I2 = 80.8%) and 13%  for T2D, 9%  and 8%  for CVDs, and 10%  and 7%  for all-cause mortality. Linear relationships were found for SSBs with T2D and CVDs. Non-linear relationships were found for ASBs with T2D, CVDs, and all-cause mortality and for SSBs with all-cause mortality. The findings from the current meta-analysis indicate that increased consumption of SSBs and ASBs is associated with the risk of T2D, CVDs, and all-cause mortality.Although studies have examined the association between habitual consumption of sugar- (SSBs) and artificially sweetened beverages (ASBs) and health outcomes, the results are inconclusive. Here, we conducted a dose-response meta-analysis of prospective cohort studies in order to summarize the relationship between SSBs and ASBs consumption and risk of type 2 diabetes (T2D), cardiovascular diseases (CVDs), and all-cause mortality. All relevant articles were systematically searched in PubMed, Embase, and Ovid databases until 20 June 2020. Thirty-four studies met the inclusion criteria and were eligible for analysis. Summary relative risks (RRs) and 95% confidence intervals (95% CI) were estimated using random effects or fixed-effects model for highest versus lowest intake categories, as well as for linear and non-linear relationships. With each additional SSB and ASB serving per day, the risk increased by 27% (RR: 1.27, 95%CI: 1.15–1.41,  Sugar-sweetened beverages  refer to the beverages with added sugar or sweeteners that have been prevalent worldwide, especially among younger adults, with their intake frequency and portion size increasing markedly in most countries over the last several decades ,3,4,5,6.Type 2 diabetes (T2D), characterized by increased blood glucose levels and insulin resistance, is a major risk factor for cardiovascular diseases (CVDs), which is mainly responsible for half the mortality in T2D patients . As a maThus, we performed an updated comprehensive systemic review and a meta-analysis of all relevant prospective cohort studies published in recent years to synthesize knowledge of the association between SSBs and ASBs consumption and risks of T2D, CVDs, and all-cause mortality and to explore their dose-response relationships. The aim of this article is to provide health evidence for the relationship between beverages and health outcomes based on previous research and to give people a clear understanding of SSBs and ASBs.This report has been prepared in accordance with the PRISMA guidelines . We systAfter the removal of duplications, two authors (Y.M and S.L) independently reviewed the titles and abstracts of all studies and selected eligible studies based on the following criteria: (1) prospective design ; (2) measured and reported SSBs or ASBs as exposure and in at least two categories, and reported T2D, CVDs, or all-cause mortality as the outcomes; (3) a study population that was healthy at baseline; (4) studies that reported relative risks (RRs), hazard ratios (HRs), or odds ratios (ORs) with 95% confidence intervals (CIs), or data to calculate these; (5) the language is English. We excluded repetitive articles, letters, comments, reviews, meta-analyses, studies with incomplete, incorrect or uncertain data, and papers with unavailable full texts. Any disagreements between the two authors were resolved through discussion under the supervision of a third author (Y.X).According to our search strategy, 11,822 published articles were identified. After removing 4982 duplicates, 6840 articles were reserved for further review; 6806 articles were excluded after screening for titles and abstracts. Finally, 34 relevant articles were selected for the systematic review and meta-analysis on the basis of full-text reviews.. For theI2 statistic [I2 greater than 50% was considered as significant heterogeneity among studies, and random-effects models could account for the variation, which provided more conservative results than fixed-effects models [I2 lower than 50% were assessed as non-significant heterogeneity among studies and conducted fixed-effects models for meta-analysis. We performed several subgroup analyses based on gender, follow-up duration (≤10 or >10 years), geographical region , number of participants , adjustments for main confounding variables  to test the association between each factor and each result and to find the potential source of heterogeneity. Sensitivity analyses were evaluated to explore that whether the pooled RR could be significantly affected by a single study. The potential publication biases were evaluated by using funnel plots and further tested by Begg’s test [p-values < 0.05 were considered as statistically significant for all tests.All statistical analyses were performed using STATA version 15.1 . The intake of SSBs or ASBs was considered as the main exposure. We defined SSBs as any sweetened beverages, including sweet sugar drinks, sweetened cola, sugar-sweetened soft drinks, sugar-sweetened sodas, orange juices, apple juices, and other fruit juices, but did not include diet or non-caloric beverages. The ASBs referred to low caloric soft drinks as reported in each study. The RRs and 95% CIs were considered as the effect size, and the reported HRs, or ORs were considered to be equal to RRs. We pooled the reported risk estimates of the highest level compared to the lowest category of SSBs or ASBs . The hettatistic . I2 greas models . On the g’s test  and Eggeg’s test . p-valuep-value conducted by the fixed-effects model was greater than 0.05, which meant that the null hypothesis could not be rejected, we used the fixed-effects model; on the contrary, the random-effects model was chosen. The regression parameter test was performed to determine the linear or non-linear model, and the linear model would be selected when the p-value was above 0.05.Additional dose-response analyses were performed by using all available data points from each study. The studies with reported sufficient information were eligible for inclusion if they: (1) considered the lowest category as the reference; (2) reported beverage intake in at least three categories; (3) reported the range, median, or mean of each category; (4) reported the number of cases and participants in each category of beverage intake; (5) reported adjusted RR, HR, or OR with 95% CI of each category. For the highest category without an upper limit, we used the lower limit plus 1/2 of the range of interval of the previous category to estimate . When thWe identified 17 prospective cohort studies with 645,658 participants from nine countries and regions that were eligible for the analysis of beverage intake and the risk of T2D. Two studies included only males , six stuI2 = 29.9%, Pheterogeneity = 0.102) , with low evidence of heterogeneity (= 0.102) a. No par= 0.102) a. Then wI2 = 80.8%, Pheterogeneity < 0.001) (p = 0.344), and the Egger’s test (p = 0.016) were used to evaluate publication bias. The results showed a linear relationship between T2D and SSBs intake  a. We seq< 0.001) a, the Bes intake a.I2 = 53.5%, Pheterogeneity = 0.028) . There were nine groups of data in ASBs intake and T2D, less than 10 groups. According to the Cochrane Handbook, we did not evaluate publication bias. ASBs intake contributed to an 18% higher risk of T2D in these cohorts  when compared the highest category with the lowest category, with moderate evidence of heterogeneity (= 0.028) b. One laI2 = 78.7%, p < 0.001)  b. After < 0.001) b.Ten prospective cohort studies with 582,082 participants from three countries were eligible for the analysis of beverage intake and the risk of CVDs. There were three male studies ,63,64, fI2 = 14.7%, Pheterogeneity = 0.293)  with low evidence of heterogeneity (= 0.293) c. No par= 0.293) b, and thI2 = 42.7%, Pheterogeneity = 0.065) (p = 1.000), and the Egger’s test (p = 0.543). A linear relationship was observed between CVDs and SSBs intake  c. No par= 0.065) b, the Bes intake c.I2 = 57.4%, Pheterogeneity = 0.021) . We did not evaluate the publication bias, because of only eight groups of data in ASB intake and CVDs, less than 10 groups, according to the Cochrane Handbook. As for ASBs intake, a 17% higher risk of CVDs was shown in these cohorts , with moderate evidence of heterogeneity (= 0.021) d. RemoviI2 = 45.5%, p = 0.119)  d. No par= 0.119) d.Eight prospective cohort studies with 999,689 participants from 3 countries were eligible for the analysis of beverage intake and the risk of all-cause mortality. There was one study for males , two stuI2 = 83.0%, Pheterogeneity < 0.001) , with high evidence of heterogeneity (< 0.001) e. We seqI2 = 86.3%, p < 0.001)  e. After < 0.001) e.I2 = 78.9%, Pheterogeneity < 0.001) , with high evidence of heterogeneity (< 0.001) f. The heI2 = 76.9%, p = 0.013)  f. After = 0.013) f.According to the results, all three diseases showed heterogeneous changes in the subgroup analysis of adjustments, such as education, energy intake, fruit and vegetable intake, and baseline hypertension. In addition, in terms of T2D and CVDs, after the subgroup analysis of such factors as gender, follow-up duration, geographical region, number of participants, and BMI, there were heterogeneous changes in each group. These subgroup analyses may be the source of inter-study heterogeneity Findings from our systematic review and meta-analysis clearly showed that long-term consumption of SSBs and ASBs was positively associated with the risks of T2D, CVDs, and all-cause mortality. In the sensitivity analysis, the associations of SSBs consumption with T2D, CVDs, and all-cause mortality were stable, as well as ASBs consumption with all-cause mortality, while the relationships of ASBs consumption with T2D and CVDs were less evident. Publication bias was not discovered between SSBs consumption and T2D but was likely to exist between SSBs consumption and CVDs. Considering the health effects of SSBs and ASBs, the bias towards positive results seems reasonable, which showed that it was necessary to improve the quality of the evidence and give the rigorous interpretation of the results. For SBBs consumption, linear associations were found with risk of T2D and CVDs, and a non-linear association was found with risk of all-cause mortality, and their risks were increased by 27%, 19%, and 10% for each serving increase, respectively. For ASBs, non-linear associations with the risk all three outcomes and their risks were increased by 13%, 8%, and 7% for each serving increase, respectively.Compared with the original research, we did the statistical analysis based on multiple studies, and the outcomes could provide more reliable guidance for nutrition practice. Although several meta-analyses have been performed, they have differences in some places. In recent years, there have been substantial studies about SSBs and a limited number of studies involved in ASBs, and we brought all the relevant studies  into the present study. We focused on the prospective cohort studies in which more people would participate when comparing with the intervention studies. Furthermore, we extracted the data with the most adjustments in order to minimize the interference of other factors on the results, subgroup analyses were performed to provide multiple explanations for inter-study heterogeneity, and the dose-response relationships were analyzed to obtain accurate results of data. Compared with previous meta-analyses ,27, six The possible biological mechanisms involved in the relationships between SSBs consumption and risks of T2D, CVDs, and all-cause mortality might be explained by several reasons. First, the previous study showed that consumption of fructose, rich in SSBs, could increase de novo lipogenesis and visceral adipose deposition and induce more production of triglyceride, resulting in dyslipidemia, obesity, or metabolic syndromes . AnotherThe adverse effects of ASBs consumption on health outcomes are still unclear. It was noteworthy that ASBs intake was found to be not accompanied by typical and expected post-ingestive consequences, such as the release of insulin after meals, and therefore, this might degrade the capacity of sweet tastes to evoke these responses, resulting in higher blood glucose levels and more consequences, such as obesity, metabolic syndromes, and diabetes ,76,77. FThere are several limitations to this study. Firstly, we extracted the effect sizes of the highest category versus the lowest category and achieved more intuitive risk outcomes, which might lead to larger risk outcomes because the results could not represent the basic consumption levels of beverages in the population. Secondly, the subgroups of dosages varied among different studies, which increased the difficulty of meta-analyses. Furthermore, dietary habits, especially for SSBs and ASBs intake, would change over time, resulting in uncertainties in their tracking process that would affect the final outcomes. Additionally, although the NOS scores in the studies were high, there was heterogeneity among them. Finally, some part of the meta-analyses was the lack of data support due to the limited number of studies. Our study also has some advantages over others. The meta-analysis was performed based on all prospective cohort studies published in recent years, which discussed the associations of SSBs and ASBs with T2D, CVDs, and all-cause mortality. The scope of our study was wide, the population was large, the quality of studies was at a high level, and the data with the most adjustments were selected for statistics so that our results were more comprehensive, representative, and reliable for clinical application.Long-term consumption of SSBs and ASBs increased the risks of T2D, CVDs, and all-cause mortality in the present study. These findings of SSBs were stable in sensitivity analyses assessing the influence of population characteristics, potential residual confounding, and publication bias. On the contrary, although ASBs have also shown the ability to increase the risks of T2D, CVDs, and all-cause mortality, the quality of the evidence is limited by potential bias and heterogeneity due to the design of the study. More evidence is needed for further analysis and to improve the accuracy of the conclusions. Although the reasons for the connections were unclear, the results suggested that people should limit their consumption of SSBs and ASBs in order to reduce the adverse health effects.


