Two independent authors reviewed studies retrieved from the initial search and excluded irrelevant studies. Abstracts and titles of remaining articles were then screened against the inclusion criteria. Included articles were critically reviewed according to a pre-defined data extraction form. Differences in opinions were resolved by discussion between the first two authors.Extracted data parameters include details on study designs, publication year, patient numbers, basic demographics, peri-operative parameters, functional outcomes and complications. Peri-operative parameters include mean operative time (minutes), mean length of stay (LoS) (days), mean blood loss (millilitres), transfusion requirement, discharge destination and post-operative opioid use. Functional outcomes of interest include Harris Hip Score (HHS), Oxford Hip Score (OHS), Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC), EuroQoL 5-Dimension (EQ-5D), Hip Disability and Osteoarthritis Outcome Score (HOOS), Visual Analogue Scale (VAS) pain scores, 12-Item Short Form Health Survey (SF12), 36-Item Short Form Health Survey (SF36), University of California Los Angeles (UCLA) activity scores, Lower Extremity Functional Scale (LEFS) and timed up and go (TUG). Complications of interest include periprosthetic fractures, dislocations, venous thromboembolism (VTE), neurapraxia, wound dehiscence, superficial infections, deep infections and revisions. Data extracted were organised using a Microsoft Excel spreadsheet.Methodology quality of included studies was assessed with the Cochrane collaboration tool for Risk of Bias (RoB) in RCT . Seven cX2 tests were used to study heterogeneity between studies. I2 statistic was used to estimate the percentage of total variation across studies, owing to heterogeneity rather than chance. Values greater than 50% were regarded as substantial heterogeneity. I2 can be calculated as: I2 = 100% x (Q−df)/Q. Q was defined as Cochrane’s heterogeneity statistics and df defined as degree of freedom. If substantial heterogeneity was present, the possible clinical and methodological reasons were explored qualitatively. This meta-analysis presented results with a random-effects model to account for clinical diversity and methodological variation between studies. All p values were two-sided. Review Manager  were used for statistical analysis.Comparative meta-analysis was performed with odds ratio (OR) and weighted mean difference (MD) primarily used as summary statistics. In this meta-analysis, both fixed- and random-effects models were tested. Fixed-effects model assumed that treatment effects in each study were identical, while random-effects model assumed that variations were present between studies. A selection process flowchart to include relevant studies is illustrated in Fig. Risk of bias assessment summary and graph for all 24 included RCTs are found in Tables A total of 2010 patients were included, with 792 in DAA versus PA and 1218 in DAA versus LA. Comparing DAA versus PA, both DAA and PA groups had 177 males and 219 females. Mean age in the DAA group was 63.5 years, while mean age of PA group was 63.3 years. Comparing DAA versus LA, 236 males and 361 females underwent DAA, while 288 males and 333 females underwent LA. Mean age was 64.7 years for the DAA group and 63.3 years for the LA group. Follow-up period was reported by 23 studies ranging from 4 days to 6.2 years. Other demographic details of each study are listed in Table P < 0.001) as seen in Fig. P = 0.80), 12 week  and 1-year  HHS did not show statistically significant difference  = 8.00, 95%CI: 5.85, 10.15, P = 0.02) as seen in Fig. P = 0.51), 6 week  and 1-year  HHS did not show statistically significant difference , but there was no significant difference between DAA and LA  , but there was no statistically significant difference between DAA and LA  . Meta-analysis for neurapraxia risk for DAA versus PA could not be performed as only Cao et al. reported neurapraxia rates [There was no significant difference in risk of neurapraxia between DAA and LA . There are several reasons that could have led to this discrepancy in dislocation rates between our analysis and other reports. Firstly, including only RCTs meant that patient numbers are limited and there may be insufficient statistical power to demonstrate a significant difference. Furthermore, a majority of RCTs focused mainly on the early post-operative period which could be too early for all dislocations to occur. It was also noted that most PA THA included in this analysis was reported to have posterior capsule repair and/or peri-operative hip precautions to minimise the risk of dislocations. Other confounding factors for this discrepancy can be due to the higher numbers of PA for THA, differing indications for PA THA, differing soft tissue closure techniques and individual patient factors including soft tissue integrity and comorbidities.There was no significant difference in risk of dislocations, periprosthetic fractures or VTE between approaches, which is also consistent with previous meta-analysis , 15–17. There are several limitations to this meta-analysis. Due to heterogeneity of reported PROMS and their follow-up intervals, only comparative analysis of HHS could be performed. PROMS that could not be quantitatively analysed are summarised in Appendix The DAA has better early functional outcomes with shorter mean length of stay and was associated with a longer operative time than PA. There was no difference in risk of neurapraxia for DAA vs LA, and there was no difference in risks of dislocations, periprosthetic fractures or VTE between approaches. Based on our results, preference of THA approach should ultimately be guided by surgeon experience, surgeon preference and patient factors.


