Psoriasis and atherosclerosis have overlapping pathophysiological mechanisms. However, the association between psoriasis and coronary artery calcification (CAC), a hallmark of atherosclerosis and a predictor of poor cardiovascular prognosis, remains to be determined. We performed a systematic review and meta-analysis to comprehensively evaluate the association between these related inflammatory conditions.Observational studies evaluating the relationship between psoriasis and CAC were retrieved by searching PubMed, Cochrane’s Library, and Embase databases. Presence of CAC was confirmed according to an Agatston’s Score >0 upon computed tomography examination. A random-effect model incorporating between-study heterogeneity was used to pool the results.p < 0.001; I2 = 57%], after matching or adjusting the conventional cardiovascular risk factors. Subgroup analyses showed that study country, comorbidity of psoriatic arthritis, baseline Psoriasis Area and Severity Index, and duration of psoriasis  did not significantly affect the association of psoriasis and CAC. However, a stronger association was observed in younger patients  compared to older patients .Sixteen studies involving 3,039 patients with psoriasis and 46,191 controls without psoriasis were included in the meta-analysis. All participants were without previously known cardiovascular diseases. Pooled results showed that psoriasis was associated with overall CAC [odds ratio (OR): 1.54, 95% confidence interval: 1.23–1.91, Psoriasis is associated with CAC, and the association may be stronger in younger patients. Psoriasis is an autoimmune and inflammatory skin disorder that primarily affects the elbows, knees, scalp, umbilicus, and lower back, with sharply defined erythematous plaques covered in silvery-white scales . The preAccumulating evidence suggests that coronary artery calcification (CAC) is a hallmark of atherosclerosis and a predictor of poor cardiovascular prognosis in the general population . ClinicaThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISM) statement , 35 was The electronic databases PubMed, Cochrane’s Library, and Embase were searched from the inception of the respective databases until June 15, 2022. A combined search term was used, including (1) “calcification” OR “coronary”; and (2) “psoriasis” OR “psoriases” OR “Pustulosis of Palms and Soles” OR “Pustulosis Palmaris et Plantaris” OR “Palmoplantaris Pustulosis” OR “Pustular Psoriasis of Palms and Soles.” The search was limited to human studies published in full-length articles. No restriction was applied regarding the language of publication. To supplement our search, we manually reviewed the citations of relevant original articles and review articles.A PICOS-based inclusion criterion was used for this study.P (patients): Adult participants with no previous history of cardiovascular diseases in a clinic or a hospital-based setting.I (exposure): Patients with a confirmed diagnosis of psoriasis, with or without psoriatic arthritis (PsA). We did not exclude patients with psoriasis of special sites  or pustular psoriasis.C (control): Participants without psoriasis.O (outcomes): The primary outcome of the meta-analysis was the odds ratio (OR) for overall CAC between patients with psoriasis and controls. The presence of overall CAC was confirmed according to an Agatston’s Score (AS) >0 upon CT examination, as previously defined . ORs forS (study design): Observational studies, including cohort studies, case-control studies, and cross-sectional studies were included in the meta-analysis. The meta-analysis excluded reviews, preclinical studies, case reports or case series, studies without psoriasis patients, studies lacking CAC evaluation, and studies without related outcome data.Two authors separately searched and analyzed the literature, collected data, and assessed study quality. A third author was consulted if discrepancies were encountered. Study information , study design, psoriasis patient characteristics , control characteristics, and CAC analysis method and results were collected. Variables that were adjusted or matched when the association between psoriasis and CAC were also recorded. Study quality was assessed using the Newcastle-Ottawa Scale (NOS)  based onp-values, followed by logarithmical transformation. Cochrane’s Q test and I2 statistics were used to estimate study heterogeneity  is presented as OR and its corresponding 95% confidence interval (CI). ORs and standard errors were calculated using the 95% CIs or ogeneity , with siogeneity . An inflogeneity . If adeqogeneity . StatistAs shown in p < 0.001; 2I = 57%; p all <0.05). Sensitivity analyses showed that the association between psoriasis and overall CAC was consistent in the meta-analysis of case-control studies only  and in the meta-analysis of studies with high quality  than older patients   .In this systematic review and meta-analysis, we pooled the results of 16 available case-control and cross-sectional studies, and the results showed that patients with psoriasis were at higher risk of overall CAC compared to controls without psoriasis. Results of influencing analysis showed consistent results. Subgroup analyses showed that study characteristics did not significantly affect the association of psoriasis with CAC; however, there was a stronger association between psoriasis and CAC in younger patients (<50 years) compared to older patients (≥50 years). Finally, a meta-analyses with five studies showed that psoriasis was also associated with moderate-to-severe CAC and severe CAC. Taken together, these findings suggest that psoriasis is associated with CAC, and the association may