A high intake of dietary fibre has been associated with a reduced risk of several chronic diseases. This study aimed to review the current evidence on dietary fibre in relation to asthma, rhinitis and lung function impairment. Electronic databases were searched in June 2021 for studies on the association between dietary fibre and asthma, rhinitis, chronic obstructive pulmonary disease (COPD) and lung function. Observational studies with cross-sectional, case–control or prospective designs were included. Studies on animals, case studies and intervention studies were excluded. The quality of the evidence from individual studies was evaluated using the RoB-NObs tool. The World Cancer Research Fund criteria were used to grade the strength of the evidence. Twenty studies were included in this systematic review, of which ten were cohort studies, eight cross-sectional and two case–control studies. Fibre intake during pregnancy or childhood was examined in three studies, while seventeen studies examined the intake during adulthood. There was probable evidence for an inverse association between dietary fibre and COPD and suggestive evidence for a positive association with lung function. However, the evidence regarding asthma and rhinitis was limited and inconsistent. Further research is needed on dietary fibre intake and asthma, rhinitis and lung function among adults and children. Epidemiologic evidence has consistently shown that a high intake of dietary fibre is associated with a reduced risk of several chronic diseases, such as cardiovascular diseases, cancer, type 2 diabetes and obesity, as well as of total and specific-cause mortality ,2,3. FibAsthma is a chronic inflammatory disorder of the airways and the most common chronic disease among children. It is a cause of substantial burden of a disease, including a reduced quality of life in people of all ages and premature death . ChildreIn recent years, epidemiological studies have also explored the association between dietary fibres and respiratory and allergic diseases. Dietary fibres may influence the development of respiratory and atopic outcomes through different mechanisms—for example, through the antioxidant and anti-inflammatory effects of whole grains, by enhancing the bio-accessibility of antioxidants from fruits and vegetables or through immunomodulatory effects induced by changes in the gut microbiota ,10,11. HThe aim of this systematic review is, therefore, to explore the existing evidence on dietary fibre intake in relation to asthma, rhinitis, COPD and lung function.This systematic review was performed according to the PRISMA guidelines  checkli, and an Original studies reporting empirical findings on the association between dietary fibre intake and at least one outcome of interest  were searched. Observational studies on humans with cross-sectional, case–control or prospective designs were included. Studies on animals, case studies (case reports or case series) and intervention studies were excluded.Systematic searches using predefined search terms were performed in multiple databases, including Medline (OVID), Embase, Cochrane Library, Web of Science and Scopus. The databases were searched from inception, limited to the English, French, German and Swedish languages. Additionally, reference lists of the articles included in the review and of relevant review studies were manually screened to identify other relevant articles. Information from conference abstracts, dissertations and grey literature  was not included.The search was conducted in June 2021 based on the term construct used for Medline see the , assisteThe search results were exported to Endnote X9, where duplicates were excluded. As the first step, relevant articles were considered based on their title and abstract. At the second step, full-text versions of the selected papers were examined. In case there were multiple publications from the same cohort study, they were all included if they referred to different outcomes of interest. Following the above inclusion and exclusion criteria, two reviewers (E.S. and A.V.G.), without consideration for the results, performed the assessment of the studies for potential inclusion independently. Any differences in opinions were resolved through discussion until a consensus was reached. A third reviewer (S.E.) was consulted when necessary.The two reviewers independently conducted the data extraction from each study using a predefined data extraction sheet. The items extracted regarding the study characteristics comprised the first author name; year of publication; objectives; country; name of cohort (if applicable); study design; sample size; source population ; exposure assessment; categorisation of exposure; outcome assessment; mean follow-up period (if applicable); statistical methods; effect measures; covariates; missing data; control for selection bias and confounding, effect modifications and sensitivity analyses.The ‘Risk of Bias for Nutrition Observational Studies’ (RoB-NObS) tool recently developed by the US Department of Agriculture (USDA) Nutrition Evidence Systematic Review (NESR) team  was usedp for trends) from each study. Associations between different sources of fibre and the outcomes, as well as the stratified analysis results, are reported in text only.We performed a qualitative synthesis of the results, including a summary table presenting the association between the total fibre intake and the outcomes of interest (highest vs. lowest category and The World Cancer Research Fund (WCRF) criteria , appliedA flowchart of the study selection is presented in One birth cohort study explored fibre intake during pregnancy , two stuAn Australian cohort study of 639 mother–infant pairs, including infants with a family history of allergic disease, found that, although the total fibre intake during pregnancy was not associated with allergic disease in the offspring, a higher resistant starch intake was associated with a reduced risk of infant wheeze up to age 12 months  .p-trend 0.034 and current asthma OR 1.38; 95% CI 0.87–2.20, p-trend 0.027) [Two cross-sectional studies reporting fibre intake during childhood were identified, with inconsistent results. An Australian study of 144 adolescents aged 12–18 years reported no association between fibre intake and self-reported wheeze . Howeverp-trend 0.092), wheeze , cough  and phlegm  [p-trend < 0.001) and allergic rhinitis, the latter, however, only for Q2 vs. Q1 , especially in males [Five studies reporting fibre intake during adulthood in relation to asthma, rhinitis and related symptoms were identified, with somewhat consistent results. In a cross-sectional study of 13,147 adults from the US NHANES, a low fibre intake was associated with increased odds of prevalent asthma  . Regardiin males . In addiin males .p-trend < 0.001) and men  [n = 64) consumed, on average, 5 g/day less fibre as compared to healthy controls  [A French cross-sectional study of 26,640 women and 8740 men reported inverse associations between the highest quintile of total dietary fibre compared with the lowest quintile and the asthma symptom scores both among women  . With re90–0.99) .p-trend = 0.044). Inverse associations were also observed with cereal or fruit fibre but not with vegetable fibre [p-trend 0.160 and OR 0.50; 95% CI 0.26–0.94, p-trend 0.174, respectively) [Eight studies reporting the fibre intake in adulthood in relation to COPD and COPD symptoms were identified, with consistent results of a protective association. A cross-sectional study of 11,897 participants of the Atherosclerosis Risk in Communities (ARIC) study in the US indicated a reduced prevalence of COPD with a higher total fibre intake  .p-trend < 0.001), fruits  and soy isoflavones  [p-trend 0.03) [p-trend < 0.001), mainly in current smokers or ex-smokers but not in never smokers [p-trend < 0.001), mainly in current or ex-smokers. For specific fibre sources, cereal and fruit fibre, but not vegetable fibre, were associated with a lower COPD risk [A study of 49,140 cohort members from the Singapore Chinese Health Study examining the association between dietary fibre and new onset of cough with phlegm reported inverse associations with non-starch polysaccharides  . Moreovend 0.03) . Inverse smokers . The secOPD risk .A cross-sectional study of 702 adults with COPD from the KNHANES evaluated the association between disease severity and dietary nutrient intake; in this study, fibre intake was associated with a decreased severity of airway impairment in elderly men (≥60 years old) with COPD but not in women . Additiop-trend < 0.001, forced vital capacity (FVC) 55.2 mL; 95% CI 18.2–92.3, p-trend 0.001 and FEV1/FVC 0.4; 95% CI −0.1–0.9, p-trend 0.040). Similar patterns were seen for the fibre intake from cereal and fruit sources, while no association was observed for vegetable fibre [p = 0.05), FVC 129 mL (p = 0.01), % predicted FEV1 2.4% (p = 0.07) and % predicted FVC 2.8% (p = 0.02)) [Six studies reporting fibre intake in adulthood in relation to lung function were identified, with generally consistent findings. The already mentioned study of 11,897 participants from the ARIC study in the US found positive cross-sectional associations between the total fibre and lung function  60.2 mL; 95% CI 27.7–92.7, le fibre . Additio= 0.02)) .p-trend ≤ 0.05 and FEV1/FVC 0.129, p-trend ≤ 0.01, but there was no association with FEV1 or FVC [p = 0.0032 and VSC 97.8 mL; SE 41.8, p = 0.045) [p = 0.001), 0.02 L (p = 0.002) and 0.2% (p = 0.035), respectively) and negatively associated with airway eosinophilia (−0.36% (p = 0.005)) among participants with asthma [Another prospective study of 12,532 adults from the ARIC study reported an increased fibre intake associated with improved lung function when followed up three years after the baseline; the coefficients per increase in one quintile of fibre intake were %FEV1 0.201, 1 or FVC . A prosp1 or FVC . A study= 0.045) . Finallyh asthma .Out of seven studies, five were cross-sectional ,19,20,22Both studies had a cross-sectional study design ,21. To aOut of eight studies, five were cohorts ,28,29,31Out of six studies, there were three cohort ,34,35 anIn the present study, we did not include intervention studies in the eligibility criteria. According to the WCRF criteria, and based on the available evidence from observational studies, the overall strength of the evidence was graded as limited/no conclusion (insufficient) with regards to asthma and rhinitis, probable (moderate) for COPD and limited/suggestive (low) for lung function.This review sought to explore if there is a protective association between dietary fibre intake and asthma, rhinitis, COPD and lung function and, if so, which sources of fibre are the most beneficial. The findings show that the current evidence from observational studies is limited and inconclusive with regards to asthma and rhinitis. There is suggestive evidence that dietary fibres may be associated with improved lung function in the general adult population, with very few studies reporting fibre intake in high-risk populations. Moreover, there is probable evidence for a beneficial role of fibres in the risk of COPD, which is considered as strong evidence according to the WCRF criteria.Based on the intake level observed to protect against coronary heart disease, an adequate intake of total fibre has been set to 30–35 g/day and 25–32 g/day for adult men and women, respectively , and 10–We were able to identify only one study on maternal fibre intake during pregnancy in relation to allergic disease in the offspring. Although these results do not support an association between