Glycemic control is an important issue in the treatment of diabetic patients. However, traditional methods, such as medication , have limitations. Cognitive behavioral therapy (CBT) might be a useful option to help control the glycemic condition. The effects can be revealed by systemic review or meta-analysis of randomized clinical trials (RCT).A systematic search and a meta-analysis for the RCT were done of the short- and long-term effects of CBT on the glycemic control of diabetic patients in a comparison with the usual treatment. Nineteen RCT studies and 3,885 diabetic patients were enrolled in this meta-analysis. Subgroup analyses of types 1 and 2 diabetes and individual and group CBT were also performed.Patients treated with CBT showed no significant difference in HbA1c when compared to the usual treatment within six months. However, CBT was more effective in reducing HbA1c when compared to usual treatment with at least six months of treatment duration . Subgroup analysis of type 1 and 2 diabetic patients supported a long-term effect of CBT on glycemic control .CBT would be a useful option for improving the glycemic control of diabetic patients undergoing long-term treatment. The advantages of the long-term effects of CBT should be considered by clinicians and staff. Diabetes mellitus (DM) is an important, chronic physical illness commonly seen in clinical practice. It is associated with physical and mental health problems, which contribute to comorbidity and increase the difficulty of treatment . GlycateFrom the above literature, the dysfunctional cognitive and behavioral responses of people with DM are crucial issues for improving their standard care. Cognitive-behavioral therapy (CBT) is commonly used in the treatment of dysfunctional cognitive beliefs and behaviors. It improves the management of DM through the replacement of dysfunctional cognition with a self-helping and realistic cognition . The resFrom the above literature, we found heterogeneity of the meta-analysis results based on previous meta-analytic studies of people with DM. This study was done to clarify and confirm the treatment duration-related treatment effects of CBT on the glycemic control of people with DM. In this systematic review and meta-analysis we enroll only the randomized clinical trials of pure CBT for people with DM. In addition, we clarify the short- and long-term treatment effects of CBT for people with DM. Finally, we perform separate subgroup analyses of type 1 and 2 DM to confirm the short- and long-term treatment effects on glycemic control.To find all articles related to the effects of CBT for patients with DM, we searched and collected prospective RCT articles from the following databases: PubMed, ScienceDirect, EmBase, Web of Science, Scopus databases, Cumulative Index for Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL). The keywords included “cognitive behavioral therapy”, “cognitive”, “behavioral”, “diabetes”, “diabetic”, “randomized”, “clinical”, “controlled”, “trial”, “HbA1c”, “glycemic control” or “outcome”, “comparison”, “versus”, “treatment”, “usual treatment”. The article search was limited to those published or e-published online before July 2022. The date of our last search of PubMed, ScienceDirect, EmBase, and Web of Science was June 30, 2022. The date of our last search of Scopus databases, CINAHL, and CENTRAL was June 29, 2022.The inclusion criteria were (1) Comparisons between CBT and usual treatment for diabetic patients. (2) Studies with an outcome of glycemic control and specific for HbA1c. (3) Studies with detailed data on the outcome of glycemic control and with data specific for HbA1c. (4) Clinical trials with a randomized design. (5) Articles written in English that were published in the journals of the science citation index database. All authors  participated the study and DN and WX performed the article selection process according to the inclusion criteria.The Cochrane Handbook for Systematic Reviews and Interventions gave us the direction to conduct the current meta-analysis . The risThe data from the enrolled articles was collected by DN and WX. First, the baseline HbA1c of diabetic patients in the CBT and usual treatment groups. Second, the short-term (less than 6 months) endpoint HbA1c after CBT or usual treatment. Third, the long-term (more than 6 months) endpoint HbA1c after CBT or usual treatment. The rationale for our classification of short- and long-term was that we aimed to find the treatment duration-related effects of CBT on the HbA1c of people with DM. Fourth, the short- and long-term endpoint HbA1c of the CBT and usual treatment groups of patients with different subtypes of diabetes (types 1 and 2 diabetes). DN and WX assessed the abstracts to screen the articles and independently evaluated the full text version of the selected citations. The clinical outcome data was independently collected from text, tables, and figures of the enrolled articles by the two reviewers. The enrolled articles basically had data on the short-term endpoint HbA1c, long-term endpoint HbA1c, or subtypes of diabetes in the full text content. All authors  participated a collaborative review to resolve any discrepancies and to achieve agreement (kappa = 0.8) and participated in the review of the final results. The GRADE  approach was used by DX and YL to assess the certainty of evidence.2 distribution test, Higgins I2 index, Cochran's Q, and Tau square test. The synthesized results were conducted by pooling the data and using a random effects model meta-analysis. Subgroup analyses of the subtypes of diabetes were performed to confirm the treatment effects of CBT or usual treatment on glycemic control. In addition, forest plotting was done to demonstrate if the meta-analysis would favor CBT or usual treatment for improving