Several studies have revealed a positive correlation between a Helicobacter pylori (HP) infection and the risk of non-alcoholic fatty liver disease (NAFLD). This meta-analysis was conducted to explore further the relationship between HP infection and NAFLD in the Asian and non-Asian populations.Relevant studies published from inception to July 22, 2021, in the following databases: PubMed, EMBASE, the Cochrane library, and Web of Science were comprehensively searched. The odds ratio (OR) and hazard ratio (HR) with a 95% confidence interval (95%CI) were pooled by the random-effects model or fixed-effects model. Additionally, subgroup and sensitivity analyses were performed. The funnel plot and the Egger test were used to estimate publication bias.P < 0.01; I2 = 94.30%, P < 0.01) and non-Asian populations . Moreover, similar results were observed in the Asian female group  but not for the Asian male group. Subgroup analyses for the Asian population showed that there were differences in the association among NAFLD diagnosis methods (P < 0.01) and the study design (P < 0.01). However, subgroup and sensitivity analyses results showed that the association for the non-Asian population was not stable enough.This meta-analysis included 25 studies involving 107,306 participants. Positive associations between HP infection and NAFLD were found both for the Asian (OR = 1.30, 95% CI: 1.13–1.49, The data obtained in this systematic review and meta-analysis suggested that an HP infection was associated with an increased risk of NAFLD for Asian and non-Asian populations. However, the association was not found for Asian males. Further studies are required to establish the causal association, especially for the non-Asian population.Identifier: CRD42021266871. Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with a prevalence rate of ~25–30%, constantly increasing –3. PatieSeveral factors are associated with NAFLD. A Helicobacter pylori (HP) infection, which is one of the most frequent gastrointestinal infections may be one of the factors. Approximately 50% of the global population suffers from HP infection , 9. In rConsidering the need of strong evidence for risk of NAFLD with HP, meta-analysis and systematic review could be helpful. Meta-analysis is commonly used for achieving high-quality evidence –16 and iTherefore, this systematic review and meta-analysis were conducted to explore further the relationship between HP infection and NAFLD in the Asian and non-Asian populations to update the evidence and fill in the gaps mentioned above. Besides, we did subgroup analysis based on the different diagnosis methods of NAFLD and HP, the degree of covariate adjustment, the study design, and gender.This systematic review and meta-analysis complied with the Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines . This stThe PubMed 1951), EMBASE (1966), the Cochrane Library (2000), and Web of Science (1900) were systematically searched to July 22, 2021 using the medical subject headings (MeSH) and related text words. 51, EMBASThis study included original publications to evaluate the association between HP infection and the risk of NAFLD. We excluded the followings studies: (1) no information of the country for included population; (2) animal experiments, case reports, case series, reviews, practice guidelines, commentaries, and editorials; (3) unavailable data; (4) non-English or non-Chinese language publications. If more than one publication on the same study population was available, only the most recent publication was included. Two reviewers  independently screened the titles and abstracts, selected relevant full texts, and assessed them for eligibility. Non-conformity was resolved by discussion.Using a predefined data collection form, two reviewers  independently extracted the following data: the first author, year of publication, country of participants, study design, publication type, sample size, participants setting, time of the study, age of participants, methods used for identification, diagnosis of the HP infection and NAFLD, adjusted in the multivariate analysis or non-adjusted effect estimates with the 95% CI. If effect estimates were not provided, the odds ratio (OR) and 95% CI were calculated. Any discrepancies between the reviewers were resolved by discussion, or by resort to a third reviewer (Xiang Yan) if consensus could not be reached.Two independent reviewers  assessed the risk of bias based on the Newcastle-Ottawa Scale (NOS)  for the I2 statistical parameter. The heterogeneity was categorized as low if I2 was 0–25%, moderate if I2 was 25–50%, and high if I2 was more than 50% , hazard ratio (HR) and 95% CI were used to explore the relationship between HP infection and NAFLD. The extent of heterogeneity was interpreted based on the total percentage of variation between the relevant studies, as measured by the than 50% . Additio studies . When th studies . If necePrevious studies found a difference in the association of the HP infection with the risk of NAFLD between the Asian and non-Asian populations. Therefore, we analyzed Asian and non-Asian populations, respectively. The Asian population was defined as the population from Asian countries, such as China, India, Iran, Japan, and South Korea. The Non-Asian population was defined as the population from a non-Asian country.Subgroup and sensitivity analyses were performed to explore the sources of heterogeneity. Subgroup analysis was conducted based on the different diagnosis methods of NAFLD and HP. The common NAFLD methods included liver biopsy, ultrasound, hepatic steatosis index (HIS), NAFLD liver fat score (NAFLD-LFS), and fatty liver index (FLI). HP methods included invasive tests, serology, breath test (UBT), and Stool antigen tests. Furthermore, subgroup analysis was also based on the degree of covariate adjustment, the study design, and gender. Because these factors may have an influence on the overall association between NAFLD and HP based on previous studies –23.Additionally, sensitivity analyses were performed to determine the influence of individual studies on the overall estimates by serially excluding each study.Funnel plots and the Egger test were used to assess potential publication bias. If the number of included studies were < 10, testing for publication bias was not performed .For this study, 612 potentially relevant studies were retrieved using the predefined search strategy, and another 28 studies were retrieved through other sources. Among these articles, 345 were duplicate publications. A total of 181 studies were excluded by screening the titles and abstracts. Of the remaining 114 potential eligible articles, 89 studies were excluded by carefully examining the abstracts or full texts. Finally, 25 studies met the inclusion criteria and were included in our meta-analysis. Two studies reported the HR , 36, andTwenty-five studies involving 117,458 participants were included . This reIn this study, quality assessments were conducted on full texts. P < 0.01; I2 = 94.30%, P < 0.01; P = 0.03; I2 = 44.90%, P = 0.09; P = 0.61). Besides, two studies reported the effect size of HR  both in Asian and non-Asian countries. Regarding The Asian population, the meta-analysis using random-effects model showed HP infection was associated with a risk of 1.30 of developing NAFLD  for Chinese . Subgroup analysis showed no significant difference among countries (P = 0.29).P = 0.05; P < 0.01; I2 = 89.30%, P < 0.01; P < 0.01; I2 = 86.90%, P < 0.01; P = 0.08; For the three main HP test methods, the positive association between HP infection and the risk of NAFLD were observed in one study that used invasive tests  but not in male group (P = 0.98). Subgroup analysis showed no significant differences between males and females  and multiple methods (P = 0.15). Subgroup analysis showed no significant differences among liver biopsy, multiple methods and ultrasound groups .Sensitivity analysis was performed by removing one study at a time, and the e enough –3. Analye enough . FurtherThis meta-analysis included 25 studies  involving 107,306 participants from 11 countries. The data studies showed a positive association between HP and the risk of development of NAFLD both for Asian and non-Asian populations. Similar results were observed in most subgroups of the Asian populations, except for the male group. However, the association for the non-Asian population was not stable enough.In several studies, the underlying mechanism involved in HP infection and the risk of NAFLD development were explained. HP infection is known to cause chronic low-grade systemic inflammation by increasing the levels of proinflammatory cytokines . AdditioA prospective multicenter pilot cohort study  showed tSubgroup analysis based on different country populations showed positive associations between HP infection and the risk of NAFLD in China, India, and Greece. Considering the small size effect, we thought that the positive association in China was more robust. This observation was consistent with the data presented in previous studies , 29. TheFive studies –23 assesA specific subgroup analysis was performed based on the country of the population, the different diagnosis methods used for NAFLD and HP, the degree of covariate adjustment, and the study design. These methods supported our conclusions. Our study had several limitations. First, the included studies had a small sample size of fewer than 500 participants, which might affect the quality of evidence. Second, the bias of the included retrospective studies might affect the quality of evidence. Additionally, the Asian and Non-Asian populations were defined as a population from the Asian or Non-Asian countries, respectively. The designation may not be reliable enough, but there is no more precise approach due to lack of data. Finally, subgroup analyses were performed based on potential confounding variables, but subgroup analyses by several important pathogenesis factors, HP test ranges, and metabolic risk factors  could not be conducted because of lacking information. Further prospective studies are required to perform an in-depth analysis of the heterogeneity.This systematic review and meta-analysis suggested that HP infection was associated with an increased risk of NAFLD in Asian and non-Asian populations. However, the association was not found for Asian males; the association for the non-Asian population was not stable enough. Further studies are required to establish a causal association between HP infection and NAFLD. Thus, eradicating HP infection might be a new approach to the clinical prevention and treatment of NAFLD.wwjou@126.com.The data analyzed in this study is subject to the following licenses/restrictions: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to ZM and XC conceptualized and designed the protocol, drafted the initial manuscript, and reviewed the manuscript. XY and ZM defined the concepts and search items and data extraction process as well as methodological appraisal of the studies. XC, XY, and WW planned the data extraction and statistical analysis. XY and WW provided critical insights. All authors have approved and contributed to the final written manuscript.