be stronger in younger patients. The presence of CAC may be one of the early and key pathological changes underlying the pathogenesis of cardiovascular diseases in patients with psoriasis.To the best of our knowledge, few meta-analyses have been performed to evaluate potential subclinical atherosclerosis in patients with psoriasis. An early meta-analysis including 16 case-control studies showed that patients with PsA had an increase in common carotid artery intima-media thickness (cIMT), a higher frequency of carotid plaques, and a lower flow-mediated dilation (FMD), indicating endothelial dysfunction and systematic atherosclerosis . AnotherCurrently, the underlying mechanisms for the association between psoriasis and CAC remain to be fully determined. Vascular inflammation and the interleukin-17a related pathway have been suggested to play a key role according to the recent preclinical studies , 47. OveI2 for the overall meta-analysis was 57%, which was reduced to eight and 35% in the subgroup analyses according to age. These findings suggest that age may be a potential source of heterogeneity. These findings are consistent with previous findings which showed that impaired FMD was more pronounced in younger psoriatic patients (mean age <45 years) compared to older patients (≥40 years)  compared to the older patients (≥50 years). The 0 years) . Interes0 years) . Collectvia reducing systemic inflammation  has been associated with reduced risks of cardiovascular events, probably ammation . Therefoammation . Clinicaammation . Future ammation  and a prammation , suggestammation , which sIn conclusion, the findings of this meta-analysis suggest that psoriasis is associated with CAC, and the association may be stronger in younger patients. Studies are needed to determine the mechanisms underlying the association between psoriasis and CAC, and to explore whether interventions against CAC could improve cardiovascular outcomes in patients with psoriasis.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.YZ designed the study and drafted the manuscript. ZL and LS performed database search, data collection, and study quality evaluation. HW performed statistical analysis. JL interpreted the results. DL revised the manuscript. All authors read and approved the final version of the manuscript.


To quantify the associations between muscle-strengthening activities and the risk of non-communicable diseases and mortality in adults independent of aerobic activities.Systematic review and meta-analysis of prospective cohort studies.MEDLINE and Embase were searched from inception to June 2021 and the reference lists of all related articles were reviewed.Prospective cohort studies that examined the association between muscle-strengthening activities and health outcomes in adults aged ≥18 years without severe health conditions.Sixteen studies met the eligibility criteria. Muscle-strengthening activities were associated with a 10–17% lower risk of all-cause mortality, cardiovascular disease (CVD), total cancer, diabetes and lung cancer. No association was found between muscle-strengthening activities and the risk of some site-specific cancers . J-shaped associations with the maximum risk reduction (approximately 10–20%) at approximately 30–60 min/week of muscle-strengthening activities were found for all-cause mortality, CVD and total cancer, whereas an L-shaped association showing a large risk reduction at up to 60 min/week of muscle-strengthening activities was observed for diabetes. Combined muscle-strengthening and aerobic activities (versus none) were associated with a lower risk of all-cause, CVD and total cancer mortality.Muscle-strengthening activities were inversely associated with the risk of all-cause mortality and major non-communicable diseases including CVD, total cancer, diabetes and lung cancer; however, the influence of a higher volume of muscle-strengthening activities on all-cause mortality, CVD and total cancer is unclear when considering the observed J-shaped associations.PROSPERO CRD42020219808. Physical inactivity is a global public health problem. Several national and international physical activity guidelines recommend regular muscle-strengthening activities for adults.et al conducted the first systematic review and meta-analysis of 11 published studies that focused on mortality.Compared with aerobic activities, muscle-strengthening activities have been less frequently investigated in terms of their influence on the prevention of premature death and NCDs. Saeidifard We therefore conducted a systematic review and meta-analysis of prospective cohort studies on muscle-strengthening activities and the risk of mortality and NCDs among adults aged ≥18 years. In addition to examining the health benefits of engaging in muscle-strengthening activities compared with the absence of muscle-strengthening activities independent of aerobic activities, we quantified the dose–response association between muscle-strengthening activities and health outcomes. We also focused on the additional benefits of combined muscle-strengthening and aerobic activities for health outcomes.This systematic review was performed following the MOOSEA systematic literature search was conducted in MEDLINE and Embase from the inception of the databases to 25 October 2020. The search syntax was designed by professional research agencies  with input from two authors (HM and RK) see . We focu10.1136/bjsports-2021-105061.supp1Supplementary dataTo select articles for full-text reading, two authors (HM and RK) independently screened the titles and abstracts using EndNote X9.2  and Microsoft Excel  after the exclusion of