the glycemic control of diabetes. Finally, a test for overall effect was done to calculate the Z and p-values for significance. The above meta-analysis steps were performed by DN and YL.The current meta-analysis was analyzed using the Cochrane Collaboration Review Manager Software Package (Rev Man Version 5.4). The CBT and usual treatment groups were compared to find which treatment would be superior for the glycemic control of diabetic patients. The overall effect size of the short- and long-term HbA1c endpoints were calculated as the weighted average of the inverse variance for the study-specific estimates. The weighted standardized mean difference was used to estimate numerical variables for the continuous variables. Heterogeneity was estimated using the χThe article selection process is presented as a PRISMA flow diagram in Fig. p = 0.36). Low heterogeneity was noted .Of the 19 articles enrolled, 13 had outcome data for short-term HbA1c. The mean difference in the short-term HbA1c of the CBT and usual treatment groups in the random effects model was -0.05 [95% confidence interval (CI): -0.16 ~ 0.06], without significance . High heterogeneity was noted  . Due to the lack of patient-level data, we performed the following subgroup analyses of types 1 and 2 DM to survey for potential clinical heterogeneity.Of the 19 articles, 13 had outcome data of the long-term endpoint HbA1c. The mean difference in the long-term HbA1c of the CBT group and usual treatment groups in the random effects model was -0.43 (95% CI: -0.58 ~ -0.27). Long-term HbA1c was significantly lower in the CBT group than in the usual treatment group , I2 = 70%]  for the type 1 DM subgroup, which indicates a significantly lower long-term endpoint HbA1c for the CBT group than was found for the usual treatment group . High heterogeneity was noted   for the type 2 DM subgroup, which indicates significantly lower long-term HbA1c in the CBT group than was found in the usual treatment group .The current meta-analysis failed to find a significant short-term effect of CBT on HbA1c, possibly for the following reasons. First, the definition of short-term effect in current meta-analyses is within six months, which might be different from the definition of previous meta-analyses. Second, the RCTs enrolled in the current meta-analysis might be more up-to-date than previous meta-analyses. However, future comprehensive review and meta-analysis will be needed to confirm the short-term effect of CBT on the HbA1c of people with DM.Our results also corresponded to those of a previous meta-analysis that showed that CBT is effective in reducing fasting blood glucose, with a long-term effect . AnotherHowever, all these meta-analyses demonstrated only that the effectiveness of CBT on glycemic control might be limited to medium- or short-term duration . UchenduThere are several limitations to the current meta-analysis. First, even though we enrolled 19 studies with a relatively large sample size, only 13 with 3,296 total participants reported short-term effects and 14 with 3,562 participants reported long-term effects. The sample size is somewhat small, which might limit the generalization of our results. The enrollment of more randomized studies with more participants will be necessary in the future. Second, the variable content of CBT limits the results. This variation includes the frequency, intensity, duration, session content, total number of sessions, group or individual, real face-to-face or web-delivered, training of the therapists, and directions of CBT. These variables might interfere the solidness of evidence for CBT. Future studies with a more consistent structure and duration of CBT will be helpful in reducing such confounding factors. Third, the types of DM and the subject’s demographic data limit the interpretations of the current meta-analysis. Our meta-analysis enrolled studies of people with type 1 and 2 DM. Even the subgroup analysis of type 1 and 2 DM separately showed consistent, significant results for the long-term effects of CBT on glycemic control. However, the pathophysiology and epidemiology of type 1 and 2 DM are different, which might have contributed to different responses to CBT. In addition, many adolescents have type 1 DM, as was reported in several enrolled studies. The variability of the age of the diabetic patients in the current meta-analysis means that our results must be interpreted with caution. In addition, the predominance of female patients enrolled in the studies may have led to a gender-specific influence on the current results. Fourth, the lack of patient-level data may also limit the interpretation of our results due to the lack of a full evaluation of patient-level covariates in cross comparisons. It is impossible to confirm a possible subgroup effect related to patient age or to explore the impact of variation in the disease condition of the patients in the enrolled studies. Fifth, due to the lack of such data in most studies, the current meta-analysis compares only the difference of the HbA1c endpoints, not the change of HbA1c. Future studies of changes in HbA1c by CBT for diabetic patients are warranted. Sixth, our method of assignment to intervention may have led to bias in our results. For interventions over a long period, only subjects who did not drop out (good adherence patients) are included in the analysis. The intention-to-treat effect was not properly evaluated as a result, which might influence the interpretation. Seventh, the variations of the interventions and significant statistical heterogeneity might influence the validity of conducting a meta-analysis under such conditions. However, because we used the random effects model, it should be appropriate due to its ability to capture uncertainty resulting from heterogeneity among studies .


