Endothelial dysfunction serves as an early marker for the risk of cardiovascular disease (CVD); therefore, it is a site of therapeutic interventions to reduce the risk of CVD.To examine the effect of the Mediterranean diet (MedDiet), as an intervention, on structural and functional parameters of endothelial function, and how it may reduce the risk of CVD and associated mortality.Medline database was searched for randomized controlled trials. Random-effects meta-analysis was conducted on 21 independent datasets. Meta-regression and subgroup analysis were performed to assess whether the effect of MedDiet was modified by health status , type of MedDiet intervention , type of parameter , study design , BMI, age, and study duration. Our study used sample size, mean, and standard deviation of endothelial function measurements for both MedDiet intervention and control in the analyses.P = 0.0001). Overall, MedDiet increased FMD by 1.39% . There was a significant improvement in endothelial function in both healthy patients and in those with an increased risk of CVD. No significant variation was observed in the effects of MedDiet on endothelial function, due to study design or type of intervention.Inverse relationship between endothelial function and intake of MedDiet was observed (SMD: 0.34; 95% CI: 0.16, 0.52; These findings support that MedDiet can reduce the risk of CVD by improving endothelial function.The online version contains supplementary material available at 10.1007/s11845-022-02944-9. The endothelium is an intricate organ that maintains vascular homeostasis through interacting with endothelial cells and the lumen of blood vessels . For exaOne such intervention, the Mediterranean diet (MedDiet) represents dietary patterns of the Mediterranean region, which has a low incidence of cardiovascular death as compared to the other populations . The patAs evidenced from various randomized clinical trials (RCTs), it is proposed that different components of the MedDiet  and functional  measures of endothelial function and how it subsequently reduces the risk of CVD and associated mortality.This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses and the American Heart Association guidelines for systematic reviews .Two reviewers  independently searched MEDLINE from inception till 14th July 2021. No time or language restrictions were set. A detailed search strategy is provided in Supplementary Table All the selected studies were imported to EndNote X9  and duplicates were identified and removed. The remaining studies were examined on title and abstract by the two reviewers, AMR and UAAM. The full text was appraised critically against the inclusion and exclusion criteria for the final selection of the articles. A third reviewer (SSJ) was consulted to resolve any discrepancies. No language restrictions were applied. Studies were included based on the following eligibility criteria: (1) randomized controlled trials; (2) studies with adults aged ≥ 18 years; (3) MedDiet (which was defined as a MedDiet by the authors of each study) administered alone or with any other intervention if a comparable and valid control group was present; and (4) studies reporting modifications in endothelial function for intervention and control groups separately. We excluded studies if they were case series, observational studies, or systematic reviews.Data were extracted by the first investigator (AMR) and then rechecked for accuracy by the second investigator (UAAM). Data extracted included study and population characteristics, and outcomes, including baseline and post-intervention values for endothelial function. In addition, two reviewers  assessed the quality of the RCTs as low, high, or unclear risk of bias according to the Cochrane risk of bias tool for randomized controlled trials .P > 0.05 as no publication bias). Heterogeneity was assessed using the Cochrane Q statistic; P < 0.1 indicates significant heterogeneity. Heterogeneity across the trials was also evaluated by the I2 test and the scale was set as a value < 25% which indicates low risk; 25–75% indicates moderate risk; and > 75% indicates high risk [p-value of < 0.05 was considered significant in all cases. All data used in meta-analysis can be found in Supplemental Tables Data were analyzed using RevMan software . For our study, sample size, and the mean and standard deviation (SD) of the endothelial function measurements for pre and post-intervention periods (for both MedDiet intervention and control) were extracted and used in the analyses. When studies used more than 1 method to evaluate changes in endothelial function , MedDiet plus supplementary nuts (n = 2), MedDiet plus supplementary extra virgin olive oil (n = 5), MedDiet plus MUFAs (n = 3), and MedDiet plus exercise (n = 1). Various control groups were also used, like a low-fat diet (n = 9), a Swedish diet (n = 1), the Atkins low-carbohydrate diet (n = 1), the participant’s normal diet (n = 2), the National Cholesterol Education Program Diet (n = 1), a non-MedDiet plus exercise (n = 1), saturated fatty acids (SFA) diet (n = 1), and a prudent diet (n = 1). In the included studies, there were several methods and parameters taken into account to investigate endothelial function, of which the most frequently used methods were FMD and carotid intima-media thickness. Some other parameters were also considered which included cutaneous microvascular function, FBF, baseline vessel size, and calculation of an endothelial function score.Our meta-analysis included a total of 2735 participants from all 15 RCTs , 28–41 wP = 0.0001; Fig. Q = 64.65; I2 = 72%; P < 0.00001). This heterogeneity of results was explained by the removal of 2 studies  with wider effect estimates , while still confirming a significant positive effect of the MedDiet on endothelial function . Subgroup analyses indicated that the effect was stronger on functional parameters , in comparison with structural parameters of endothelial function . Overall, the MedDiet increased FMD by 1.39%  and in those with an increased likelihood of CVD . Moreover, there was no significant change (p = 0.22) in the effects of the MedDiet on endothelial function, due to the study design  or type of intervention  (Table p = 0.618), BMI (p = 0.497), or study duration (in weeks) (p = 0.527) (eTable given in supplementary data). Thus, it is confirmed that the impact of MedDiet on endothelial function was not influenced by age, BMI, or study duration. However, a significant association was demonstrated between study duration (weeks) and functional parameters  protecting against oxidative stress, inflammation, and platelet aggregation (b) modifying cancer-related hormones and growth factors (c) by having a lipid-lowering effect, and (d) by modulating gut microbiota-mediated production of metabolites influencing metabolic health . Additiol-arginine, an amino acid that can be utilized to enhance nitric oxide (NO) bioavailability. NO accounts for the relaxation of vascular tone [l-arginine in amounts 4–24 g per day can be seen through cardiovascular benefits such as reduced BP wherein systolic and diastolic BP can decrease by approximately 5- and 3-mm Hg, respectively. Additionally, nitrate is also an important precursor for NO production and can be found in vegetables, which are included in the MedDiet; nitrate also presents with similar benefits [The MedDiet is a complex diet enriched by foods such as nuts, legumes, and fish. All of which are key sources of lar tone , 50 and lar tone  as well lar tone . The impbenefits .Another known effect of the MedDiet is on inflammatory markers. Prior studies have reported that some components of the MedDiet such as nuts may downregulate inflammatory markers related to atherosclerosis, such as serum C-reactive protein (CRP), interleukin 6 (IL-6), cell adhesion molecule-1 (CAM-1), and intercellular adhesion molecule-1 (ICAM-1) . For exaThe overall quality of the studies involved in our meta-analysis was moderate. In most RCTs, the participants were aware of the intervention while the information was kept confidential in a few studies. This can be viewed as a notable limitation, keeping in mind that expectation bias can play its part, where the anticipation of beneficial effects can produce the most advantageous outcome. At the same time, it has been observed that blinding patients in a clinical trial, in which the intervention is a diet, is a difficult task to achieve. In some of the studies, analysis of endothelial function was done more than once during the trial period, so for studies with a longer period of intervention, this may have impacted the results. To eliminate doubts of having biases in our study related to intermediate measurements of endothelial function, we opted for a systematic approach by including only the last measurement in our study.We revised previous meta-analysis and offer the most recent data. Our meta-analysis results are similar with earlier meta-analysis findings, bolstering the notion that MedDiet is helpful in decreasing CVD and FMD risk values. Furthermore, our findings open the door to additional research that should be conducted to evaluate the efficacy of MedDiet in structural aspects of endothelial function using more robust trials. Our findings could aid in the development of MedDiet diet plans and will help improve the guidelines for patients with CVD. A limitation of our research was that the mean age of participants was 50 years old, which may have minimally decreased the impact fullness of our results, although meta-regression negates the linkage of effects of the MedDiet with age. Furthermore, because there is no general definition of what defines a MedDiet, the nature of the dietary interventions varied across research, and it is probable that certain MedDiet variations may be more beneficial than others in terms of increasing endothelial function, as evidenced by the substantial degree of heterogeneity in our analyses. Similarly, the control group used had variation that there was no a consistent standard against which the MedDiet was measured, which could lead to the high heterogeneity in our analysis. We only considered those studies in our meta-analysis in which the author mentioned intervention as the MedDiet; therefore, we may have missed some studies in which the MedDiet was directed at patients without using the actual name of the diet, and therefore this can be considered a methodological limitation. More studies are required to evaluate the effect of MedDiet on endothelial function, with larger cohorts and longer durations. More robust trials are required to assess the disparities in effects on MedDiet on endothelial function based on gender, age, and previous history of comorbidities so that more rigorous analysis can be performed to better understand the association between MedDiet and endothelial function.The current meta-analysis depicts that the MedDiet has positive effects on cardiovascular health by improving the functional and structural parameters of endothelial function. We did not observe any variation due to age, BMI, study duration, or study design in the effects of MedDiet on endothelial function. Moreover, the quality of evidence in our research was modest but future clinical trials with a good sample size and age diversity are required to strengthen the proof that the MedDiet has beneficial cardiovascular health effects.Supplementary file1 (DOCX 150 KB)Below is the link to the electronic supplementary material.