prenatal exposure to dietary fibre and allergic disease, the association is biologically plausible. In two recent birth cohort studies, the faecal concentration of SCFAs during pregnancy was inversely associated with asthma and allergic rhinitis in the offspring up to 6 years ,39. In oAdditionally, the two selected studies on dietary fibre intake during childhood showed inconsistent results. However, previous reviews have reported protective associations between fruit and vegetable consumption, or dietary patterns rich in fruits, vegetables, legumes and cereals (such as the Mediterranean diet), and asthma or wheeze among children ,44,45. MWe were able to identify only two studies on fibre intake in relation to allergic rhinitis, with inconsistent results, and no study on nonallergic rhinitis. Allergic rhinitis is associated with sensitisation to inhalant allergens, whereas nonallergic rhinitis is a nasal mucosal inflammation without systemic signs of allergic inflammation, associated with exposure to irritants, hormonal dysfunction and specific medications ,50. RegaIn our review, we identified eight studies on fibre intake in relation to COPD and related symptoms reporting consistent results of a protective association, which has also been suggested by two previous systematic reviews of studies on fibre intake in relation to COPD, partly based on the same studies ,54. The The strength of evidence is primarily related to the methodological quality of the included studies. Most of the studies used questionnaires to assess dietary fibre intake, which might have led to some misclassification of the exposure, however nondifferential with regards to the outcomes of interest. Although the absolute fibre intake may be difficult to be estimated by FFQs, the ranking of participant intakes is possible and sufficient in this type of analytic epidemiologic studies . In studIn conclusion, the current evidence from observational studies on dietary fibre intake is probable (moderate) for an inverse association with COPD and limited/suggestive (low) for an association with lung function in the general adult population. In contrast, there is insufficient evidence for an association with asthma or rhinitis in adults. Thus, further research is needed with regards to asthma, rhinitis and lung function in adults, as well as among children.


Purpose: The aim of this study was to compare the effect of brachytherapy (BT) versus external beam radiotherapy (EBRT) on sexual function in patients with localized prostate cancer (PCa).Methods: Data were retrieved from the PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang Database until March 4, 2021. Analysis was performed by using RevMan 5.4.1. The main clinical outcomes were the Prostate Cancer Symptom Indices (PCSI) scale and the Expanded Prostate Cancer Index Composite (EPIC) scale scores for sexual function. A meta-analysis was performed to calculate standardized mean differences (SMDs) and their 95% CI. This study has undergone PROSPERO registration (No. CDR42021245438).Results: Among the 962 studies retrieved, eight prospective cohort studies met the inclusion criteria, covering a total of 2,340 patients, including 1,138 treated with BT alone and 1,202 treated with EBRT alone. The results demonstrated that BT was to some extent advantageous over EBRT in overall sexual function scores in patients with localized PCa during the immediate post-treatment period , but this difference was not detectable at 3 months , 12 months , and 24 months  after treatment.Conclusion: Our analysis showed that BT showed a short-term advantage over EBRT in terms of sexual function in patients with localized PCa, but this difference diminished over time, though the conclusion needs to be further verified by a longer-term follow-up study. In addition, it can also be used for remedial treatment of local recurrence after radical surgery. Radiotherapy for PCa mainly consists of external beam radiotherapy (EBRT) and brachytherapy (BT). Many studies have been reported to compare the efficacy of these two treatments. For instance, a meta-analysis reported that BT alone was superior to EBRT alone in low-risk patients with localized PCa in terms of 5-year biochemical progression-free survival (PFS), overall survival (OS), and the incidence of gastrointestinal (GI) toxicity (Prostate cancer (PCa) is the most common malignancy of the male genitourinary system. According to the International Agency for Research on Cancer (IARC) GLOBOCAN database in 2020, the global incidence of PCa is second only to lung cancer among male malignancies . The widtoxicity , while otoxicity .The ultimate goal of tumor treatment is no longer simply to remove the tumor or prolong the survival of the patient. More importantly, maintenance of a high quality of life has become one of the basic requirements of cancer treatment. One of the most important consequences of PCa treatment is the loss of sexual function. There has been a consensus that radical surgery with preservation of the neurovascular bundle (NVB) as tumor conditions permit is beneficial for the recovery of postoperative sexual function and urinary control. However, existing evidence related to the effects of different radiotherapy methods on sexual function is scarce, and the conclusions are inconsistent . The aimAccording to the PICOS, we developed inclusion criteria: 1) participants (P)—all the patients were diagnosed with localized PCa without infiltration or invasion of the prostate outside the envelope or adjacent organs, without lymph node metastasis, and with a follow-up period ≥3 months after radiotherapy. 2) Interventions (I) and comparisons (C): comparing the efficacy on sexual function of BT versus EBRT. 3) Outcomes (O): the indicators were the scores of the PCSI scale and the EPIC scale regarding sexual function. 4) Study design (S): prospective and retrospective studies (including cohort studies and case–control studies).We excluded the following articles: 1) the literature without relevant indicators; 2) duplicate publications; 3) reviews; 4) animal experiments; and 5) conference abstracts.We identified relevant studies by searching PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang database up to March 4, 2021. The search was performed using MeSH terms, such as “Prostatic Neoplasms,” “Brachytherapy,” “Radiotherapy,” and “Erectile Dysfunction.” In addition, we scanned through the reference lists of included studies to find additional pertinent articles. We also contacted the corresponding author to acquire information if the research results were incomplete or could not be found.Two authors independently screened the titles and abstracts of retrieved articles and then reviewed the full texts according to the inclusion and exclusion criteria. Then, the two authors extracted the data available in the included studies to fill out the well-designed form and check with each other. Any disagreement between the two authors was reviewed and resolved through a third author. For articles that only provided data such as the mean, sample size, and CI, RevMan calculator was used to convert them and calculate the required variables for the statistics. For articles that only provided X–Y scatter plots, WebPlotDigitizer was used to extract the data.The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of the included studies from the following aspects, with the maximum score of 9 points: 1) representativeness of the exposed cohort; 2) selection of the nonexposed cohort; 3) ascertainment of exposure; 4) demonstration that the outcome of interest was not present at the time of initiating the study; 5) comparability of cohorts on the basis of the design or analysis; 6) assessment of the outcome; 7) the follow-up period long enough for the outcome to occur; and 8) adequacy of follow-up of cohorts. The studies with scores ≥6 were considered as high quality, and those with scores <6 were considered as low quality.The risk of bias was assessed in four domains—selection bias, loss to follow-up bias, information bias, and confounding bias—based on which the risk of bias was classified as “low risk,” “unknown risk,” and “high risk.”2 test. If there was no significant statistical difference , the fixed-effects model was used for analysis, and otherwise, the random-effects model was used. Heterogeneity was dealt with through subgroup analysis or sensitivity analysis. The means and SDs of the baseline were assumed to be X1 and S1, and the means and SD of the endpoint were X2 and S2. Then, we input “mean = X2 − X1” and “SD = The meta-analysis was performed using the RevMan 5.4.1 software provided by the Cochrane Collaboration. Continuous data are presented as standardized mean difference (SMD) as effect size, with 95% CI calculated. Heterogeneity was evaluated by using the chi-square test and IA total of 962 citations were obtained through electronic databases, and 158 duplicates were eliminated by using EndNoteX9 software. After the titles and abstracts of the remaining 804 articles were screened, 792 articles we excluded due to irrelevancy. The full texts of the remaining 12 articles were reviewed, and finally, 8 articles were included for formal analysis according to the inclusion criteria, as detailed in All the eight included studies were observational cohort studies, containing 2,340 patients who met the predefined inclusion criteria. All included studies involved the comparison of the effects of BT versus EBRT on sexual function, with 1,202 patients receiving EBRT and 1,138 patients receiving BT. The NOS scores of all the 8 articles were ≥6, with a mean score of 7.0. The basic characteristics are shown in The participants included in the 8 articles met the diagnostic criteria for localized PCa and had clear recorded medical histories regarding the treatment. In addition, the follow-up plan was defined appropriately before the evaluation of the sexual function and implemented as scheduled. Three studies  independ2 = 25%), so the fixed-effects model was used. The test for overall effect showed that Z = 2.15, SMD = −0.09, 95% CI: −0.18 to −0.01, with the merged interval located to the left of the invalid line and the difference was statistically significant (p = 0.03), illustrating that BT had less impact on the sexual function than EBRT in patients with localized PCa.Among the eight studies, five  used the2 = 24%), using the fixed-effects model. The test for overall effect indicated that Z = 2.65, SMD = −0.14, 95% CI: −0.24 to −0.04. The combined interval fell to the left of the invalid line (p = 0.008), demonstrating that the sexual function of localized PCa was less affected by BT than EBRT by the EPIC scale. In the three articles using the PCSI scale (2 = 0%), using the fixed-effects model. The test for overall effect showed that Z = 0.05, SMD = 0.00, 95% CI: −0.14 to 0.15, the merged interval crossed the invalid line, and there was no significant difference (p = 0.96).Subgroup analysis was performed according to the two scales shown in SI scale , no hete125I and the prescription dose being 144 Gy to the reference isodose (100%) according to the TG-T43 (2 = 9%). The test for overall effect showed that Z = 2.88, SMD = −0.15, 95% CI: −0.26 to −0.05, with the combined interval located to the left of the invalid line, with a significant difference (p = 0.004).Given that the radiation dose may have some impact on the study, we conducted an in-depth analysis. After careful review, we found that two studies  did not e TG-T43 . So foure TG-T43  were sele TG-T43 . The fix2 = 0%), using the fixed-effects model. The test for overall effect suggested that