Several studies have reported on hepatitis E virus (HEV) prevalence in various regions of China, but the results vary widely. Herein, we conducted a systematic review and meta-analysis to assess the seroprevalence, RNA-positive rate, genotype distribution of HEV in China, and its risk factors.We included 208 related studies involving 1,785,569 participants published between 1997 and 2022. Random-effects models were used to pool prevalence, and subgroup analyses were conducted by population, gender, age, study period, regions, and rural–urban distribution. The meta regression models and pooled odds ratios (OR) were performed to identify risk factors for HEV infections.The pooled anti-HEV IgG, IgM, and Ag seroprevalence, and RNA detection rates in China from 1997 to 2022 were 23.17% [95% confidence interval (CI): 20.23–26.25], 0.73% (95% CI: 0.55–0.93), 0.12% (95% CI: 0.01–0.32), and 6.55% (95% CI: 3.46–12.05), respectively. The anti-HEV IgG seropositivity was higher in the occupational population  and older adult aged 50–59 years . The dominant genotype (GT) of hepatitis E in China was GT4. Notably, drinking non-tap water , consumption of raw or undercooked meat , and ethnic minorities  were risk factors of anti-HEV IgG seroprevalence.Overall, the prevalence of hepatitis E was relatively high in China, especially among older adults, ethnic minorities, and humans with occupational exposure to pigs. Thus, there is a need for preventive measures, including HEV infection screening and surveillance, health education, and hepatitis E vaccine intervention in high-risk areas and populations.https://www.crd.york.ac.uk/prospero/, identifier CRD42023397036. In the 1980s, Balayan and other scholars used immuno-electron microscopy to discover virus-like particles in the feces of infected volunteers . HEV bel3) can be considered a risk factor for HEV infection  are infected with hepatitis E, and 15–110 million people have been recently or persistently infected with HEV . GloballHowever, the prevalence of hepatitis E reported in these studies varied widely and mostly focused only on anti-HEV IgG positivity rates. Anti-HEV IgG is a marker of previous infection, anti-HEV IgM indicates acute infection, HEV RNA is the gold standard for detecting HEV infection , and ant2.This study is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement  and has 2.1.Our meta-analysis divided populations into the general population, occupational population, pregnant women, volunteer blood donors, and hospital attendees. The general population referred to community-dwelling populations with unknown hepatitis E infection status. The occupational population was those who worked in occupations associated with pigs or with known risk factors for hepatitis E, such as pig farm workers, butchers, and food processing industry practitioners. Hospital attendees were those who came into medical facilities for consultation, examination, or treatment, including patients (acute hepatitis and asymptomatic patients) and healthy individuals who attended medical examinations.Hepatitis E virus infection can be diagnosed either indirectly by detecting anti-HEV antibodies in the serum or directly by detecting HEV RNA or capsid antigen in the blood or other body fluids . Hepatit2.2.All publications about hepatitis E infection in China between 1997 and 2022 were searched in the Chinese databases  and English databases . We used the following subject terms for the search:  AND [“Prevalence” OR “Infections” OR “Serology”] AND [“Chinese” OR “China”] AND [(“1997” [Date - Publication]: “2022” [Date - Publication])].2.3.The inclusion criteria for this meta-analysis were: (1) Studies with data on hepatitis E IgG and IgM antibodies, antigens and RNA; (2) Studies that did not conduct trials or interventions; (3) Studies conducted from 1997 to 2022 in China; (4) The study subjects were human beings; and (5) Studies with a sample size of more than 50 to prevent random error.We excluded the following studies: (1) Systematic reviews, meta-analyses, case reports, opinions, and abstracts; (2) Studies with no data on humans; (3) Studies not conducted in China from 1997 to 2022; (4) Studies with incomplete or duplicate data; (5) Studies on HEV outbreaks; (6) Studies conducted on high-risk groups , transplant patients, drug addicts, hemodialysis patients, individuals living with the human immunodeficiency virus, and other immunodeficient people.The following data were extracted from the included studies: first author, year of publication and implementation, population, age, gender, region, urban and rural distribution, risk factors, sample size, and the number of anti-HEV antibody-positive, antigen-positive and HEV RNA-positive individuals. Two reviewers (KC and MY) independently