To dig the PD-L1 rs2890658 polymorphism with susceptibility of non-small-cell lung cancer (NSCLC) in northern China.There were 600 NSCLC patients and 600 age and sex matched controls from the same ethnic origin recruited in the present research. Polymerase chain reaction-restriction fragment length polymorphism method genotyped PD-L1 rs2890658 polymorphism. PubMed and Embase were searched to get eligible literature for meta-analysis. The association between PD-L1 rs2890658 polymorphism and NSCLC risk was calculated with odds ratio and 95% confidence interval.  It is more likely that individuals who have CC genotype and C allele are 2.15 and 1.41 times to develop NSCLC compared with individuals with AA genotype and A allele, respectively. Meta-analysis showed that the individuals who have C allele and CA genotype increased the risk of suffering from NSCLC.  PD-L1 rs2890658 polymorphism increased NSCLC risk in northern China population and it might predict the occurrence of NSCLC. A large number of studies have shown that smoking is closely related to the incidence of lung cancer, and the risk of lung cancer among smokers is nearly 10 times higher than that of nonsmokers. In addition, China currently has more than 33% of the world's smokers , 3. For Immune checkpoint inhibitors physiologically control the immune response by blocking inhibitory pathways, restoring and maintaining the immune system against cancer cells. As the earliest clinically developed receptor targeting immune checkpoints, CTLA-4 . RecentlThere were 600 registered patients in Hebei who were diagnosed with NSCLC in the First Affiliated Hospital of Hebei North University from 2011 to 2021 in the case group. According to the classification standard of lung cancer tissue type of the WHO, the case group was divided into squamous cell carcinoma or adenocarcinoma by pathological type. In addition, the international lung cancer clinical staging system was used for clinical staging, and the case group was divided into stages I, II, III, and IV. The inclusion criteria for the case group are as follows: (a) newly diagnosed lung cancer cases with registered residence in Hebei province; (b) the patients who had not received antitumor therapy such as radiotherapy or chemotherapy; (c) the patients who had not suffered from other malignant tumors or other systemic diseases. There were 600 healthy subjects who received physical examination in the First Affiliated Hospital of Hebei North University in the control group. The inclusion criteria for the control group are as follows: (a) individuals with registered residence in Hebei Province; (b) they had no lung space occupying lesions, no irritating dry cough, bloody sputum, chest pain, or other malignant tumors. All subjects were unrelated Han individuals. The Ethics Committee of the First Affiliated Hospital of Hebei North University agreed the research protocol and experimental method of the current research, and all the individuals participating in this study have known and signed informed consent.The collection of a 5 mL venous blood sample was made by applying ethylenediamine tetraacetic acid  or heparin anticoagulation. Using a whole blood genomic DNA extraction Kit, DNA was extracted. The concentration and purity of DNA were measured by an ultrafine uV-vis spectrophotometer. Polymorphism was genotyped by the PCR-RFLP technique. The PCR reaction process was as follows: predenaturation at 94°C for 3 min, denaturation at 9, denaturation at 94°C for 15 s, annealing at 55°C for 15 s, and extension at 72°C for 30 s, with a total of 35 cycles. Finally, it was extended for 3 min at 72°C. PCR amplified products were digested by enzyme and agarose gel electrophoresis was performed to observe the band position of the digested product and determine the genotype. The primer sequences product sizes for PD-L1 rs2890658 polymorphism were as follows according to the literature : ForwardTwo authors independently searched Pubmed and EMBASE. Search time starts on a database basis and ends in December 2021. And the keywords were shown below: “polymorphism” or “polymorphisms,” “non-small-cell lung cancer” or “NSCLC,” “PD-L1” or “programmed cell death ligand-1.” Only English and Chinese language studies were recruited. Furthermore, for no negligence of related literature, the references were searched.The inclusion standards are as follows: (a) a case-control research evaluating the relationship between PD-L1 rs2890658 polymorphism and NSCLC risk; (b) enough data to count OR and 95% CI. The exclusion standards are shown below: (a) not a case-control research; (b) no adequate information to count OR and 95%CI. (c) experiment object of animals.The first author and second author strictly searched and evaluated all the data and information based on inclusion and exclusion criteria. Literature name, control source, genotyping methods, Newcastle-Ottawa Scale mark and HWE are necessary elements. In the case of different opinions between the first and second authors, the corresponding author will take part in the exploration and determination of the final outcomes. A similar approach was equally adopted to evaluate literature quality. The current meta-analysis evaluated the quality of each literature with the risk evaluation criteria of Newcastle-Ottawa Scale (NOS) bias. The major criteria were made up of three aspects, namely, selecting enrolled research subjects (0–4 marks); between-group comparability (0–2 marks); and exposure results and elements (0–3 marks). In addition, the ethics review and patient agreement were waived because neither human beings nor animals were involved.Q-statistic and I2 statistics. There were four genetic models adopted to evaluate the relationship between PD-L1 rs2890658 polymorphism and NSCLC risk as the past literature reported. The fixed-effects or random-effects model was selected on the basis of the heterogeneity degree. It was considered that I2 < 50% is low heterogeneity, 50 ≤I2 < 75% is moderate heterogeneity, and I2 ≥ 75% is great heterogeneity. If I2 < 50% and P > 0.1, the fixed-effects model would be adopted. If I2 ≥ 50% or P ≤ 0.1, the random-effects model would be adopted. Sensitive analysis and publication bias were according to past meta-analysis. The current meta-analysis was made and disclosed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist [t test, χ2 test. The association between risk factors and ovarian cancer was evaluated by counting OR together with 95%CI and performing binary logistic regression. P < 0.05 was considered as great diversity.This relationship's power was evaluated with both the OR and 95%CI. The heterogeneity degree was evaluated with the hecklist . SPSS 18P > 0.05).The PCR-RFLP method detected three kinds of genotypes  in both the NSCLC group and the control group. Significant associations were found between the NSCLC group and the control group for genotype and allele comparison. Individuals who have the CC genotype are 2.15 times more likely to develop NSCLC individuals than who have the AA genotype. Similarly, individuals who have the C allele are 1.41 times more likely to develop NSCLC than individuals who have the A allele. The detailed information is shown in The PRISMA 2009 flow diagram displayed the flow diagram of the current meta-analysis search process . Four ChP = 0.013) is shown in P = 0.030) is shown in P = 0.019) is shown in Thepositive outcomes between PD-L1 rs2890658 polymorphism and NSCLC risk by allele contrast  after subgroup analysis was performed. If we eliminated the study from India, the degree of heterogeneity obviously reduced as almost no heterogeneity was found in the Brazilian or Caucasian population . Therefore, we conduct subgroup analysis based on ethnicity to detect the heterogeneity source. Consequently, ethnicity was the main source of heterogeneity as the Ipulation .P = 0.560).Regardless of the literature excluded, the outcome of our meta-discussion was the same, suggesting the conformance and steadiness of the current meta-discussion. The outcome of sensitive discussion displayed stable present outcomes. No significant asymmetry was observed by funnel plot, and Egger's test also indicated that there was no significant asymmetry (Immune checkpoint inhibitors have achieved good efficacy in the treatment of various tumors –30. Its Immunotherapy has become an emerging cancer treatment method in recent years. Different from traditional chemotherapy, immunotherapy enhances or normalizes the antitumor immune response by using the body's immune system so as to inhibit and kill tumor cells. Immunotherapy, shown by PD-1/PD-L1 checkpoint inhibitors, is one of the most potential study directions in the field of cancer therapy. It offers long-lasting benefits and is gradually becoming a first-line treatment in the guidelines. However, current studies suggest that not all populations benefit from pD-1/PD-L1 checkpoint inhibitors, especially first-line therapy in patients with advanced NSCLC. Therefore, it has become a hot topic to find an optimal detection index to screen the best beneficiaries. Many existing researches have displayed that the different expression levels of PD-L1 have a certain impact on the efficacy. With the accumulation of more and more clinical data, PD-L1 has become a relatively effective detection index at present, but its critical value is still controversial, and it has not been decided whether to take various treatments for patients with different expression results of PD-L1. However, the association between PD-L1 polymorphism and NSCLC susceptibility is still unclear. Therefore, the present study has evaluated the PD-L1 rs2890658 polymorphism with NSCLC susceptibility based on experimental data and meta-analysis. The outcomes of the meta-analysis indicated that AC genotype and C allele increased NSCLC risk. Our experimental data indicated that CC genotype and C allele grew NSCLC risk. Although we are driving somewhat inconsistent results, it is a very normal phenomenon when conducting gene polymorphism association studies , 32. ChiWith the continuous development of bioinformatics and medicine and the arrival of the era of big data, people are no longer satisfied with research at the level of tissue cells but have begun to shift to research at the level of molecular medicine –35. ThisPD-L1 rs2890658 polymorphism increased NSCLC risk in northern China population and it might predict the occurrence of NSCLC.