To examine the patient‐related factors that have been linked to glycaemic control in people living with type 2 diabetes mellitus in Middle Eastern countries.A systematic review and meta‐analysis.A computerized search was conducted using the databases MEDLINE (via PubMed and Ovid), EMBASE, Scopus and CINAHL to identify peer‐reviewed articles published in English between 1 January 2010 and 21 May 2020. On 28 June 2021, the search was updated with the same keywords and databases; however, no further relevant studies were identified.Extracted data were analysed using Review Manager 5.4.p = .010], obese patients , patients with elevated waist to hip ratio  and longer disease duration . A lower risk of inadequate control was associated with physical activity  and self‐management .The final sample consisted of 54 articles with a total of 41,079 participants. Pooled data showed an increased risk of inadequate glycaemic control in smokers [OR = 1.26, 95% confidence interval (CI): 1.05, 1.52; These findings highlight the opportunity to address factors to improve glycaemic control. Further longitudinal studies are required to better understand these variations, to assess all predictors of glycaemic control in participants with type 2 diabetes, and to provide a strong basis for future measures to optimize glycaemic control. Rising rates of diabetes, particularly in Middle Eastern regions, make it imperative to identify factors linked to glycaemic control among patients with Type 2 Diabetes in these areas.Smoking, obesity, disease duration, physical activity and self‐management were the main factors linked to glycaemic controlResults will be relevant for policymakers, physicians, medical staff and patients with diabetes in the MENA region, informing them of key factors that should be considered concerning the management of diabetes.1Diabetes is a major public health issue with an increasing burden globally .This systematic review and meta‐analysis followed the Preferred Reporting Items of Systematic Reviews and Meta‐analysis , E  and O (outcome). The search strategy was structured as follows:P: Participants with T2DM living in Middle Eastern countries   vs. younger aged (<50 years), obese  was reported in 63% of the participants. Table 3.3The quality of included studies, assessed using the NOS tool, ranged from good to very good for cross‐sectional studies, and was deemed very good for all included cohort studies participants Table .3.43.4.1p = .49). Overall pooled data were heterogenous . A subgroup analysis showed no significant association between risk of inadequate glycaemic control and older age in Saudi Arabia  and Jordan . In studies conducted in Palestine, older participants were associated with a lower risk of inadequate glycaemic control . Pooled data in the subgroup analysis were homogenous , Figure p = .02), and the pooled data were homogenous , see Overall effect estimates of 17 studies showed no significant association between risk of inadequate glycaemic control and older age (>50 years) . Overall pooled data were heterogenous . Subgroup analysis showed no significant association between risk of inadequate glycaemic control in female compared with male participants in Saudi Arabia , Jordan , Kuwait , and Iran . For Palestine and other countries, female gender was associated with higher risk of inadequate glycaemic control , respectively. Pooled data from Palestine were homogenous . The heterogeneity in the other subgroup was resolved by excluding the data from Noureddine et al. , with an effect estimate of , see Figure Overall random‐effect estimates of 22 studies showed no significant association between risk of inadequate glycaemic control for female compared with male participants . Pooled data were homogenous , see Figure Pooled data of two studies demonstrated a significant elevation of the risk of inadequate glycaemic control in patients with elevated waist to hip ratio (WHR)  . Overall pooled data were heterogenous . Subgroup analyses showed a significant elevation in the risk of inadequate glycaemic control in obese participants in Saudi Arabia , Jordan  and Kuwait , see Figure 2, 95% CI: −1.85, −0.47; p = .001), and the pooled data were heterogenous . The heterogeneity was managed by excluding the data from Channanath et al. , see 2) than participants with BMI >30 . Pooled data were homogenous , see Overall random effect estimates of 16 studies showed a significantly increased risk of inadequate glycaemic control in obese patients . Overall pooled data were homogenous , see Figure Overall random‐effect estimates of 10 studies showed that the risk of inadequate glycaemic control was significantly elevated in smokers . Overall pooled data were heterogeneous , see Figure p < .0001). Subgroup pooled data were homogenous . Moreover, participants with adequate glycaemic control tended to report shorter duration of diabetes , see Overall, random‐effect estimates of 13 studies showed an increased risk of inadequate glycaemic control in patients with longer duration of diabetes . Overall pooled data were heterogenous , see Figure I2 = 31%, p = .23), with the overall effect estimate still significant .Pooled analysis of seven studies showed a significant association between lower risk of inadequate glycaemic control and self‐management . Overall pooled data were heterogenous , see Figure I2 = 49%, p = .10), with the overall effect estimate still significant .Overall random‐effect estimates of eight studies showed a significant association between the lower risk of inadequate glycaemic control and physical activity . Overall pooled analysis was heterogenous . Subgroup analysis showed no significant association in Saudi Arabia  and other countries , see The pooled analysis of four studies showed no significant association between diabetes knowledge and glycaemic control . Overall pooled data were homogenous . Subgroup analysis showed no significant association in Saudi Arabia  and Iran , see Pooled analysis of three studies demonstrated no significant difference between depressed and non‐depressed participants in terms of glycaemic control . Overall pooled data were homogenous . Subgroup analysis showed no significant association in Saudi Arabia  and Iran , see Data from three studies indicated no significant association between anxiety and glycaemic control . Overall pooled data were homogenous . Subgroup analysis showed no significant association in Saudi Arabia  and other countries , see The overall fixed‐effect showed no significant association between employment and glycaemic status . Overall pooled data showed minor heterogeneity . Subgroup analysis showed no significant association in Saudi Arabia , Iran , Jordan , and Palestine , see The overall random‐effect estimate demonstrated no significant association between marital status and glycaemic control . A cross‐sectional analysis of 1438 participants by Berkowitz et al. (p < .001). Similarly, a nationwide cross‐sectional study of 697 American patients with T2DM showed that adequate glycaemic control was prevalent among older patients. Moreover, these authors suggested that young patients undergo HbA1c assessments at least annually . Such results are congruent with the findings from  and the risk of developing T2DM . Similarly, Aune et al. (Regarding physical activity, this review found that increased physical effort led to a significant reduction in the risk of inadequate glycaemic control (e et al.  presentee et al. . The cone et al. . Alternae et al.  pointed e et al. . This pre et al. . On sense et al. . The fire et al.  ascribede et al. .Another factor frequently included in lifestyle‐modification interventions is self‐management (Ali et al., Lastly, a highly significant link was demonstrated between longer disease duration and inadequate glycaemic control. By contrast, a UK‐based cross‐sectional study found an inverse relation between the two variables. This finding may be attributed to the different healthcare systems of developing and developed countries. Abubakari et al.  hypothes4.1There are several limitations to this meta‐analysis. First, most included studies used self‐report to collect outcome data, potentially leading to recall bias, which might either exaggerate or underestimate the true effect size. Second, in terms of the anthropometric markers, only two measures were observed, WHR and BMI. These measurements have been reported as less informative measures of obesity than other measurements such as waist circumference and the waist‐to‐height ratio (Rajput et al., The strengths of this review include the relatively large number of included studies, adding to the strength of association between the predictors of glycaemic control.In conclusion, the current evidence suggests an increased risk of inadequate glycaemic control in patients with elevated WHR, longer disease duration, obesity and smokers, with lower risk of inadequate control associated with physical activity and self‐management. Further longitudinal studies are required to better understand these variations and to assess all predictors of glycaemic control in participants with T2DM, and to further provide a strong basis for future recommendations to optimize glycaemic control.5Review findings illustrated some variability in variables which exert significant impact across the countries of the Middle East and North Africa. Irrespective of whether they are middle‐income or high‐income, countries should use national and regional data to inform the development of strategies sensitive to local and global influences. Broadly, however, policymakers and clinicians should pay attention to spreading awareness campaigns to educate people living with diabetes regarding the seriousness and implications of obesity and smoking for glycaemic status. Regular exercise is essential, especially in people with living with diabetes for long periods, who should be encouraged to follow a balanced physical program to improve their glycaemic status. Diabetes education and self‐care management should be integral to the management of all people living with diabetes regardless of their medication and management pathways.None.6https://publons.com/publon/10.1111/jan.15255.The peer review history for this article is available at Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.