Z = 1.15, SMD = −0.07, 95% CI: −0.18 to 0.05, with the merged interval crossing the invalid line, and the difference was not statistically significant (p = 0.25).Four studies  carried 2 = 65%), and the random-effects model was applicable. The test for overall effect showed that Z = 0.05, SMD = −0.01, 95% CI: −0.21 to 0.20, with the combined interval crossing the invalid line, and with no statistical difference (p = 0.96).Five clinical trials  performe2 = 44%), using the fixed-effects model. The test for overall effect showed that Z = 1.71, SMD = −0.09, 95% CI: −0.20 to 0.01, with the merged interval across the invalid line, and the difference was not statistically significant (p = 0.09).Five studies  conducteWith the use of the RevMan software, the 8 clinical trials were eliminated one by one in sequence for sensitivity analysis. Change in the total combined effect was observed to determine whether the results of the meta-analysis were stable. It was found that the SMD of the combined effect value after exclusion of a single article fluctuated between −0.04 and −0.12, which was basically consistent with the combined total effect value, indicating that the research results were stable.With the innovation of modern technology, the application of radiotherapy as one of the radical therapies for localized PCa has become increasingly mature. A prospective randomized controlled trial reported that there was no significant difference in cancer-specific survival (CSS) and 10-year OS between radiotherapy and radical surgery for localized PCa . EBRT ha2 = 25%), subgroup analysis was carried out to make the study more convincing, because two different scales were adopted in the different studies included. The results showed less intragroup heterogeneity (I2 = 24%) in the five studies using the EPIC scale (2 = 0%), but there was no significant difference in sexual function scores, and with higher heterogeneity between the two subgroups (I2 = 58.2%). The result may be due to the smaller number of both studies using the PCSI scale and cases on the one hand; and on the other hand, it may be that the studies using the PCSI scale had a shorter mean follow-up period. Considering that the difference in radiation dose may have a certain influence on the results, we analyzed four studies (2 = 9%), and the difference between BT and EBRT was statistically significant (p = 0.004). This also greatly increased the persuasiveness of the article.After the integrated analysis of the eight articles included in this study, we found that the sexual function was less affected in patients with localized PCa who received BT as compared with that in patients who received EBRT in terms of the integrated scores of EPIC and PCSI. Although the overall heterogeneity was small  for comparison. Further in-depth research is required to verify our findings and conclusion.


Aim: To study the association between non-SARS, non-MERS human coronavirus (HCoV) infections and Kawasaki disease (KD). Methods: Meta-analysis of observational studies published until 1 May 2021. Results: Out of 571 papers retrieved through database search, 10 provided data of 17,732 children. Age ranged from 2 months–14.9 years with 66% being male and 71% being complete KD. Compared with controls, there was an increased risk of developing KD in those detected to have HCoV infection . The GRADE evidence for all outcomes was of ‘low-certainty’. Conclusion: A ‘low certainty’ of evidence suggests an increased risk of KD in children infected with HCoV. We need multi-center, prospective studies to support or refute this finding.PROSPERO protocol registration: CRD42021251582. Kawasaki disease (KD) is a common childhood vasculitis whose etiology remains unknown . A complHuman coronaviruses (HCoV) belong to Orthocoronavirinae subfamily of Coronaviridae family . Of fourIn recent times, there has been a spate of reports on KD/KD-like disease triggered by SARS-CoV-2, termed as pediatric multisystem syndrome temporally associated with SARS-CoV-2 in EU (PIMS-TS), and multisystem inflammatory syndrome children (MIS-C) in the USA . HoweverThis systematic review protocol is registered at PROSPERO: CRD42021251582Observational studies that aimed at studying the association of HCoV infection with KD in both community and hospital settings were included.Children of all age groups/sexes were included.Participants in exposure group included those with HCoV infection (confirmed by either RT-PCR or serology) and KD. In control group, children had HCoV infection but no features of KD.Risk of development of KD in those infected with HCoVs.Risk of development of KD in those infected with different serotypes of HCoVs .Pre-prints.org). The PubMed/MEDLINE search strategy used the various MeSH and free text terms for ‘coronavirus’, ‘coronavirinae’, ‘novel coronavirus’, HCoV, SARS CoV-2, COVID-19, MERS-CoV, ‘Kawasaki disease’, ‘Kawasaki syndrome’, ‘mucocutaneous lymph node syndrome’, ‘observational studies’, ‘children’, ‘pediatric’, using the Boolean operators. No language restrictions were applied. The search results were reviewed to identify relevant studies.The following databases were searched systematically from the year 1967 to 1 May 2021: PubMed/MEDLINE, Google Scholar, Embase and pre-print servers , study design, setting , method of recruitment, inclusion criteria, risk of bias, participants , exposure , outcomes , lost to follow up and miscellaneous data .The data were extracted by using a pre-designed data extraction form and tested We independently assessed quality by using the Newcastle–Ottawa scale (NOS) for observational studies . It asseThe missing data were described that included dropouts in selected studies. Difference in dropout rates may lead to biased estimates of the effect size. Furthermore, bias may arise if the reasons for dropouts vary across different groups in different studies.2 p < 0.10) and quantified by I2. An I2 ≥50% indicated ‘substantial’ heterogeneity and ≥75% indicated ‘considerable’ heterogeneity . Of. Of15]. None of the studies was having a risk of bias in selection of cases, but four were at a high risk of bias for selection of controls ,18,20,212 = 58%; p = 0.03). There was an increased risk (odds) of developing KD in those detected to have infection with HCoV as found in both the models . Overall analysis was not significant for studies employing either RT-PCR/viral detection  or antibody assay . As there was significant heterogeneity among studies, we did sensitivity analysis by removing one study . Pooled We separately analyzed data from included studies that reported different serotypes of HCoV . However, none of the serotypes was individually associated with risk of development of KD.Funnel plot was asymmetrical showing publication bias .Evidence generated was of ‘low certainty’ for all outcomes (primary and secondary). Likely reasons were heterogeneity among studies, poor methodological design and selective outcome reporting. A detailed analysis of the summary of evidence for primary outcome is provided in After an extensive search of the literature, we included ten studies with data of 17,732 children. As compared with controls, those having documented infection with HCoV were at a higher risk of developing KD. No particular serotype of HCoV was found to be associated with this increased risk. The evidence, however, is of ‘low certainty’.et al. first demonstrated the association between HCoV infection and KD [et al. confirmed this association in 2014 [In a case-control study published in 2005, Esper n and KD . Chang e in 2014 . However in 2014 ,20,21 whIn the present meta-analysis, we have analyzed the association of HCoV infections with KD. This has not been evaluated comprehensively to date. Recognition of association between HCoV with KD predates the KD or KD-like illnesses (in the form of multisystem inflammatory syndrome in children) seen in the ongoing SARS-CoV-2 pandemic by about a decade and a half. KD, KD-like illness (MIS-C/PIMS-TS) and severe COVID-19 infection induced vasculitis represent a similar disease spectrum characterized by a dysregulated immune response. It suggests that SARS-CoV-2 may just represent a ‘new kid on the block’ of various coronavirus infections associated with KD. In fact, KD has also been reported in association with the H1N1-pdm09 influenza infection that resulted in a pandemic a decade ago . BesidesExact etiology of KD remains an enigma. Many infectious illnesses can trigger KD in a genetically susceptible host. Of the various microbial agents, respiratory viruses have come up as the most important triggers for KD . CausaliIt is plausible that HCoV infections may trigger KD illness in susceptible individuals. A number of genetic polymorphisms have been associated with an increased risk of developing KD in certain populations. Variability in HCoV-associated KD in different studies can therefore be easily explained by genetic differences among study populations . It is pThe exact pathogenesis of KD following HCoV infection is poorly understood and multifactorial. Endothelial dysfunction or inflammation is the hallmark of both KD and KD-like conditions that follow HCoV and SARS-CoV2 infection. HCoV has spike like protein that binds to angiotensin converting enzyme 2 (ACE2) receptors on surface of the target cell. A systematic review and meta-analysis have documented a significant risk of KD with ACE2 polymorphism . AdditioA comprehensive literature search, robust analysis and grading of evidence are strengths of the present review. Inclusion of only retrospective studies into the pooled analysis is a limitation  of our review as the small sample size and retrospective nature may have introduced bias to overall estimate of results. Another limitation is that only three authors were involved in search methodology, risk of bias assessment and data extraction. This overlapping role might have introduced some bias in the review process. Furthermore, all studies were hospital based and were conducted mostly in developed countries. Hence, it may not be prudent to extrapolate the findings of this meta-analysis to the community at large.A ‘low certainty’ of evidence suggests an increased risk of KD in children infected with HCoV. We need multi-center, prospective studies to support or refute this finding. The findings will be of great public health importance as KD/KD-like illnesses are closely associated with SARS-CoV-2 pandemic.There should be elucidation of actual link between Kawasaki disease, and human coronaviruses (both SARS and non-SARS) at molecular level so that targeted therapy can develop as a form of prophylaxis.Many studies have analyzed the association between SARS-CoV-2 and Kawasaki disease (KD)/KD-like illnesses with conflicting results, however, systematic review(s) or meta-analyses that have studied the association between human coronavirus (HCoV) infection (non-SARS and non-MERS) and KD are lacking.We included data of 17,732 children from ten observational studies, there was an increased risk (odds) of developing KD in those detected to have infection with HCoV .None of the HCoV serotype was individually associated with risk of development of KD.‘Low certainty’ evidence suggests an increased risk of KD in children infected with HCoV. Likely reasons were heterogeneity among studies, poor methodological design and selective outcome reporting.Publication bias was noted among the published studies.We need multi-center, prospective studies to support or refute this finding. The findings will be of great public health importance as KD/KD-like illnesses are closely associated with SARS-CoV-2 pandemic.