Respiratory diseases related to chronic pulmonary ventilation dysfunction are mainly composed of chronic obstructive pulmonary disease (COPD) and asthma. Our meta-analysis aimed to illustrate the association of COPD or asthma with risk of atrial fibrillation (AF).We systematically searched the databases of the PubMed, Embase, and Cochrane library until December 2021 for studies focusing on the relationship between COPD or asthma and AF risk. Due to the potential heterogeneity across studies, the random-effects model was used to pool the studies.Our meta-analysis included 14 studies. Based on the random-effects model, the pooled analysis showed that COPD  and asthma  were significantly associated with an increased risk of AF. The results did not change after each study was excluded.Our current data suggested that COPD or asthma with associated with an increased risk of AF. Chronic obstructive pulmonary disease (COPD) is characterized by irreversible obstruction and abnormal inflammation in the airways, and progressively or partially leads to pulmonary heart disease and respiratory failure . As the Romiti et al.  reportedWe systematically searched the PubMed, Embase, and Cochrane library until December 2021 for all the potential studies focusing on the relationship between COPD or asthma and AF risk. We applied the following keywords and search terms to search the relevant studies: (COPD OR chronic obstructive pulmonary disease OR asthma OR lung function OR pulmonary disease) AND . For example, Studies were included if they reported the relationship between COPD or asthma and the risk of AF after the multivariate analysis (expressed as adjusted effect estimates). The study type was not restricted in our meta-analysis. COPD, which is widely regarded as the result of chronic emphysema and bronchitis, is characterized by irreversible obstruction and inflammation in the airways. Based on the pathological physiology of asthma, reversible inflammation and airway hyperresponsiveness contribute to the progression and development of airway obstruction. The definitions of disease conditions (COPD or asthma) and outcome (AF) were applied according to the originally included studies.We excluded studies that only reported the crude event rate of AF associated with COPD or asthma. Studies with certain study types, such as reviews, editorials, letters, commentaries, trial protocols, meta-analysis and case reports, were excluded because they had no relevant data used in the pooled analysis. In addition, we did not include the meeting abstracts due to the insufficient data for study quality assessment, and the different objectives for our study.Two reviewers first independently screened the titles and abstracts of the records from the databases to pick up the potential studies, the full text of which were subsequently screened to identify the final studies that met the eligibility criteria. Discrepancies and disagreements were resolved by consensus. The baseline characteristics of the included studies were extracted, such as the authors, design of the study, data source, sample size, age and sex of the studied population, definitions of COPD or asthma, method of AF assessment, follow-up time, and effect estimates.And then, the quality assessment was performed by using the Newcastle-Ottawa Scale (NOS) including three domains: the selection of cohorts (0–4 scores), the comparability of cohorts (0–2 scores), and the assessment of the outcome (0–3 scores). In this meta-analysis, the NOS of ≥ 6 and <6 scores were regarded as moderate-to-high quality and low-quality, respectively.P value as well as the I2 values. In our present meta-analysis, P < 0.1 and I2 > 50% suggested significant heterogeneity.We assessed the heterogeneity across the included studies by using the Cochrane Q test and P-value of > 0.1 indicated no significant publication bias.For each included study, adjusted odds ratios (ORs), risk ratios (RRs), or hazard ratios (HRs), as well as their confidence intervals (CIs), were extracted. In this study, we opt to refer to all the effect estimates as RRs, and this choice would not affect our results. The natural logarithms of the RR (Ln[RR]) and their standard errors (SELn[RR]) were calculated, and then pooled using a random-effects model weighted by the inverse-variance method. In the sensitivity analysis, we excluded one study at a time to examine the effect of each study on the pooled results. In addition, we used the fixed-effects model to re-perform the above-mentioned meta-analysis. The subgroup analyses were not performed due to the limiting studies. The publication bias was evaluated by employing the funnel plots for visual inspection of asymmetry., and was further assessed statistically by using The Egger's and Begg's tests were used for assessing the statistical publication bias, where a P-value of < 0.05.All the statistical analyses were performed using the Review Manager version 5.4 software , and the Stata software . In this study, the statistical significance threshold was set at a As shown in The baseline characteristics of included studies are shown in A total of 12 included studies assessed the association of COPD with AF risk –19, 23. In the pooled analysis using the random-effects model, the effect estimate of COPD on AF risk was 2.24  tests also showed no significant publication bias. For the section on asthma and AF, it was unsuitable to assess the publication bias because <10 studies were included for the quantitative analysis according to the Cochrane handbook.When assessing the effect of COPD on AF risk, the funnel plot presented in The leading advantage of our study was the first meta-analysis to identify the association between COPD or asthma and AF risk. Especially, we quantified the correlation between the magnitude of AF and chronic pulmonary ventilation diseases (COPD and asthma). The pooled results demonstrated that the increased incidence of AF was associated with COPD or asthma. There was no variance in results when one study was excluded at a time.Several previous studies have revealed that the increased risk of AF was commonly observed in patients with COPD or asthma. Yucel et al. reported that the biomarker cancer antigen 125 (CA-125) reached a higher level in patients with cardiopulmonary diseases, such as AF and COPD . This stRecent studies have demonstrated the potential pathophysiological mechanisms which induce AF in patients with COPD or asthma. Among these pathological manifestations, hypoxia plays a significant role in oxidative stress response, which contributes to the abnormal electrophysiological change of atrial muscle cells and finally leads to AF , 31. YanBy analyzing our results of this meta-analysis, it showed that the presence of AF was more common in COPD and asthma patients. Grymonprez M et al.  and KoneUnderstanding the relationship between chronic pulmonary ventilation dysfunction diseases and cardiovascular complications, such as AF, plays an important role in disease management. For example, some targeted treatments and medication usages will be emphasized in the novel handbook of COPD (and asthma) management. Some independent studies have substantially identified the increased cardiovascular risks in patients with COPD and asthma, and some associated evidence was provided by retrievable researches and reviews , 10. HowOur current meta-analysis had several limitations. First, although the observed results were significant based on the statistical aspects, the heterogeneity was still evident across the included studies. Potential causes included inconsistent definitions of COPD or asthma, different study types, and various studied populations. Further prospective cohort studies containing larger sample size, longer-period follow-up, and more subgroups analysis could confirm our findings. Second, we were unable to perform the subgroup analysis based on the types of AF because the originally included studies did not report them separately. Third, due to the inadequate raw data and confounding factors , we did not perform the subgroup analyses. Finally, among the patients with COPD, the association between the frequency and severity of COPD and AF incidence was observed in some related studies. However, due to the limited number of these studies, our meta-analysis was not able to evaluate this situation.Currently available data suggested an association of COPD or asthma with the increased AF risk. Further high-quality studies should be conducted to confirm the relationship between COPD or asthma and AF risk.The original contributions presented in the study are included in the article/All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This study was funded by National Natural Science Foundation of China (82100273 and 21866019).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The meta-analyses were performed using the generic inverse variance in R software with a random-effects model. Subgroup analysis was used to determine if the lung function was influenced by a potential study effect or by the participants’ characteristics. A total of 5562 participants from 24 studies were included. No significant difference was found between firefighters’ predicted FEV1 from wildland, 97.64% , and urban fires, 99.71% . Similar results were found for the predicted FVC. Nevertheless, the mean values of firefighters’ predicted lung function varied significantly among studies, suggesting many confounders, such as trials’ design, statistical methods, methodologies applied, firefighters’ daily exposure and career length, hindering an appropriate comparison between the studies.Firefighters are exposed to a range of harmful substances during firefighting. Exposure to fire smoke has been associated with a decrease in their lung function. However, the cause–effect relationship between those two factors is not yet demonstrated. This meta-analysis aimed to evaluate the potential associations between firefighters’ occupational exposure and their lung function deterioration. Studies were identified from PubMed, Web of Science, Scopus and Science Direct databases (August 1990–March 2021). The studies were included when reporting the lung function values of Forced Expiratory Volume in 1 s (FEV Exposure to fire smoke represents a severe health risk and is a growing concern for occupational and community exposures . Fire smIn general, individuals exposed to fire smoke can undergo different health effects, both physical and mental, with varying severity levels. Some of the hazards and concerns for public health are airway and eye hypersensitivity, changes in vascular, pulmonary and cardiopulmonary function, different types of cancer and, in more severe cases, death ,7,8,9,10The most vulnerable groups of the population include children, the elderly, pregnant women, individuals diagnosed with chronic cardiopulmonary diseases and occupational groups, especially emergency workers such as firefighters (including volunteers), police, rescue workers and health workers ,11. Fire1 and FVC [In an attempt to understand the impacts of fire smoke exposure on firefighters’ health, some studies evidenced that fire smoke may cause pulmonary embolism, pneumonia, bronchitis, chronic obstructive pulmonary disease (COPD) and asthma, as well as their exacerbations ,13,14,15 and FVC . However and FVC ,18. On t and FVC ,20,21. T and FVC ,23.The majority of those studies in the literature described urban fires, mostly related to the collapse of the World Trade Centre (WTC) on 11 September 2001 (9/11) ,25,26, wAs far as known, only systematic reviews have been published in this area. Thus, this study aimed to perform a meta-analysis to understand and quantify the impact of fire exposure on firefighters’ pulmonary health.Four databases, namely, PubMed, Web of Science, Scopus and Science Direct, were accessed in March 2021, using the same search terms: “firefighter”, “health effects”, “spirometry”, “asthma”, “occupational exposure”, “obstructive airway”, “lung”, “FEV”, “forest”, “wildland”, “chronic obstructive pulmonary disease” and “meta-analysis”. References cited in individual or review articles were systematically analysed through a manual search and included in this meta-analysis. No language limitation was applied. Duplicates were removed. The authors were not contacted for further information. This meta-analysis followed the PRISMA  guidelines .1 and FVC values, were included. The primary search results were reviewed, and some of the articles were eliminated after reviewing their title and abstract.Only cohort or case–control studies, which specifically evaluated the lung function and reported