Dietary antioxidants have long been thought to be likely to prevent the development of gliomas. Previous studies have reported vitamin A, C, and E protective effects against gliomas. B vitamins, one of the main vitamins in the diet, are closely related to human health, but the association with gliomas has rarely been reported.This study aimed to evaluate the relationship between five B vitamins and glioma.In this Chinese population-based case–control study, 506 glioma cases and 506 matched (age and sex) controls were included. The dietary intake of study participants was assessed using a valid 111-item food frequency questionnaire. The intake of five B vitamins was calculated based on participants’ dietary information from the food frequency questionnaire. The logistic regression model was used to examine the association between B vitamins and glioma, and the restriction cubic spline evaluated the dose–response relationship between the two.After adjusting for confounding factors, thiamine , riboflavin , nicotinic acid , folate  and biotin  in the highest tertile were associated with a significantly decreased risk of glioma compared with the lowest tertile. The results of thiamine and biotin in glioma with different pathological types and grades were different. The restricted cubic spline function showed significant dose–response relationships between the intake of five B vitamins and the risk of glioma. When B vitamins exceeded a specific intake, the risk of glioma did not change.Our study suggests that higher dietary intake of thiamine, riboflavin, nicotinic acid, and folate are associated with a decreased risk of glioma, but the results of biotin are not consistent among different populations. In the future, prospective studies should be conducted better to validate the effects of B vitamins on gliomas. B vitamins are a group of water-soluble micronutrients required by all forms of cellular life, from bacteria to humans . Unlike Studies showed that the lack of B vitamins was closely related to cardiovascular diseases , neurodeAlthough these studies suggested that B vitamins were closely related to cancer, few studies reported the relationship between B vitamins and glioma. The pathogenesis of glioma was still unclear. It was currently believed that this mechanism may be related to genetic mutation of genes , 23, disThis case–control study was initiated in 2021 and completed in 2022 at the Beijing Tiantan Hospital, Affiliated with Capital Medical University. Based on previous studies, we assumed that about 80% of Chinese people took in B vitamins below the recommended level . We furtn = 9), whole grains (n = 2), tubers (n = 2), legumes and products (n = 5), vegetables (n = 23), fungi and algae (n = 4), fruits (n = 20), red meat (n = 4), poultry (n = 2), animal offal (n = 4), fish and seafood (n = 5), egg (n = 1), dairy products (n = 4), nut (n = 4), sweet food (n = 5), sugary drink (n = 3), tea and coffee (n = 3), condiment (n = 4), curing food (n = 3), processed products (n = 3), and alcohol (n = 4), a total of 114 items, basically covering the daily type of diet. The intake assessment for each food item consisted of three aspects: whether or not, the frequency of intake (daily/weekly/monthly), and single intake. In the questionnaire, g or ml was used as a unit to measure food intake, and pictures of different food volumes and qualities were provided as references to help subjects accurately assess intake. The daily intake of each food was calculated according to the frequency and single intake.The food frequency questionnaire was used to collect information on the type and amount of food intake of the research subjects in the past 12 months through face-to-face interviews. The food frequency questionnaire has been validated in previous studies, and its authenticity and reliability can meet the purpose of the study . Based oFive B vitamins were involved in the study, including thiamine, riboflavin, nicotinic acid, folate, and biotin (vitamin B7). The intakes of the five B vitamins were calculated using the China Food Composition Tables . Chinese2).In addition to the food frequency questionnaire, all participants were asked to complete other surveys, including basic information, disease history, and lifestyle habits. Basic information mainly included date of birth, sex, education levels , occupation , and household income . Disease history included allergies, head trauma, and family cancer, which have been reported as “yes” or “no.” Lifestyle habits included smoking status and physical activity. The subjects were classified as never smoking, former smoking, or current smoking according to their current smoking status. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ) , and metTo ensure survey quality, all surveys were conducted by one-on-one interviews with uniformly trained investigators with medical or epidemiological education.t-test for continuous variables and the χ2 test for categorical variables to compare the general characteristics of the case and control groups. The Spearman correlation coefficient was used to evaluate the correlation between five B vitamins. We divided them into three groups based on the distribution of B vitamin intake. To explore the association between B vitamins and glioma, we used the lowest group as a reference and calculated the OR and 95%CI of each group by logistic regression. The univariate model (Model 1) was a crude model without adjusting for any confounding factors. The multivariate model (Model 2) adjusted for factors associated with the risk of glioma and B vitamin intake: age, BMI, occupation, education level, household income, high-risk residential areas, smoking status, history of allergies, history of head trauma, family history of cancer, physical activity, and energy intake.We used the We conducted a series of sensitivity analysis to test the robustness of our estimates by excluding participants with different ages, different sexes, different BMI, middle school and below, below 3,000 ¥/month, smoking, history of allergy or family history of cancer, and repeated regression analysis. In addition, to overcome the inherent limitations of B vitamins analysis as grade variables, the restricted cubic spline function was used to model the dose–response relationship in the multivariate adjustment model, with four nodes located at the 20th, 40th, 60th, and 80th percentiles of B-vitamin intake. The 10th percentile was used as the reference group (OR = 1) , slightly fewer education levels (p < 0.001), more smoking (p = 0.039), more physical activity (p < 0.001), and were less likely to have allergies (p < 0.001) but more likely to have cancer in their families (p = 0.001). There were also differences in occupation (p = 0.024) and household income , household income (p < 0.001), and physical activity (p < 0.001) of glioma patients with different pathological grades were the same as the general population. In addition, compared with the corresponding control group, the group with grade I + II glioma had a higher BMI (p = 0.004), the group with grade III glioma had a higher percentage of family history of cancer (p = 0.003), the group with grade IV glioma had a higher BMI (p = 0.002) and a higher percentage of family history of cancer (p = 0.022), and the group with other glioma had more manual workers (p = 0.009), a lower history of allergies (p = 0.007) and a higher history of head trauma (p = 0.042). There were no significant differences in others , nicotinic acid , folate  and biotin  were associated with a significantly decreased risk, but the result of thiamine was not significant . For glioblastoma, thiamine , riboflavin , nicotinic acid , and folate  were associated with a significantly decreased risk, but the result of biotin was not significant . Due to the small sample size of oligodendroglioma, further analysis was not possible .The association between B vitamins and the pathological grade of glioma showed similar results. For low-grade gliomas, riboflavin , nicotinic acid , and folate  were associated with a decreased risk, but the results of thiamine  and biotin  were not significant. For high-grade gliomas, thiamine , riboflavin , nicotinic acid , folate  and biotin  were associated with a decreased risk .The results of sensitivity analysis showed that after excluding participants with different ages, different sexes, different BMI, middle school and below, below 3,000 ¥/month, smoking, history of allergy or family history of cancer, we observed that most results of thiamine, riboflavin, nicotinic acid and folate were consistent with the overall results. However, biotin was not significant in people with low BMI .-nonlinearityP < 0.0001). There was a linear dose–response relationship between riboflavin and the risk of glioma, and the risk of glioma decreased significantly with the increase in intake. After the intake exceeded 1.06 mg/day, the risk of glioma tended to stabilize (-nonlinearityP = 0.4040). There was a nonlinear dose–response relationship between nicotinic acid and the risk of glioma, and when intake exceeded 12.83 mg/day, the risk of glioma decreased significantly with increasing intake. After the intake exceeded 18.03 mg/day, the risk of glioma tended to stabilize (-nonlinearityP = 0.0211). There was a linear dose–response relationship between folate and the risk of glioma. When the intake exceeded 224.27 μg/day, the risk of glioma decreased significantly with the increase in intake. After the intake exceeded 404.93 μg/day, the risk of glioma tended to stabilize (-nonlinearityP = 0.2168). There was a nonlinear dose–response relationship between biotin and the risk of glioma, and when intake exceeded 28.81 μg/day, the risk of glioma decreased significantly with increasing intake. After the intake exceeded 40.62 μg/day, the risk of glioma tended to stabilize (-nonlinearityP < 0.0001).In Previous observational studies on vitamins and glioma focused on vitamins A, C, and E, while studies on B vitamins were relatively rare. Our study evaluated the association between the intake of five B vitamins and glioma in the Chinese population. The results showed that thiamine, riboflavin, nicotinic acid, folate, and biotin were significantly negatively associated with the risk of glioma. The results of different pathological classifications were different. Thiamine only had a significant impact on glioblastoma. Similarly, it also existed between biotin and astrocytoma, and riboflavin and folate seemed to have a greater effect against astrocytoma. The results of different pathological grades were similar to those of pathological types. Thiamine and biotin only had significant effects against high-grade gliomas and had no significant correlation with low-grade gliomas, but the effects of riboflavin, nicotinic acid, and folate had a greater effect against low-grade glioma. The results of sensitivity analysis suggested that thiamine, riboflavin, nicotinic acid, and folate had relatively robust associations with glioma. Still, the results of biotin were not consistent with those of the general population, suggesting that its effects on glioma were different. The restricted cubic spline model further confirmed significant dose–response relationships between the five B vitamins and the risk of glioma, in which the dose–response relationships between thiamine, nicotinic acid, biotin, and glioma were nonlinear. In contrast, the dose–response relationships between riboflavin, folate, and glioma were linear.