The mitochondrial manganese superoxide dismutase (MnSOD) enzyme protects lungs against oxidative stress by neutralizing the free radical superoxide produced in the respiratory function. This has relevance to asthma. Therefore, it is of interest to describethe potential effect of MnSOD Ala16Val genetic polymorphism to asthma risk. Known data in this context is inconclusive in nature. The possible link between MnSOD Ala16Val polymorphism and asthma is explored using sequence meta-analysis. Data from the pooledanalysis of MnSOD Ala16Val polymorphism using five genetic models i.e., allelic  is discussed. Homozygous  and heterozygous  data using the described models are documented. Data from the dominant model  and the recessive model  analyses for several ethnic subgroups in this context is reported. Asthma is a complex disease, chronic in nature and is highly prevalent across countries, which affect almost 334 million people in all age group . It causLungs are more exposed to oxidative damages because of continuous higher oxygen tension prevalence. The body has an active defense antioxidant system to protect the lung tissues against oxidative injuries caused by various genes responsible for oxidation. Thegene encoding the enzyme mitochondrial manganese SOD (MnSOD) is located on the long arm 6q25) of chromosome 6. This arm contains five exons and four introns with each subunit consisting of 196 amino acids  of chrom. The SNPThe MnSOD encoding gene contains SNP, which has genetic variants comprising of a structural mutation wherein cytosine (C) changes to thiamine (T) in the exon 2. The above stated substitution further affects codon number 16, mutating alanine (GCT) to valine(GTT) changes at the 9th position . This polymorphism alters the helix structure and variant allele formed as result of this produces a β-sheet secondary structure in place of the expected α-helix, which can lead to increase in theproduction of H2O2 and contribute to the accumulation of ROS . HoweverA web-based systematic search was performed for the studies having association between MnSOD Ala16Val gene polymorphism and asthma. The online databases searched for the current study were PubMed (Medline), Google Scholar, and EMBASE. The last search was updatedon 28th February 2019 to retrieve the most compatible and peer reviewed research articles. The combination of the words used for the search was: 'mitochondrial manganese SOD OR MnSOD AND Asthma OR Asthmatic susceptibility OR risk in combination with single nucleotidepolymorphism (SNP) OR polymorphism OR genetic variant OR mutation. The articles retrieved were assessed by their titles and abstracts. The ones matching the established eligibility criteria were taken up for this meta-analysis. We also did some manual search of thereferences listed in the retrieved articles for other eligible articles.The criteria used for the inclusion of pertinent research articles in the current meta-analysis study were: (a) it should have evaluated the association between MnSOD Ala16Val gene polymorphism and asthma risk, (b) should have used a case-control study design,(c) should have done the recruitment of confirmed asthma cases and healthy controls, (d) should have the availability of genotype frequency in both case and control studies to count the odds ratio (OR) and must have 95% confidence intervals, (e) the publication ofthe studies should be in English language. In the same way, there were some preset criteria applied for the exclusion of studies as well. The key basis for the exclusion of the studies were: (i) studies not designed as case-controls, (ii) reviews, abstracts only oroverlapping studies, (iii) studies with no reported frequencies for genotypes. The schematic flow diagram depicting the selection of eligible studies, following the established criteria for inclusion and exclusion, for this meta-analysis is shown in Two investigators (FLA & RKM) independently evaluated all the titles and abstracts available from the retrieved publications using the selected online databases search in a chronological manner. The full-texts of all the publications, deemed potentiallyqualified, were retrieved. In order to assess the eligibility for the inclusion of the study, one investigator (RKM) thoroughly appraised all the full-text articles. Following this step, the second investigator  repeated the same evaluation processindependently by randomly selecting 10% of the full-text articles. The two investigators were in full agreement regarding the selection criteria and study exclusion. Subsequently, for identification of the final set of the eligible articles, a third investigator(SK) extrapolated the relevant data from all the studies. To crosscheck the above step, a fourth investigator (MK and ML) independently reappraised the collected information from all the included studies. Any discrepancy associated with the study selection wasresolved by a comprehensive discussion with fifth investigator (SH and SAA), who contributed as an arbitrator.The electronic searches performed on selected web-databases fetched out fifty-four research articles in the initial stage. But, after many rounds of screening by applying above stated pre-set selection (inclusion/exclusion) criteria only five studies werefound eligible to be included here in this analysis. The selected five studies dealt with MnSOD Ala16Val gene polymorphism and occurrence of asthma risk. Two types of studies were straightway excluded which involves MnSOD polymorphism to predict survival inasthma patients and those considering MnSOD variants as indicators for response to therapy. Similarly, studies indicating the levels of MnSOD mRNA or protein expression and other relevant review articles were also disqualified. This study includes only case-control studies reporting the frequency of all the three genotypes. Furthermore, in addition to the database search, the reference lists of the available eligible retrieved articles were also scrutinized for other potential articles, but no pertinent studiesfitting the above criteria were found.Two investigators , independently, evaluated the quality of the selected studies for this meta-analysis by using the preset NOS criteria . The preThe methodological data extraction was performed independently in duplicate. It was done independently by FLA,RKM,MK following a standard validated protocol. Using the strict preset selection criteria in standard data collection form ratified the accuracy ofabstracted data. The major characteristic abstracted was name of the first author, year of publication, the country of origin, the number of cases and controls, type of study, genotype frequencies, and association observed for cases and controls. Any disagreementor discrepancies in the items abstracted were fully resolved to the point of agreement following many rounds of discussions involving the adjudicator (SH and SAA).The publication bias present in the included studies was checked by funnel plot asymmetry and Egger's regression statistics. A p-value of less than 0.05 was fixed for considering the significant publication bias. Additionally, all included MnSOD gene polymorphismrelated studies were checked for heterogeneity using Q-test and I2 statistics.The association strength between MnSOD Ala16Val gene polymorphism and the risk of developing asthma was evaluated precisely using OR and 95% CI. The pooled ORs were calculated for allele contrast, log-additive, dominant, and recessive genetic models .HeterogIn order to be the best, the meta-analysis has to contain all the eligible trials as per Cochrane handbook. But, it may not be able to produce sufficient satisfactory evidences. There are always chances of systematic (bias) or random (by chance) errors in meta-analysis.There, these errors were minimized using a novel statistical analysis program named Trial Sequential Analysis (TSA) tool made by Copenhagen Trial Unit, Center for Clinical Intervention Research, Denmark. It accurately estimates the required information size,adjusts threshold statistical significance and calculates the power of conclusion of the meta-analysis studies -24. The Table 1 and 2 (see PDF) depict the major characteristics like distribution of genotypes, minor allele frequency (MAF) in controls and cases of all the five studies included in this meta-analysis. The The shape of the funnel plots and the results of Egger's test have negated the presence of publication bias in all the five genetic models of MnSOD Ala16Val polymorphism  - see PDF.The Q-test and I2 statistics revealed absence of heterogeneity in Val Ala vs. Ala Ala genetic model. However, heterogeneity was observed in other four studied genetic models. Hence, random effects model was further used for synthesizing the data (Table 4 - see PDF).The pooled five pertinent and legible studies resulted into 800 confirmed asthma cases and 1009 healthy controls. All the subjects involved were scanned for the association between MnSOD Ala16Val polymorphism and overall asthma risk. The overall pooled analysissuggested no risk between MnSOD Ala16Val polymorphism and overall asthma susceptibility in all the genetic models, i.e., allelic , homozygous ,heterozygous , dominant  and recessive  .The sub-group analysis of Asian ethnicity population scrutinized three studies, which involved a total number of 445 asthma cases and 577 control cases. All the studied genetic models showed heterogeneity (Table 5 - see PDF). No publication bias was found inthe studies examined in this section of meta-analysis . On combining all the three studies, it was observed that allelic , homozygous , heterozygous , dominant model  and recessive  genetic models did not reveal any association with asthma risk .The leave-one-out sensitivity analysis was performed to evaluate the effect of each individual study on the overall analysis. The pooled ORs were recomputed after the exclusion of one study at a time. The sensitivity analysis did not show any differences fromthe primary values for overall risk  and Asian subpopulation risk  related to asthma. This further suggested that the results of this meta-analysis were stable and robust.Using the data of the dominant model, the TSA analysis showed that the cumulative Z curve did not cross with TSA monitoring boundary-confirming necessity of further relevant trials for overall  and AsiaThe presence of excess reactive oxygen species (ROS) or insufficient protection in the form of less antioxidants leads to an oxidative stress, which further contributes to the development of cutaneous disease and challenges the enzymes that metabolize ROS andother inhaled toxic compounds. ROS has been considered as vital mediators of host of cellular processes like cell adhesion, apoptosis, and the immune response . The ROSThe earlier published studies have demonstrated the elevated amounts of ROS such as superoxide radicals and hydrogen peroxide (H2O2) in asthmatic patients . The antThe genes that regulate defense mechanism in the form of antioxidants form important part of the cells' response. The cell shows this response against the production of excessive amount of ROS. The change in expression or function of MnSOD may affect mitochondrialfunction and the overall health of cells as a result of oxidative damage to various localized mitochondrial metabolic processes that leads to the development of different diseases. As the lungs are exposed to high oxygen concentration, changes in antioxidant defensecould be one of the important mechanisms in asthma pathogenesis. The earlier published articles have many evidences showing that SNPs are a major factor in asthma susceptibility. Similar to many other common diseases, many researchers have investigated the geneticsof asthma using both family-based and population-based approaches . HoweverThis gene polymorphism has a very important characteristic feature that its occurrence can vary sufficiently among different races or ethnic populations. Therefore, the current study has performed subgroup analysis of ethnicity, which further reveals no associationof MnSOD Ala16Val with Asthma in the Asian population. In addition