FEV1 or FVC; (v) overlapping study population; and (vi) published in books/book chapters, reviews, textbooks and reports.The applied criteria for exclusion of a study were: (i) not related to lung function; (ii) not related to firefighter workers; (iii) not related to fire exposure; (iv) not reporting FEVThe studies were independently researched and screened by two authors. Agreement between them was reached after a consensual discussion. For studies considering the same or overlapping populations, we selected the one with a larger population and more comprehensive information.1 (%) and FVC (%) were collected as indicators of lung function. When FEV1 and FVC were expressed in litres, the corresponding predicted values were estimated using the Global Lung Function calculator, which is based on the age, gender, height and ethnicity of the study participants [After applying the exclusion criteria, the studies were analysed, and data were extracted with the following information: author’s surname, publication year, study design, study location, sample size, participants’ mean age, fire type and main objective. Predicted FEVicipants .The missing standard deviations (SD) data were calculated from trial statistics, namely, confidence intervals and standard errors of the mean .2), Tau squared (τ2) and the standard chi-squared test (χ2). I2 is the proportion of the dispersion of the results observed in the studies included in a meta-analysis that is real, rather than specious. The I2 index can be considered as the percentage of the total variability in a set of effect sizes due to true heterogeneity (variability between studies). τ2 is the variance of the effect size parameters between the populations of studies, reflecting the variance of the true effect sizes. χ2 tests the statistical hypothesis that the true treatment effects (the parameters of effect size) are the same in all the primary studies included in a meta-analysis [2 values > 75%, moderate for values between 50% and 75% and low for values < 25%. The level of statistical significance was set at 0.05.Meta-analyses of the lung function values were carried out using the generic inverse variance in R software version 3.6.1 , with the meta package . Data ananalysis . HeterogSubgroup analyses were used to determine if the lung function was influenced by a potential effect of the study or by participants’ characteristics, such as publication year , study location , participants’ age , smoking practices (non-smokers and smokers) or type of fire (wildland or others).For the subgroup analysis by smoking practices, the studies were divided according to the number of smoking participants included in each study, with “non-smokers” and “smokers” assigned to the studies wherein less than or equal to 10% of the participants were non-smokers and more than 10% of the participants were smokers, respectively. Hereafter, whenever these terms are mentioned, it is intended to be understood as smoking and non-smoking participants.The methodological quality and the risk of bias for each of the included studies were assessed by two independent authors based on the Study Quality Assessment Tools . This to1 values were not available or were not eligible. Finally, the 24 studies obtained were divided into wildland (9 studies) and others/urban fires (15 studies). The PRISMA flow diagram is provided in After removing duplicates and including the records identified through manual reference analysis, the literature search identified 4297 studies. After screening the titles and abstracts, 4205 studies were excluded according to the exclusion criteria. Regarding specifically the criterion of overlapping study populations, several studies related to the WTC fire were found. However, as the analyses were performed based on the same population of firefighters exposed to the pollution of the WTC fire, only one study (the most complete) was considered in this meta-analysis. After reading the full text of the 92 remaining studies, 68 more were excluded, since the FEV1 mean values reported in the studies included in this meta-analysis varied from 82.94% to 113.39%. The overall predicted FEV1 mean value obtained for the 24 studies was 99.23% (95% CI: 94.65–103.80%), with a heterogeneity of I2 = 100%  in the studies performed before 1996, to 103.34%  in the studies published after 2014. This evident increase over the years was also observed in the predicted FVC mean values , while the participants from Australia showed the higher mean value of lung function, 105.19% . There were no significant differences between the participants from Europe, 98.11% , and those from North America 99.18% . The results obtained for the predicted mean values of FVC with the participants from Australia were also the highest, 111.10% ; however, the FVC values of the study performed in Asia, 103.90% , were slightly higher than those registered both in Europe, 102.65% , and in North America, 101.60%   .1 in firefighters according to their age. The youngest individuals (groups 20–30 and 31–40 years old) showed similar predicted FEV1 mean values , while the oldest participants (older than 40 years) showed a higher predicted mean value of FEV1, 101.95% . The same behaviour was observed for the predicted mean values of FVC (s of FVC .2 = 98%) and 97.03% , respectively  and those fighting other/urban fires . Similarly, there was no difference in the predicted FVC mean values  and missing or unclear information about the participants’ selection (inclusion/exclusion criteria). Finally, only four studies defined control groups.Two articles were rated as low-quality, 14 studies as moderate-quality, and 8 studies as high-quality . Conside1 and FVC mean values. Moreover, no statistically significant difference was observed in the pooled predicted FEV1 mean value in firefighters . This hindered definitive conclusions about the impact of firefighting exposure on the lung function. Still, the subgroup analysis allowed relevant interpretations.The results from this meta-analysis were obtained from 24 studies conducted along 31 years, including studies with distinct designs, in various countries and considering different types of fires and firefighters of different ages and with different smoking practices. The results showed a large variability in the predicted FEV1 and FVC values) was observed, although not statistically significant. However, the comparison between newer and older studies is difficult, as the studies’ procedures may have changed with time, namely, the recruitment strategies, the equipment used for lung function tests (past vs. modern devices), different or newer methodologies, or different standards for lung function tests [1 and FVC), which have been reviewed or modified over the years. The Global Lung Function Initiative developed in 2012 (GLI-2012) reports the latest reference equations for spirometry, based on the pooled resources of various countries and on data obtained from more than 74,000 healthy non-smokers tests from all over the world [Regarding the publication year, an increase in firefighters’ lung function along the years . Schermer et al. (2010) and Slattery et al. (2017) also reported high FEV1 values and associated them with the “healthy worker effect”. This effect describes the reduction of morbidity or mortality associated with employment factors when occupational cohorts and the general population are compared [Although non-statistically-significant differences were observed between different studies’ location, low pooled predicted FEVcompared ,64. In acompared . On the compared ,62.The lung function did not significantly vary with the firefighters’ age. It is known that with age, individuals undergo anatomical and physiological changes , which are responsible for the reduction in their lung function . Scherme1 predicted mean values compared to those of non-smokers was observed, though not statistically significant. Jacquin et al.’s study (2011), which was the wildland study with the highest score in the quality rating/lowest risk of bias assessment (0.92), reported that firefighters are likely to develop respiratory impairments after fire smoke exposure; however, the authors did not observe any statistical differences between smokers and non-smokers.Smoking is a known significant confounder. A slight reduction in smoking firefighters’ FEV1 mean values of both wildland and urban firefighters. Although this meta-analysis included 5562 participants, only 693 were firefighters dedicated to wildland fires, which probably may have contributed to overestimating the results obtained. Otherwise, some studies from North America assessed the lung function of firefighters who participated in WTC rescue operations. The collapse of the WTC generated a high-intensity pollution discharge, including extremely high Particulate Matter (PM) concentrations, exposing the population to extremely hazardous physical and chemical pollutants [The pooled analysis was unable to demonstrate a significant difference in the predicted FEVllutants . After tllutants . On the Heterogeneity was always above 90%. Perhaps, other factors that were not taken into account by most of the authors in the studies reviewed may have affected the results of the individual studies. Those include the duration of the intervention, i.e., the period between the end of the exposure and the lung function assessment (spirometry), the type of fire, and issues directly related to firefighters, namely, their age, other types of daily exposure besides that of firefighting, the annual number of working days and the career length.Other factors that may have contributed to not having found significant differences in lung function reduction was the use of respiratory protective equipment and firefighter’s type of career. The protective apparatus attempts to minimize the respiratory hazards which firefighters are exposed to, filtering particulates from the surrounding air or providing breathable air when working in oxygen-deficient or toxic atmospheres . On the Therefore, the results of this meta-analysis should be interpreted with caution due to the potential heterogeneity between the trials.1 and FVC).There was significant heterogeneity in the studies’ aims, designs, statistical methods and methodologies applied, which can influence the quality of the results or lead to variations in the reported values of the lung function parameters , and vice-versa, may have introduced bias in this study. Nevertheless, this is the most used methodology allowing an appropriate comparison between studies.The use of the GLI-2012 equations to transform the FEVFurther, due to the differences observed in how the data were reported, particularly, data measured in different units due to the use of different methodologies or data published in graphical figures, impairing the data extraction, it was necessary to exclude some studies or to perform recalculations (whenever possible) through the equations. Thus, this fact may have contributed to reduce the accuracy of the results.1 rates (between 82.94 and 113.39%) hindered definitive conclusions. Further, the pooled analysis was unable to demonstrate a statistically significant difference in firefighters’ predicted FEV1 mean values. Several factors could have contributed to this result, such as the methodologies applied, the equipment used, the reference equations for spirometry , the differences in the recruitment strategies of firefighters according to their countries or the publication year, hampering an appropriate comparison between studies.The present study’s goal was to assess the potential associations between firefighters’ occupational exposure to fire smoke and its effect on the lung function. The large variability observed in the reported predicted FEVSeveral reasons for statistical heterogeneity were identified. Since the results of the studies included in this meta-analysis may not have taken into account the possible confounding factors, they should be interpreted with caution due to the potential heterogeneity between the trials.Although there are some limitations, this study’s conclusions are of upmost importance because they highlight the necessity for further studies to assess firefighters’ lung function, especially in those combating wildland fires. This will allow to understand the impacts of fire on firefighters’ health, which are still unknown, and develop strategies to protect them. Moreover, further development could also include an analysis of the composition of the pollutants in each study, enabling to understand if the fire smoke composition influences firefighters’ lung function reduction.