-nonlinearityP < 0.0001). But the mechanism of the effect of thiamine on glioma was still unclear, which was related to the antioxidation of thiamine in vivo  and interacted with methionine synthetase reductase . Based oin vitro and in vivo. The primary mechanism was that nicotinic acid promoted snail1 degradation and enhanced intercellular adhesion, indicating that epithelial-mesenchymal transition in glioma cells was inhibited   . However< 0.001) . From th< 0.001) . Folate < 0.001) . In addi< 0.001) .The study of biotin and cancer has mainly focused on biotin as a ligand in the treatment of new drugs , 68. FewThis study had several advantages. First, we explored the relationship between five dietary B vitamins and glioma. As previous studies have paid more attention to the relationship between vitamin A, vitamin C, vitamin E, and glioma, the results of this study supplement the evidence of the preventive effect of B vitamins against glioma. Secondly, the studies on B vitamins and glioma often stayed in cell and animal experiments. The results of this study were mutually confirmed with the existing experimental evidence, especially for thiamine, nicotinic acid, and folate, which were lack of clinical study. Third, we thoroughly explored the relationship between gliomas with different pathological subtypes, pathological grades, and B vitamins. The dose–response relationships between B vitamins and the risk of glioma were described for the first time, which were consistent with the existing dose–response relationship between B vitamins and cancer. These provided further population evidence for the prevention and treatment of glioma by B vitamins. However, there were still some limitations in this study. On the one hand, B vitamins participated in one-carbon metabolism in different forms, such as the synthesis of nucleotides and the metabolism of amino acids, which was of great significance for maintaining normal cell growth. However, because the food composition table failed to provide a broader content of B vitamins, such as vitamin B12, this study only evaluated the five common B vitamins, and could not explore the association between more B vitamins and glioma, especially the interaction between B vitamins. But this has been far the most comprehensive result about B vitamins and gliomas. On the other hand, the association between the concentration of B vitamins in the body and glioma has not been evaluated. Although the food frequency questionnaire had been verified and had good repeatability and validity. However, due to the limitation of methods, there was still a certain bias in the assessment of the intake of B vitamins through the food frequency questionnaire. Assessing the concentration of B vitamins in the body can reduce this uncertainty. Since the concentration of B vitamins in the subjects was not detected in this study, the association between internal exposure and glioma should be evaluated in future studies in combination with the circulating concentration of B vitamins in or biomarkers. In addition, since this study was a case–control study, their causality cannot be verified.In summary, in this study of B vitamins and gliomas, we observe that thiamine, riboflavin, nicotinic acid, and folate were associated with a significantly decreased risk of gliomas. Still, the roles of biotin are different in different populations. The relationship between them should be further verified by prospective cohort studies in the future.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University (no. KY2022-203-02). The patients/participants provided their written informed consent to participate in this study.WL and WZ contributed to the conception or design of the work and wrote the manuscript. WZ, JJ, and SH contributed to data collection and analysis. XK, CW, FC, BZ, and SL contributed to data collection and management. All authors contributed to the article and approved the submitted version.This study was supported by the Talent Introduction Foundation of Tiantan Hospital (no. RCYJ-2020-2025-LWB) and Advanced Research and Training Program of Beijing Double Leading Scholars from China academy of Chinese Medical Science (no. 2-759-02-DR).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fnut.2023.1122540/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


To determine the association between thyroid cancer and coronary artery disease, atrial fibrillation, cerebrovascular disease, and cardiovascular disease mortality.The PubMed, Embase, and Cochrane Library databases were searched for eligible studies from inception to September 22, 2022. Keywords included “thyroid cancer”, “atrial fibrillation”, “coronary artery disease”, “cerebrovascular disease”, and “mortality”. Primary outcomes included the incidence of coronary artery disease, cerebrovascular disease, atrial fibrillation, and cardiovascular disease mortality among patients with thyroid cancer. Secondary outcomes included cardiovascular disease events among those with thyroid cancer that received or did not receive radioactive iodine or lenvatinib. Estimates were pooled using fixed- and random-effects meta-analysis.A total of 771,220 patients who underwent thyroidectomy in 15 studies were included. Risk for cerebrovascular disease  1.10–1.21]) and atrial fibrillation [RR 1.59 (95% CI: 1.45–1.73)] were significantly increased. Risk for coronary artery disease was significantly increased [RR 1.12 (95% CI: 1.08–1.17)] in the common effect model. Cardiovascular disease mortality associated with thyroid cancer was not significant [RR 0.93 (95% CI: 0.59–1.45)]. Radioactive iodine had a neutral effect on cardiovascular disease [RR 1.00 (95% CI: 0.87–1.16)], and there was no beneficial nor harmful effect among different RAI doses.Thyroid cancer was significantly associated with a higher risk for cerebrovascular disease and atrial fibrillation; however, the hazard risk was not different between patients with and without radioactive iodine treatment. Thyroid cancer treatment should be individualized considering the potential harms and benefits to cardiovascular health. P < 0.0001) for patients who received I-131 (The incidence of thyroid cancer (TC) is ranked 11th according to the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer . Such aned I-131 . Tyrosined I-131 . To sum 173,710 patients with TC from the Surveillance, Epidemiology, and End Results (SEER) database showed that 29.1% and 21.7% of death were attributable to TC and cardiovascular disease (CVD) . Older aOwing to the increasing incidence and relatively good prognosis of TC, an updated and comprehensive quantitative review is needed to assess the long-term effects on the cardiovascular system among patients with TC after thyroidectomy, RAI and TKIs. We aimed to examine the incidence of coronary artery disease (CAD), Af, cerebrovascular disease and CVD mortality in patients with TC; and the risk for CVD among patients who underwent RAI or lenvatinib (TKI).Two authors (W.H.T and M.C.T) independently identified articles published before September 22nd, 2022, that investigated and reported on “thyroid cancer”, “atrial fibrillation”, “coronary artery disease”, “cerebrovascular disease”, and “mortality”.  by systeTwo reviewers initially screened the titles and abstracts of all retrieved articles for eligibility. Studies with the following characteristics were excluded: target population(s) not related to TC; data that did not address the outcome of interest; reviews, meta-analyses, or commentaries. The inclusion criteria included all patients with TC that received either thyroidectomy, thyroxine, RAI or TKIs. After initially screening articles for inclusion based on title and abstract, the full text of each was reviewed. Disagreements were resolved by the third author. The PECOS framework was demonstrated in The following information was extracted from each study: year of publication; author(s); country; number of participants (TC/control); proportion of women; age at diagnosis; mean years' follow-up; statistical analysis; and adjusted variable and outcomes with hazard ratio (HR). The Risk of Bias in Non-randomized Studies‒Exposure (ROBINS-E) was used to assess the risk of bias .I2 statistic, for which I2 > 75% indicated substantial heterogeneity. Random-effect meta-regression was performed to investigate sources of heterogeneity .Outcome ascertainment was variably defined as CAD, cerebrovascular disease, Af, and CVD mortality. In the first analysis, pooled risk estimates of CAD, cerebrovascular disease, Af and CVD mortality between patients with TC and the general healthy population were calculated. The risk for CVD between TC patients with and without RAI or lenvatinib was also examined. We extracted the number of CVD adverse events among the clinical trials and calculated the difference in the observed percentages of patients. We used logistic regression to perform the odds ratio with 95% confidence interval (CIs) of the CVD adverse events among clinical trials. When ≥ 2 studies assessed the same outcome, results were pooled using both fixed- and random-effect meta-analysis, which specifically accounted for heterogeneity among studies. Extracted pooled HRs for individual outcomes were combined to construct summary pooled HRs. Heterogeneity was assessed using standard chi-squared tests and the P < 0.10 (2-sided)  from RAI dose categories to determine the association with the risk of CVD . Two stu2-sided)  which leP < 0.05. All analyses were performed using R version 3.5.1 .Bias secondary to small study effects was assessed using visual inspection of funnel plots but could not be examined by Egger test plots because there was fewer than 10 studies. Statistical significance was defined as two-sided As shown in Meta-analytic pooling of hazard estimates of CAD between patients with TC and the general healthy population in 5 studies  revealedP = 0.2). P = 0.52]. The findings demonstrated no beneficial nor harmful effect on CVD among different RAI doses.The pooled risk for CVD between patients with TC that received or did not receive RAI in 5 studies  demonstrSystematic review of the association between CVD risk and different dosages of levothyroxine is summarized in The risk of publication bias was found to be non-significant for studies addressing CAD, cerebrovascular disease, Af, and CVD mortality . Meta-reThe present study showed that TC patients were prone to experience cerebrovascular disease and Af. The incidence of CAD and CVD mortality among TC patients did not appear to be different from the general healthy population. In addition, there was no significant association between RAI and CVD in patients with TC. However, according to limited evidence, lenvatinib may increase CVD risk.3,822 patients from Utah Population Database (UPDB) demonstrated that male, overweight or obese, older at cancer diagnosis, TSH suppression therapy, distant metastases at cancer diagnosis, and a higher Charlson comorbidity index score were associated with an increased CVD risk among TC survivors . In our The pathophysiological mechanism of increased cerebrovascular disease in patients with TC remains unclear. Suh et. al found a low incidence of Af in patients who developed ischemic stroke, which may suggest that Af is not a primary factor associated with ischemic stroke . Both alFurther investigations of CVD mortality rate demonstrated no difference after follow up of 4,082 patients with TC for 3 years . PajamäkTyrosine kinase inhibitors (TKI) has become the final treatment option for metastatic TC that is refractory to surgery or RAI, to improve the prognosis of patients with distant metastasis and progressive disease . AccordiOur meta-regression analysis demonstrated no statistically significant association between risk for CAD, cerebrovascular disease, Af and CVD mortality and mean age, women proportion, and follow up years. Whether age and sex effect the development of CVD in patients with TC remains unclear. A cohort study from UPDB revealed that TC survivors diagnosed at <40 years have an increased risk for several circulatory conditions when compared with the matched cancer-free population . Both paOur study has two advantages over prior meta-analyses. First, we included more qualified cohort studies. We also included RCTs due to lack of cohort studies. Second, the present study is the first meta-analysis to investigate the relationship between TC and RAI or lenvatinib. However, the evidence is still scarce. On the other hand, the present study had several limitations, the first of which was the limited number of eligible studies. Despite efforts to search using specific keywords to retrieve all relevant articles, the number of included studies was small. Further studies investigating the association between TC and CVD are needed to further optimize risk identification. Second, the heterogeneity of exposure measurement, end point ascertainment, statistical analysis , and data acquisition methods reduced our ability to compare the studies with one another. Pooled estimates could not be calculated on part of studies due to insufficient data. Future investigations are still needed to explore the potential causal pathways between exposure and outcome. Third, some of the studies lacked information of cancer parameters, such as cytology, staging, or TSH concentrations. Further understanding of the effects of treatment for TC on the cardiovascular system can be improved by stratifying detailed cancer information into covariates in future research. Fourth, despite the subgroups of each study were not overlapped, each of the subgroup was compared with the same control group to evaluate the risk for CVD. Finally, the meta-analysis could not exclude unmeasured residual confounders because most of the included evidence was derived from observational studies. However, the odds in these studies were adjusted for multiple relevant confounders to eliminate potential bias.TC was significantly associated with a higher risk for cerebrovascular disease and Af, although the hazard risk was not different between patients who did and did not undergo RAI ablation. Lenvatinib may increase CVD risk according to limited evidence. These results provide insights toward optimizing TC strategies that should consider the potential harms and benefits on cardiovascular health during cancer treatment.