determined whether the studies met the inclusion and exclusion criteria and collected data. Any inconsistencies were resolved through mutual discussion or by a third reviewer (CC).2.4.We used the Joanna Briggs Institute (JBI) checklist to assess the quality of prevalence studies . The JBILiterature scoring was done independently by two researchers (KC and XW), and studies with inconsistent scores were judged by a third researcher (CC).2.5.2 > 50%). When the raw data did not follow a normal distribution, it was transformed using the arcsine transformation or Freeman-Tukey double arcsine transformation. Subgroup analyses and meta-regression were performed to investigate sources of heterogeneity. Individuals were further divided into subgroups according to population, gender, age, study period, region, and urban and rural distribution. In studies that lasted for several years, we divided the study period by median implementation time. Considering that there is a certain time interval between the study publication time and implementation time, the research period of studies without an implementation time was divided by the year of publication minus 2 years.Random-effects models were used to pool the rates as forest plots showed high heterogeneity  of anti-HEV IgG seropositivity were pooled to report risk factors for hepatitis E infection. We pooled adjusted ORs with the following risk factors: nation, consumption of raw or undercooked meat, water sources, and working years for the occupational population. We excluded studies with JBI quality scores ≤5 and sample sizes <200, < 300, and < 500 to evaluate the robustness and reliability of the overall pooled rate. The meta-analyses were conducted by the R version 4.2.1 using the 3.3.1.We initially retrieved 11,506 publications. After removing duplicates, 5,933 records were excluded after reading the titles and abstracts. The remaining 1,942 full articles were assessed, and 1,734 publications were excluded according to the inclusion and exclusion criteria. Finally, we included 208 studies published between 1997 and 2022 involving 1,785,569 participants .3.2.We systematically assessed the infection of HEV in China from 1997 to 2022. The pooled seroprevalence of anti-HEV IgG in China from 152 studies was 23.17% [95% confidence interval (CI): 20.23–26.25; The provinces of Zhejiang  and Hebei  had the highest prevalence of HEV antibodies. Gansu province had the highest rate of antigen positivity . Yunnan  had the highest RNA detection rate –S8.3.3.Twenty studies involving 10 provinces and cities showed that the dominant genotype for hepatitis E in China was GT4 . GT4 was3.4.The population was divided into five groups. The highest anti-HEV IgG positivity rate was found in the occupational population , while the population with the highest anti-HEV IgM seroprevalence was hospital attendees , and the risk in the 50–59 age group was 1.53 times higher than the 0–9 age group . The detection rate of the Wantai kit for hepatitis E IgG antibodies was higher than that of other kits , and Southern China reported a higher risk of detecting IgG antibodies than Northern China , consumption of raw or undercooked meat , and ethnic minorities  were the risk factors of anti-HEV IgG positive rates. Moreover, working years for the occupational population  were not statistically significant .3.6.After excluding studies with a JBI score ≤ 5 and sample sizes ≤200, ≤ 300, and ≤ 500, the results of the sensitivity analysis were consistent with the primary results, indicating that the current conclusions are robust , S36.4.Hepatitis E infection is considered a pending issue in industrialized countries , and itsThe sensitivity and specificity of hepatitis E assays vary widely . CompareChina is classified as a highly endemic area, where males seem to be more susceptible to HEV infection , 37. In The prevalence of hepatitis E infection differs between rural and urban areas . Our stuFurthermore, we divided these studies into five groups according to the year of publication or implementation. We found that the highest anti-HEV IgG positivity rates occurred during 2001–2005, possibly because there was no hepatitis E vaccine for prevention and sanitary conditions were relatively poor during this period. Moreover, we found that ethnic minorities are more susceptible to hepatitis E infection, which aligns with the findings of a large multi-ethnic cohort study . This fiRisk factors are closely related to HEV genotypes, and exposure to polluted water commonly results in GT1 infection. The dominant genotype of hepatitis E in China has changed from GT1 to GT4, which is also confirmed by data from Zhejiang Province in our meta-analysis. To a certain extent, transitions in dominant genotypes shows that the water environment