New onset diabetes patients are a high-risk group for pancreatic cancer. Since pancreatic cancer is responsible for less than 1% of new-onset diabetes cases, testing all of them might lead to an unfavorable risk/benefit balance. Additional risk factors can contribute to a better definition of the population that needs further screening. Currently, 22 studies examining additional risk factors have been published, but often they have a limited number of participants for the individual risk factor. By pooling their results in a meta-analysis, we could establish the magnitude of several risk factors. We found that pancreatic cancer cases were older than controls by 6.14 years . Among new-onset diabetes patients, the highest risk of pancreatic cancer involved a family history of pancreatic cancer , pancreatitis , gallstones , weight loss , and high/rapidly increasing glycemia  leading to more insulin use . Risk factors or symptoms were distinct in the new-onset diabetes patient group. They are strongly connected to pancreatic cancer and are ideal for targeted screening, using a score or model as the first step.(1) Background: Patients with new-onset diabetes (NOD) are at risk of pancreatic ductal adenocarcinoma (PDAC), but the most relevant additional risk factors and clinical characteristics are not well established. (2) Objectives: To compare the risk for PDAC in NOD patients to persons without diabetes. Identify risk factors of PDAC among NOD patients. (3) Methods: Medline, Embase, and Google Scholar were last searched in June 2022 for observational studies on NOD patients and assessing risk factors for developing PDAC. Data were extracted, and Meta-Analysis was performed. Pooled effect sizes with 95% confidence intervals (CI) were estimated with DerSimonian & Laird random effects models. (4) Findings: Twenty-two studies were included, and 576,210 patients with NOD contributed to the analysis, of which 3560 had PDAC. PDAC cases were older than controls by 6.14 years . The highest risk of PDAC involved a family history of PDAC , pancreatitis , cholecystitis , weight loss , and high/rapidly increasing glycemia  leading to more insulin use . Smoking  and alcohol  have a smaller effect. (5) Conclusion: Important risk factors for PDAC among NOD patients are age, family history, and gallstones/pancreatitis. Symptoms are weight loss and rapid increase in glycemia. The identified risk factors could be used to develop a diagnostic model to screen NOD patients. The incidence of pancreatic ductal adenocarcinoma (PDAC) doubled over the last 2 decades . The cumIt has been established that all cancers discovered in the first years after diabetes diagnosis were already present and caused the diabetes, and several underlying mechanisms are under research ,10,11,12As pancreatic cancer is responsible for less than 1% of NOD cases, using a biomarker test for every patient with NOD might lead to an unfavorable risk/benefit balance if the performance of the test is not exceptional  Figure .To further stratify the group that would need biomarker and then imaging testing, the use of a simple model or score is interesting. This strategy of 3 sieves would be more cost-effective and cause less harm than a strategy leaning on biomarkers and imaging alone.Currently, 22 studies examining additional risk factors have been published, but often they have a limited number of participants for the individual risk factor. Pooling their results in a meta-analysis should increase the precision.Based on a systematic review with meta-analysis, this paper aims to assess PDAC risk in NOD individuals and to identify risk factors among NOD patients, which are needed for a stepwise diagnostic strategy.We performed a systematic literature search and last updated it in June 2022 in the three major databases, PubMed (RRID:SCR_004846), Embase (RRID:SCR_001650), and Google Scholar (RRID:SCR_008878), using the terms described in We included observational studies (both cohorts and case-control studies) reporting on NOD patients and assessing additional factors regarding the risk of developing PDAC. Our objectives were to identify these risk factors that further enrich the NOD population in PDAC occurrence. Also, we aimed to analyze the risk of PDAC in NOD patients compared to non-diabetic persons.We excluded studies with the sole focus on biomarkers or medication. We did not include case reports, small case series, reviews, opinions, or articles without an English abstract. When we found interesting conference abstracts, we searched with the author's names for follow-up publications, and, if relevant, included those. As the data was presented in a very heterogenous way, we sometimes contacted the authors for additional data to be included in their study. However, not all authors answered , following the updated PRISMA 2020 guideline .Studies reporting associations were used in the meta-analysis. Using the method of DerSimonian & Laird (an estimate of heterogeneity after the Mantel-Haentzel model), we performed a random-effects meta-analysis of risk factors that were reported in at least 3 papers either with a Risk Ratio or an Odds Ratio or with raw numbers that allowed us to calculate the Odds Ratio. All Confidence Intervals (CI) are 95%. All analyses were performed with STATA, version 16.1 .First, the authors (C.M. & V.D.B.) performed a quality assessment using 10 criteria as defined in the paper by Hoy et al. in a specific bias assessment tool for prevalence studies . We judgWe extracted data on the definition of NOD/subgroups of duration, age, sex, ethnicity, lifelong smoking, alcohol abuse, family history of PDAC, gall stones/cholecystitis, pancreatitis, a rapid increase of glycemia, weight loss, insulin use, obesity, and hyperlipidemia. When more than 2 groups were reported, we combined groups, for example, former smokers + current smokers = lifelong smokers. Or introduced the most meaningful cut-off; for example, for groups of BMI (Body Mass Index) reported, we distinguished BMI < 30 = not obese, BMI ≥ 30 obese  and the OR for PDAC for NOD versus no diabetes in the case-control studies.The search yielded 779 references, which we imported into Covidence. After removing duplicates and excluding irrelevant studies, we selected 15 studies for data extraction. Reference lists and citation searches  provided an additional 6 studies to be included in the analysis. There was one paper from other sources. Twenty-two studies were included. In total, 576,210 patients with NOD contributed to the analysis, of which 3560 had PDAC .n = 13), case-control studies (n = 8), and one small prospectively recruited screening study, with recruitment at a diabetes clinic [The study designs were heterogeneous, including retrospective cohorts  , which seemed to be even more pronounced in European studies. Sex was not a statistically significant risk factor: the overall effect size  in overall studies was 1.07 for the male gender . Race was analyzed in only a few studies, which showed that whites had a slightly higher risk for PDAC   .2 = 44.0%, 9 studies); the same was true for alcohol . Pancreatitis  and gall stones/cholecystitis  showed an increased risk. Positive family history of pancreatic cancer was a very strong risk factor, with an effect size of 3.78 . Obesity (defined as BMI ≥ 30) was not associated with more pancreatic cancer cases within the studied populations of NOD .Concerning other risk factors, smoking was a just barely statistically significant risk factor . A rapid increase in glycemia was significant in 7 studies [2 = 6.7%, 4 studies). The rapid increase in glycemia could lead to more insulin use  in pancreatic cancer patients. A few studies showed a negative association with high blood lipids [Weight loss was a significant symptom, with an effect size of 4 , with a clear tendency of the ES to be higher when the interval since NOD diagnosis was shorter: in the first year after diabetes diagnosis, it was 5.52 .All studies identified a strong association between NOD and PDAC. The overall effect size was 3.35   .Despite our systematic approach, we could have overlooked critical studies through our choice of search terms. We minimized this by using several formulations and searching references regarding the included papers. The most significant limitations of our findings are biases in the included studies and the disparity of representation of geographical regions. Many studies are from the USA, Europe, and Asia, and one is from Australia, but we could not identify any South American or African studies.In extracting the data, we were limited by the heterogeneity of the included studies. To have enough data to analyze, we included studies with slightly different definitions. Definitions of how we extracted the data are in A strength of our review is that it gives a complete, systematic overview of the current body of evidence regarding additional risk factors for PDAC in NOD populations. Our paper is, to our knowledge, also the first to conduct a meta-analysis on the risk factors.The association between diabetes and PDAC has long been recognized. Several papers have shown that the risk is highest directly after diagnosis and then decreases over subsequent years . The assIt is essential to look specifically at the group of NOD patients, as they differ from the general population. For instance, NOD patients tend to be more obese than the general population, as obesity is a very important risk factor for diabetes mellitus. Within the population of NOD patients, obesity is not associated with more PDAC cases, as our analysis shows. In fact, the mean BMI of pancreatic cancer cases was lower than that of NOD controls. This might be even more pronounced through tumor-induced recent weight loss. It was surprising to find at most a weak association of smoking and alcohol abuse in this meta-analysis. Possibly these risk factors are more important for non-diabetic PDAC patients, or their importance has generally been overestimated.Risk factors or symptoms that are distinct in the NOD patient group and are strongly connected to pancreatic cancer are ideal for targeted testing. They can be used for statistical model fitting. Our analysis showed that age, family history of PDAC, pancreatitis/cholecystitis, weight loss, and rapid increase in glycemia/necessity of insulin are robust candidates. A tendency to lower lipids, unusual in newly diagnosed diabetes patients, is also interesting. Unfortunately, some of the strongest risk factors are rather rare, which negatively impacts the sensitivity of such models. The correct balance between the frequency and magnitude of those risk factors remains to be found.Screening programs aim to diagnose cancer in the asymptomatic, early stages amenable to curative treatment. Scrutiny regarding balancing benefits and burdens, cost, survival extension, and quality-life years gain is essential. As pancreatic cancer has a low incidence in the total population, this is a challenge. The main risk of pancreatic cancer screening is a too-high rate of false-positive results, leading to unnecessary further investigations. Including the identified additional risk factors or symptoms can help define the target population.A stepwise approach of first identifying a group with increased risk of pancreatic cancer within the NOD population through a scoring or diagnostic model and then further reducing the number of patients needing imaging by a biomarker test has been proposed by Pannala et al. . Several


Engaging in leisure activities was suggested to protect older adults from dementia. However, the association between playing a musical instrument and the risk of dementia is not well-established. This study aimed to investigate this association in older adults using a systematic review and meta-analysis of prospective cohort studies.I2 statistic to detect heterogeneity across studies and the test for funnel plot asymmetry to assess publication bias. The risk of bias assessment was conducted using the modified Newcastle–Ottawa Scale.Pooled hazard ratio (HR) and 95% confidence interval (CI) of having dementia for older adults playing a musical instrument were calculated using the random-effects model. We performed the I2 = 23.3% and p-heterogeneity = 0.27) or publication bias (z= -1.3 and p-publication bias = 0.18) were identified.A total of three prospective cohort studies were found eligible: two from the U.S. and one from Japan. Playing a musical instrument, in the meta-analysis, was significantly associated with a decreased risk of dementia  among older adults. No signs of significant heterogeneity across studies (Playing a musical instrument was associated with a decreased risk of dementia among older adults. Older adults should be encouraged to engage in leisure activities, especially playing musical instruments.The online version contains supplementary material available at 10.1186/s12883-022-02902-z. The incidence and prevalence of dementia have been increasing worldwide, especially in the aging societies in North America, Europe, and South-East Asia . It is eHowever, dementia is not inevitable, and some lifestyle risk factors such as avoiding smoking, refraining from excessive alcohol drinking, and practicing physical activity could reduce its risk , 5. AmonPlaying a musical instrument is a common leisure activity that carries several favorable cognitive effects and improves mental health , 20. HowFirst, we searched PubMed, Scopus, and Google Scholar for potential studies published in English before the 28th of February 2022 using the following terms:  AND (dementia). A complete search strategy of PubMed was provided (Supplementary file 1). We also manually searched the reference lists of retrieved articles to obtain additional studies. We did not apply limitations regarding the year of publication, but no efforts were made to access unpublished data. We obtained 2,392 studies from PubMed, 2,614 from Scopus, and 28,100 from Google Scholar and the manual search of reference sections. After removing duplicates, we screened the titles and abstracts of 28,322 studies before removing non-English, irrelevant, and review articles, leaving 36 articles for full-text assessment  with 95% confidence intervals (CIs) of dementia for playing a musical instrument in the most adjusted regression models before calculating the pooled HR (95% CI) of the three studies using the random-effects model . We also studies  and the  studies . The ris studies . The fir studies .A shortlist of five studies was obtained –13. We fI2 = 23.3% and p-heterogeneity = 0.272)  = 0.64 , and the heterogeneity across studies was minimal .The two cross-sectional studies that were eliminated from the main meta-analysis investigated older adults ≥ 65 years from the Swedish HARMONY Co-twin Study (27 pairs where at least one twin was a musician) and the Japanese National Center for Geriatrics and Gerontology Study for Geriatric Syndromes Study  , 13 (SupThis study provided epidemiological evidence from prospective cohort studies indicating an inverse association between playing a musical instrument and the risk of dementia among older adults. No signs of significant heterogeneity across studies or publication bias were detected, and the results did not change after including cross-sectional studies. Our findings came in line with a previous meta-analysis that suggested a protective effect of playing a musical instrument against dementia . Yet, thThe biological explanation of the inverse association between playing a musical instrument and the risk of dementia is not well-understood. However, it could be attributed to the role of music in enriching cognitive reserve, enhancing executive functioning and working memory, stimulating brain plasticity to restore sensorimotor brain networks, reducing stress and depression, and developing social cohesion –40. CognEngaging in other musical activities, such as karaoke, a type of interactive singing with music accompaniment and synchronized lyrics displayed on a video screen, was associated with a reduced risk of dementia in the JAGES . InteresOur study included some limitations that should be considered. First, the outcome in the included studies was all-cause dementia. Risk factors for dementia could differ by dementia type . Second,In this meta-analysis, playing a musical instrument was associated with a reduced risk of dementia. Our findings support the evidence suggesting that engaging in cognitive leisure activities can reduce the risk of dementia. From a preventive perspective, older adults should be encouraged to engage in musical activities and other cognitive leisure activities. Given that leisure activities, including playing musical instruments, are modifiable lifestyle factors, the findings of our study highlight the importance of targeting leisure activities in risk prevention interventions and health education. Still, more prospective studies that consider the duration of playing music and the type of musical instruments are needed. Further studies to elaborate on the biological explanations of this association are warranted as well.Below is the link to the electronic supplementary material.Additional File 1.