The high intake of yogurt was associated with a 35% reduction in the risk of earlier menarche . Girls with severe food insecurity experienced later menarche . Conversely, due to the high intake of protein, the risk of early menarche increased by 8% . High intake of yogurt, longer duration of breastfeeding, and food insecurity decreased the possibility of earlier menarche, while high intake of protein increased that risk. As a modifiable factor, diet and nutrients in infancy and childhood provide new insights into the future prevention of early puberty.The onset of puberty has become earlier over the decades, and nutrients and diet are related to the timing of puberty onset. Hence, we aimed to investigate the association between diet or nutrients in infancy, childhood and early puberty. PubMed, Embase, and Cochrane library were searched systematically up to 15 April 2022. The pooled relative risks (RRs) or regression coefficients (beta) were estimated using the random-effect model or fixed-effect model according to the heterogeneity between studies. Twenty-two articles on diet or nutrients in childhood and six about breastfeeding in infancy were included. The prolonged breastfeeding duration in infancy could reduce the risk of early menarche (beta 0.31, 95% CI: 0.01, 0.60,  Puberty is a pivotal period in the lifecycle. During this period, people experience the transformation from children to adults, attaining both somatic growth and reproductive maturity. For boys, genital growth, pubic hair development, and voice break are recognized as major puberty milestones. For girls, breast growth, pubic hair development, and menarche are the main secondary sexual characteristics in puberty . There iMKRN3) and delta-like noncanonical Notch ligand 1 (DLK1) are key genetic drivers in the progression of central precocious puberty [The timing of puberty is determined by numerous risk factors with their complex interplay. Genes partly determine when an individual’s puberty begins. For instance, makorin ring finger protein 3  guideline. This study was registered with PROSPERO (CRD42022349856).We searched comprehensively in PubMed, Embase, and Cochrane library for relevant studies published from inception to 15 April 2022. We did not impose any language restrictions nor limit the research types. To ensure a thorough literature search, the following keywords were used, food, diet, breastfeeding, milk, meat, dairy, carbohydrate, fat, protein, food insecurity, early puberty, precocious puberty, premature, thelarche, and menarche. Boolean operators “OR” and “AND” were used to combine these search terms. To retrieve articles more accurately, we limited the age of the research subjects to less than 18 years old, as puberty generally ends at this age. We also reviewed references of included articles to identify relevant literature.To be eligible, the published articles should meet the following criteria: (a) They were epidemiological studies, including cross-sectional, case-control, or cohort studies. (b) Different levels of diet or nutrient intake were considered as exposure. The way of assessment was food frequency questionnaires, food diaries, or dietary recall interviews. The outcome of interest was the number of children at different pubertal stages and/or the age at pubertal milestones. Pubertal indicators were obtained by clinical diagnosis, questionnaire, or self-reporting. (c) Studies investigated the association between early puberty and diet or nutrient intake. The adjusted odds ratio (OR), relative risk (RR), hazard ratio (HR), or regression coefficients (beta), as well as its 95% confidence interval (CI), were provided.Studies were excluded if they (a) did not study specific diet or nutrients but focused on only dietary patterns; (b) selected subjects with medical conditions or diseases that would cause early puberty, such as adrenal dysfunction, pituitary tumor, thyroid hypofunction; (c) did not assess pubertal outcomes  according to the Tanner staging; (d) were the only one article to show the relationship and could not be combined using meta-analysis.The studies obtained through the search strategy were screened to rule out duplicates. Then, the review of the title and abstract was performed. Among the full-text articles, ineligible articles were removed according to the exclusion criteria. For all included studies, the following characters were extracted, including first author, year of publication, country, study design, health status, age, gender, sample size, type of diet or nutrients, the pubertal outcome of interest, ORs, RRs, HRs or beta with 95% CIs for the relationship between diet or nutrients and early puberty. Confounding factors were taken into consideration.The Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of cohort and case-control studies. It assessed the risk of bias from three domains of selection, comparability, and outcome, giving scores ranging from 0 to 9. In this article, we defined the criterion controlling important confounding factors: maternal age at menarche, maternal education level, household income, weight, and height. Referring to the previous meta-analysis , the stuI2 and p statistical variables were used to evaluate the heterogeneity between studies. A random-effect model was used in the presence of significant heterogeneity (I2 > 50% or p < 0.1), otherwise, the fixed-effect model was selected. For the issues with more than three articles, sensitivity analysis was performed by omitting one study sequentially to assess the robustness of the results. Besides, Egger’s test was conducted to inspect the publication bias. Unfortunately, we were unable to conduct the subgroup analysis to explore possible sources of heterogeneity between studies owing to the limited number of studies. All statistical analyses were performed using Stata 16.0 .The effect size measures used to report the relationship between diet or nutrients and puberty outcome were ORs, RRs, HRs, or beta with 95% CIs. We selected the risk estimates for the highest exposure group compared to the lowest or reference group with the adjusted model. Given that the relevant articles are scarcely available, the ORs and HRs were deemed equivalent to RRs and then pooled together directly . The pooThe process of the systematic search is shown in The characteristics of the 28 included articles are presented in The details of quality assessment based on NOS are shown in p = 0.045). The combined beta indicated 0.31 months later timing of menarche onset for every additional month of breastfeeding duration in girls.As illustrated in p = 0.296, p = 0.072, p = 0.965, p = 0.016, We did not observe an association between early menarche and total energy intake . A similar relationship was observed for vitamin A  and vitamin B12 . Besides, Wolff et al. [The pooled RR for the association between vitamins and earlier menarche onset is shown in f et al.  and Mervf et al.  found lif et al.  discoverp = 0.008, p = 0.527, p = 0.965, We found that yogurt may reduce the risk of early menarche .As shown in p = 0.027).The significant association between food insecurity in developing countries and the timing of menarche is presented in p = 0.006) and fat intake (Egger’s test: p = 0.000).The sensitivity analysis confirmed the robust association between the delay of age at menarche and prolonged breastfeeding duration or food insecurity . HoweverIn this systematic review and meta-analysis, our findings suggested that prolonged breastfeeding duration and high intake of yogurt had protective effects on earlier menarche. In addition, we observed a significant association between food insecurity and delayed menarche onset. In contrast, girls with a high intake of protein were more likely to experience earlier menarche. However, we did not observe significant associations of early puberty with total energy intake, carbohydrate, fat, milk, dairy, meat, vitamin, lignan, flavonols, and soy intake.DYN) on gonadotropin-releasing hormone (GnRH) [The present meta-analysis suggested that delayed timing of menarche is related to breastfeeding duration early in life. Studies have also pointed out a preventive effect of prolonged breastfeeding duration on earlier breast development ,25. Insue (GnRH) . The evie (GnRH) ,46. Moree (GnRH) . Studiese (GnRH) ,49. Furte (GnRH) . Childree (GnRH) . The rise (GnRH) , is feasGirls with high yogurt intake might have a lower likelihood of earlier menarche onset. Obesity is a recognized cause of early puberty, and several studies have focused on yogurt protein and anti-obesity, with mixed findings ,54. MeanAs defined, food insecurity is limited or uncertain availability of nutritionally adequate and safe foods or limited or uncertain ability to acquire acceptable foods in socially acceptable ways . In undeHigh protein intake during childhood might be an effective predictor