pollution situation in Zhejiang Province has improved. Besides, GT4 was identified in more regions of China; since GT4 is zoonotic, it is essential to be cautious about contact with animal hosts and the consumption of animal products. For GT7, camel meat and milk consumption is a possible trigger for hepatitis E infection . NotablyThis research had several limitations. First, a comprehensive analysis could not be performed due to the number of studies on RNA detection, genotype, and influencing factors of hepatitis E. Second, there was a high heterogeneity in our analysis as a large number of studies were included, including studies from different economic, cultural, and healthcare contexts. Additionally, there was heterogeneity between commercial or in-house serological tests. Third, since most of the previous studies on hepatitis E antibodies were cross-sectional, there is a lack of prospective studies to strengthen the causal association between risk factors and hepatitis E infection. Finally, the lack of data in some provinces and cities, particularly Taiwan and Macau, limits the generalization of pooled estimates to represent hepatitis E seroprevalence.5.Our study indicated that the prevalence of hepatitis E in China was relatively high , and theThe original contributions presented in the study are included in the article/SY and ZM designed and supervised this study. KC, MY, and XW conducted literature search, data extraction and analysis, and manuscript writing. CC provided solutions to disagreements and analytical guidance. WZ, DC, YY, YD, XZ, DJ, RY, JQ, and MC revised draft and provided opinions. All authors contributed to the article and approved the submitted version.This study was supported by grants from the National Natural Science Foundation of China  and the Mega-Project of National Science and Technology for the 12 and 13th Five-Year Plan of China (grant numbers: 2018ZX10715-014-002 and 2014ZX10004008).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.


Several meta-analyses reported glycemic-lowering effects of cinnamon, while others reported conflicting findings. In the present study, we aimed to perform an umbrella meta-analysis of previous interventional meta-analyses on the effects of cinnamon on glycemic control in patients with type 2 diabetes (T2D) or with polycystic ovary syndrome (PCOS).Relevant studies were searched in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar up to June 2022. Meta-analyses of randomized clinical trials (RCTs) investigating the effects of cinnamon on glycemic indices including fasting plasma glucose (FPG), homeostatic model assessment for insulin resistance (HOMA-IR), insulin, and hemoglobin A1C (HbA1c) were included. Random-effects models were used to perform the umbrella meta-analysis and pool the weighted mean difference (WMD) or standardized mean difference (SMD) and their 95% confidence intervals (CI).Overall, 11 meta-analyses of RCTs were included. Cinnamon supplementation was effective in reducing serum FPG , insulin , HOMA-IR levels , and HbA1c .Cinnamon can be used as an anti-diabetic agent and an add-on treatment to control glycemic indices among patients with T2D or PCOS.The online version contains supplementary material available at 10.1186/s13098-023-01057-2. Type 2 diabetes mellitus (T2D), as a metabolic disorder, is a public health problem worldwide. It is predicted that the number of diabetic patients will reach 600 million by 2035 . High prCinnamomum (cinnamon), is a dietary component and a traditional herbal medicine , 13, 14.Supplementary Table 1). To increase the sensitivity of the search strategy, the wild-card term‘‘*’’ was used. Two independent reviewers (VM and MK) screened the articles based on the eligibility criteria. In the first step, the title and abstract of the articles were reviewed. Secondly, the full-texts of related articles were assessed to ascertain the suitability of the study to include in the umbrella meta-analysis. Any disagreement was resolved through the judgment of the third author (MZ).The scientific international databases including PubMed, Scopus, EMBASE, Web of Science, and Google Scholar were searched for relevant studies published up to June 2022. The search strategy was developed using the appropriate MeSH and title/abstract keywords  were included in the current umbrella meta-analysis, if such respective pooled effect sizes and their corresponding confidence intervals (CIs) were reported. In vitro, in vivo, and ex-vivo studies, case reports, observational studies, and quasi-experimental studies were excluded from this umbrella meta-analysis. Only articles in English language were included in the study.The methodological quality assessment of the eligible papers was examined by two reviewers