Second-trimester monobenzyl phthalate (MBzP) exposure was positively associated with systolic and diastolic BP in the third trimester . Conversely, first-trimester mono-2-ethylhexyl phthalate (MEHP) exposure demonstrated a negative association with mean systolic and diastolic BP during the second and third trimesters . Additionally, monoethyl phthalate (MEP) exposure was found to be associated with an increased risk of HDP . Our study found that several phthalate metabolites were associated with increased systolic and diastolic BP, as well as the risk of HDP across pregnancies. Nevertheless, given the limited number of studies analyzed, additional research is essential to corroborate these findings and elucidate the molecular mechanisms linking phthalates to BP changes during pregnancy.Phthalates are commonly found in a wide range of environments and have been linked to several negative health outcomes. While earlier research indicated a potential connection between phthalate exposure and blood pressure (BP) during pregnancy, the results of these studies remain inconclusive. The objective of this meta-analysis was to elucidate the relationship between phthalate exposure and BP in pregnancy. A comprehensive literature search was carried out with PubMed, EMBASE, and Web of Science, and pertinent studies published up until 5 March 2023 were reviewed. Random-effects models were utilized to consolidate the findings of continuous outcomes, such as diastolic and systolic BP, as well as the binary outcomes of hypertensive disorders of pregnancy (HDP). The present study included a total of 10 studies. First-trimester MBP exposure exhibited a positive association with mean systolic and diastolic BP during both the second and third trimesters (β = 1.05, 95% CI: 0.27, 1.83, I Hypertensive disorders of pregnancy (HDP) rank among the top contributors to maternal and neonatal mortality and morbidity ,2. HyperRecent evidence suggests that environmental factors, such as exposure to ambient air pollution and environmental chemicals, may also contribute to hypertensive disorders. Among these chemicals, phthalates—a group of non-persistent chemicals commonly used in consumer and personal care products—were linked to widespread exposure in pregnant women ,8. PhthaPrevious studies examining the association between phthalate metabolites and gestational BP and pregnancy-induced hypertension (PIH) have yielded mixed results. In an Ohio-based birth cohort study, prenatal urinary monobenzyl phthalate (MBzP) was associated with increased diastolic BP and the risk of PIH diseases . HoweverWhile some epidemiological studies have reported associations between gestational urinary phthalate concentrations and elevated BP or increased HDP risk, others have not. To better understand the reasons behind these divergent findings, further investigation is necessary to determine the potential adverse effects of phthalates on pregnancy outcomes. As such, we conducted a systematic review and meta-analysis of human epidemiological studies to evaluate the relationship between gestational urinary phthalate levels, BP during pregnancy, and the risk of HDP. http://www.prisma-statement.org/ (accessed on 5 March 2023)) (The present study adhered to PRISMA guidelines (h 2023)) , and wasWe conducted a search for studies published up to 5 March 2023 using three databases: Embase, PubMed, and Web of Science. Relevant keywords were determined based on the PECO framework . To geneNo restrictions were placed on study designs during the search process. Relevant studies were also identified by screening reviews and reference lists of search results. After removing duplicates, titles and abstracts underwent an initial screening, followed by a full-text review. Two authors (MYZ and JCQ) independently assessed all articles, with their findings reaching a consensus. In cases of disagreement, a third reviewer (CYH) examined the article and made the final decision.In alignment with the PECO elements, we applied the following inclusion criteria: (1) the population (P) consisted of pregnant women; (2) exposure (E) was determined by phthalate exposure measured from biological samples; (3) the comparator (C) involved a group with lower exposure levels; (4) the outcomes (O) included BP during pregnancy and risk of HDP, which were verified by physicians, medical records, or according to the International Classification of Diseases codes; and (5) the study was accessible as a full text and in English. The exclusion criteria included: (1) studies focusing on the general population; (2) studies concentrating on occupational exposure; and (3) studies without a reference group. Two authors (MYZ and JCQ) independently carried out the data extraction and quality assessment. From each eligible study, we collected the source (author name and publication year), location, study period, study design, phthalates examined, exposure assessment, exposure period, outcomes, covariates adjusted for, and main findings. Additionally, we contacted several corresponding study authors to request supplementary results not included in their published articles but relevant to our research. Additionally, if necessary, we contacted several corresponding study authors to request supplementary results not included in their published articles but relevant to our research.In our systematic review and meta-analysis, we assessed the quality of the incorporated studies by employing the Newcastle–Ottawa Scale (NOS) specifically designed for observational research . The NOSWe carried out a meta-analysis employing a random-effects model to accommodate variations both within and across studies. By utilizing the reported odds ratios (ORs) and their associated 95% confidence intervals (95% CIs), we calculated the combined ORs for the binary outcome of HDP. Additionally, coefficients from linear regressions were combined in a meta-analysis to estimate the effects of phthalate exposure on continuous outcomes, including diastolic and systolic BP. We performed separate meta-analyses for each trimester-specific exposure  and outcomes (diastolic BP and systolic BP) when at least three studies were available. Given the limited number of studies addressing various HDP types, we included all research on HDP , regardless of the employed definition, in order to provide an adequate basis for random-effects meta-analyses. 2 statistic (range: 0–100%). I2 values were classified as low, medium, or high based on values of 25, 50, or 75%, respectively [p-value of <0.05 for Egger’s test. If the p-value was less than 0.05, publication bias was present, and vice versa [p-values were two-sided with a significance level set at 0.05.For the purpose of facilitating effect estimate comparisons across studies, we transformed the documented ORs and 95% CIs to align with a standardized exposure increment . We assessed statistical heterogeneity among the selected studies using the Q-test and the Iectively . We emplce versa . For anaThe PRISMA flowchart, illustrating our literature search process, can be found in The majority (N = 7) of the included studies documented preeclampsia ,23,24,26The Newcastle–Ottawa Scale (NOS), ranging from 0 to 9 stars, was utilized to evaluate the quality of the studies, with a higher number of stars indicating superior quality. As shown in The meta-analysis synthesized outcomes regarding the associations between multiple different phthalates, BP during pregnancy, and HDP risk, which are presented in 2 = 93%; β = 0.40, 95% CI: 0.05, 0.74, I2 = 71%), respectively. The second trimester MBzP exposure was positively associated with the systolic BP and diastolic BP of the second trimester , respectively. In contrast, the first trimester MEHP exposure was negatively associated with the mean systolic BP and diastolic BP of the second and the second trimester , respectively.The aggregated findings on the impact of trimester-specific phthalates exposure throughout pregnancy on BP displayed varying outcomes. Some demonstrated a negative association with both diastolic and systolic BP. The first trimester MBP exposure was positively associated with the mean systolic BP and diastolic BP of the second and the second trimester . The collective findings indicate that trimester-specific phthalate exposure during pregnancy was not associated with HDP, with the exception of monoethyl phthalate (MEP) exposure. The combined effect estimates ranged from 1.01 to 1.18, with a low 95% confidence interval (CI) spanning from 0.86 to 1.02 and a high 95% CI extending from 1.09 to 1.41. However, almost all these combined effect estimates were not statistically significant. The only exception was MEP exposure, which was found to be associated with an increased risk of HDP , suggesting no evidence of publication bias. However, given the relatively small number of studies in our meta-analysis, these test results should be interpreted cautiously, as they may lack the power to detect publication bias in meta-analyses with a limited number of studies [The sensitivity analysis results demonstrated that the combined effect estimates remained generally stable when individual studies were excluded. Due to the limited number of studies included for each exposure and outcome combination, funnel plots were not conducted. Nonetheless, for all exposures, the  studies .In this meta-analysis, we synthesized data from 10 human epidemiological studies to investigate the connection between phthalate exposure, BP, and HDP risk. Our findings suggest that, aside from MBP, MBzP, and MEHP, the majority of phthalate metabolites show no association with BP. Notably, only MEP exposure was associated with a heightened risk of HDP.The impact of phthalate exposure on BP during pregnancy and HDP risk has attracted considerable interest in recent years. Soomro et al. found that prenatal exposure to phthalates, particularly MBP and MEP, could play a vital role in PIH . Werner Numerous factors could account for the discrepancies observed in the results of prior studies. Inconsistencies between studies investigating the same phthalate might arise from inadequate statistical power, variation in outcome assessment, divergent analysis methods, or differing study populations. While the majority of studies assessed phthalate levels during one trimester, the timing of exposure evaluation was not consistent across studies. It is well-established that phthalate plasma/serum concentrations decrease as pregnancy progresses due to the expansion of plasma volume and the distribution of phthalates into the fetal compartment .In terms of outcomes, three studies exclusively examined BP during pregnancy, one study focused on PE, and others investigated GH or other HDPs. Only a single study explored the association with repeated BP measurements throughout pregnancy . RecentlThe precise mechanisms underlying phthalate-induced elevated BP remain uncertain; however, current research provides some understanding. Phthalate metabolites function as agonists for PPARγ (peroxisome proliferator-activated receptor gamma), known to inhibit the renin-angiotensin-aldosterone system, an essential BP regulator ,33. PhthMeta-analyses can offer more accurate conclusions than individual studies by increasing statistical power, which is particularly crucial for rare outcomes. In our meta-analysis, we identified several significant relationships between phthalates and BP during pregnancy and risk of HDP, even though many individual studies failed to do so. The robustness of our findings was evident as the exclusion of individual studies typically had minimal impact on the results. Additionally, our meta-analysis showed no significant signs of small-study bias.However, our study has several limitations that should be considered when interpreting the results. First, while we included all available studies in three databases examining the effect of phthalates on BP during pregnancy and the risk of HDP up to 2023, insufficient data on this research topic prevented us from conducting subgroup analyses based on study design, location, and offspring gender. Second, the studies were conducted in various geographic regions and populations, leading to differences in phthalate exposure. This factor may further affect the measured concentrations of these phthalates at different times. Furthermore, the range of exposure varied among the included studies, which could influence the meta-analysis results. Third, we exclusively included studies that assessed phthalate levels in urine samples to maintain consistency and comparability in our analysis. Although phthalate metabolites in urine are considered suitable biomarkers for short-term exposure to parent compounds due to their rapid excretion and short half-life in humans , urinaryWhile some epidemiological evidence and potential mechanisms suggest that phthalates may be risk factors for elevated BP during pregnancy and HDP, additional research is necessary to verify this relationship and guide medical recommendations and environmental policies. Such research faces challenges, including logistical issues related to sample collection, timing, and the selection of specific phthalate metabolites for investigation. Acquiring well-timed samples from pregnant women and confirming their HDP diagnosis is both difficult and costly. Prior studies have indicated variations or interactions influenced by factors such as parity and fetal sex ,43. To dTo fully understand the effects of phthalates on health outcomes, future research must take into account their cumulative burden. Methods for exposure assessment and strategies for categorizing phthalates during risk assessment are being developed ,47. As eOur meta-analysis determined that there was a strong association between several phthalate metabolites  and BP during pregnancy, while MEP was found to be associated with an increased risk of HDP. However, these results should be interpreted cautiously due to the relatively small number of included studies. Given the considerable maternal and fetal morbidity and mortality associated with HDP, this study has significant public health implications. Nonetheless, additional research is required to clarify the underlying mechanisms.