of early menarche. As previously stated, insulin resistance is related to earlier puberty onset. The long-term consumption of high-protein diets brings a higher risk of insulin resistance . With thControversy remains as to whether the total energy and carbohydrate intake affect the pubertal onset. We did not find the effects of energy and carbohydrate intake on early puberty in our study, but this finding was not robustly supported by sensitivity analysis. A previous meta-analysis suggested that girls with a higher level of total energy and carbohydrate intake were prone to earlier menarche onset . BesidesThe impacts of micronutrients and phytochemicals on pubertal milestones remain poorly studied. Although a prior meta-analysis indicated a link between vitamin C and earlier menarche , evidencDespite a positive relationship between milk consumption and IGF1 ,85, we fSome strengths deserve to be highlighted. To date, this is the first meta-analysis to simultaneously investigate the association between diet or nutrient intakes during infancy and childhood and subsequent puberty timing. Second, the sample size of studies in our meta-analysis was relatively large. Ten studies were conducted in developing countries, and eighteen were done in developed countries. Since socioeconomic and demographic characteristics could be controlled to some extent, the findings were more generalizable. Third, the risk of early puberty was predominantly estimated with hazard ratios through prospective design. The above provided strong evidence for the causal relationship between early puberty and diet or nutrients. Furthermore, notwithstanding significant heterogeneity shown by several results, the quality of included studies was all moderate or high.Some limitations also merit attention. We chose the risk estimates using the most-adjusted model, but the confounding factors adjusted in the included studies were still diverse. Besides, we selected the risk of early menarche in the highest intake group compared with the lowest or reference group, while the classification criteria of exposure groups were divergent in each research. Moreover, several methodologies were used to assess diet or nutrient intake, raising concerns about measurement accuracy in practice. Hence, the high heterogeneity would inevitably flaw the robustness of the final results. Unfortunately, we could not perform the subgroup analysis because of the scarcer studies. In addition, due to a lack of information to transform, the risk estimates  were directly described as the RRs. When the ORs are pooled with RRs and HRs, the risk of early menarche is overestimated.Prolonged duration of breastfeeding, high intake of yogurt, and food insecurity had inverse associations with earlier menarche. In contrast, girls with a high intake of protein were more likely to experience earlier menarche. To sum up, the diet and nutrients in infancy and childhood may play a relevant role in pubertal development.


For site-specific cancer analysis, the risk of non-lymphoid leukemia was elevated with high ASB intake , while risk of colorectal cancer was decreased . Dose–response analysis indicated a positive linear association between ASB intake and the risk of leukemia (-linearp = 0.027). The risk increased by 15% per one serving (355 mL) daily ASB intake increment . In conclusion, ASB consumption might be positively associated with the risk of leukemia and negatively associated with the risk of colorectal cancer.The impact of artificially sweetened beverages (ASBs), alternatives to sugar-sweetened beverages, on cancer incidence remains controversial. We conducted a meta-analysis of prospective studies to assess the association of daily ASB intake with cancer risk. A systematic search was performed between January 1967 and September 2022. Risk ratios (RR) or hazard ratios (HR) were extracted and pooled. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was used for the assessment of the certainty of evidence. The study was registered at PROSPERO (CRD42022312171). Overall, 14 articles with 17 cohorts were included. There was no significant association between daily ASB consumption and risk of overall cancer (highest versus lowest category:  High sugar-sweetened beverage (SSB) consumption was one of the risk factors for the overall attributable burden of death between 1990 and 2017 ,4. StudiThough initially considered a healthier alternative to SSBs, the long-term health implications of ASBs remain to be answered . Some LCIn accordance with in vitro and in vivo studies, results from epidemiological studies were unable to reach a consensus. A case–control study suggested that patients with bladder cancer had more frequent ASB consumption than healthy controls  CoincideThis work was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , and theThe literature search for articles published between January 1967 and September 2022 was conducted using the PubMed and Web of Science databases by two independent investigators. The following search terms were used without language or calendar date restriction:  AND  AND . The reference lists of reviews and eligible studies were checked as well for additional studies. RRs or HRs for the highest versus lowest category could not be obtained. For dose–response analysis, studies should provide a quantitative measurement of intake, the number of cases, and follow-up person-years for each category  with at least three categories classified based on the dosage of exposure. Two authors performed the study selection independently, and disagreements were resolved by the intervention of a third author.Studies were included if they met the following criteria: (1) studies with a prospective cohort design; (2) ASB intake as the exposure; (3) cancer incidence as the outcome; and (4) reported estimates of risk ratio (RR) or hazard ratio (HR) and corresponding 95% confidence intervals (CIs) in the highest versus lowest categories. Studies that treated the exposure as a continuous variable were excluded, as RRs or HRs and corresponding 95% CIs for all categories, and confounding variables adjusted in multivariable analysis. For the highest versus lowest category comparison, we extracted information about the classification of the highest and lowest categories and the levels of daily ASB consumption in these two groups, respectively. The mean or median daily intake of ASBs, number of cases, and follow-up person-years in each intake category were further extracted for dose–response analysis. The method described by D. Aune et al. was used to estimate person-years for each category in studies that only reported the total number of person-years and distribution of cases [RR for each category. If only ranges of intake were reported, the average of the lower and upper boundaries was calculated as an estimated midpoint. When the highest category was open-ended, the average intake level was assigned at 1.5 times the lower boundary. When the lowest category was open-ended, the average intake level was estimated by dividing the higher boundary by 1.5 [The following data were extracted from each study by two independent authors: first author, year of publication, cancer type, age and sex at entry, cohort name, area, follow-up duration, number of cases, number of participants, exposure assessment, exposure dosages, minimally and maximally adjusted of cases . The mosy by 1.5 . ASB inty by 1.5 . When thy by 1.5 , 355 mL y by 1.5 , and 375y by 1.5 . When LCy by 1.5 . Cancersy by 1.5 .We used the preliminary Risk of Bias in Non-randomized Studies of Exposure (ROBINS-E) tool to assess the methodological quality of included studies . AccordiI2 > 50.0% or p < 0.10, or unexplained interstudy heterogeneity), indirectness , imprecision (the 95% CI for effect estimates crosses no effect and fails to exclude important benefit or important harm), and publication bias [The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of the evidence, which comprises the following items: risk of bias (the results of the ROB assessment), inconsistency .All the RR reports with exposure regarded as a continuous variable instead of highest versus lowest category), resulting in 14 eligible articles. No additional studies were identified after checking the reference lists of included studies.The process of study identification and selection is presented in n = 4), non-Hodgkin lymphoma (n = 4), pancreatic cancer (n = 4), colorectal cancer (n = 3), non-lymphoid leukemia (n = 3), multiple myeloma (n = 3), endometrial cancer (n = 2), prostate cancer (n = 2), gastric cancer (n = 1), gliomas (n = 1), Hodgkin lymphoma (n = 1), kidney cancer (n = 1), ovarian cancer (n = 1), and thyroid cancer (n = 1). All 17 cohorts reported maximally adjusted RRs or HRs, and 11 reported minimally adjusted RRs. The studies were published between 2006 and 2022, including 