P = .731). In addition, another adjusted OR data showed a significant increased risk between the rs735482 and susceptibility of several cancers  and the stratification analysis by ethnicity indicated the rs735482 is associated with an increased risk of cancer in Chinese group . However, the ERCC1 rs735482 is associated with a decreased risk of cancer in Italian group . The results of this meta-analysis do not support the association between rs735482 polymorphism and cancer risk. But stratified analysis showed that rs735482 significantly increased the risk of cancer in Chinese while decreased the risk of cancer in Italian. Because of the limited number of samples, larger and well-designed researches are needed to estimate this association in detail.Several studies have inspected the relationship between rs735482 polymorphism and the risk of some human cancers, but the findings remain controversial. We designed this meta-analysis to validate the association between rs735482 polymorphism and cancer risk. All articles were published before September 1, 2018 and searched in Pubmed, Embase, Web of Science, China National Knowledge Infrastructure, WangFang, and Chinese BioMedical databases, STATA 12.0 software was used for statistical analysis, which provides reasonable data and technical support for this article. A total of 10 studies were included in the meta-analysis, including 2652 cancer cases and 3536 rs735482 polymorphic controls. Data were directly extracted from these studies and odds ratios with 95% confidence intervals were computed to estimate the strength of the association. By pooling all eligible studies, the rs735482 polymorphism showed no significant association with susceptibility of several cancers in all the five genetic models (the allelic model: OR = 1.019, 95% CI: 0.916–1.134,  The complex interactions of multitudinous gene loci and various environmental factors play an important role in the development of cancer.Cancer is one of the major causes of morbidity and mortality and poses a major threat to public health worldwide. The occurrence of different cancer varies widely among different racial and ethnic groups which may be partly due to the lifestyle and genetic background. In humans, the CD3EAP has the same part of the coding sequence as ERCC1. This indicated that these genes are linked to some important biological functions. Large population studies have shown that CD3EAP rs735482 polymorphism has a potential impact on the risk of lung cancer and Italics represent significant association with susceptibility of lung cancer.,6 CD3EAP rs735482 on Chr19q13.3 were strongly associated with lung cancer risk both in Asian Chinese and in Caucasian Danes.rs735482 maps in the 3-UTR of excision repair cross complementation group 1 (ERCC1) gene and it also maps in the coding sequence of CD3EAP, a gene that overlaps with ERCC1 but is transcribed in the opposite direction. But their functions are different. The CD3EAP is located between ERCC2 and ERCC1 in the chromosomal region 19q13.3. The CD3EAP products can mediate the activation signal generated by interleukin-2 in T cells.–10 is an important factor involved in the DNA damage incision, and its products play an important role in nucleotide excision repair (NER). ERCC1 protein, as a highly conserved enzyme, is the main component in the NER process and an essential part of the NER cutting procedure. ERCC1 acts as an endonuclease that incises 5-′ damaged DNA strand, allowing the removal of the damaged strand, polymerization, and relegation.The CD3EAP rs735482 polymorphism results in changes in amino acid 259 (AAA to ACA: K [lysine] to T [threonine]). The missense mutation might affect CD3EAP protein function. ERCC1 located on chromosome 19q13.3–13 Two independent genes, ERCC1 and ERCC2, encode the same mature ERCC1 sequence. Currently, many studies detected the association between ERCC1 rs735482 polymorphism and risk of various cancers, including breast cancer, cervical cancer, esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, neuroblastoma, non-small cell lung cancer and other cancers, but the results are still controversial.–23 Therefore, we conducted a meta-analysis to find out the effect of rs735482 polymorphism on cancer risk.Epidemiological studies have shown that genetic mutations in ERCC2 and ERCC1 may be associated with various cancer risks.Comprehensive literature searches were conducted for all articles published up to September 30, 2019 in Pubmed, Embase, Web of Science, China National Knowledge Infrastructure, WangFang Date, and Chinese BioMedical databases. These articles described an association between rs735482 polymorphism and cancer risk. The search keywords were “cancer, polymorphism, rs735482.” The process of identifying qualified studies is shown in Figure (1) the original studies;(2) studies on the association between rs735482 polymorphism (s) and cancer risk;(3) studies that reported odds ratio (OR) with 95% confidence interval (CI) values or sufficient data to calculate OR and 95% CI.The exclusion criteria were:(1) case-only studies, family-based studies, conference summaries, and review article;(2) overlapping data;(3) insufficient genotype information provided. Because this study is a meta-analysis, ethical approval is not necessary.Two authors searched the literature independently, extracted relevant data, and any disagreement was decided by the third author through discussion. The following data were extracted for each study, including the first author’s name, year of publication, country, ethnicity of participants, number of genotypes in the case–control groups, results of the Hardy–Weinberg equilibrium (HWE) test Table . AnotherP < .05, the genotypes of the control group were inconsistent with HWE. The relationship between rs735482 polymorphism and cancer risk was estimated by ORs and 95% CIs. Pooled ORs and 95% CIs for codominant (AC vs AA and CC vs AA), dominant (AC + CC vs AA), recessive (CC vs AC + AA), and the allelic (C vs A) genetic models were estimated. As for adjusted OR data, pooled ORs and 95% CIs for codominant (AB vs AA and BB vs AA), dominant (AB + BB vs AA), recessive (BB vs AB + AA) genetic models were estimated. Z test was used to evaluate the significance of the pooled OR, and P < .05 was considered statistically significant. The results of the heterogeneity test were used to determine whether the fixed effect model or the random effect model. The heterogeneity test was measured by Q test and I2 statistics. If the test result is I2 ≥ 50% or P < .1, indicating the presence of heterogeneity, the random effect model is selected. Otherwise, the fixed-effects model is adopted. Begg’s funnel plots were conducted under all genetic models to assess the publication bias, and the asymmetric plots implied potential publication bias. The degree of asymmetry was measured using Egger’s test and P < .1 was considered a significant publication bias. The robustness was tested by leave-one-out sensitivity analyses.Meta-analysis was performed using STATA 12.0 software. HWE for each study was determined by the chi-square test to verify the representativeness of the study population. If Our meta-analysis included 10 case–control studies that met the inclusion criteria, including 2652 cancer cases and 3536 controls. Tables According to the results of the meta-analysis of 10 eligible studies, it was found that there was no correlation between rs735482 polymorphism and cancer risk of the general population in the codominant, dominant, recessive and allele model test . However, rs735482 was associated with a decreased risk of cancers in Italian group  , and the stratification analysis by ethnicity indicated the rs735482 was associated with an increased risk of cancers in Chinese group  and a decreased risk of cancers in Italian group .A variety of studies have been conducted to determine whether rs735482 polymorphism affects the susceptibility of several types of cancer, and these findings have been controversial. In this meta-analysis, a total of 10 eligible case–control studies were included and their combined results were used to assess the relationship between rs735482 polymorphism and cancer susceptibility. Our meta-analysis showed that the rs735482 polymorphism had no significant effect on cancer risk. While the adjusted OR data showed a significantly increased risk between the rs735482 and susceptibility of several cancers (the codominant model BB vs AA, OR = 1.353, 95% CI: 1.033–1.774, –26In the stratified analysis of the adjusted OR data by ethnicity, we found that individuals carrying the variant C allele could increase the cancer susceptibility in Asians, but reduce cancer susceptibility of Italians, suggesting that racial differences might play an important role in genetic background variation.CD3EAP is a complementary nucleoprotein to ERCC1 and can participate in cell proliferation as part of the RNA polymerase I transcription complex.,27–29 However, the most important studies that ERCC1 polymorphisms may be involved in are the functional studies relating to ERCC1 gene variant, repairability, and gene expression levels. All these results strongly support a possible role of ERCC1 in cancer risk. The ERCC1 rs735482 is located in the chromosomal region19q13.3, and haplotypes of chromosome 19q13.2–3 have been associated with cancer risk in previous studies. ERCC1 rs735482 is involved in the identification and removing platinum-induced intra-strand adducts in DNA, and is resistant to platinum-based chemotherapy in many cancers, including non-small cell lung cancer, ovarian cancer, bone tumor, and colorectal cancer.,28–31Many studies have been published on the possible association between ERCC1 polymorphisms and cancers.There are several limitations in our meta-analysis. Firstly, there is heterogeneity between some studies. Heterogeneity can be attributed to differences in ethnicity, source of control, status, and type of cancer. Secondly, the language of the study is limited to English. Thirdly, although the combination of genetic factors and environmental exposure was taken into account in the adjusted OR, the number of studies and the sample size were small. Fourthly, different genotyping methods may lead to bias in the analysis. Finally, our meta-analysis was limited to Asian, Caucasian, Italian population and lack of other ethnicities.To sum up, our meta-analysis showed that rs735482 polymorphism was not a risk factor for cancer, but the pooled adjusted OR showed that there was an association between the rs735482 polymorphism and susceptibility of several cancers, and the stratification analysis by ethnicity indicated the rs735482 was associated with an increased risk of cancer in Chinese while a decreased risk of cancer in Italian. To clarify the possible role of this mutation in cancer, further well-designed studies with a wide ethnic background, detailed biological characteristics, and larger samples number are required. Qianye Zhang, and Jiaoyang Yin,,34 for they have provided the frequencies of rs735482 C/A polymorphism between the cases and controls in detail.We greatly acknowledge Tao Yu,Shilin Xue, Wenya Shen, and Jianning Cai wrote the main manuscript text and prepared all figures and tables. All authors reviewed the manuscript.Data curation: Bingshuang Wang, Dan Zhao.Funding acquisition: Xiaolin Zhang.Methodology: Shan Zhang.Software: Jinhai Jia.Supervision: Xiujun Zhao.Validation: Ning Ma, Wenjuan Wang.Writing – original draft: Wenya Shen, Xuehui Liu.Writing – review & editing: Fengxue Yu, Jianning Cai, Shilin Xue.