duplicates. Articles with ambiguous eligibility were included in the full-text reading step. The two authors also independently performed full-text reading of each article and a hand-search of the reference lists in the selected articles. No additional studies were found. Disagreements were resolved through discussion. An update of the primary search was conducted in June 2021.Three authors  independently extracted the following information from each eligible study after dividing the selected papers among them: first author, publication year, study location, cohort name, sex, age of participants, number of participants and person-years, years of follow-up, number of deaths, cause of death, number of incident outcomes, subtype of incident outcome, assessment details for outcomes, assessment details for muscle-strengthening activities, covariates included in the analyses, and effect estimates and 95% confidence intervals (CIs) of mortality or incidence of NCDs. If relevant information about the assessment of outcomes and exposures was missing from the eligible studies, we obtained the information from other studies of the same cohort. The most adjusted effect estimates in the main and sensitivity analyses were extracted. For each study, one of the three authors extracted the data and the remaining two authors cross-checked the data. Disagreements were resolved through deliberation to achieve consensus. Because most of the studies eligible for our meta-analyses reported hazard ratios, if other effect estimates such as ORs were reported, we asked the corresponding authors to provide the hazard ratios.The quality of the studies was assessed using a modification of the Newcastle–Ottawa Scale (NOS) for Quality Assessment of Prospective Cohort Studies see .22 We exA meta-analysis was conducted if at least two studies reported the effect estimate for the same outcome. Reported hazard ratios were considered equivalent to relative risks (RRs). When only ORs were available,et al.We also conducted a dose–response meta-analysis to investigate the influence of muscle-strengthening activities on health outcomes using the method described by Greenland and LongneckerThe joint benefit of muscle-strengthening activities and aerobic activities was also examined using the studies that reported the effect estimates of both muscle-strengthening and aerobic activities. The categories of muscle-strengthening  and aerobic activity  were defined on the basis of the included studies.2 statistic. I2 statistic with values of 25%, 50% and 75% corresponded to low, moderate and high level of heterogeneity, respectively.Statistical heterogeneity between studies was examined using Cochrane’s Q test and ISubgroup analyses were performed according to sex , age (>65 or ≤65 years), exposure assessment  and NOS quality score . However, subgroup analyses according to age and sex with cancer as the outcome were not performed owing to insufficient data.Publication bias was assessed by visually inspecting the funnel plots of estimates against the SE of each study and by using Egger’s test of funnel plot asymmetryAll analyses were performed using Stata 17 . Statistical significance was set at p<0.05.The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the overall certainty of evidence for outcomes.A total of 1252 records were identified through systematic searches in MEDLINE and Embase after the removal of duplicates. Of these, 47 records were retrieved for full-text review and 29 studies were eligible based on the inclusion criteria.The detailed characteristics of the studies included in the meta-analysis are presented in In the risk of bias assessment using the NOS , the incThe overall certainty of the evidence for each outcome and its details are shown in 2=83.0%; p<0.001), the association was in the same direction, with an RR of <1.00 in all studies. A similar result was obtained when Sheehan’s study,Seven studies with 42 133 cases of all-cause mortality among 263 058 participants were included in the two-group analysis. Muscle-strengthening activities were associated with a 15% lower risk of all-cause mortality  . AlthougSix studies were eligible for the dose–response analysis of muscle-strengthening activities per 10 min/week increase, with a total of 236 331 participants and 37 178 cases. Although there was no clear linear association , a non-l2=59.3%)  were associated with a 40% lower risk of all-cause mortality  .The overall quality of the evidence on all-cause mortality was rated as ‘very low’.2=72.9%; p=0.001) (2=0.0%) when the study by Liu et alSeven studies with 16 056 cases of CVD among 257 888 participants were included in the two-group analysis. Three studies focused on CVD mortality or CVD morbidity,p=0.001) . AlthougFive studies were eligible for the dose–response analysis of muscle-strengthening activities per 10 min/week increase, with a total of 226 746 participants and 11 263 cases. Although there was no clear linear association , a non-l2=62.6%)  .The overall quality of the evidence on CVD was rated as ‘very low’.2=75.8%; p<0.001)  . The excp<0.001) . When th1) et al, a simil1) et al.Four studies were eligible for the dose–response analysis of muscle-strengthening exercise per 10 min/week increase, with a total of 212 323 participants and 13 033 cases. Although there was no linear association , a non-l2=84.8%)  .The overall quality of the evidence on total cancer was rated as ‘very low’.2=35.8%; p=0.18) (2=9.5%) when the study by Mielke et alFive studies with 9548 cases of diabetes among 202 486 participants were included in the two-group analysis. Muscle-strengthening activities were associated