However, VLCSFAs were inversely associated with CRC risk . Specifically, lauric acid, myristic acid, palmitic acid, heptadecanoic acid, and arachidic acid were positively associated with CRC risk, while behenic acid and lignoceric acid were inversely associated with CRC risk. This study indicates that higher levels of total serum SFAs and lower levels of serum VLCSFAs were associated with an increased risk of CRC in Chinese population. To reduce the risk of CRC, we recommend reducing the intake of foods containing palmitic acid and heptadecanoic acid such as animal products and dairy products, and moderately increasing the intake of foods containing VLCSFAs such as peanuts and canola oil.The association between circulating saturated fatty acids (SFAs) including very long-chain SFAs (VLCSFAs) and colorectal cancer (CRC) risk has not been clearly established. To investigate the association between serum SFAs and CRC risk in Chinese population, 680 CRC cases and 680 sex and age-matched  controls were recruited in our study. Serum levels of SFAs were detected by gas chromatography. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between serum SFAs and CRC risk. Results showed that total SFAs were positively associated with the risk of CRC (adjusted OR  Colorectal cancer (CRC) is the third most prevalent malignancy worldwide, with more than 1.9 million new CRC cases occurring in 2020, representing about one-tenth of cancer cases . Recent Although circulating SFAs have been suggested to play a promoting role in the development of breast cancer ,10, prosVery long-chain saturated fatty acids (VLCSFAs) have 20 or more carbons. Recent research suggests that VLCSFAs have a deep influence on inflammation resolution and ceramide-induced apoptosis, which could affect tumour growth ,18. SomeMost previous studies investigating the association between circulating SFAs and CRC risk were conducted in Western countries or developed countries, where dietary habits differ from Chinese population ,3,23. ToThis case-control study was conducted as part of a research program on dietary and lifestyle factors related to CRC in China. The study design has been described previously ,25. CaseControls were selected from two groups. One group was recruited from the Departments of Otorhinolaryngology, Vascular Surgery, and Plastic Surgery in the First Affiliated Hospital, Sun Yat-sen University, during the period of case collection for CRC. They mainly had sudden deafness, chronic otitis media, chronic sinusitis, polyp of the vocal cord, trigeminal neuralgia, varicose veins, orthopaedics, and facial paralysis. There was no evidence that the above diseases were related to dietary causes, so we selected the controls from these departments. The other group was enrolled from residents of the same community via advertisements, written invitations, or referrals from participants. Control subjects had the same inclusion and exclusion criteria as the cases, with the exception that they had no history or diagnosis of CRC. Totally, 2004 controls were recruited, and 1836 blood samples were successfully collected, with a response rate of 91.62%. A total of 680 controls  frequency-matched to the cases on 5-year age and sex were recruited for laboratory measurement.All participants gave written informed consent, including permission for medical records. This study was approved by the ethical committee of the School of Public Health of Sun Yat-sen University .2). Current smoking meant smoking a minimum of one cigarette per day for more than 6 consecutive months [All participants completed a structured questionnaire about sociodemographic characteristics, lifestyles , family history of cancer in first-degree relatives, and an 81-item semiquantitative food frequency questionnaire (FFQ) with trained interviewers. Relevant clinical information, such as tumour node metastasis (TNM) stage and histological diagnosis were extracted from medical records. Body mass index (BMI) was calculated by dividing weight (kg) by the squared height , 200 μL of physiological saline, and 50 μL of butylated hydroxytoluene ethanol to 50 μL of serum samples and vortexed them for 1 min. The serum samples were centrifuged at 8000 rpm for 5 min at 4 °C, then the organic layer (lower chloroform layer) was transferred to a reaction vial and dried with a nitrogen-blowing apparatus to obtain the extract. Then we added 750 μL of 14% boron trifluoride-methanol solution to the extract, vortexed for 1 min, and sealed the reaction vial at 90 °C for 1.5 h. After the reaction material cooled to room temperature, we added 1 mL of hexane and 0.9% sodium chloride solution and mixed thoroughly for 1 min. The serum samples were centrifuged at 8000 rpm for 5 min at 4 °C, and then the organic layer was extracted and blown dry with nitrogen blowing. Finally, 100 μL of fatty acid methyl esters was added with hexane and transferred to a brown sample vial.Serum levels of fatty acids were detected by gas chromatography (GC). Fatty acid methyl esters were extracted by the method previously reported ,33. In bThe fatty acid methyl esters were analysed by Agilent 7890A gas chromatography  on a capillary column DB-23 . We applied the standard product of fatty acid methyl esters as a standard. Individual fatty acid was validated using a commercial standard with known retention times. The analysers of fatty acids were completely blinded to information on participants, and peaks were calculated automatically. The serum levels of individual fatty acids were presented as the percentage (%) of total fatty acids, and we assumed undetectable levels for fatty acids values with missing data and assigned them a value of zero. To perform quality control, a quality control sample was put in every 50 samples tested, and the quality control samples were repeated every 50 samples. The intra- and inter-assay coefficients of variation ranged from 0.58 to 12.65% and 2.39 to 18.94%, respectively, which were consistent with previous results ,34,35.We selected the following fatty acids in this study: lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), heptadecanoic acid (C17:0), stearic acid (C18:0), arachidic acid (C20:0), behenic acid (C22:0), and lignoceric acid (C24:0). We summarized the data into the following two groups: VLCSFAs (C20:0 + C22:0 + C24:0) and total SFAs (C12:0 + C14:0 + C16:0 + C17:0 + C18:0 + C20:0 + C22:0 + C24:0).t-test, and the χ2-test for categorical variables. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between serum SFAs and CRC risk. Serum levels of SFAs were categorized into four levels  using the quartiles of each fatty acid distribution in the control group for men and women separately, and the Q1 with the lowest serum level was used as the referent group. Trends in the quartiles were tested by assigning each category to its median and using it as a continuous variable in the logistic regression model.All dietary intakes were adjusted for total energy intake using the residual method . We compPotential confounders were selected according to the comparison of factors between cases and controls, combined with previous relevant studies. Variables contained in all regression models were as follows: sex, age, residence, type of job, education, marital status, income, working physical activities, household and leisure-time physical activities, smoking, passive smoking, drinking, family history of cancer in first-degree relatives, BMI, total energy intake, dietary red and processed meat intake, dietary calcium intake, dietary fibre intake, serum MUFAs, and serum PUFAs.Stratified analysis by sex was carried out for the associations between serum SFAs and CRC risk. The interactions between sex and serum SFAs were evaluated by multiplicative models, containing the product term in the multivariable logistic regression models. Moreover, we also conducted subgroup analyses by cancer sites  and cancer stages (TNM stage I–II or TNM stage III–IV). Heterogeneity in the results between cancer sites or cancer stages was assessed using case-only analyses. Cancer sites or cancer stages were used as the dependent variable and serum SFAs as independent variables in the logistic regression model.p-values were two-sided and considered significant at p < 0.05.All data analyses were carried out using Stata software version 15.1 . All Among the 680 cases, there were 350 men and 330 women. In total, 403 were diagnosed with colon cancer and 277 with rectal cancer. There were 343 cases at TNM stage I-II, and 326 cases at TNM stage III-IV. Compared to controls, more cases had a low level of education, high proportions of being married and lower income, and were likely to engage in more physical activities in work. Smoking or passive smoking was more frequent in cases than in controls. The cases tended to have a family history of cancer in first-degree relatives, consume more red and processed meat and less calcium and fibre, and have lower levels of serum PUFAs .Q4 vs. Q1 = 2.64, 95%CI: 1.47–4.74, p-Trend < 0.001). However, serum VLCSFAs were inversely associated with CRC risk . Regarding the individual SFAs, lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), heptadecanoic acid (C17:0), and arachidic acid (C20:0) were positively associated with the risk of CRC . In contrast, behenic acid (C22:0) and lignoceric acid (C24:0) were inversely associated with CRC risk . However, the association of stearic acid (C18:0) with CRC risk was not statistically significant (p-Trend = 0.108).As shown in Q4 vs. Q1 = 14.65, 95% CI: 5.60–38.32, p-Trend < 0.001) but not among men (p-Interaction < 0.001) (p-Interaction < 0.05). In contrast, no significant interaction was observed between sex and serum lauric acid (C12:0), heptadecanoic acid (C17:0), behenic acid (C22:0), and VLCSFAs . Serum VLCSFAs were inversely associated with CRC risk only in men , but there was no significant interaction (p-Interaction = 0.067).Total SFAs were associated with an increased risk of CRC among women (adjusted OR < 0.001) . Signifip-Heterogeneity > 0.05) (p-Heterogeneity > 0.05)  , and sim > 0.05) .This study aimed to investigate the association between serum SFAs including VLCSFAs and CRC risk. The results showed that total SFAs were positively associated with CRC risk, whereas serum VLCSFAs were inversely associated with CRC risk. Specifically, serum levels of lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), heptadecanoic acid (C17:0), and arachidic acid (C20:0) were positively associated with CRC risk, while behenic acid (C22:0) and lignoceric acid (C24:0) were inversely associated with CRC risk.To our knowledge, no published studies have investigated the association of circulating lauric acid C12:0) with CRC risk. Our observation of the positive association between lauric acid (C12:0) and CRC risk was supported by a cellular study, which demonstrated that lauric acid induces cyclooxygenase overexpression in human tissues . One stu:0 with CConsistent with our results, two studies ,15 foundHeptadecanoic acid (C17:0) is mainly extracted from dairy products, thus heptadecanoic acid (C17:0) can be a biomarker of dairy product consumption . We founAt present, no other studies have been reported to investigate the association between circulating VLCSFAs and CRC risk. Studies examining the association of VLCSFAs with cardiovascular diseases ,20,43, dPositive