Background: Since the association of homocysteine and clinical results of observational studies are controversial on non-alcoholic fatty liver related disease, we compute the two-sample Mendelian Randomization (MR) study.Objective: To evaluate whether the plasma level of homocysteine has an effect on the risk of Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and Cirrhosis after its progress, we investigated the causal relationships between plasma homocysteine and the three non-alcoholic fatty liver related diseases mentioned above.Design and methods: Summary estimates were elicited from the inverse-variance weighted (IVW) method through 12 single nucleotide polymorphisms (SNPs) which related to the plasma homocysteine, the SNPs were obtained from a large genome-wide association studies (GWAS) of 44,147 European participants. And the summary statistics for the latest and largest GWAS datasets for NAFLD , NASH  and Cirrhosis  were collected from Ristey FinnGen website where the association of genetic variations with blood metabolite levels was conducted using comprehensive metabolite profiling. The study was performed through two-sample MR method.Results: The result indicated that the plasma homocysteine is not significantly associated with NAFLD, and its progression, NASH and Cirrhosis.Conclusion: The evidence in this study is quite deficient to support the causal association of the individual plasma homocysteine with NAFLD, NASH and Cirrhosis, the putative of associations is not exist. Non-alcoholic fatty liver disease (NAFLD) was firstly used by Ludwig in the 1980s to describe patients diagnosed with fatty degeneration of the liver, which histologically mimics alcoholic hepatitis but without over alcoholic drinking . NAFLD iHomocysteine (Hcy) is a sulfur-containing amino acid. It can be synthesized from methionine by removing the terminal methyl group, and also be recycled into methionine or converted into cysteine with the aid of certain B-vitamins . ElevateMR is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in observational studies , which mp < 5 × 10–8) from the hitherto largest GWAS meta-analysis, with up to 44,147 individuals of European ancestry  from the largest genome-wide association studies (GWAS). The meta-analysis included 10 cohorts collected from different studies. Plasma homocysteine levels were measured in each cohort by different chromatography and spectrometry techniques such as isotope-dilution liquid chromatography–tandem mass spectrometry, gas chromatography–coupled mass spectrometry, high-performance liquid chromatography (HPLC), or enzymatic, immune, or chemiluminescence , which was a suite of web-based applications designed to examine LD in population groups, and we use LD < 0.05 as a threshold to ensure the SNPs we selected were independent. Three of the 18 SNPs were excluded   , and pot2921383)  to exclu2921383) .https://r7.risteys.finngen.fi/phenocode/NAFLD), statistics for NASH including 99 cases and 309055 controls (https://r7.risteys.finngen.fi/phenocode/NASH), and statistics for Cirrhosis including 826 cases and 306145 controls (https://r7.risteys.finngen.fi/phenocode/CHIRHEP_NAS). The analyses for this study were all based on publicly available summary statistics. The participants have provided written consent, and all the studies contributing data to our MR analysis were approved by the relevant ethical review boards.The outcomes include NAFLD, NASH and Cirrhosis. Summary data for NAFLD was extracted from the largest GWAS meta-analysis including 1,578 cases and 307576 controls of European ancestry , NASH , and Cirrhosis . There was no relationship between homocysteine levels and overall NAFLD, NASH and Cirrhosis. The effect of every SNP was demonstrated in the Specifically, the outcomes of homocysteine level in plasma showed no evidence to support causal association  on NAFLDIn order to confirm the robustness of the causal association between homocysteine and NAFLD, NASH and also Cirrhosis, the sensitivity analysis was processed through WM, MR-Egger and MR-Presso analysis . The resNAFLD is one of the most common chronic liver diseases worldwide , especiaVarious factors are involved in the development and progress of NAFLD. As the largest solid organ, liver is constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota , and it Hepatic cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) system (CBS/CSE system) is an emerging therapeutic target in NAFLD for it is the system which regulates homocysteine and cysteine metabolism and it is a key role in endogenous hydrogen sulfide (H2S) biosynthesis , which mFor reasons not limited to those we have demonstrated above, important genetic and epigenetic modifiers of NAFLD progression provide the potential to design novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers . To undeOur study still has some limitations. On one hand, patients and controls for the analysis are all from Europe whose genetic characteristic may differ from other populations, which make the generalizability discount to our study, and most ongoing prospective studies are probably too limited to find disease markers , therefoIn summary, the results of our Mendelian Randomization study do not suggest a causal role of plasma homocysteine levels in NAFLD and its progression, NASH and Cirrhosis as well.


ADAM12 polymorphisms and genetic susceptibility to osteoarthritis, but the results remain inconclusive.Osteoarthritis of the knee is an irreversible disease that causes great pain, and genetic factors play an important role in its occurrence and development. There have been many studies on the correlation between ADAM12 rs3740199, rs1871054, rs1044122, and rs1278279 polymorphisms and osteoarthritis were searched. Fixed or random effects models were used for pooled analysis with OR values and 95% confidence intervals (CI), and publication bias was assessed. In addition, the false-positive reporting probability test was used to assess the confidence of a statistically significant association.Papers from PubMed, Web of Science, EMbase, Springer, SCOPUS, Google Scholar and other databases were systematically retrieved with a cut-off of January 2022. All case–control studies on ADAM12 was associated with osteoarthritis in dominant, recessive, allelic, and homozygote genetic models . Our subgroup analysis revealed an association between the ADAM12 polymorphism rs1871054 in Asians and osteoarthritis , albeit this was only for three studies. In addition, the ADAM12 polymorphism rs1871054 is associated with osteoarthritis in patients younger than 60 years of age ; however, the ADAM12 gene rs3740199, rs1044122, and rs1278279 site polymorphisms were not significantly. Furthermore, when assessing the confidence of the positive results, the positive results were found to be credible (except for Age < 60).Eleven articles were included, which included 3332 patients with osteoarthritis and 5108 healthy controls. Meta-analysis showed that the rs1871054 polymorphism of ADAM12 is associated with genetic susceptibility to osteoarthritis, but rs3740199, rs1044122, and rs1278279 site polymorphisms are not.Polymorphism at the rs1871054 site of  ADAM12, vitamin D receptor, matrix metalloproteinases, estrogen receptor, and interleukins , as shown in Fig. P = 0.876) and Egger’s test (P = 0.841), and the results showed that the analysis results were fairly robust without obvious bias. No statistical significance was found in the other gene models .A total of eight included studies focused on the correlation between the m and OA , 37–42, ADAM12 rs3740199 and OA susceptibility between Europeans and Asians. In addition, in the subgroup analysis based on sex, six studies were not statistically analyzed according to sex; therefore, only three studies were subjected to sex subgroup analysis, and the results were only meaningful in the female-dominant model . This does not seem to indicate that female patients are more susceptible to the disease. Subgroup analysis with an average age of 60 years indicated that the rs3740199 polymorphism of ADAM12 and susceptibility to OA may not be significantly associated with age, as shown in Table According to regional subgroup analysis, there were four studies on Asians and six studies on Europeans, but only one study on North Americans, so subgroup analysis was not carried out on the North American population. The results showed that there were no significant differences in the alleles of ADAM12 and OA was analyzed in seven studies , as shown in Fig. P = 0.907, I2 = 0%], suggesting patients carrying the TC allele and those with TT had the same risk of disease. In summary, patients with the C allele may be more susceptible, which is consistent with the Kerna result  , OR = 1.33, 95% CI (0.91–1.95), P = 0.019, I2 = 66.0%], suggesting that Asian patients carrying the C allele are more prone to the disease. In addition, in the subgroup analysis based on sex, four studies were not statistically analyzed based on sex, so only three studies were analyzed based on sex subgroups. Kerna et al.  , OR = 1.02, 95% CI (0.80–1.30), P = 0.926, I2 = 0%]  and Egger’s tests (P = 0.520) were used to detect publication bias, and the results showed that the analysis was fairly robust without obvious bias. Since all four articles were conducted on Asian populations, subgroup analysis was not performed. In addition, in the subgroup analysis based on sex, only two studies analyzed by sex. The results showed no significant correlation between ADAM12 rs1044122 and OA susceptibility in male and female patients. Subgroup analysis with an average age of 60 years indicated that the rs1044122 polymorphism and susceptibility to OA may not be significantly related to age, as shown in Table The correlation between the ectively –26, 39. ADAM12 polymorphism and OA. The FPRP results show  have been associated with OA. The study included 3332 patients with OA in the case group and 5108 patients without OA in the control group. The results show that in dominant, recessive, allelic, and homozygous models, rs1871054 polymorphism was associated with OA. In the subgroup analysis, we found that rs1871054 was associated with OA in Asian populations, but there was no statistical significance in European populations. In addition, people younger than 60 years who carry the C allele may be highly susceptible to the disease, and this conclusion may be a false positive. These differences may be the result of the gene-environment or gene–gene interactions, but the number of studies included is limited. However, the polymorphisms rs3740199, rs1044122, and rs1278279 in ADAM12 were not significantly correlated with OA, and the results showed no significant correlation after excluding heterogeneity.This meta-analysis aimed to explore the relationship between ADAM12 rs1871054 may be a predictor of OA, and individuals carrying the C allele may be highly susceptible to this disease; in addition, the Asian population may also show high susceptibility. Furthermore, rs3740199, rs1044122, and rs1278279 may not be predictors of OA. Although some studies have been published on the rs3740199, rs1871054, rs1044122, and rs1278279 polymorphisms of the ADAM12 gene and susceptibility to OA, the conclusions are not uniform and lack the support of sufficient homogeneity and large samples in research. If consistent conclusions can be drawn, it will be of great significance for the detection and treatment of OA. Heterogeneity may also be increased due to the different genotyping methods of the included studies. Age and sex differences in region, population, and included population are also important factors affecting the results. Due to the small number of included articles, it is impossible to analyze various interfering factors, and there is certain heterogeneity; therefore, the results need to be carefully interpreted. Whether ADAM12 polymorphisms are related to susceptibility to OA needs to be supported by higher quality case–control studies with larger samples to provide more effective evidence for the pathogenesis and treatment of OA.In conclusion,


Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies, affecting approximately 1 to 3% of women worldwide. Scientific data highlight a possible correlation between thrombophilic genetic variants and RPL. H1299R variant in the factor V gene would lead to an increased thrombotic risk associated with frequent miscarriages. However, the data are often conflicting, making this an interesting question for further investigations by evaluating genotype-phenotype correlations to improve the clinical management and genetic counseling of couples. A systematic review and meta-analysis will follow the preferred reporting elements for systematic review and meta-analysis protocols (PRISMA-P). The Pubmed (MEDLINE) and Embase (OVID) databases will be explored to identify suitable articles based on inclusion and exclusion criteria. Inclusion criteria are: (a) H1299R genotyping with clear data reported, referred to as Heterozygous (Het) and/or Homozygous (Hom); (b) articles written in English; (c) analyses of only RPL female patients having at least two or more previous pregnancy losses and compared with a control group. This analysis will present selected scientific evidence, addressing the questions concerning the association between the H1299R variant and RPL, hoping to clarify this still unresolved issue. PROSPERO registration number: CRD42022330077. Human reproduction is a process extremely delicate, in which a vast complexity of biological, hereditary, and environmental factors plays an important part ,2. AlthoIt is known how the risk of spontaneous abortion increases with advancing maternal age, but many factors remain largely unidentified.Pregnancy loss can be considered a quite common complex trait with a genetic risk factor involved ,5.Most of the studies have focused on the associations of maternal genetic variants with recurrent spontaneous abortion, often reporting inconclusive results and failing to estimate the possible risk of recurrence after a first abortion .The up-to-date guidelines of ESHRE, the European Society of Human Reproduction and Embryology, report 38 suggestions on risk factors, prevention, and clinical management in couples with recurrent pregnancy loss (RPL) . ESHRE gIn particular, clinicians should pay attention to the medical conditions present in the family and the reproductive history of the couple. Based on the ESHRE recommendations, both the number of previous abortions and the woman’s age represent important information for the prognosis of RPL patients .Similarly, the American Society for Reproductive Medicine (ASRM) and Royal College of Obstetricians and Gynecologists (RCOG) reported guidelines using different definitions for RPL. It recommended criteria to investigate the genetic, anatomical, hormonal, infectious, and thrombophilic factors involved .Thrombophilia is an abnormal blood coagulation condition leading to a hypercoagulability status. Thrombophilia can be an inherited or acquired tendency to form blood clots, commonly manifested as an increased risk of venous thromboembolism (VTE) ,10.Pregnancy difficulties such as RPL and recurrent implantation failure have been related to thrombophilic gene variants ,12.Particularly, scientific findings advised an increased risk of RPL in pregnant women with hereditary thrombophilia compared with the corresponding control group.However, the link between hereditary thrombophilia conditions and RPL is still discordant due to the divergences in sample size, nationality, and other aspects investigated by the insufficient studies performed.factor V (FV) gene, a single chain procofactor that acts in regulating blood coagulation with other plasma factors, are V Leiden variant, c.1691G>A substitution resulting in Arg in Glu replacement at amino acid 506 (R506Q) (rs6025); FV A4070G  (rs1800595); FV Hong Kong and Cambridge, associated with substitution of Arg306 by Gly (FV Hong Kong) and Thr (FV Cambridge) [Of interest, reported variants in the coagulation mbridge) ,14,15,16mbridge) .FV gene, known as A4070G; His1299Arg, R2, was identified and linked to hereditary thrombophilia. Previous studies have shown that His1299Arg change will increase 2–3 folds the VTE risk [In contrast, the well-known mutation Factor V Leiden causes Activated Protein C (APC) resistance determining a hypercoagulable state, which constitutes a lifelong risk factor for thrombosis and pregnancy complications, such as RPL ,14. AnotVTE risk .Therefore, based on this evidence, the objective of this study protocol will be to lay the foundation for an updated and exhaustive systematic review and meta-analysis on the relation between hereditary thrombophilia variant H1299R and its association with the risk of RPL.This review protocol has been registered in the PROSPERO international prospective register of systematic reviews; the registration number is CRD42022330077. We will use The Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) as guidelines for reporting present protocol and consequent meta-analysis. Consequently, we will illustrate the screening process through the (PRISMA-P) flowchart, thus reporting the preferred items for systematic review and meta-analysis see .We will serve online databases as the principal method to identify eligible studies. Moreover, we will also implement a manual search of relevant papers. The study will also conduct reference research back to other reviews and consult experts in medical genetics and biostatistics.The bibliographic databases MEDLINE (Pubmed) and EMBASE (Ovid) will be searched for literature clinical studies that evaluated the correlation between the presence of variant H1299R in Heterozygosity (Het) or Homozygosity (Hom) and RPL. Both databases will be investigated for terms related to thrombophilia genes and RPL. Citations, titles, and abstracts will be exported into Endnote X9. The search plan will be aligned with the support of the Cochrane handbook. Keywords combinations used during the search strategy are scheduled in Original clinical articles that report a numerical and well-distinguished (Het or Hom) presence of the H1299R variant will be included. We will consider observational studies, case-control studies, cross-sectional studies, and cohorts.Papers analyzing only females with RPL, studies on couples will not be considered.RPL patients having at least two or more previous pregnancy losses compared to a healthy control group with at least one successful pregnancy; studies using male patients or literature data as control will not be eligible.Only articles written in English; articles that aren’t available in English will be excluded.Specifically, during the selection of studies, we will also consider the following inclusion criteria:No geographic exclusion criteria or temporary restrictions will be imposed. The searches will be re-run just before the final analyses and further studies retrieved for inclusion.Editorials, letters, reviews, guidelines, case reports, abstracts and conference proceedings, systematic reviews and meta-analyses, and ongoing studies will be excluded.Studies will also be excluded if they did not report the year in which the measure of occurrence was estimated, the data are not clearly reported .Data on the following items will be collected: data source, study population, study years, study design, H1299R outcomes description as number of patients with H1299R variant or wild type, geographical area, mean age of patients, number of previous abortions for the RPL group. Our future systematic review and meta-analysis will be based on the outcomes of previous clinical studies. Subsequently, ethical approval is not necessary. Further, the results will be submitted to a peer-reviewed journal of the relative field for consideration for publication.Afterward, duplicates will be removed from the two different databases; two review authors will screen individually the titles and abstracts of all records identified to discard articles that will be off-topic. After this, full-text articles will be scrutinized to determine their eligibility for inclusion in the systematic review and meta-analysis. Every divergence will be resolved through the intermediation of a third review author.The Newcastle Ottawa Scale (NOS) recommended by the Agency for Healthcare Research and Quality will be employed to assess the quality of articles, as previously reported by Ingrosso et al. . A totalAs far as we know, there are enough studies in the literature, so the likelihood of a meta-analysis is well supported. The meta-analysis will include four procedures: first, the evaluation of the risk of bias for each study; second, data acquisition and consequent correlation between the H1299R variant and RPL; third, to compare, through separate assessments , the correlation between H1299R and RPL based on geographic origin and the mean age as parameters; finally, sensitivity analysis will be performed. Review Manager  will be used to perform a meta-analysis of the extracted data in the systematic review.Odds ratio (OR) will be employed as a statistical measure of the association between the H1299R variant and RPL. Random-effects model meta-analysis will be applied to calculate the pooled ORs and 95% CIs .2 and the I2 statistics will be evaluated. p < 0.10 denote statistically significant heterogeneity, and I2 statistic will be evaluated based on the following criteria: I2 > 75% indicates an extremely high degree of heterogeneity, I2 51–75% indicates a high degree of heterogeneity, I2 26–50% indicates a moderate-degree of heterogeneity, and I2 ≤ 25% indicates a low degree of heterogeneity [To estimate the heterogeneity between the studies, the Chiogeneity ,21.p > 0.01, I2 < 50%. Otherwise, a random-effects model will be applied in the case of high heterogeneity  [The recommendation of Cushing et al. will be applied . Based o2 > 50%) . FurtherThe purpose of the subgroup analysis will be to validate the impact of the FV H1299R variant, considering additional parameters that could provide a different interpretation. Subgroup analysis will be conducted using the following characteristics: the geographic origin of the population and the average age of RPL patients.One of the fundamental problems for the meta-analysis is the unavailability of some estimations from published and unpublished studies.Disclosure bias could contribute to this incompleteness. For this reason, the possibility of carrying out sensitivity analysis should always be considered to allow for the most reliable conclusions.In accordance, at the end of our study, we will perform a sensitivity analysis excluding the possible studies with “high-risk bias” or having obtained the lowest scores on the NOS