with a 17% lower incidence of diabetes , with a low to moderate level of heterogeneity (I p=0.18) . The het2=58.7%; p=0.09)  . Moreove p=0.09) .The overall quality of the evidence on diabetes was rated as ‘low’.2=0.0%; p=0.69)  . p=0.69) . A linea p=0.81) . For oth p=0.81) .Sensitivity analysis and any subgroup analysis were not performed because of the small number of included studies.The overall quality of the evidence on the incidence of each site-specific cancer was rated as ‘very low’.For all outcomes included in the meta-analysis, the test for funnel plot asymmetry was not performed because of the small number of included studies (n≤7).This systematic review and meta-analysis of cohort studies found that muscle-strengthening activities were inversely associated with the risk of CVD, total cancer, diabetes, lung cancer and all-cause mortality independent of aerobic activities among adults aged ≥18 years without severe health conditions. Moreover, J-shaped associations were found between muscle-strengthening activities and all-cause mortality, CVD and total cancer, with the maximum risk reduction (approximately 10–20%) at approximately 30–60 min/week of muscle-strengthening activities. We also observed an L-shaped association between muscle-strengthening activities and diabetes, showing a large risk reduction before 60 min/week. Finally, combined muscle-strengthening and aerobic activities (vs none) were associated with a lower risk of all-cause, CVD and total cancer mortality.et al reported that engaging in muscle-strengthening activities was associated with a lower risk of all-cause mortality, although there was no clear association with CVD mortality and total cancer mortality.et al showed an inverse association for kidney cancer, but not lung cancer, even when the same studies were included.et al extracted the effect estimate from the highest category of muscle-strengthening activities whereas we used pooled effect estimates when the included studies had two or more exposed groups.Saeidifard Joint analysis between muscle-strengthening and aerobic activities showed that a greater benefit for all-cause, CVD and total cancer mortality was obtained when these two types of activities were combined. These results confirm the findings of previous meta-analyses.et al showed a quadratic association between strength training and all-cause and CVD mortality, and the lowest risk of all-cause mortality was observed at 82 min/week of strength training.One of the strengths of this study was the quantification of the dose–response association between muscle-strengthening activities and health outcomes. Several previous cohort studies have reported a non-linear association between muscle-strengthening activities and health outcomes.In addition, our study is the first to systematically evaluate the longitudinal association between muscle-strengthening activities and the risk of diabetes. Although the potential of muscle-strengthening activities to reduce the risk of diabetes is supported by several biological mechanisms,Our systematic review has some limitations. The first and most important limitation is that the meta-analysis included only a small number of studies. The limited number of studies precluded some examinations. For example, it did not allow us to conduct some subgroup analyses to explain the heterogeneity in our findings and, even when performed, few studies were included. Moreover, we could not test for publication bias. Therefore, the pooled estimates in this study might have been overestimated because of potential publication bias. Second, the included studies evaluated muscle-strengthening activities using a self-reported questionnaire or the interview method. Although measures of muscle-strengthening activities have been reported to have higher reliability than those of aerobic activities,Several physical activity guidelines recommend that adults perform muscle-strengthening activities at least twice a week.Engaging in muscle-strengthening activities was associated with a lower risk of all-cause mortality and major NCDs such as CVD, total cancer, diabetes and lung cancer. However, the influence of a higher volume of muscle-strengthening activities on all-cause mortality, CVD and total cancer is unclear, considering the observed J-shaped associations. In addition, the combination of muscle-strengthening and aerobic activities may provide a greater benefit for reducing all-cause, CVD and total cancer mortality. Given that the available data are limited, further studies—such as studies focusing on a more diverse population—are needed to increase the certainty of the evidence.Physical activity guidelines recommend regular muscle-strengthening activities for adults, and this recommendation is primarily based on the benefits for musculoskeletal health.Previous meta-analyses have shown that muscle-strengthening activities are associated with a decreased risk of all-cause mortality and kidney cancer, although the dose–response association is unknown.Further studies are needed to update the literature and expand on previous studies that did not provide evidence on the optimal dose of muscle-strengthening activities.Muscle-strengthening activities were associated with a 10–17% lower risk of CVD, total cancer, diabetes, lung cancer and all-cause mortality independent of aerobic activities among adults.The maximum risk reduction for all-cause mortality, CVD and total cancer was obtained at approximately 30–60 min/week of muscle-strengthening activities, and the risk of diabetes sharply decreased until 60 min/week of muscle-strengthening activities, followed by a gradual decrease.