associations of total serum SFAs with CRC risk were consistent with some previous studies. A case-control study in Japan showed that total serum SFAs were positively associated with the risk of colorectal adenoma , a precuTotal serum SFAs were found to be associated with an increased risk of CRC among women, but not among men, which is consistent with the Singapore Chinese Health Study . One posWe found no significant heterogeneity in CRC risk estimates for total serum SFAs and individual SFAs by cancer sites. Similarly, we found no significant heterogeneity in CRC risk estimates for total serum SFAs and individual SFAs by cancer stages. No previous studies have evaluated differences between circulating SFAs and the risk of CRC by cancer sites or cancer stages. Due to the small number of cases after stratification in our study, studies with more cases are needed to verify the relationship between circulating SFAs and the risk of CRC by cancer sites or cancer stages.To our knowledge, this is the first study to examine the association between serum SFAs and CRC risk in China. We used serum SFAs to estimate the link between SFAs and CRC risk, which can directly reflect the association between SFAs in vivo and CRC. Additionally, information on sociodemographic characteristics, lifestyles, and family history of cancer in first-degree relatives was collected and adjusted in multivariable regression models, which could reduce residual confounding as much as possible. Moreover, the levels of total serum SFAs in our study were comparable to the results of some studies among Chinese population ,62. A poThere are some limitations of our study. Firstly, selection bias might occur since the CRC patients we recruited were from the same hospital. However, Sun Yat-sen University Cancer Centre is the largest cancer centre in southern China, and patients with CRC at this centre have similar clinical characteristics to patients from other hospitals in China . TherefoThis study suggests that higher levels of total serum SFAs were associated with an elevated risk of CRC in Chinese population, while higher levels of serum VLCSFAs were associated with a lower risk. Herein, we report the first evidence that higher concentrations of serum VLCSFAs are associated with a lower risk of CRC, and this might provide new insights into the prevention of CRC. Further molecular biology studies are needed to identify the possible mechanisms of the protective roles of VLCSFAs. Since SFAs are either absorbed from dietary sources or derived from de novo fatty acid synthesis ; there s


Lymphovascular space invasion (LVSI) is a prognostic factor in the existing TNM classification system. The present meta-analysis assessed the role of LVSI in predicting the prognosis of stage IA to IIB cervical cancer (CC).PubMed, EMBASE, and Cochrane Library electronic databases were searched to determine relevant articles published in the English language. Our search deadline was May 2022. Critical Appraisal of Prognostic Studies was used to assess the quality for each article. Pooled hazard ratios (HRs) were used to evaluate the performance of LVSI in prognosis prediction.P = .006) and disease-free survival  for patients with CC. However, the disease-free survival and overall survival were significantly different on univariate analysis based on the subgroup analysis stratified by analysis method, but no obvious heterogeneity was found across diverse articles.We enrolled 8 studies involving 25,352 patients published after 2010. Thus, high LVSI was an unfavorable factor in predicting overall survival (HR, 2.08; 95% confidence interval, 1.63–2.66; The present study showed that LVSI predicts the poor prognostic outcome of stage IA to IIB CC. However, well-designed clinical articles should further assess the independent prognosis prediction performance of LVSI in CC. Surgery is the most favorable modality to treat stages ≤ IIA CC classified based on the International Federation of Gynecology and Obstetrics, whereas chemoradiotherapy has been recommended for more advanced stages.,3 The elevated lymph node dissection level affects the metastasis number based on normalized pN classification. Moreover, it possibly influences the altered tumor TNM stage while affecting prognosis prediction performance.,5 An important factor affecting CC prognostic outcome is lymph node metastasis (LNM).,7 In addition, myometrial invasion is considered the first well-recognized sign of aggressive behavior, whereas positive lymphovascular space invasion (LVSI) may predict an increased LNM risk, indicating an increased relapse risk, and it may be the factor that can independently predict prognosis.–10Cervical cancer (CC) is the fourth most common cause of morbidity and mortality among malignant tumors in women. In 2020, 604,000 patients were newly diagnosed with CC, with 342,000 deaths reported worldwide.,12 However, the association was not detected in the study by Haesen et al. Consequently, our study was conducted to analyze the prognosis prediction performance of LVSI for patients with stage IA to IIB CC.The survival prediction of stage IA to IIB CC based on LVSI is still controversial. Some studies reported that increased LVSI was associated with the poor prognostic outcome of CC. Ethical approval or patient consent was not necessary because of our study’s retrospective nature.This study was reported following the guidelines of the preferred reporting items of the systematic review and meta-analysis.We comprehensively searched Embase, PubMed, and Cochrane Library databases using keywords such as “lymphovascular space invasion” AND “cervical cancer” OR “cervical neoplasm.” Our search deadline was May 2022. The search procedure was implemented until no new relevant articles were detected. Moreover, the reference lists of the articles were also examined to determine potential studies. Eventually, 2 authors evaluated articles in line with the pre-set criteria.First, the articles were searched using keywords, and irrelevant articles were removed after evaluating their titles and abstracts. Second, the rest of the articles were screened according to study eligibility standards. We included articles conforming to the following criteria: patients pathologically diagnosed with stage IA to IIB CC, outcomes were overall survival (OS) and disease-free survival (DFS), and available or calculable hazard ratios (HRs) and 95% confidence intervals (CIs). Additionally, we excluded the following articles: letters, meeting summaries, commentary articles, posters, and those with unavailable results.Two authors collected data, and another author was invited to negotiate in case of any dispute. Data features included first author, publication year, subject origin, study design, case number, tumor stage, neoadjuvant therapy, threshold generation approach, cancer-specific results, LVSI threshold, and HRs with 95% CIs. This study mostly analyzed the performance of LVSI in the prognosis prediction in patients with CC. DFS is defined as the time from the first treatment to the date of disease progression, suggesting the period after successful treatment with no symptoms or disease effect. In this meta-analysis, we pooled progression-free survival (PFS) and recurrence-free survival (RFS) from the enrolled articles into DFS. Moreover, OS is defined as the duration from the first treatment to all-cause mortality.,17 We obtained multivariate HRs and 95% CIs and used univariate HRs to replace missing HRs from multivariate analysis. If HRs from uni- and multivariate analyses could not be obtained, the HRs were estimated using the approach of Parmar et al Kaplan–Meier method was used to analyze related variance using Engauge Digitizer (version 9.4). High LVSI plus HR of >1 and <1 were associated with dismal and good prognoses, respectively. Moreover, statistical heterogeneity was analyzed using chi-square Q test and I2 statistics. Obvious heterogeneity was determined by P < .05 and I2 > 50%, suggesting the adoption of a random-effects model; otherwise, the fixed-effects model must be used. RevMan version 5.3  and STATA version 12.0  were used for statistical analysis. Begg and Egger’s tests used STATA version 12.0 to evaluate bias. A P value of <.05 was considered statistically significant.We analyzed the association of LVSI with survival in patients with stage IA to IIB CC. Pooled HRs and 95% CIs were used to assess CC survival based on the same approach used in our previous study.–13,19–35 , case reports n = 12), non-relevance to CC (n = 11), and unavailable creditable data (n = 11). Finally, 20 qualified articles involving 25,352 cases in 2010 to 2021 were included in the meta-analysis2, non-reAll eligible articles published in 2010 to 2021 were retrospective, with a sample size of 47 to 10,314. Fifteen studies were from Asia , one from Belgium, one from France, and one from Italy. Each article analyzed stage IA to IIB CC cases, including treatments and histological characteristics. The follow-up duration was 3 to 338 months. Table https://www.cebm.net/wpcontent/uploads/2018/11/Prognosis.pdf; Fig. The study quality was assessed using Critical Appraisal of Prognostic Studies . Inter-study heterogeneity was detected, and the random-effects model was used to obtain significant outcomes  , suggesting significant results. Moreover, the funnel plots showed no obvious publication bias  , and 4 European articles showed obvious associations . In method-stratified analysis, the HR of the studies on uni- and multivariate regression was 2.21  and 2.33 , respectively. Endpoint-stratified analysis showed that qualified studies were classified into DFS, PFS, and RFS groups, indicating pooled HRs of 2.27 , 2.07 , and 2.25 , respectively.Eighteen studies evaluated the association between LVSI and DFS. When HRs were combined, high and higher LVSI indicated poor and worse DFS, respectively. The fixed-effects model was used to determine statistical significance  Fig. A. MoreovP = .006; I2 = 58.1%), with inter-study heterogeneity. Moreover, the random-effects model showed significant results  , suggesting significant results. The funnel plots showed no obvious publication bias  , and 2 European articles did not show any significant relationship . In the method-stratified analysis, the HRs of studies on uni- and multivariate regression were 2.04  and 2.26 , respectively.Twelve articles examined the association between OS and LVSI. When HRs were pooled, high and higher LVSI indicated poor and worse OS, respectively. The fixed-effects model showed a significant difference  is listed in the updated International Federation of Gynecology and Obstetrics 2018 classification system, and it markedly upstages uterine cancer and CC from stage I to stage III. Additionally, LVSI can be used to predict cancer prognosis of non-small cell lung carcinoma, rectal carcinoma, and oral squamous cell carcinomas based on the associated meta-analyses.