23,039 to 487,922 participants followed for 5.1 to 28.97 years. Ten of the cohorts reported separate RRs by sex. Eleven cohorts recruited participants from North America, four from Europe, and two from Australia. The assessment of ASB intake was performed using lifestyle questionnaires (n = 4) or validated Food Frequency Questionnaires (FFQs) (n = 13). Among the 17 included cohorts, 6 cohorts compared the lowest and highest quintiles, 5 compared the lowest and highest quartiles, 3 compared the lowest and highest sextiles, and the other 3 used the lowest tertile as a reference. Partly due to the inconsistent classification of category, ASB consumption in the lowest category of 9 cohorts was none, and the remaining 8 cohorts had low levels of ASB consumption in the lowest category group. RRs were adjusted for sociodemographic  and lifestyle factors . Thirteen cohorts further adjusted for adiposity measures . Three cohorts did not adjust for adiposity measures, and one did not adjust for lifestyle factors. More detailed information on the confounders for each study is presented in The grades for ROB in the seven domains and the detailed reasons for assessments are exhibited in n = 17, highest versus lowest category, pooled RR = 1.03, 95% CI: 0.96–1.11, p = 0.407, I2 = 53.0%). Fifteen cohorts that reported three or more categories of adequate ASB intake values were enrolled for dose–response analysis. There was no significant linear  relationship between ASB intake and overall cancer risk.A total of 17 cohorts reported an association between ASB intake and the risk of different types of cancers. We found a null association of high ASB intake with maximal adjusted risk of overall cancer .Minimally adjusted associations between ASB consumption and the risk of overall and site-specific cancers are presented in n = 3), multiple myeloma (n = 3), non-Hodgkin (n = 3) and Hodgkin lymphoma (n = 1). All four cohorts were included to facilitate the dose–response analysis. Non-Hodgkin lymphoma contained common subtypes, which included chronic lymphocytic leukemia, small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma [RR of 1.08 . There was no evidence of a linear  between ASB consumption and the risk of overall hematopoietic cancer.Four cohorts reported association of ASB consumption with the risk of hematopoietic cancers, including non-lymphoid leukemia , with no indication for heterogeneity . No association was found between ASB intake and multiple myeloma , non-Hodgkin lymphoma , or Hodgkin lymphoma .A subgroup analysis showed a significant association of dietary ASB intake with leukemia , pancreas (n = 4), and gastric cardia (n = 1). The studies produced a pooled RR of 0.97  relationship between ASB intake and the risk of cancers in the digestive system.Seven cohorts reported a risk of digestive system cancers, including cancer of the colorectum  or nonlinear (-nonlinearp = 0.055) relationship. No significant association was found in cancer of gastric cardia  or pancreas .Risk of colorectal cancer decreased with high ASB intake with low heterogeneity between studies , endometrium (n = 2), ovary (n = 1), and prostate (n = 2). For female hormone-related cancer, the studies produced a pooled RR of 0.97 . Site-specific cancer analysis showed no significant association between ASB intake and the risk of cancer of the breast , endometrium , or ovary .Five cohorts reported the association between ASB intake and hormone-related cancer, including cancer of the breast  relationship between ASB intake and female hormone-related cancer risk.The five cohorts that reported a risk of female hormone-related cancer were enrolled for dose–response analysis. The results suggested that there was no significant linear . One cohort demonstrated a null association between ASB intake and thyroid cancer, with an RR of 1.16 . The association between ASB consumption and risk of gliomas was also insignificant from one cohort study . One cohort reported a non-significant association between ASB intake and kidney cancer, with an n = 9, highest versus lowest category, RR = 0.99, 95% CI: 0.87–1.12, p = 0.832, I2 = 48.7%) or non-obesity-related cancers  or nonlinear , gastric cardia, colon and rectum, liver, gallbladder, pancreas, breast , corpus uteri, ovary, kidney , meningioma, thyroid, and multiple myeloma—as linked to being overweight and obese with sufficient evidence . To expln = 4, highest versus lowest category, RR = 1.10, 95% CI: 1.01–1.19, p = 0.025, I2 = 0.0%) while not significant in Americans  and Australians . The risk of cancers increased in studies that used lifestyle questionnaires  instead of validated FFQs  for ASB intake measurement. The risk of cancers was also increased in studies with three-category classification of ASB consumption . No significant effect of ASB intake on cancer risk was observed in the other subgroups , measurements of exposure (ASB measurement approach and frequency), outcome assessment (ascertainment of cancer), and data analysis  are shown in p = 0.783) and Begg’s test (p = 0.869).No publication bias was observed between the 17 cohorts included in the meta-analysis on ASB intake and cancer risk through both the visual inspection of the funnel plot  and the I2 = 0.0%), the 95% CI of the RR did not overlap the effect , and the positive dose–response relationship (-linearp = 0.027) upgraded the evidence by one level. A low certainty of evidence supported the negative association of ASB intake with the risk of colorectal cancer. The null associations between ASB intake and the risk of gliomas, multiple myeloma, and non-Hodgkin lymphoma showed low certainty of evidence. The remaining ten results displayed a very low certainty of the evidence, including the risk of Hodgkin lymphoma and cancer of the breast, endometrium, gastric cardia, kidney, ovary, pancreas, prostate, and thyroid.A very low certainty of evidence supported the null association regarding ASB intake on the risk of overall cancer according to the GRADE table . For sitThe current meta-analysis covered prospective cohort studies regarding ASB consumption and the risk of cancers and explored their potential dose–response relationships for the first time. Overall, we included 14 population-based prospective studies with a total of 2,821,922 participants. The results suggested that high ASB consumption increased the risk of leukemia with moderate certainty of evidence and decreased the risk of colorectal cancer with low certainty of evidence. For dose–response analysis, the risk for leukemia increased by 15% per one serving (355 mL) daily ASB intake increment.Our results demonstrated a significant positive association between ASB consumption and increased risk of leukemia, which was consistent with a previous meta-analysis published in 2021 . A serien = 3) and lack of acknowledgment of the type of LCSs used in the ASBs, more studies are still needed to confirm the effect of ASB consumption on colorectal cancer risk.For digestive system cancers, recent animal studies suggested that LCSs could affect gut microbiome status ,73,74. SPrevious studies that suggested a higher consumption of SSBs rather than ASBs were associated with a larger increase in visceral adipose tissue volume . VisceraAccording to the National Heart, Lung, and Blood Institute Growth and Health Study, the risk of early menarche was positively associated with a higher intake of aspartame . Earliern = 3), more investigations among Europeans are needed for further verification. The risk of cancers also increased in studies that used lifestyle questionnaires instead of validated FFQs. The four studies that used lifestyle questionnaires recruited subjects among Europeans. In addition, we found a significant association between high ASB consumption and cancer risk in studies with three-category classification instead of further multiple-category classification of ASB consumption. A nonlinear model of ASB consumption with cancer risk might explain the results. However, our results should be further investigated due to the limited relevant studies and the insufficient study subjects in the included studies.In the subgroup analysis stratified by area, the positive association of ASB intake with overall cancer risk was observed among Europeans, with the exception of Americans and Australians. The high ASB consumption among Europeans at recruitment may be one reason for this difference. Due to the limited number of studies  increase in daily ASB intake was related to a 15% increase in the risk of leukemia. Furthermore, the results suggested a protective effect of ASB intake on the risk of colorectal cancer with low certainty of evidence. Given the low and moderate certainty of evidence and the limited number of included studies, further prospective cohort studies and randomized controlled trials are needed to expound the associations.