A meta-analysis of cohort studies was performed to evaluate the association between COPD and the risk of dementia or cognitive impairment.Cohort studies that evaluated the association between COPD and the risk of dementia or cognitive impairment were identified by a systematic search of PubMed, Embase, Web of Science, and Cochrane Library databases. The search time frame was from database establishment to April 12, 2022, with two reviewers independently screening the literature and extracting data. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to conduct the quality evaluation. Then, a meta-analysis was performed using Stata 15.1 software.RR = 1.24, 95% CI = 1.03 ~ 1.50, I2 = 96.6%, z = 2.25, p = 0.024) and cognitive impairment . Subgroup analysis suggested no significant difference in the risk of dementia among COPD patients of different genders. Nevertheless, in terms of age, the risk of dementia varied among COPD patients of different ages, which was most distinguished in patients younger than 65 years.Six cohort studies including 428,030 participants were included. The overall quality of the included studies was high, with an average NOS score of over 7. Meta-analysis showed that compared to those without COPD at baseline, patients with COPD were associated with a significant increased risk of dementia (COPD patients have a higher risk of developing dementia or cognitive impairment compared to those without COPD, and this risk is not affected by gender but seems to be associated with age.https://www.crd.york.ac.uk/prospero/, identifier CRD42022325832. Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability worldwide  stated that the average prevalence of cognitive impairment in COPD is 32%   terms and keywords used in the search were as follows:  AND (“dementia” OR “Alzheimer's disease” OR “vascular dementia” OR “multiinfarct dementia” OR “cognition disorders” OR “cognitive defect” OR “cognitive decline” OR “cognitive deficit” OR “cognitive dysfunction” OR “cognitive impairment” OR “mild cognitive impairment” OR “neurocognitive disorder” OR “memory impairment”). The references of the included studies and existing systematic reviews were hand-searched to find additional relevant articles. The full search strategy was included in OR), Relative Risk (RR) or Hazard Ratio (HR).The included studies were required to meet the following criteria: (1) cohort study design; (2) the exposed group consisting of patients with confirmed COPD diagnosis, and the control group consisting of patients without COPD; (3) the risk of dementia or cognitive impairment as the outcome, expressed as an adjusted Odds Ratio (Exclusion criteria were as follows: (1) conference abstracts or study protocols; (2) duplicate publications; (3) studies with incomplete data or no relevant outcome.Five reviewers  independently screened the literature. Duplicate and irrelevant articles were first excluded according to their titles and abstracts. Thereafter, the full texts of the potentially eligible articles were downloaded and read to identify all eligible studies. In case of disagreement, discussions were conducted with an independent adjudicator (JL) until a consensus was reached.RR/OR/HRs provided by different analytical models, we selected suitable RR/OR/HRs based on whether their confounders adjusted were similar to other studies. In the results section, all relative effects metrics were referred to as RRs, which did not affect our results or their interpretation  independently extracted the following data using predesigned forms according to the guideline for data extraction for systematic reviews and meta-analysis  Stang,  was usedRR/OR/HRs and 95% CI from each study were used to assess the risk of dementia or cognitive impairment in COPD. We assessed heterogeneity using the chi-square test and I2 value, and p < 0.1 or I2> 50% was considered to indicate heterogeneity; in such instances, the random-effects model was adopted. Otherwise, the fixed-effects model was employed. We performed sensitivity analyses to verify the robustness of the overall results and explore the sources of heterogeneity. Since few studies were included, we only performed subgroup analysis on gender and age. Considering the differences in physiological structure and living habits of COPD patients of different genders may be an important factor affecting the risk of dementia. Furthermore, age as a risk factor for dementia and COPD may have a significant impact on the relationship between them. All statistical analyses were performed using the Stata