to this, the TSA analysis has further confirmed the evidences that necessary trials are needed to reach on a more precise conclusion. Earlier study revealed that the host genetic factors are potentiallyaccountable for the development of asthma disease . It has Although, the current trial sequential meta-analysis has achieved various important findings, still it suffers from few limitations. First, the heterogeneity existed in between the studies used for the analysis of genetic models, which may have affected theresults, although a random effects model additionally was adopted for this analysis. Second, this study has included only those studies published in the English language, which restricted the number of studies used. Third, the stratification analysis was done insub-group ethnicity with a lesser number of individual studies that might have a small statistical power to detect the actual association, and lastly, the results are based on unadjusted estimates. The same potential confounders like age, sex, and exposure werenot used to adjust the ORs in all the included studies. Notwithstanding, the above-mentioned limitations, our analysis was associated with advantages like applying NOS scale stringently did the quality assessment of the selected studies. The studies used herescored five or more stars that indicated their moderate to good quality. They had clearly mentioned the sample size, genotype, and inclusion criteria for confirmed asthma patients and healthy controls. Secondly, the publication bias was completely eliminated togive more robust conclusion. Thirdly, the likelihood of bias was minimized to the extent possible by following a thorough protocol of study identification, statistical analysis and data selection. Fourthly, sensitivity and trial sequential analysis have strengthenedthe conclusion of our study largely.Data shows that MnSOD Ala16Val polymorphism is not associated with asthma risk. Therefore, well-designed studies with wider spectrum of subjects from different ethnicities including the consideration of various environmental factors are warranted to comprehensivelyinvestigate the association of MnSOD Ala16Val polymorphism and asthma risk.This research was funded by the Scientific Research Deanship at university of Ha'il - Saudi Arabia through project number RG-I91226.Supplementary file is provided as "97320630016789S1.pdf" is provided separately containing supplementary figures


Objective: Previous studies suggested that insomnia was associated with an increased risk of cardiocerebral vascular diseases (CVDs) but not clear in different insomnia symptoms. We performed a meta-analysis to investigate the association of individual insomnia symptoms and risk of CVDs.Methods: In this meta-analysis, we systematically searched published articles by using electronic databases including PubMed, Cochrane Library, MedLine, and Google Scholar. Studies were enrolled if they indicated clear insomnia symptoms, prospective, and evaluated the association of insomnia symptoms and CVD outcome in adults free of CVDs at baseline.Results: There were seven prospective cohort studies with sample sizes ranging from 2,960 to 487,200 included in this meta-analysis. Mean follow-up duration was 10.6 years. Insomnia symptoms of having difficulty initiating or maintaining sleep (DIS or DMS), non-restorative sleep (NRS), and early morning awakening (EMA) were analyzed in this study. All studies were compared under a random-effects model. NRS, DIS, and DMS were, respectively, related to 16% , 22% , and 14%  higher risk of first-ever CVD incidence during the follow-up. Based on our analysis, EMA was not a risk factor of CVDs .Conclusion: This study suggested that symptoms of DIS, DIM, or NRS were associated with a higher risk of CVD incidence in insomnia patients free of CVDs at baseline. But this association was not significant in insomnia patients complaining about EMA. Insomnia, defined as a person feeling of having difficulty initiating (DIS) or maintaining sleep (DMS) or feeling of non-restorative sleep (NRS), is the most common sleep disorder throughout the world, with an average prevalence of 33% –3. As a There were about 35.7% of Chinese residents who complained about poor sleep quality in the research of China Chronic Disease and Risk Factor Surveillance –8. In reDIS and DMS were identified as risk factors of CVDs, while early morning awakening (EMA) was associated with an increased risk in the study of Zheng et al. but insignificant in a Swedish cohort , 14.Therefore, the aim of this study was to systematically review related prospective cohort studies and conduct a meta-analysis of all the available studies in order to investigate the association between different insomnia symptoms and the risk of first-ever CVDs.We systematically searched published articles  by using electronic databases including PubMed, Cochrane Library, MedLine, and Google Scholar. The keywords relating to insomnia as MeSH terms and text words  were used in combination with keywords relating to CVD . We limited our search to prospective cohort studies, supplemented by manually reviewing the reference of all retrieved papers. There was no language restriction of the studies. The inclusion criteria for the eligible articles were as follows: (1) the study should be prospective cohort or longitudinal cohort with follow-up; (2) patients with age >18 years, free of CVDs at baseline; (3) report specific insomnia symptoms and clear methods of sleep disorder assessment; (4) primary or secondary outcome should be the association of sleep disorder and CVDs; (5) the quantitative estimates of the univariate or multivariate adjusted hazard ratio (HR) and 95% confidence intervals (CIs) for CVD outcomes associated with insomnia symptoms should be provided. Relative risks (RRs) were considered equivalent to HR in the prospective cohort study; (6) the follow-up duration of each study should be longer than 2 years. Any study that did not meet the inclusion criteria was excluded. The articles were initially included or excluded based on title, abstract, and finally based on the complete article, decided by two independent interviewers.The following data were extracted from the final included studies as the baseline characteristics: first author's name, year of publication, country, number of subjects at baseline, male gender proportion, mean age at baseline, insomnia symptoms of subjects, methods of insomnia disorder assessment, study outcome, follow-up duration, variables adjusted for confounding factors at the univariate or multivariate model. We also extracted HR and 95% CIs for CVD outcomes associated with insomnia symptoms for the statistical analysis.I2 statistic. Heterogeneity across studies was considered substantial if I2 > 50%. In order to identify the source of heterogeneity, we performed sensitivity analyses by eliminating each included study step by step and a subgroup analysis according to gender. Publication bias was evaluated by means of the Egger's test. We performed the statistical analysis by STATA version 15 , and statistical significance was considered when a two-tailed p < 0.05.The HR we used for analysis was from the most complete adjustment for confounders in the original study  , 15 whilI2 = 56.8% (p < 0.001).After pooling all 10 studies' comparisons under a random-effects model, which were divided by different insomnia symptoms, the meta-analysis showed patients with NRS was in 16% higher risk of CVDs compared to those without corresponding symptoms . Subjects who complained DIS and DMS had 22 and 14% increased risk of suffering CVDs, respectively, with respect to those without these two complaints . The association of EMA symptom and CVD incidence risk was not significant in data analysis . OverallI2 = 62.5%, p = 0.04; after being excluded, I2 = 51.3%, p = 0.036). Therefore, we did not include this study in our final analysis. In order to figure out other possible difference across the studies, we performed a subgroup study based on gender for the sensitivity analysis. Since not all included studies had separate HR and 95% CI for CVDs and insomnia symptoms according to male and female, we only use the available data. The subgroup analysis based on the available studies showed that females with DIS and DMS symptoms reported much higher heterogeneity compared to males (p = 0.097).As we had mentioned above, studies of patients with DIS and DMS symptoms reported borderline significant heterogeneity. Actually, according to our search strategy, the study of Eaker et al.  was alsoto males . Egger'sInsomnia is the most common sleep disturbance globally, which can cause both mental and physical illness. Previous studies have indicated insomnia disorder as a new risk factor of CVDs, other than the traditional atherosclerotic risk factors. However, insomnia patients may complain about different symptoms, including difficulty falling asleep, difficulty maintaining asleep, waking up too early in the morning, and feeling restless after one-night sleep. Patients might have all or just some of these symptoms. It is not clear if all these symptoms had the same association with CVD incidence risk. As a result, this meta-analysis aimed to investigate the relationship between each insomnia symptom and the risk of first-ever CVDs.Our meta-analysis showed an overall increased risk of CVDs in patients with insomnia symptoms, which was consistent with findings of previous studies. Patients with complaints of DIS , DIM , or NRS  were in higher risk of CVDs individually in this study. Our data indicated that insomnia patients complaining of DIS had much higher risk of CVD than other insomnia symptoms, which was consistent with previous literature. Zheng et al.  combinedThe mechanisms of increased risk of CVDs in patients with insomnia symptoms are still unclear. The elevated sympathetic and hypothalamic–pituitary–adrenal axis activity is one of the possible mechanisms . DIS andThere were several limitations in the present meta-analysis. Firstly, the insomnia symptoms of enrolled studies were assessed by self-reported questionnaires or interviews. This may lead to a possible higher risk of selection bias due to the interviewers as well as recall and report bias caused by the participants. Some objective instrument  could be used in future investigations, but the medical expense is still an unsolved problem. Secondly, since we only included studies with clear insomnia symptoms instead of a general conception, this led to the limited number of entered articles compared to previous reviews. However, with the acceptable quality score and large scale of each cohort study and the result of different associations between individual insomnia symptom and CVD risk, our meta-analysis still provided a remarkable reference for future research. Additionally, we could not enter all the included studies in the sensitivity analysis because not all studies provided the separate HR and 95% CI according to male and female. But the primary results showed that there were much more higher heterogeneity across the female subgroup in all insomnia symptoms, especially for DIS and DMS, which showed borderline heterogeneity in the overall analysis. Therefore, female was accepted as the possible origin of heterogeneity and needs to be further investigated in a future study of CVD incidence risk in insomnia patients with different symptoms.In conclusion, this meta-analysis indicated that symptoms of DIS, DIM, or NRS were associated with a higher risk of CVD incidence in insomnia patients free of CVDs at baseline. But this association was not significant in insomnia patients complaining of EMA.The original contributions presented in the study are included in the article/LR and YW conceived and designed the study. TL and SH independently extracted data from the eligible studies and any argument was resolved either by discussion or by involving YW when necessary. SH performed the paper writing with the assistance of TL. All authors contributed to the article and approved the submitted version.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.