–41The status of the lymph node has a critical effect on CC. Some studies indicate that positive LNM has a negative impact on patient survival, regardless of the stage at diagnosis. To the best of our knowledge, this meta-analysis was the first to analyze the significance of LVSI in CC prognosis prediction. This study included 20 qualified articles describing the associations between CC and LVSI. Although LVSI might be influenced by varied reasons, high LVSI indicated poor DFS  and OS  in stage IA to IIB CC based on the pooled analysis.The LVSI burden in CC remains unclear. Patients with CC can benefit if LVSI level predicts OS and DFS. LVSI represents the better approach to predict prognosis because it integrates data on locoregional metastasis burden and neck dissection type, thus combining the advantages of both parameters and overcoming their disadvantages.P = .000; I2 = 65.6%). Sensitivity analysis was performed to predict whether an individual article affected the pooled HRs, which showed unchanged results after removing every article, suggesting significant results. Funnel plots and Egger and Begg tests were performed to analyze possible publication bias, and no significant publication bias was obtained. However, the relationship between LVSI and survival was possibly impacted by some confounders. Consequently, subgroup analysis stratified by region, analysis method, and the endpoint was performed for EFS to investigate the heterogeneity source. In the method-stratified subgroup analysis, univariate analysis showed statistical significance, but no heterogeneity was detected. Among the 3 subgroups showing diverse survival end points, only two showed significant differences in PFS  and RFS , but no heterogeneity was detected. Therefore, the analysis method, HR source, and endpoint were the heterogeneity sources for DFS. Likewise, heterogeneity was detected for OS in LVSI prediction . We conducted a sensitivity analysis to analyze the effect of 1 individual article on pooled HRs, and the results remained unchanged when eliminating any 1 article, suggesting significant results. Significant publication bias was not detected after performing funnel plots and Egger and Begg tests. Therefore, we performed subgroup analysis stratified by region and analysis method for OS to investigate the heterogeneity source. Based on the region-stratified analysis, the European group showed statistical significance, but no heterogeneity was detected. Based on the analysis method-stratified subgroup analysis, the univariate analysis group showed statistical significance, and no heterogeneity was detected. Therefore, the analysis method, HR source, and endpoint were the possible heterogeneity sources for OS.Significant heterogeneity was found for LVSI in predicting DFS (The article quality should be considered, which is our study’s limitation. First, the Cochrane risk bias approach was used to assess the included articles, and we included high-quality articles. However, some had incomplete patient data. Moreover, these articles were retrospective; thus, more prospective studies that combine CC survival with LVSI are warranted. Second, because of CC heterogeneity, patients with different histological grades and stages and those receiving diverse treatments were included, which might affect patient survival and event occurrence. Third, only articles published in the English language were included, which might induce language bias. Finally, published articles were included in database searching, which could lead to publication bias. However, our results were reliable upon publication bias analysis.Patients with CC of different subtypes were administered with different treatments. Our study suggests that high LVSI predicts poor prognostic outcomes in patients with stage IA to IIB CC. However, our results should be further verified in larger, high-quality studies.Conceptualization: Yuan Huang, Xiangdan Li.Data curation: Xiangdan Li.Formal analysis: Yuan Huang, Xiangdan Li.Funding acquisition: Xiangdan Li, Lan Liu.Investigation: Weibo Wen, Xiangdan Li, Dongyuan Xu, Lan Liu.Methodology: Yuan Huang, Weibo Wen, Xiangdan Li, Dongyuan Xu, Lan Liu.Project administration: Yuan Huang, Weibo Wen, Dongyuan Xu, Lan Liu.Resources: Weibo Wen, Dongyuan Xu, Lan Liu.Software: Weibo Wen, Dongyuan Xu, Lan Liu.Supervision: Weibo Wen, Dongyuan Xu.Validation: Weibo Wen, Dongyuan Xu.


The effect of passive smoking exposure on the risk of type 2 diabetes has not been systematically studied. A meta-analysis was conducted to assess the association between passive smoking exposure and the risk of diabetes.We searched three major databases up to 31 October 2022 to identify relevant prospective cohort studies on the association between passive smoking and the risk of type 2 diabetes. The pooled relative risk (RR) and 95% confidence interval (CI) for the association between passive smoking exposure and the risk of type 2 diabetes were analyzed using a fixed-effect model.Ten prospective cohort studies were included in this meta-analysis, with a total of 251,620 participants involved. The pooled RR showed a significantly positive association between nonsmokers exposed to passive smoking and type 2 diabetes as compared to non-smokers who were not exposed to passive smoking . Sensitivity analysis indicated that the pooled RR was not substantially affected by any of the individual studies.Exposure to passive smoking increases the risk of type 2 diabetes. This study may have a positive effect on the prevention of type 2 diabetes.https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023372532. In partAlthough tobacco control is a major success story in public health after the adoption of the Framework Convention on Tobacco Control, smoking remains a leading risk of premature death and disability worldwide . EnvironEvidence of a significant association between type 2 diabetes and active smoking has been documented , 12. In To provide an up-to-date quantitative assessment of the association between passive smoking and type 2 diabetes, we conducted a meta-analysis based on the currently published prospective cohort studies to provide scientific and theoretical evidence for the prevention of type 2 diabetes.2The design, implementation, analysis, and reporting of our meta-analysis were reported in accordance with the PRISMA statement Table S12.1We conducted a systematic search of PubMed, Web of Science, and Cochrane Library up to 31 October 2022 to identify relevant prospective cohort studies on the association between passive smoking and the risk of type 2 diabetes. We used the following Mesh terms and combinations of words:  AND [“tobacco smoke pollution” (Mesh) OR “passive smoking” OR “secondhand smoking” OR “environmental tobacco smoke pollution” OR “air tobacco smoke pollution” OR “involuntary smoking”]. The search terms used in different databases are shown in 2.2We identified the possible eligible studies by performing an initial screen of identified abstracts or titles and then read the full articles to include eligible studies. The studies were selected if they met all of the following criteria: (1) being a prospective cohort study; (2) the exposure was passive smoking and the outcome was type 2 diabetes; (3) reported estimates of the relative risk (RR) or odds ratio (OR) or hazard ratio (HR) and its 95% confidence interval (CI). The studies were excluded if they met any of the following criteria: (1) being duplicate publications; (2) not being a prospective cohort study; (3) not being relevant; (4) being reviews, meta-analyses, meeting abstracts, and letters; (5) RR or OR or HR and its 95% CI not be reported. Studies with larger sample sizes were chosen among duplicate publications from the same prospective cohort study. Reviews or studies that did not report available information were excluded. The flow chart of the selection of studies is shown in 2.3Two investigators independently evaluated all relevant articles and identified eligible studies from the databases. Any disagreement about whether a study met the inclusion criteria was resolved through discussion to come to an agreement. The following information of the identified studies was recorded: first author, year of publication, sample size, new cases of type 2 diabetes, follow-up year, RR or OR or HR with corresponding 95% CI, age range, percentage of female, country, define of exposed groups, exposure site, and adjusted variables for each study.The Newcastle–Ottawa Scale (NOS) was used to assess study quality . This sc2.42I statistic was used to estimate the heterogeneity among the studies, and a larger value of 2I indicates a greater heterogeneity, with a p-value < 0.10 deemed to be significant. The RRs and 95% CIs in the included studies were visualized using forest plot. A funnel plot was used to visualize potential publication bias, Egger’s linear regression test was used to measure the asymmetry of the funnel plot, and a p-value < 0.05 was considered significant. Sensitivity analysis was used to examine the impact of a single study. When heterogeneity is high, possible sources of heterogeneity need to be explored by subgroup analyses. All tests were two-tailed, and statistical significance was defined as p < 0.05.When the incidence of an outcome of interest in the study population is low, OR is close to RR . In addi33.1The selection process of the study is shown in 3.23.3p = 0.252, 2 = I20.8%). The funnel plot in p < 0.05, Egger’s test).There were 10 prospective cohort studies evaluating the risk of passive smoking with type 2 diabetes. 3.4Sensitivity analysis examined the effect on the pooled RR by deleting one study each time. 4p < 0.001].Previous epidemiological studies have found that passive smoking is associated with the risk of type 2 diabetes , 27. On Type 2 diabetes is influenced by a variety of environmental factors, among which tobacco exposure may be an important risk factor . Active Our findings suggest that passive smoking is associated with type 2 diabetes, which is consistent with other research findings , 15. ThiIn recent years, environmental pollution caused by passive smoking has received more attention. Passive smoking not only affects the occurrence of type 2 diabetes but also is associated with respiratory diseases, cardiovascular diseases, and cancer , 39. In There are several potential limitations in this study. First, our meta-analysis included only the literature published in English, and, thus, the actual total number of eligible studies may be larger than the number of studies that we included. Second, because the exposure status of passive smoking is self-reported, there may be inaccurate reporting by participants that influence the risk estimates. Finally, on the basis of the fact that the research studies that we included are observational studies, they cannot clarify the causation. Furthermore, there was publication bias in our meta-analysis, whose main source was due to negative results that are not reported.5In conclusion, our study suggests that exposure to passive smoking increases the risk of developing type 2 diabetes. The finding has important public health implications for guiding the prevention of type 2 diabetes. By taking appropriate measures to reduce indoor tobacco smoke exposure, the risk of type 2 diabetes may be decreased. An additional meta-analysis that includes well-designed cohort or intervention studies is needed to confirm the current findings.The original contributions presented in the study are included in the article/Conception and design: QZ and Z-ZF. Search strategy, data extraction, analysis, and writing: G-QQ and LC. Statistical expertise and corrections: JZ, X-MW, YL, KY, and T-FL. All authors contributed to the article and approved the submitted version.