software (version 15.1).The adjusted n = 1,582; manual check: n = 655). Furthermore, 6,025 articles were excluded from a two-step screening according to the title and abstract, firstly, the literature that focused on diseases was obviously inconsistent with this study was eliminated ; secondly, those that did not match the research topic and type were eliminated through careful review . Then 18 articles after full-text reading, including case-control study (n = 3), conference abstracts (n = 3), study with no interested outcome (n = 4), full text failed to download (n = 1)   to ; one latest study . The pooling analysis shows that COPD was associated with an increased risk of dementia , we performed a sensitivity analysis by omitting each study to explore the source of heterogeneity and found that the results were identical to the primary results after removing any one of the studies one at a time. This indicated that the overall results were relatively robust, no single study exerted a substantial influence on the pooled RRA total of five studies   .RR = 1.80, 95% CI = 1.00~3.22, I2 = 89.1%, z = 1.97, p = 0.049), and the COPD patients aged between 65 and 74 found an increase in the risk of dementia , the COPD patients with 75 years or older also showed a significant increase in the risk of dementia .Two studies  can be found in the article/JL, XL, and JW conceived the study. JW, XL, SL, DZ, SZ, HZ and JL performed literature search, selection, and data extraction. XL, JW, and SZ contributed to data interpretation and analysis. XL, SL, DZ, HZ, and JL revised the manuscript. All authors reviewed and approved the manuscript.This work was funded by the Chinese Medicine Inheritance and Innovation Hundred and Ten Million Talent Project—Chief Scientist of Qi-Huang Project [(2020) No. 219]; Zhong-Yuan Scholars and Scientists Project (No. 2018204); and Characteristic Backbone Discipline Construction Project of Henan Province (STG-ZYX03-202123).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.


Noise-induced hearing loss is a leading occupational disease caused by gene-environment interaction. The Grainy Like 2, GRHL2, is a candidate gene. In this regard, many studies have evaluated the association between GRHL2 and noise-induced hearing loss, although the results are ambiguous and conflicting.The purpose of this study was to identify a precise estimation of the association between rs3735715 polymorphism in GRHL2 gene and susceptibility of noise-induced hearing loss.A comprehensive search was performed to collect data up to July 8, 2018. Finally, 4 eligible articles were included in this meta-analysis comprising 2410 subjects. The pooled odds ratios with 95% confidence intervals were used to evaluate the strength of the association.Significant association was found in the overall population in the dominant model  and allele model . When stratified by source of the subjects, we also found association between rs3735715 and noise-induced hearing loss risk in the dominant model  and allele model .Rs3735715 polymorphism in GRHL2 gene may influence the susceptibility of noise-induced hearing loss. Additional large, well-designed and functional studies are needed to confirm this association in different populations. The search time was not limited. The last search update was done on July 8th, 2018. Articles investigating GRHL2 and NIHL before July 8th, 2018 were all included in this meta-analysis. The first study was in 2013. Four literatures were included in our meta-analysis according to the following criteria: (1) was a case-control study; (2) was a study about the GRHL2 polymorphism and NIHL susceptibility; (3) with usable data for allele frequency; (4) was a paper written in English or Chinese. Two of the authors extracted the available data independently according to the criteria mentioned above. We extracted the information including publication year, the name of the first author, country, ethnicity, source of the subjects, and genotype distributions of the GRHL2 rs3735715 polymorphisms among cases and controls. The controversies were discussed within our research team, and we reached a consensus eventually.We searched all literatures from PubMed, CNKI, Wang Fang, Web of Science and Springer databases, using the keyword /Q) was also used to quantify heterogeneity. I2 greater than 50% indicated heterogeneity among studies. The fixed-effects model and random-effects model were used to pool the data appropriately.Summary Odds Ratios (ORs) with 95% Confidence Intervals (CIs) determined by To test for