The incidence rate of metabolic-associated fatty liver disease (MAFLD) is increasing annually; however, there are still no effective methods for establishing an early diagnosis and conducting real-time tracing. Vaspin can affect the metabolic processes in the body, and it is closely associated with many metabolic diseases. Many previous studies have speculated on the association between vaspin and MAFLD, but the results of these studies have not been conclusive. This meta-analysis examined the differences in circulating vaspin levels between patients with MAFLD and healthy individuals.Six databases and other sources were searched with free terms and Medical Subject Headings terms, and a total of 13 articles were included (900 cases and 669 controls). RevMan 5.3 and Stata 16 were used for analysis. The standardised mean difference (SMD) and 95% confidence interval (CI) were used to assess the overall outcomes. Cohen’s kappa coefficient was applied to examine the differences between the two authors in the selection of studies and in the evaluation of the quality of evidence for the studies.P = 0.005 and P < 0.001, respectively). Furthermore, BMI may better explain the source of heterogeneity (P = 0.032) in the multivariate meta-regression analysis.The results demonstrated that there was no significant difference in the circulating vaspin levels between the MAFLD group and healthy group . The subgroup analysis suggested that area and body mass index (BMI) may be the sources of heterogeneity, and the results of univariate meta-regression analysis were consistent with those of the subgroup analysis (In summary, no significant correlation was observed between the circulating vaspin levels and MAFLD. BMI may be an important factor affecting this correlation, which may provide a reference for further studies on mechanism and diagnosis of MAFLD.The online version contains supplementary material available at 10.1186/s12944-022-01658-2. Nonalcoholic fatty liver disease (NAFLD), a common type of chronic hepatic disease, may affect approximately 25–30%  adults iAdipokines are peptides  producedThe protocol for this meta-analysis was published in PROSPERO (registration ID: CRD42022301367). The published protocol is provided in Additional file Two researchers in the team searched six databases: Cochrane Library, EMBASE, PubMed, CNKI, CBM, and Wanfang. Additionally, a supplementary retrieval was performed using Google Scholar. The search was performed until 13 February 2022. A combination of subject words, keywords, and free words were used for the retrieval. The following MeSH terms and search words were used: ‘NAFLD’, ‘Non-alcoholic fatty liver disease’, ‘Nonalcoholic fatty liver disease’, ‘NASH’, ‘Non-alcoholic steatohepatitis’, ‘Nonalcoholic steatohepatitis’, ‘MAFLD’, ‘Metabolic associated fatty liver disease’, ‘Fatty liver’, ‘Nonalcoholic fatty liver’, ‘Vaspin’, ‘Vaspin protein’, ‘Serine Proteinase Inhibitors’, ‘Serpins’, ‘SERPINA12 protein, human’, and the specific strategy is detailed  the MAFLD group consisted of patients with or without T2DM who met the imaging or histological clinical diagnostic criteria and were clearly diagnosed with MAFLD, NAFLD, SS, nonalcoholic fatty liver (NAFL), or NASH; (2) the control group included only healthy individuals with normal liver ultrasonography and normal liver function test results; (3) both groups included adults (age ≥ 18 years); (4) studies with the outcome of circulating vaspin levels in either serum or plasma; and (5) observational studies, including case-control and cohort studies.The exclusion criteria consisted of the following: (1) studies on secondary liver fat accumulation, such as hereditary disorders, a history of heavy alcohol consumption, or have taken steatogenic medication, and studies involving patients who had severe organic disease; (2) vaspin levels not derived from the serum or plasma; (3) studies conducted by the same team on the same study cohort, with overlapping datasets, or duplicate publications; (4) studies for which the full-text was unable to be obtained, with missing critical data, or without any relevant data obtained after contacting the authors; and (5) case reports, reviews, protocols, comments, or letters.The data extraction was performed by two authors without any communication, and any confusing parts were judged by a third reviewer. The extracted information included: last name of the first author, published year, country, number of each group, basic information of each group , homeostasis model assessment of insulin resistance (HOMA-IR) values, diagnostic methods, vaspin measurement method, and circulating vaspin levels in each study.https://gdt.gradepro.org).The Newcastle–Ottawa scale (NOS)  score waCohen’s kappa coefficient  was perfI2 test and Q-test of Cochran were used to evaluate the heterogeneity among the included studies. The fixed-effects model was implemented when heterogeneity was low (P ≥ 0.1). And the random-effects model was implemented when heterogeneity was high (P < 0.1) .The pooled meta-analysis of the 13 studies is shown in Fig. Obvious heterogeneity was also observed in the Galbr diagram Fig. . More thP < 0.00001, I2 = 96%; Others: P < 0.00001, I2 = 92%). The pooled analysis demonstrated that the circulating vaspin levels of the MAFLD patients showed significant higher than those of the healthy group in the Asian subgroup. In contrast, in the other areas, the circulating vaspin levels exhibited no significant difference between the MAFLD and healthy individuals . Perhaps area may be the source of heterogeneity, but this requires further verification.Subgroup analysis divided by the area is shown in Fig. P < 0.00001, I2 = 95%; age > 50: P < 0.00001, I2 = 98%), a random-effects model was selected again. No significant difference was found in the circulating vaspin levels between MAFLD patients and healthy group, regardless of whether the age of MAFLD patients was greater than 50 or less than 50 .The outcomes of the subgroup analysis divided by age is displayed in Fig. 2 was defined as overweight, and obesity was defined as a BMI greater than or equal to 30 kg/m2 [2 and 25 kg/m2 ≤ BMI < 30 kg/m2, the circulating vaspin levels were significantly higher than those in healthy individuals . And no significant difference was found in the circulating vaspin levels between the patients with MAFLD with a BMI ≥ 30 kg/m2 and the healthy controls . High heterogeneity  still existed and a random-effects model was selected again.Subgroup analysis was implemented in terms of BMI Fig. . The sub30 kg/m2 . For theP < 0.00001, I2 = 97%; HOMA-IR > 5: P = 0.006, I2 = 80%) .Subgroup analysis by severity used the random-effects model shown in Fig. P < 0.00001, I2 = 96%). The circulating vaspin levels of the MAFLD patients with NOS score ≤ 5 and NOS score > 5 were not significantly different from those of the healthy controls .The NOS score was used as the basis of the subgroup analysis Fig. . The ranP = 0.545; BMI: P = 0.739; NOS score: P = 0.418). The multivariate meta-regression results for area and BMI demonstrated that BMI may better explain the existance of high heterogeneity (P = 0.032). The figures of meta-regression for all analyses are shown in Additional file A meta-regression analysis was performed for further exploration Table . The uniThe method of sensitivity analysis is to remove each single study individually Fig. . The resP > 0.05), indicating a low probability of publication bias , while no such association was discovered in overweight individuals. As vaspin is mainly produced from visceral adipose tissue, it can be expected there are associations between vaspin and BMI or body fat percentage, and may be positively correlated before reaching a certain threshold. Differences in circulating vaspin levels in MAFLD patients with different BMI may be the focus of future research. Furthermore, obesity may be an important cause of metabolic syndrome and further rise the risk of cardiovascular disorders [The present meta-analysis included 13 studies with 900 cases and 669 controls, including patients from China, Turkey, Poland, Iran, Greece, and Egypt. The pooled results showed the circulating vaspin levels in MAFLD patients had not significant difference compared with those in healthy controls, with high heterogeneity. Subgroup analysis confirmed that area and BMI could be considered as the sources of the high heterogeneity, and univariate meta-regression further verified this. Age, HOMA-IR, and the NOS score may not be sources of heterogeneity. Multivariate meta-regression analysis revealed BMI was the only source of heterogeneity. Geographically, the MAFLD group in Asia had higher vaspin levels than those in health individuals, whereas no significant difference existed between the MAFLD patients in other areas and the healthy individuals. In addition to ethnic differences, the insufficient number of studies in other areas may also contribute to this outcome. When analysed based on BMI, the MAFLD groups with BMI < 25 kg/mz et al.  observedisorders . AssuminAs far as team can find, this meta-analysis is the first one to focus on the correlation between circulating vaspin levels and MAFLD. Subgroup, univariate, and multivariate meta-regression analysis were applied to identify BMI as the source of heterogeneity, and a detailed explanation and discussion were made around it. In addition, Egger’s test, Begg’s test, sensitivity analysis, and funnel plot all confirmed the robustness of the pooled results. However, there are several limitations could not be neglected in this meta-analysis. First, the number of articles included in this study was insufficient, which may be slightly insufficient in representativeness. Additionally, most articles come from Asia and have certain regional tendencies. Second, there were significant differences between the values in each study, even though the indicator of circulating vaspin levels was converted into the same units. The maximum is 91.89 ng/mL and the minimum is 0.05 ng/mL. This may be associated with the different detection methods used in different studies and the different experimental kits from different manufacturers. Third, MAFLD can usually be divided into mild, moderate, and severe, and can also be divided into SS and NASH, according to pathology. Many other similar studies have suggested a link between biological indicators and severity, but the results of this study are not consistent. This may be due to insufficient relevant subgroup data. Finally, because the indicators involved in each study were different, the study only selected the common indicators: area, age, BMI, HOMA-IR, and severity. It is believed that there must be other factors affecting heterogeneity, such as sex, while the included studies related to vaspin and MAFLD have provided limited data. More research is needed to address these points.2 and 25 kg/m2 ≤ BMI < 30 kg/m2 had significantly higher vaspin levels than those in the health. Subgroup and univariate meta-regression analysis indicated that BMI and area could be the sources of heterogeneity. Further multivariate meta-regression verified that BMI could be the soruce of heterogeneity. Owing to the limited number of included articles, it can only provide a reference for the correlation between vaspin and MAFLD and promote new ideas for clinical and scientific research. The characteristics of vaspin levels in non-obese patients with NAFLD might be worth exploring for clinical application. In the immediate future, multi-centre, multi-regional, and multi-faceted research is still an important premise to draw more comprehensive and perfect conclusions.In summary, this meta-analysis revealed no significant difference was observed between MAFLD patients and healthy people in circulating vaspin levels. However, in Asia, the circulating vaspin levels were significantly higher in MAFLD group than healthy individuals, with high heterogeneity. MAFLD group with BMI < 25 kg/mAdditional file 1. PROSPERO: Number CRD42022301367.Additional file 2. PRISMA 2009 checklist.Additional file 3. Databases retrieval strategy.Additional file 4. The results of GRADE system.Additional file 5. Figures of meta-regression for all analysis.Additional file 6. Figures of Egger’s test and Begg’s test.