To evaluate the diagnostic accuracy of the ADNEX model for ovarian cancer at the 15% cut-off value.Studies on the identified diagnosis of the ADNEX model for ovarian cancer published in PubMed, Embase, the Cochrane Library and Web of Science databases from January 1st, 2014 to February 20th, 2021 were searched. Two researchers independently screened the retrieved studies and extracted the basic features and parameter data. The quality of the eligible studies was evaluated by Quality Assessment of Diagnostic Accuracy Studies-2, and the result was summarized by Review Manager 5.3. Meta-Disc 1.4 and STATA 16.0 were used in statistical analysis. Heterogeneity of this meta-analysis was calculated. Meta-regression was performed to investigate the potential sources of heterogeneity. Sensitivity analysis and Deek’s funnel plot analysis were conducted to evaluate the stability and publication bias, respectively.280 studies were initially retrieved through the search strategy, and 10 eligible studies were ultimately included. The random-effects model was selected for data synthesis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and the area under the summary receiver operating characteristic curve were 0.92 (95% CI: 0.89–0.94), 0.82 (95% CI: 0.78–0.86), 5.2 (95% CI: 4.1–6.4), 0.10 (95% CI: 0.07–0.13), 54.0 (95% CI: 37.0–77.0) and 0.95 (95% CI: 0.91–0.95). Meta-regression based on study design, country, enrollment and blind method was not statistically significant. This meta-analysis was stable with no obvious publication bias.The ADNEX model at the 15% cut-off had high diagnostic accuracy in identifying ovarian cancer. Ovarian cancer is seen as the most aggressive gynecological tumor. The morbidity of ovarian cancer is second to cervical cancer and endometrial cancer, but the mortality ranks first of gynecological tumors. So it is called the “silent killer”. More than 310,000 new cases of ovarian cancer were diagnosed globally in 2020, with nearly 210,000 new deaths, significantly higher than in 2018  defines the terms, definitions and measurements used to describe the ultrasonic appearance of ovarian tumors . Based oThere are limited studies on the diagnosis of the ADNEX model for ovarian cancer because it was published recently. Besides, the cut-off value of the overall risk for ovarian cancer is flexible. In the guideline, the cut-off selected should depend on the centers’ type and the patients’ clinical characteristics. Still, it did not give a recommended cut-off . In presTo my best knowledge, there is no summary estimate of the 15% cut-off. Therefore, this meta-analysis aimed to discuss the diagnostic accuracy of the ADNEX model at the 15% cut-off of ovarian cancer.We conducted this meta-analysis in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses.We searched for studies in PubMed, Web of Science, Embase and the Cochrane Library databases published from January 1st, 2014 to February 20th, 2021. A combination of Medical Subject Headings (MeSH) and free text were used to identify related articles. Search terms included “Ovarian Neoplasm”, “Neoplasm, Ovarian”, “Ovarian Neoplasm”, “Ovary Neoplasms”, “Neoplasm, Ovary”, “Neoplasms, Ovary”, “Ovary Neoplasm”, “Neoplasms, Ovarian”, “Ovary Cancer”, “Cancer, Ovary”, “Cancers, Ovary”, “Ovary Cancers”, “Ovarian Cancer”, “Cancer, Ovarian”, “Cancers, Ovarian”, “Ovarian Cancers”, “Cancer of Ovary”, “Cancer of the Ovary”, “Adnexal model”, “ADNEX model” and “Assessment of Different NEoplasias in the adneXa model”. The search was designed to identify all studies on the diagnosis of ovarian cancer with the ADNEX model. Reference lists of the retrieved studies were also screened manually.The inclusion criteria in this meta-analysis were as follows: (1) the subjects were women with ovarian tumors; (2) the diagnostic method was the ADNEX model for ovarian cancer; (3) the reference standard was pathological examination after surgery; (4) retrospective or prospective diagnostic studies; (5) outcome indicators were sensitivity and specificity; and (6) true positive (TP), false positive (FP), true negative (TN), false negative (TN) could be extracted directly or indirectly from the study.Studies were excluded from these criteria: (1) guidelines, case reports, systematic reviews, and conference studies; (2) lack of original data; (3) duplicate data; (4) unclear cut-off or other cut-off; and (5) inconsistent outcome indicators.vs. others), publication year, study design (prospective vs. retrospective), enrollment type (consecutive vs. unreported), blind method (blind from the reference standard vs. unreported), patients’ number, malignant tumors’ number, benign tumors’ number, TP, FP, FN, TN, sensitivity and specificity.The following information was extracted from the eligible studies and drawn into tables: name of the first author, country (Europe Two investigators (XH and ZW) assessed the quality of the eligible studies by Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) independently. Every signature question in QUADAS-2 was rated as “yes”, “no” or “unclear”. QUADAS-2 consisted of four assessment sections. Only in one section did all the signature questions answer “yes”, and the corresponding risk of bias was rated as “low”; once any answer was “no”, the risk of bias was rated as “high”; in other cases, the risk of bias was rated as “unclear”. If the evaluations of the two investigators were inconsistent, it would be negotiated by discussion. The final result was presented by Review Manager 5.3 .2). I2 ≦50% indicated no obvious non-threshold effect among the eligible studies. The result of heterogeneity analysis decided the model and effect size selected for data synthesis. The Moses–Shapiro–Littenber model was selected when P-value of the Spearman correlation coefficient <0.05. If so, the simple effect sizes like sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) could not be pooled. Under the premise that P-value of the Spearman correlation coefficient >0.05, the simple effect sizes can be pooled. The fixed-effects model was selected when I2 ≦50%, and the random-effects model was selected when I2 >50%. Meta-regression analysis was performed to investigate the potential sources of heterogeneity, and the relative diagnostic odds ratio (RDOR) was the evaluation index. RDOR >1 indicated that the studies with this feature had higher diagnostic accuracy than those without, but it was statistically significant only when the corresponding P-value <0.05. Sensitivity analysis was conducted to evaluate the stability of the eligible studies, and Deek’s funnel plot analysis was used to evaluate the publication bias in this meta-analysis.Meta-Disc 1.4 and STAT 16.0 were used for statistical analysis , 15. Het280 studies were initially retrieved through the search strategy. According to the inclusion and exclusion criteria, a total of 10 studies were ultimately included. There were 5,170 ovarian tumors included, 1,629 were ovarian cancer, and 3,541 were benign tumors. The specific selection process was presented in 2 = 65.12% (>50%) meant the existence of non-threshold effect heterogeneity , which indicated no threshold effect in this analysis. Iogeneity Figure 3According to the result of heterogeneity analysis, there was no threshold effect but non-threshold effect in this meta-analysis. The random-effects model was selected to pool the effect sizes. The pooled sensitivity, specificity, PLR, NLR, DOR and the area under the curve (AUC) were 0.92 (95% CI: 0.89–0.94), 0.82 (95% CI: 0.78–0.86), 5.20 (95% CI: 4.10–6.40), 0.10 (95% CI: 0.07–0.13), 54.0 (95% CI: 37.0–77.0), 0.95 (95% CI: 0.91–0.95).According to the features of the 10 eligible studies, meta-regression was performed based on the following factors: study design, country, enrollment, blind method. As shown in As shown in Deek’s funnel plot analysis showed that scattered points were evenly distributed on both sides of the regression line, and P-value was 0.96 (>0.05). There was no significant publication bias among the eligible studies Figure 5In this meta-analysis, a total of 10 studies on the preoperative diagnosis of the ADNEX model at the 15% cut-off for ovarian cancer were eligible. The pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.92 (95% CI: 0.89–0.94), 0.82 (95% CI: 0.78–0.86), 5.2 (95% CI: 4.1–6.4), 0.10 (95% CI: 0.07–0.13), 54.0 (95% CI: 37.0–77.0), 0.95 (95% CI: 0.91–0.95), respectively. It meant that the ADNEX model at the 15% cut-off had high specificity while ensuring sensitivity. Higher sensitivity meant identifying more suspicious patients and referring them for further examinations. It helped minimize the risk of delaying treatment for suspicious patients. Higher specificity meant reducing the false positive rate. It was of great significance for optimizing the allocation of medical resources and reducing the unnecessary costs of patients.There was no threshold effect in this meta-analysis, but the non-threshold effect heterogeneity could not be ignored. Meta-regression was conducted to investigate the potential sources of heterogeneity. In general, studies with the prospective design, consecutive enrollment and blind method could substantially reduce the subjective influence from the researchers. From the previous report, the incidence of ovarian cancer varies in different regions, and it is significantly higher in European countries than in others . TherefoThere are many prediction models for the diagnosis of ovarian cancer. At present, Risk of Malignancy Index (RMI) is the most widely used model and recommended by most oncology centers. Studies showed that RMI I has the highest diagnostic accuracy among RMI I–IV , 25. WhiTherefore, the ADNEX model deserved to be promoted in clinical practice.The model proposed by Stukan  inspiredFirstly, we should consider the selection of tumor markers in the ADNEX model. Studies demonstrated that the absence of CA-125 has no significant effect on the diagnostic performance of the ADNEX model , 17, 21.Secondly, more researchers have noticed that a high D-dimer level is an important diagnostic marker for ovarian cancer patients. The level of D-Dimer has traditionally been used to assess the risk of thrombosis in patients with ovarian cancer , 42. WhiThirdly, Color Doppler is used widely in clinical practice, but the ADNEX model only includes two-dimensional morphological ultrasonic indexes. The blood flow signals within the ovarian tumor are also important to identify the nature of ovarian tumors . As we kThe strengths of this meta-analysis were summarized as follows. Firstly, this was the first summary estimate of the diagnostic accuracy of the ADNEX model at the 15% cut-off value. Secondly, the included studies were of high quality. Among the 10 eligible studies, six were prospective studies, eight were consecutive enrollment studies, and five were blind from reference standard. Thirdly, this meta-analysis was stable without significant publication bias.This analysis had some limitations. Firstly, there were only 10 eligible studies included in this meta-analysis. More studies are needed to verify the diagnostic performance of it. Secondly, the limitation of territory should be taken into account. Five studies were carried out in Europe and four in Asian countries, but only one study in South America. In fact, the ADNXE model is not implemented widely in America . So it wIn summary, the ADNEX model at the 15% cut-off was in high diagnostic accuracy for identifying the risk of ovarian cancer, which should be accepted and promoted more widely. At the same time, more studies on the diagnostic accuracy for different subtypes and the optimization of this model deserve exploring and expecting.