publication bias in this meta-analysis, we performed both Egger's and Begg's test.All analyses were performed using Stata software version 8.2 .A total of 25 relevant studies were identified through database screening. Seven were excluded for duplicated records. After a detailed evaluation of the full-text of the 18 studies, 14 were excluded: two concerned about other polymorphisms, 4 reviews, 1 not for human, 6 not about NIHL and one lack of genetic distribution data. 4 articles were eventually included in the analysis. The flow of studies through this meta-analysis was shown in The average of age in cases was 40.7 ± 8.4, 40.5 ± 8.1, 39.3 ± 5.8, and 40.4 ± 8.3 for Yang's (2018), Yang's (2016), Li's (2013), and Xu's (2016) study, respectively. The average of age in controls was 40.0 ± 8.4, 39.8 ± 8.1, 39.8 ± 5.8, and 39.5 ± 8.2 for Yang's (2018), Yang's (2016), Li's (2013), and Xu's (2016) study, respectively. The hearing threshold level in cases was 51.0 ± 9.0, 37.6 ± 11.7, and 51.4 ± 8.8 for Yang's (2016), Li's (2013), and Xu's (2016) study, respectively. The hearing threshold level in controls was 11.7 ± 10.7, 14.2 ± 3.9, and 9.3 ± 9.1 for Yang's (2016), Li's (2013), and Xu's (2016) study, respectively. The demographics of the subjects of the 4 studies in this meta-analysis were detailed in Overall, our meta-analysis showed a significant association between rs3735715 and NIHL risk in both dominant model and allele model. For dominant model (GA/AA vs. GG) OR = 0.707, 95% CI = 0.594–0.841. For allele model  OR = 1.189, 95% CI = 1.062–1.333 .Table 4MStratification by source of the subjects identified a significant association in steel factory population between GRHL2 rs3735715 polymorphism and NIHL risk. Among the subjects chosen from steel factory, significant association was found in the dominant model (GA/AA vs. GG) OR = 0.634, 95% CI = 0.514–0.783, and allele model  OR = 1.206, 95% CI = 1.054–1.379 . We did The meta-analysis was performed using a fixed-effects model based on the Mantel-Haenszel method because the between-study heterogeneity was not found .t = −1.92, p = 0.194 for GRHL2 rs3735715 GA/GG vs. GG).Publication bias is always a concern in a meta-analysis. As shown in In the present study, the GRHL2 rs3735715G > A polymorphism was found to be associated with NIHL risk in the dominant model (GA/AA vs. GG) and allele model  including 1199 NIHL cases and 1211 controls. Comparing with the GG genotype, GA/AA genotype showed a decrease risk of NIHL. The G allele showed increasing risk comparing with A allele. In the subgroup analysis, the association was also found in steel factor workers, but not among chemical fiber company members. These results suggest that the potentially functional polymorphism rs3735715 may affect susceptibility to NIHL. As far as we know, this is the first comprehensive meta-analysis to estimate the association between the GRHL2 polymorphism and NIHL risk.GRHL2, also known as Brother of Mammalian grainyhead (BOM) and Transcription Factor Cellular Promoter 2-Like 3 (TFCP2L3) is a member of GRHL transcription factor family which controls the development of multicellular epithelia by regulating cell junction formation and proliferation genes.In 2009, Konings et al.An advantage of this meta-analysis was that numbers of subjects were pooled together from each independent study, which increased the statistical power significantly. Second, the quality of articles included in this analysis was satisfactory according to a consistent selection criterion. Third, based on this meta-analysis, functional study of rs3735715 in GRHL2 might be conducted to replicate these observations. There were some limitations of our meta-analysis. First, in the present study potential confounding factors  were not adjusted. Second, we only chose four papers written in English or Chinese. Although we estimated the publication bias using Egger's and Begg's test, we cannot ignore the possibility of bias. Third, we did not perform further evaluation of the potential interactions. The gene–gene or gene–environment interactions may modulate NIHL risk.In conclusion, this meta-analysis found an association between the GRHL2 rs3735715 polymorphism and NIHL risk, suggesting GRHL2 might influence the susceptibility of NIHL. In the future, more extensive studies are still required to confirm these findings in different ethnic populations.This work was supported by the Humanities and Social Sciences of Ministry of Education Planning Fund of China (grant no. 16YJA840014).The authors declare no conflicts of interest.