It is still uncertain whether the risk of dementia and cognitive impairment is related to thyroid disease. we carried out a meta-analysis and systematic review (PROSPERO: CRD42021290105) on the associations between thyroid disease and the risks of dementia and cognitive impairment.We searched PubMed, Embase, and Cochrane Library for studies published up to August 2022. The overall relative risk (RRs) and its 95% confidence interval (CIs) were calculated in the random-effects models. Subgroup analyses and meta-regression were conducted to explore the potential source of heterogeneity among studies. We tested and corrected for publication bias by funnel plot-based methods. The Newcastle-Ottawa Scale (NOS) or Agency for Healthcare Research and Quality (AHRQ) scale were used to evaluate the study quality of longitudinal studies and cross-sectional studies, respectively.A total of 15 studies were included in our meta-analysis. Our meta-analysis showed that hyperthyroidism  and subclinical hyperthyroidism  might be associated with an elevated risk for dementia, while hypothyroidism  and subclinical hypothyroidism  did not affect the risk.Hyperthyroidism and subclinical hyperthyroidism are predictors of dementia.PROSPERO, Identifier: CRD42021290105. Dementia is a progressive brain disease, which has brought heavy care and economic burdens to their families and society  and hypothyroidism (Hypo) are very common thyroid diseases which exert potentially devastating effects on the elderly and they are characterized by abnormal thyroid-stimulating hormone (TSH) and free thyroid hormones  to deeply explore the effect of thyroid disease on cognitive impairment and dementia. Our study may have immense clinical implications for the prevention and treatment of dementia.A previous meta-analysis reported a significant increase in the risk of cognitive impairment among people with subclinical hypothyroidism (SHypo)   OR (Dementia)) OR (Cognition)) OR (Cognitive)). There were no restrictions on the publication year. In addition, reference lists of previous review articles were hand-searched for additional relevant studies.We systematically search in PubMed, EMBASE, and the Cochrane Library for relevant studies published from inception to May, 2022, using the following search strategy: ((((((((Thyroid Diseases) OR (Thyroiditis))) OR (Goiter)) OR (Hyperthyroidism)) OR (Hypothyroidism)) OR (Thyroid Dysgenesis)) OR (Thyroid Neoplasms) OR (thyrotoxicosis)) AND  they were published in English, (2) they used a cohort or cross-sectional study design to examine the association between thyroid disease and the risk of cognitive impairment or dementia, (3) they included participants aged > 18 years, and (4) they provided relative risks (RR), hazard ratios (HR), odds ratios (OR) with corresponding 95% confidence intervals (CI) or the raw data that can be utilized to calculate these numbers. Studies were excluded if they met any of the following criteria: (1) the risk estimate was not accessible, (2) only the abstract was available and (3) the article was a case report, an animal study, a letter to the editor or a comment. Additionally, if an article studied two different cohorts, both cohorts were included in our meta-analysis. Literature selection was conducted by two independent investigators (LYM and ZB), and any disagreement on study inclusion was discussed to reach a consensus. The following data were extracted from each studies: study characteristics, population characteristics, and result assessments. We would contact the corresponding authors if the above data was not available. A specific formula would be used to convert OR to RR when a study only reported OR   and their 95% confidence intervals (CIs) from individual studies were pooled using a random-effects model . A two-sided P < 0.05 was considered statistically significant.All the statistical analyses were conducted using STATA  . The participants had a mean age of 66.81 years, with a female proportion of 58.71%. Among these studies, six cohort studies reported the association of Hype with dementia . The participants had a mean age of 76.49 years with a female proportion of 55.90%. Among these studies, two studies reported the association of Hype with dementia  rather than AD  or VaD  (p = 0.299). A symmetric funnel plot  . Meta-re2 = 20%) . Sensiti2 = 20%) . Subgrou2 = 20%) . Publicanel plot  also ind2 = 94%). In the subgroup analysis according to subtypes of dementia, Hypo was associated with a decreased risk of AD  rather than VaD risk  (2 = 94%) was observed in the studies on the association between Hypo and dementia. Meta-regression revealed that adjusted vascular factors were the source of heterogeneity (p < 0.05)  . The hig < 0.05) . Sensiti < 0.05) . Hypothy < 0.05)  (RR = 1. < 0.05) . Subgrou < 0.05) .p = 0.858, p = 0.744, No publication bias was revealed in the association between Hypo and dementia .We conducted two separate subgroup analyses of the included studies on Hype and Hypo according to whether the abnormal thyroid function status was clinical or subclinical. A meta-analysis of four studies with 28,997 individuals showed that patients with SHype had an increased risk of dementia . Additionally, the greater heterogeneity may be caused by different abnormal thyroid function statuses.Another meta-analysis of four studies with 20,594 individuals showed that patients with SHypo were not associated with the risk of ACD compared to patients without SHypo  in patients with Hype compared with those without Hype (2 = 0%), and then a meta-analysis of 2 studies with 2,110 individuals showed that Hypo was also not associated with the risk of cognitive impairment   .The results of our study showed that in longitudinal studies, Hype and SHype would increase the risk of ACD, whereas Hypo and SHypo were not associated with ACD risk; and both Hype and Hypo were not associated with ACD risk in cross-sectional studies.Our analyses revealed that in longitudinal studies, Hype would increase the risk of ACD with moderate heterogeneity, but it was not associated with the risks of ACD subtypes (AD and VaD). The observed heterogeneity might be due to cardiovascular factors. We performed a meta-regression to explore whether cardiovascular factors were the source of heterogeneity, which yielded positive results. To eliminate the interference of cardiovascular factors, we conducted a subgroup analysis according to whether the study had adjustment for cardiovascular factors, which showed that Hype still significantly increased the risk of dementia after the adjustment. This further demonstrated that Hype was associated with dementia risk, independent of cardiovascular factors, which was validated by sensitivity analyses. This association was partly due to the decreased functional connectivity between the hippocampus and cortex .Our meta-analysis showed that in longitudinal studies, Hypo was not associated with ACD, with high heterogeneity. Based on the results of meta-regression, the heterogeneity might come from adjusted confounders (cardiovascular factors and APOEε4), and the source of participants in cohorts. The heterogeneities were significantly reduced in the subgroup analyses according to whether the cardiovascular factors were adjusted and the female proportion (>55% vs. < 55%). Interestingly, the associations became significant when specific factors  were included as covariates, suggesting the stratified or mediating effects might exist. Moreover, Hypo was negatively associated with AD. Sensitivity analysis showed the association between Hypo and AD became not significant after the exclusion of one study. In addition, we found that SHypo was not associated with the risk of dementia.The strengths of our meta-analysis should be mentioned. Firstly, only observational studies were included in our meta-analysis, interventional studies were excluded. Hence, all the included articles were studies of medium-to-high quality. Secondly, this meta-analysis did not show evident publication bias, indicating no small-study effects. Thirdly, since the longitudinal and cross-sectional studies were discussed separately in our meta-analyses, our results were more reliable with reduced bias. Fourthly, there were moderate-to-substantial heterogeneities in the main analyses. The possible sources of these heterogeneities were systematically evaluated using subgroup analyses. Lastly, our study is a comprehensive study. We explored the relationships of thyroid diseases with dementia as well as dementia subtypes. And we updated our data and included more studies.This study also has some limitations. (1) The primary analysis showed significant heterogeneity. After carrying out subgroup analyses, the heterogeneity of results may be due to differences in sample size, methodological quality, demographic and ethno-racial characteristics, various covariate assessments, follow-up duration, subtypes of dementia, and methods for TSH measurement. Owing to inadequate information, it was difficult to analyze the heterogeneity further. (2) Studies focused on the relationships of thyroid cancer and thyroiditis with the risk of dementia are rare. Additional reliable evidence is needed for these relationships. (3) The associations identified by the analyses based on observational studies, but little is known about the causality. Randomized controlled trials are warranted in the future to test the roles of thyroid disease in preventing cognitive decline or dementia. (4) Due to the small scale of observational studies exploring the subtypes of dementia, it was difficult to conduct a meta-analysis of the relationships between thyroid diseases and the subtypes of dementia. More high-quality cohorts or nest case-control studies on the subtypes of dementia are warranted in the future.Our systematic review and meta-analysis could provide evidence for positive associations of Hype and SHype with an increased risk of incident dementia. Hypo was found to reduce the risk of AD. Hence, Hype and SHype might be potentially modifiable causes of dementia, and enhanced screening services, timely intervention, and efficient treatment for Hype and SHype would reduce the incidence of dementia. In addition, more observational studies are urgently needed to explore the associations between thyroid diseases and the risk of dementia.The original contributions presented in the study are included in the article/Concept, design, obtained funding, administrative, technical, and material support: LT. Drafting of the manuscript, statistical analysis, and chart design: L-YM and BZ. Acquisition, analysis, or interpretation of data, and critical revision of the manuscript for important intellectual content: all authors. All authors contributed to the article and approved the submitted version.