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.XH, HL, ZW, and MZ: study design and manuscript review. XH and ZW: literature screen, data extraction, quality assessment. HL and MZ: inconsistency negotiation and quality control. XH and MZ: statistical analysis and manuscript composing. All authors contributed to the article and approved the submitted version.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.


Farmers exposed to certain insecticides may have an increased risk of asthma and asthmatic symptoms, but further research on that issue is urgently needed.The incidence of respiratory disease is increasing. In relation to this, in addition to infection, factors associated with working with chemical insecticides are a cause for concern. Some of the chemicals involved have been shown to affect the respiratory system, and consequentially workers are at increased risk of conditions such as asthma. However, medical opinion around this area is still controversial; therefore, the objective of this study is to investigate the association between exposure to insecticides and asthma by means of a systematic review of the relevant literature. Relevant literature was identified, and a systematic review was conducted to investigate the association between exposure to insecticides and asthma. A total of five studies  including 45,435 subjects were identified as relevant. The summary odds ratios related to the impact of exposure to specific insecticides on asthma were organophosphates 1.31 (95%CI = 1.17–1.48, I Chronic respiratory disease and asthma are major public health issues that cause physical and psychological morbidity and mortality . They alThis study was conducted in accordance with the systematic literature review and meta-analysis reporting guidelines of the Preferred Reporting Items for Systematic Re-views and Meta-Analysis (PRISMA). The current studied is registered under PROSPERO registration number: CRD42021270516, 28 August 2021. The team searched for relevant articles published in the following databases: Web of Science, Scopus, PubMed, Google Scholar, and Google, using the following keywords: “non-atopic asthma” OR “atopic asthma” OR “asthma” plus “pesticide” OR “Insecticides”.The articles that were included were the ones that met the following criteria: (1) original article; (2) published in a journal or thesis; (3) published as a full article; (4) published between 1990 and 2021; (5) assessed the effect of pesticide use on asthma in farmers; (6) occupational exposure; (7) written in English; and (8) data analyzed by correlation coefficient analysis, regression analysis, or discriminant analysis to identify the direction of association by adjusting any interference factors. The exclusion criteria were as follows: (1) articles without variables of interest; (2) review articles; (3) articles with irrelevant information.The data were extracted from the identified articles by the name of the first author, publication year, country, study design, number of the population, age, gender, length of work, diagnosis of asthma, name of the chemical, adjusted odds ratio (OR), and confounding variables. The adjusted OR is the result of estimating the association between insecticide exposure with asthma risk in farmers. Two investigators extracted the data independently.https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools (accessed on 7 June 2021). The NIH checklist consists of 14 items for assessing the quality of the selected observational studies. Two reviewers (RS and JC) independently assessed the quality of reporting in each study. Assessment criteria require reviewers to rate studies to assess the risk of bias in the study due to defects in study design or execution. Ratings are given for a range of items included in each tool to judge each study, with the quality being categorized as “good,” “fair,” or “poor”. The first criterion, “good” means there is the least bias. The second criterion, “fair,” is susceptible to some bias, but the level is considered insufficient to invalidate the results. The final score of “poor” indicates a risk of study bias.  statement: Guidelines for Reporting Observational Studies. dy bias. .2 tests against each other. We determined heterogeneity using the value of I2. An I2 value < 25% equated to low heterogeneity; I2 25–50% indicated moderate heterogeneity; and I2 > 50% indicated large heterogeneity. Funnel plots displaying the log OR of individual studies on the horizontal axis and standard error on the vertical axis were used to detect potential bias from small study effects . All of the statistical tests were two-tailed, and p <0.05 was used to denote statistical significance. Quantitative synthesis of the data and all of the statistical analyses were performed using the STATA software package .The criterion of interest was occupational exposure to insecticides, including organophosphates, carbamates, and organochlorines. The outcome of interest was reported asthmatic symptoms by the patient or diagnosis by a medical doctor. From the eligible studies, adjusted odds ratios (aORs) with 95% confidence intervals (95%CIs) were retrieved and were utilized as a summary measure for a meta-analysis of the study results. The pooled estimates of the relationship between exposure to insecticides and asthmatic symptoms were analyzed using a fixed-effect model utilizing the Mantel–Haenszel method and a random-effect model using the DerSiomonian and Laird method. To assess heterogeneity, we used the Cochran Q and IThe flow diagram in The five studies identified for inclusion in the study included a total of 45,435 subjects ,19,20,21All of the studies in rural and farming areas included occupational exposure. In four studies, the reviewers collected information using a structured questionnaire ,18,19,21Hoppin et al. (2009)  found thSenthilselvan et al. 1992)  found th92  foundTwo studies ,19 found2 = 27%, p = 0.172).The multivariable-adjusted ORs of exposure to organophosphates from all of the studies are shown in 2 = 56.7%, p = 0.031).The multivariable adjusted ORs of exposure to carbamates from all studies are shown in 2 = 37.3%, p = 0.131).The multivariable-adjusted ORs of exposure to organochlorines from all studies are shown in The funnel plots showed an asymmetrical funnel plot from the overall analysis, which may be because the size of effect differs according to study size, but there is little location bias .The existence of an association between insecticides and asthma was systematically assessed in this study using a meta-analytical approach. The relationship between insecticide exposure and risk of asthma has generated an increasing amount of interest in recent years. The results of our meta-analysis showed a significant increase in the risk of asthma among subjects with a history of insecticide exposure. The overall OR was 1.44, 95%CI 1.08–1.92, with an OR = 1.31, 95%CI 1.17–1.48, and OR = 1.31, 95%CI 1.19–1.64 in carbamates, organophosphates, and organochlorines, respectively. One previous study investigated the relationship between non-specific pesticides and the risk of asthma. Beard et al. (2003)  conducteSome studies describe the mechanisms involved in the aggravate of asthma as a result of pesticide use. One example is that direct exposure to chemical pesticides, especially insecticides, will stimulate the bronchial tubes to cause inflammation in the immune system and will increase allergens in the body . PesticiThe occurrence of asthma could also be explained by the neurogenic inflammation caused by pesticide inhalation, the chemicals irritating sensory C-fibers in the airways, providing the release of vasoactive sensory neuropeptides ,33. ThusOur study is a comprehensive meta-analysis investigating a possible link between insecticide exposure and the risk of asthma. However, the sensitivity level of the analysis of the study did not add weight to the substantiation of the association between insecticide exposure and the risk of asthmatic symptoms, indicating instability in the results. Therefore, more studies are needed.The results of this systematic review and meta-analysis suggest that insecticides are associated with the risk of asthma. Exposure to organophosphates, carbamates, and organochlorines is closely related to asthmatic symptoms. Long-term occupational exposure to pesticides is associated with a diagnosis of asthma and asthmatic symptoms. However, the impact of the concentration of pesticides concerning the relationship to asthmatic symptoms is unclear. These findings provide powerful evidence in support of the hypothesis that insecticide exposure is related to an increased risk of asthma. Further research should be conducted to confirm the findings in our study and to clarify the mechanisms involved by more high-quality and large-sample case-controlled and cohort studies.