independently , using the AMSTAR questionnaire . The AMSNo small study effect was performed for any of the outcomes as none of them included at least 10 studies .Publication year, sample size, study location, cinnamon supplementation dosage and duration, effect sizes and their respective CIs for FPG, HOMA-IR, insulin, and HbA1c were extracted from the selected meta-analyses.2 index and Cochrane’s Q test. I2 value > 40% or P < 0.1 for the Q-test was considered as a statistically significant between-study heterogeneity [Pooled weighted mean differences (WMDs) and standardized mean differences (SMDs) and their respective 95% CIs were extracted to obtain the overall effect sizes for each meta-analysis. Heterogeneity was determined by Iogeneity . To findSupplementary Table 2).Eleven meta-analyses of RCTs  published between 2008 and 2021 were included in the current study. The flow diagram for the selection of the included meta-analyses is presented in Fig. . A significant between-study heterogeneity was identified , which was reduced when subgrouping by each of gender and study population   2 = 28.3%, p-heterogeneity = 0.20) . This was especially seen in studies with sample sizes of ≥ 1000 and in patients with T2D, where the decrease was statistically significant (Table 2). Sensitivity analysis indicated no individual study’s impact on the overall effect size.Combining the data from seven meta-analyses with eight effect sizes indicated a significant effect of cinnamon supplementation on HbA1c levels , without significant between-study heterogeneity (I), and the SMD analysis    had high methological qualities. To the best of our knowledge, this is the first umbrella meta-analysis examining the effects of cinnamon supplementation on glycemic indices among patients with T2D or PCOS.The current study demonstrated that cinnamon supplementation significantly reduced serum FPG levels among T2D patients. Recent trials and animal studies releaved that chronic intake of cinnamon promoted satiety and diminished mean food consumption, which contributed to lower FPG and 2-h post-prandial blood glucose concentarions , 35. A rThe potential beneficial impact of cinnamon on FPG concentration is due to its effective role in increasing the levels of PI3-kinase and phosphorylated intracellular protein IRS-1, and therefore stimulating the activity of insulin receptors, and increasing cellular glucose uptake . This meIn the current study, four meta-analyses have shown a significant reduction of serum HOMA-IR levels by cinnamon supplementation . A recent narrative review demonstrated that insulin resistance had a central role in the pathology of PCOS and was prevalent in 70% of PCOS patients. . This puCinnamon can improve HOMA-IR levels through various mechanisms including downregulating insulin signaling in adipocytes , inhibitIt is suggested that the reduction of insulin resistance among insulin-resitant subjects should be an important goal of disease treatment. The compensatory hyperinsulinemia occurs as the initial response to insulin resistance . The resThe results of current umbrella meta-analysis have shown significant differences in HbA1c levels between cinnamon and placebo groups. Out of the seven included meta-analyses investigating the effect of cinnamon on HbA1c concentations, Namazi et al.  and KutbThis study had some limitations. First, the type of cinnamon and its prepration were different in the included studies, which might have affected the contents of active agents and their hypoglycemic activity. Second, we were not able to conduct subgroup analyses according to supplementation dosage and study duration, as such information was now provided by all of the included studies, which might have contributed to some heterogenity. Third, the potential differences in the baseline values of the different T2D biomarkers across the different meta-analyses might have diluted the effect of cinnamon on glycemic control, as participants with less favorable values would benefit the most. Notwithstanding, our study had some strengths. Conducting the different subgroup analyses helped investigate the effects of cinnamon on glycemic indices more accurately. Furthermore, segragating SMD and WMD in the umbrella meta-analysis made the results more reliable and easier to interpret.Cinnamon can be used as an anti-diabetic agent and an add-on treatment to control some glycemic indices among T2D patients and women with PCOS. Future studies with focus on the different dosage of cinnamon supplementation, the bioactive ingredients of cinnamon prepreations, and longer duration are needed to shed light on these specific aspects and their potential role as effect modifiers.Below is the link to the electronic supplementary material.Supplementary Material 1