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the upper and lower motor neurons. Though the pathogenesis of ALS is still unclear, exploring the associations between risk factors and ALS can provide reliable evidence to find the pathogenesis. This meta-analysis aims to synthesize all related risk factors of ALS to understand this disease comprehensively.We searched the following databases: PubMed, EMBASE, Cochrane library, Web of Science, and Scopus. Moreover, observational studies, including cohort studies, and case-control studies, were included in this meta-analysis.A total of 36 eligible observational studies were included, and 10 of them were cohort studies and the rest were case-control studies. We found six factors exacerbated the progression of disease: head trauma , physical activity , electric shock , military service , pesticides , and lead exposure . Of note, type 2 diabetes mellitus was a protective factor for ALS. However, cerebrovascular disease , agriculture , industry , service , smoking , chemicals , and heavy metal  were not risk factors for ALS based on meta-analyses.Head trauma, physical activity, electric shock, military service, pesticides, and lead were risk factors for ALS onset and progression. But DM was a protective factor. This finding provides a better understanding of ALS risk factors with strong evidence for clinicians to rationalize clinical intervention strategies.https://inplasy.com/inplasy-2022-9-0118/, INPLASY202290118. Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) affecting the upper and lower motor neurons in the spinal bulb, cerebral cortex, and spinal cord  guidelines  were searched for unpublished data. The search strategy of PubMed is shown in We searched the following electronic databases PubMed, EMBASE, Web of Science, Cochrane library, and Scopus to identify relevant studies from January 2012 to June 2022, using a combination of MeSH terms and keywords: “Amyotrophic Lateral Sclerosis,” “risk factors,” “case-control studies,” “cross-sectional studies,” and “Cohort Studies.” Meanwhile, we comprehensively searched observational clinical trials including cohort and case-control studies, which are ongoing via the WHO International Clinical Trials Registry Platform (WHO ICTRP) and Observational studies include cross-sectional studies, case-control studies, and cohort studies. For the part of cross-sectional studies and case-control studies, the inclusion criteria for the meta-analysis were as follows: (1) the original studies reported the relationship between specific risk factors and ALS, as well as odds ratio (OR) and 95% confidence interval (CI); (2) participants were diagnosed with ALS by professional medical institutions regardless of nation, age, sex, or race; (3) healthy dwellers or patients without neurodegenerative disease were assigned to the control group; (4) NOS assessment with higher than 7 scores. For the part of cohort studies, the original studies were required to provide adjusted relative risk (RR) or hazard ratio (HR) and 95% CI, and other criteria were the same as for the case-control studies.The exclusion criteria were as follows: (1) ALS patients accompanied by other neurodegenerative diseases; (2) systematic review, randomized controlled trials, case reports, animal research, and conference papers; (3) repeated publications and data-missing studies; (4) studies with no risk factor reported, or studies reported risk factors but no OR, RR; (5) unreasonable statistical methods; (6) the NOS quality assessment below seven stars.All retrieved studies were managed with NoteExpress 3.0 software. Firstly, two independent reviewers excluded studies not meeting the inclusion criteria after reading the title and abstract. And then, we downloaded the rest of included studies and read the full text to check which studies followed the inclusion criteria. We reached a consensus by discussing any disagreements in the systematic review process with a third reviewer.Two reviewers independently extracted the following items of included studies: title, published year, first author, type of study design, source of cases and controls, numbers of patients and controls, risk factor (s), OR, RR, HR, and CI. After extracting data, two investigators cross-checked the data. For the potential studies with missing data, we contacted the corresponding author for raw data via email. Any disagreement would be resolved by discussion.Two independent reviewers assessed the quality of case-control and cohort studies by the Newcastle-Ottawa scale (NOS) Stang, . A case-I2 statistics assess heterogeneity . Therefore, the fixed-effects model was performed for the meta-analysis of head trauma, and it was a risk factor for ALS , which indicated that a 1.26 times higher risk of developing ALS with head trauma than without experiencing head trauma , and the random effects model was performed for the meta-analysis. The results indicated that CVD was not a risk factor for ALS . After reading the above five studies comprehensively, we found three case-control studies  in the case-control study group. A fixed-effects model was performed for meta-analysis. The results indicated that DM was a protective factor for the onset and progression of ALS . Besides, the risk of developing ALS was 26% lower in those with DM than those without DM  AgricultureI2 = 8.8%). A fixed-effects model was performed for meta-analysis. Based on the forest plot, agriculture was not a risk factor for ALS  IndustryI2 = 0%), and a fixed-effects model was performed for meta-analysis, concluding that industry was not a risk factor for ALS   .(3) ServiceI2 = 56.6%), and a random-effects model was performed for meta-analysis. From the forest plot, we could learn that the service industry was not a risk factor for ALS , and a random-effects model was performed for the meta-analysis. The result indicated that smoking was not a risk factor for ALS . To find the source of heterogeneity, we performed sensitivity analysis and found that Rosenbohm et al. (I2 = 24.1%). Finally, a fixed-effects model was chosen for meta-analysis, and vigorous physical activity was considered a risk factor for ALS . Moreover, we concluded that about 1.06 times higher as much as in those who did not take the vigor exercise . A fixed-effects model was chosen for the meta-analysis. From the result, we concluded that electric shock was a risk factor for ALS , which indicated the risk of suffering from ALS in electric shock environments was 2.78 times higher than in non-electric shock environments , and a fixed-effects model was selected for meta-analysis. From the result of the forest plot, military service was a risk factor for ALS , and those with military service had 1.34 times the risk of ALS of those who did not experience it , and a fixed-effects model was selected for meta-analysis. From the forest plot, we concluded that pesticide was a risk factor for ALS . In addition, the risk of suffering from ALS in those exposed to pesticides was 1.96 times higher than in those who were not . Based on the sensitivity analysis result, Su et al. , though it was still present. A random-effects model was performed for meta-analysis. We concluded that lead was a risk factor for ALS . The risk of ALS in those exposed to lead was 2.31 times higher than in those not exposed  according to the forest plot. Moreover, the random effect model was selected for meta-analysis. In conclusion, the chemical agent was not a risk factor for ALS , and the fixed-effects model was selected for meta-analysis. Based on the statistical result, we concluded that heavy metals were not risk factors for ALS  were not feasible. Observational studies, as a component of epidemiological studies, are effective study types for exploring risk factors for the disease. This study aimed to explore the risk factors for ALS and perform a systematic review and meta-analysis based on observational studies.We used STATA 15.0 software and Review Manager 5.3 for meta-analysis. Based on the statistical analyses, we concluded that head trauma, physical activity, electrical shock, military service, pesticides, and lead were related to the onset and progression of ALS, but diabetes mellitus was its protective factor.In this study, head trauma was a risk factor for ALS, and the relationship between the progression of ALS and head trauma has drawn attention among researchers. Head trauma is known to result in neurodegenerative diseases and cognitive impairment  category. Of note, due to the limited number of studies, five risk factors, including CVD, smoking, military, chemical, and heavy metal, only had two studies when meta-analyses were performed. Nevertheless, the PRISMA guideline recommends that a meta-analysis of one outcome be conducted with more than three studies. Under this circumstance, we should interpret the results with caution. We hope more relevant and high-quality observational studies will be included and provide a more reliable result. In addition, although ORs with fully adjusted models were used in our study, confounders varied across studies and may have had some degree of influence on the results. Finally, the only included studies were papers that could be published in the public domain, so we need to consider the effect of publication bias on the results of this study.Besides, we classified the risk factors into lifestyle, underlying disease history, and occupation according to the nature of the risk factors. Physical activity, electric shock, and smoking could be defined as a lifestyle. CVD, DM, and head trauma are defined as underlying diseases. Lead, pesticides, military service, chemicals, and heavy metals are considered occupations. Due to inconsistencies between studies, effect sizes could hardly be combined according to the inclusion and exclusion criteria. However, we still hope that interaction and possible superpositions effects between a class of factors could be analyzed with more high-quality studies.Taken together, we investigated the following risk factors associated with the onset and progression of ALS: head trauma, physical activity, electric shock, military service, pesticides, and lead. However, in meta-analyses, CVD, occupation, smoking, chemicals, and heavy metals were not associated with ALS onset and progression. In addition, DM was considered as a protective factor, which helped patients with DM complicated by ALS to assess their prognosis better. Moreover, we look forward that more longitudinal studies will be conducted to further elucidate the relationship between the type of DM and ALS onset and progression.The original contributions presented in the study are included in the article/BC and DX contributed to the studies retrieval and data extraction. QZ and YZ designed and developed the framework for the manuscript. JZ and YZ analyzed the data. HH and JH manipulated the software. All authors contributed to the article's writing, read the manuscript, and agreed to submit this version.