scale.This will allow us to estimate the overall effect more precisely and interpret the results obtained more appropriately.Spontaneous abortion indicates a sudden termination of pregnancy which usually occurs within 20–24 weeks of gestation .Otherwise, ectopic pregnancies and molar pregnancies are not included in the definition of recurrent pregnancy loss ,24.Unfortunately, the percentage of cases in which a pregnancy loss occurs is greater than 20% of clinically recognized pregnancies , and in RPL, unlike sporadic abortion, is considered a disorder that requires medical intervention to ensure access to specialized clinics and thorough medical investigations, as well as increased assistance and monitoring in future pregnancies .This event has an important emotional impact on the woman who experiences it, and in general, on the couple, who very often need psychological support to overcome the traumatic event ,28.The pathophysiology of RPL is based on several factors, including maternal age and gestational age, although various mechanisms can converge on a common pathway that triggers miscarriage ,30.Others risk factors that predispose to spontaneous abortion are viral infections, structural abnormalities of the reproductive organs, use of drugs or smoking, diabetes, and especially genetic anomalies ,33,34,35Notably, common mechanisms of RPL include chromosomal errors in the conceptus that preclude further development and rupture of the maternal-fetal interface, both of which result in bleeding, cramping, and miscarriage. However, reliable risk factors have not yet been identified in over 50% of RPL women ,37.RPL represents a complex clinical picture in reproductive medicine, thus resulting in a clinical challenge for the affected women, their families, and the healthcare team . PhysiciIn this perspective, careful and accurate genetic counseling could be an important step in evaluating couples planning a pregnancy to consider the presence of one or more individuals/familiars’ risk factors ,40.Numerous investigations analyzed the role of inherited thrombophilia variants by studying gene polymorphism associated with RPL .AURKB gene, Lopez-Carrasco et al. discovered non-synonymous low-frequency (0.5%) variants  that induce changes p.A52V, p. I79T and p.A294T in the polypeptide chain respectively; 236T>C and 880G>A linked with RPL [It has been well investigated how chromosomal abnormalities induce implantation defects. In particular, the aberration in chromosomal structure can originate from deficiencies in the checkpoint mechanisms, which represent a quality control pool of the cell able to distinguish abnormalities of meiosis. This complex machine is called Assembly Checkpoint (SAC) and is formed by various proteins such as Mad1, Mad2, Bub1, Bub3, BubR1, and Mps1 . Accordiwith RPL .These results are promising and underscore the need for additional efforts to investigate the association between RPL and genetic polymorphisms.Our study will focus on the H1299R variant in FV, which significantly increases the risk of fetal loss during pregnancy . AlthougRelatedly, recent studies have not observed any significant correlation between the factor V H1299R mutation and the incidence of RPL, thus confirming the high variability of results regarding the association of this polymorphism with RPL .Based on this dualism, we believe that this study may lead to several clarifications for geneticists, gynecologists, obstetricians, and researchers.Indeed, despite the discordant findings, clinicians continue to screen women aiming to clarify the combination between thrombophilic genetic variants and reverse pregnancy outcomes .Thus, elucidating the associations between the H1299R variant and RPL through the combination of multiple clinical studies could represent an important goal in pregnancy and childbirth research.Furthermore, our study will aim to evaluate the impact of the H1299R heterozygous and homozygous variants carefully and separately, in order to carry out a comprehensive analysis of the genetic risk associated with RPL.In addition, the subgroup analysis will allow us to estimate the influence of the H1299R variant on RPL in relation to the geographic area  and the mean age of analyzed RPL patients.In addition, a sensitivity analysis will be performed by estimating the outcome, excluding high-risk bias studies.FV gene on RPL. Therefore, the present study will have a key role in providing evidence for future research in examining hereditary thrombophilia variant H1299R and recurrent miscarriage. This could also be a valid support for specified clinical centers and genetic counselors, thus remarking the importance of genetic screening and counseling for all couples who desire a child.The comprehension of thrombophilic genetic variants in RPLs represents a complex topic in which several parameters should be considered. To the best of our knowledge, this will be the first comprehensive systematic review and meta-analysis to shed light on the specific influence of the H1299R variant in the


Other results from the meta-analysis were as follows; Heterogeneity: Chi2 = 585.13, df = 6 (P < 0.00001). A test of the overall effect of ever use versus never use of oral contraceptives was Z = 21.85 (P < 0.00001). All the studies had a pooled risk ratio (RR) of 0.53. The use of oral contraceptives is associated with reduced risk of developing colorectal cancer. There is a need for further research into the biological mechanisms underlying these relationships, which may lead to insights into potential preventive interventions for colorectal carcinogenesis in women. The keywords used to locate studies included in this meta-analysis include Keywords targeting oral contraceptives included oral contraceptive pills, and birth control pills. Search keywords targeting colorectal carcinogenesis included neoplasms, tumors, or colon and rectal cancer.There is limited understanding of the potential relationship between the risk of colorectal cancer and oral contraceptive use among women of different ages. Further investigation on the issue helps develop an informed choice of contraception. Data for this meta-analysis were derived from case-control and cohort studies of colorectal cancer and oral contraceptive use conducted between June 2000 and May 2022. The studies had a very high heterogeneity, as shown by an I •Oral contraceptive use in woman does affect the risk of developing colorectal cancer.•Colorectal cancer has many identifiable and nonidentifiable risk factors.•OCP usage in women of various age groups shown a lower risk of colorectal cancer development than those who never used OCPs.•Regarding the population at risk for colorectal cancer due to a variety of reasons, many studies have deemed OCP usage safe. The incThe study was conducted to identify the association between marital status and human carcinogenesis among 31,658 catholic nuns from 41 denominations in the United States (US). Cancer mortality rates in nuns of old age were considerably higher than in controls. The incidence of colorectal cancer and other types of cancers among nuns in the post-menopausal ages showed increased frequency. Together with other findings, this observation implicated the effect of infertility and marital status. It also suggested that cancers of the large colon, rectum, and specific reproductive sites had common biological mechanisms with hormonal characteristics. Other studies have been conducted on the subject since this observation was made five decades ago. Regarding this topic of ever-use versus never-use of oral contraceptives, a meta-analysis done by Ref. , and 14 Birth control pills/oral contraceptives are medications that contain hormones that are taken orally to avert pregnancy. The administration of these drugs avert pregnancy by preventing ovulation and prevent viable sperm from reaching the cervix. Some common oral contraceptives in developed countries like the United States (US) contain synthetic versions of the female hormones progesterone and estrogen - often referred to as a combined oral contraceptive. The other type of oral contraceptive contains only progestins/synthetic progesterone and is, therefore, referred to as the mini pill.Most research on the association between cancer risk and oral contraceptives comes from population-based case-control studies and large prospective cohort studies. However, observational studies cannot be used to establish that exposure to oral contraceptives increases or reduces the incidence of colorectal cancer among women of different age groups. This may be the case because women who actively take birth control pills may differ from those who do not take oral contraceptives in other ways apart from their birth control pill use. It is, therefore, possible that these other disparities are responsible or can explain these differences in cancer risk. In general, however, these studies have been a source of consistent evidence supporting the hypothesis that oral contraceptives are associated with a reduced risk of contracting a range of cancers like ovarian, endometrial, and colorectal cancers.On the other hand, they have shown that women who take oral contraceptives face an increased risk of developing breast and cervical cancers. Oral contraceptives influence cancer risk through different mechanisms. Endogenous and exogenous female sex hormones, i.e., estrogen and progesterone, may lower the risk of colorectal cancers in multiple ways, including reducing the number and frequency of ovulation females experience throughout their lifetime, therefore, reducing the time of exposure to potentially carcinogenic sex hormones as in the case of ovarian cancer. Second, oral contraceptives may suppress endometrial cell proliferation as in endometrial cancer. Finally, birth control pills reduce bile acids in the blood, as seen in women under regular oral conjugated estrogens regimens . This stThe incidence of colorectal cancer among women was investigated in relation to reproductive and menstrual factors. This cohort study featured 93,676 women, among which 1149 colorectal cancer cases were reported over 11.9 years. In this study, having had two or more children was inversely correlated with the risk of developing colorectal cancer. Females previously exposed to oral contraceptives had a lower risk of colorectal cancer ; there was however, no association observed between the duration of oral contraceptive use and the risk of colorectal carcinogenesis . The study results concluded that prior use of oral contraceptives and parity were the two significant factors that could be directly linked to a lower risk of developing colorectal cancer among women of different age groups. Several studies have sought to investigate this phenomenon and have provided information on the association between colorectal cancers and the use of combined oral contraceptives (OCs).Endogenous and exogenous hormones could also influence the risk of developing colorectal cancer, as indicated by several epidemiological, metabolic, and animal data studies. A recent Swiss case-control study  on 373 hA cohort study by the Oxford Family Planning Association on 46 cases of colorectal cancer and 17,032 women also reported similar results . On the This study found a greater reduction of risk for current oral contraceptive users (OR = 0.38) than former users (OR = 0.89). Lin et al. , found lTo quantify the association between colorectal cancer and oral contraceptive use, it was necessary to conduct this meta-analysis and systematic review, which includes select published articles up to June 2000. Eight articles were handpicked for conducting this meta-analysis. Of these, 3 were case control studies  while fo22.1The protocol of this meta-analysis was prepared in lieu of the investigation according to the standards of systematic reviews outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The criteria of inclusions followed these guidelines without interference from external factors. Therefore, this systematic review and meta-analysis results have been generated credibly to offer genuine and accurate insights into the topic question. The systematic review and meta-analysis use the PRISMA extension published in the Cochrane Handbook for systematic reviews and interventions – Chapter 4 .2.2Databases of Cochrane Library, PubMed, and EMBASE were used to identify publications assessing the relationship between oral contraceptive use and the incidence of colorectal cancers among women through an electronic search. This meta-analysis was conducted in May 2022, and studies focusing on the oncological outcomes in women of different ages who used oral contraceptives (birth control pills) were considered. Articles considered for this study included published research papers on colorectal cancer in English language up to June 2016. To maximize the search strategy results, this meta-analysis incorporated three techniques to create three search queries to be used on Cochrane Library, PubMed, and EMBASE. These techniques included keywords, Boolean operators, truncations, and field tags. The search strategy adhered to the PRISMA statement and publication bias standards outlined by Ref. . The sea2.3The studies used for this meta-analysis were retrieved from the stated databases using the following search string: [‘colorectal’ OR ‘colon’ OR ‘rectal’ OR ‘rectum’] AND [‘oral contraceptives’ OR ‘exogenous hormones’] AND [‘cancer’ OR ‘neoplasm’] AND [‘case –control study’ OR ‘cohort study’].2.4In this meta-analysis, case-control studies and cohort studies were included for analysis. The inclusion criteria focused on studies that evaluated the oncological outcomes of individuals/patients with a history of use of oral contraceptives. Studies were eligible only if information had been obtained directly from each woman, and oral contraceptives could be distinguished from other hormone replacement treatments , 16], , , 18], , , [8],  to find the association between the use of oral contraceptives (birth control pills) and the incidence of colorectal cancer among women. Two study populations (test and control) were analyzed to demonstrate the relationship between the use of oral contraceptives and the incidence of colorectal cancers. The number of cancer cases in each section of two populations was the main outcome of interest. A confidence interval of 95% was used for data analysis. Details extracted from each study include, study design, number of subjects (cases and controls or person-years), prevalence of oral contraceptive use, and confounding factors. Primary analysis of the data involved making comparisons between ever-users and never-users of oral contraceptives. Also, wherever possible, the influence of recency and duration of use was assessed. In most studies, the primary outcome was the combination of cancers of the rectum and colon, but some outlined colon cancer only, while some studies considered colon and rectum carcinogenesis as two separate outcomes. No study was assigned a quality score. Also, no studies there was no exclusion of studies a priori for weaknesses of data quality or study design.2 test [The most significant measure of effect for most studies was the relative risk (RR) for cohort studies, which was approximated by the odds ratio (OR) in case-control studies, with a 95% confidence interval (CI). Summary estimates of the RR were derived using fixed effects models. Heterogeneity of the studies was evaluated using a I2 test . In this2 test . The RRs2 test .33.1A total of 317 studies were screened and considered for inclusion. A total of 197 studies were excluded due to duplication, and 120 studies were submitted for a title, and abstract screening. 11 systematic reviews and meta-analysis, 21 commentaries, and 18 animal studies were excluded. Also, 33 studies were excluded for irrelevance in the intervention used, not measuring the targeted outcomes and use of undesired population. The next stage was a full-text screening of 37 studies, eliminating 22 for lack of full-text publications. Further eligibility reasons such as the method of reporting used, lack of a control group, and the outcomes reported in the results sections were used as grounds for the elimination of a further 31 studies. A total of 6 studies were then left for inclusion, with an additional two studies identified in reference lists of former systematic reviews and meta-analyses being brought in to make 8. 3.22 of 99% and a confidence interval of 95% was considered significant. Other results from the meta-analysis were as follows; Heterogeneity: Chi2 = 585.13, df = 6 (P < 0.00001). A test of the overall effect of ever use versus never use of oral contraceptives was Z = 21.85 (P < 0.00001). Eight studies  evaluated the association between use of oral contraceptives among women and the incidence of colorectal cancer. Of these, 3 were case–control studies ,28,40 wh4The strength of proof for the impact of oral contraceptive pill use on large intestine cancer incidence was moderate. Results were mostly consistent across studies, and the summary estimate showed high preciseness with a good CI. Future studies won't probably have an impression on the direction of the impact however could slightly influence the magnitude of the effect. The strength of proof for the duration of therapy was insufficient; the check was underpowered and that we found vital heterogeneity. From this meta-analysis and systematic review, there was a 21% reduction within the risk of developing large intestine cancer among ever-users of oral contraceptives. 2191 cases of colorectal cancer among 271,222 study participants reported using oral contraceptives. The use of oral contraceptives is associated with 0.46 RR of developing colorectal cancer. There was pronounced reduction in RR in subjects that showed recent oral contraceptive pill use, however, this impact wasn't duration dependent. This finding is consistent with other meta-analyses ,8 which There was a very high heterogeneity of the studies probably because case-control and cohort studies were considered for use in the meta-analysis to create a common odds ratio and risk ratio pools. On publication bias, it was decided not to search for unpublished data, and to exclude papers that did use personal questionnaires to gather data. Studies with small sample sizes or null results were not included as they are very likely to be published . There wOral contraceptives influence cancer risk through different mechanisms, increasing the risk of some types of cancer e.g breast cancer, while reducing the risk of developing other types e.g colorectal cancer. It has been found that endogenous and exogenous female sex hormones i.e. estrogen and progesterone may lower the risk of colorectal cancers through multiple ways that include: reducing the number and frequency of ovulations females experience throughout her lifetime, therefore, reducing the time of exposure to potentially carcinogenic sex hormones as in the case of ovarian cancer. Second, oral contraceptives may suppress endometrial cell proliferation as in endometrial cancer. Finally, birth control pills reduce the levels of bile acids in the blood, as seen in women under regular oral conjugated estrogens regimens . In thisFemale hormones confer protection against colorectal carcinogenesis through different mechanisms but chief among them is by influencing changes in bile synthesis and secretion. The overall effect of these changes is a reduced concentration of bile acids in the colon . Other bSome of the major strengths of this meta-analysis include the comprehensive analysis of menstrual and reproductive patterns in a range of well-characterised prospective cohort and case control studies featuring more than 2191 verified colorectal cancer cases in 271,222 study participants. The cohort studies also had relatively long follow-up periods of the study participants. Furthermore, the large sample sizes enabled the researchers to carry out stratified analyses with sufficient statistical power, allowing the assessment of women according to waist circumference strata or hormone therapy use in some studies , which aA potential drawback of this meta-analysis is that all the primary variables of interest were based on self-reported reproductive history since most of the data was collected mainly through questionnaires and, therefore, the possibility of recall bias cannot be undermined. However, some validation studies have found that self-reported reproductive history shows good agreement with medical records ,53. Also5In conclusion, oral contraceptive use is associated with a reduced risk of colorectal cancer. This observation has been backed up by the studies in the meta-analysis which show a reduction in risk ratios for women who had taken oral contraceptives at any point of their lives. There is a need for further research into the biological mechanisms underlying these relationships, however. This will help to better understand potential preventive interventions against colorectal cancer in women. The meta-analysis includes detailed studies, data and information that can be used to inform the strategic use of oral contraceptives in women to reduce the morbidity of cancers in the global population. For instance, the study's major strength is that it provides a comprehensive analysis of menstrual and reproductive patterns in a range of well-characterised prospective cohort and case control studies providing a large data set of more than 2191 verified colorectal cancer cases in 271,222 study participants. Also, the use of both cohort and case-control studies for this meta-analysis provides a broad view of the topic in diverse data sets.Not Applicable (N/A).This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.1*.Fadi Abusal: Conceived and designed the analysis and Wrote the paper.1*.Mohannad Aladwan: Conceived and designed the analysis and Wrote the paper.*: Both authors contributed equally to this paper.2. Yazan Al Omari: Collected the data and Contributed data or analysis tools.3. Saja Obeidat: Collected the data and Contributed data or analysis tools.4. Salah Abu warde: Collected the data and Performed the analysis.5. Haya AlDahdouh: Collected the data and Performed the analysis.6. Qotadah al shami: Collected the data.7. Qusai: Collected the data and Performed the analysis.Not Applicable (N/A).Not Applicable (N/A).1. Name of the registry: Not Applicable (N/A).2. Unique Identifying number or registration ID: Not Applicable (N/A).3. Hyperlink to your specific registration (must be publicly accessible and will be checked): Dr_fadi@outlook.com.Fadi Abusal, General Surgery, Al Bashir Hospital, Amman (11151), Jordan. Telephone Number: +962790850815, Email:The Authors declare that there is no conflict of interest.