Antiphospholipid syndrome (APS) is a chronic autoimmune disease with a high prevalence in females. Published data have identified pregnant women with APS may suffer from recurrent miscarriage, fetal death. However, the association between antiphospholipid antibody (aPL) and fetal growth restriction (FGR) remains controversial. This study aims to systematically review the literature on population-based studies investigating an association between aPL and FGR.  The literature was searched on 1 November, 2021, using Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), following the MOOSE checklist. Study inclusion criteria focused on peer-reviewed published articles that reported an association between aPL and FGR. Quality assessment was performed based on the Newcastle-Ottawa scale. The between-study heterogeneity was assessed by the Q test. Publication bias was assessed by funnel plots. β2GP1), and FGR was 1.26 , 2.25 , and 1.31 , respectively. Lupus anticoagulant (LA) did not increase the chance of FGR .  Twenty-two studies (with 11745 pregnant women) were included in the final analysis. Pooled odds ratio for association of aPL, anticardiolipin antibodies (ACA), anti-beta2 glycoprotein 1 antibodies (β2GP1 are strongly associated with FGR. There are currently insufficient data to support a significant relationship between LA and FGR. Our meta-analysis showed that aPL increased the risk of FGR. The risk of FGR varies with the aPL types. ACA and  The current diagnosis of APS requires at least one laboratory and clinical criterion each . Laboratβ2GP1) . Furtherβ2GP1) . APS is β2GP1) –8. Childβ2GP1) . HoweverWe followed the methods of Xu et al. . A systeTwo reviewers (JFX and YT) independently evaluated the titles and abstracts. Duplications were removed using EndNote online software. Disagreements were resolved by the third reviewer (BP). Only case-control study, cohort study, and cross-sectional study were evaluated. We excluded the studies with the following criteria: (1) presence of other autoimmune diseases; (2) patients undergoing serious internal and surgical diseases; and (3) multiple pregnancies.We used a standard form to extract data, including the journal, first author's name, publication year, country, study design, time of study conduct, the age of patients, ascertainment method of diseases and control or comparison group selection, types of aPL, the definition of FGR, risk factors for FGR, number of population analyzed, odd ratios (ORs) or relative risks (RRs) and 95% confidence intervals (95%CIs), and statistical methods. When effect estimates for association between aPL and FGR were not listed in the original article but enough information was available, their effect estimates were calculated by STATA 12.0 statistical software. Authors were contacted if important information was lost. Data extraction was conducted independently by two of the reviewers (JFX and YT).The outcome indicator was the occurrence of FGR. The FGR positivity is defined as ultrasound estimated fetal weight less than 10th percentile  or birthTwo researchers (JFX and DJC) independently assessed the methodological quality of studies, using the Newcastle-Ottawa quality assessment scale (NOS) for cohort and case-control study . A scoreI2 statistic. A random effects model was used because we assumed the presence of heterogeneity in these clinical studies with different clinical settings [P values <0.05 were considered statistically significant. We conducted a sensitivity analysis to exclude these studies, which varied dramatically from all other included studies in methodology or findings. Subgroup analysis by study type was also conducted to assess the potential sources of heterogeneity. Publication bias was assessed by funnel plots and Begg's test.We used the MOOSE checklist and PRISMA guidelines for this systematic review , 15. We settings . P valuen = 358), Embase (n = 265), and Cochrane Central Register of Controlled Trials (CENTRAL) database (n = 104). After removing 173 duplicates using EndNote software (EndNote X7) and 12 duplicates manually, the titles and abstracts of 542 papers were scrutinized. The reference lists of relevant reviews were hand searched. A total of 119 articles were assessed for eligibility. Of them, 97 were excluded for the reasons, such as presence of other autoimmune diseases (n = 56), patients undergoing serious internal and surgical diseases (n = 39), and multiple pregnancies (n = 2). Of the 119 citations identified, 22 articles with 11745 cases  was observed in our analysis  –29, 31. analysis .I2 = 0%, P = 0.540) was observed in analysis of ACA.Results derived from ten included studies , 32–34 wβ2GP1 and FGR  among four cohort studies [I2 = 0%, P = 0.780) was observed in analysis of β2GP1. studies , 18, 22 I2 = 50.3%, P = 0.05).P = 1.000, P = 0.721, P = 0.734, and P = 1.000, respectively.Funnel plots were used to explore the publication bias of the included studies Figures –S1C. FunA sensitivity analysis for each meta-analysis with at least three studies was conducted. Within each meta-analysis, each study was taken out, respectively, to assess for its influence on the overall risk estimates.The association of FGR with APS has been reported by some studies , 37–39. β2GP1. In the present study, we demonstrated that women with aPL positivity have a higher risk of FGR. According to our analysis, the presence of aPL increases the odds of FGR 1.26 times . This is concordant with recently published data by Högdén et al. showing that the persistent presence of aPL is associated with FGR [In this systematic review and meta-analysis, we aimed to provide a comprehensive overview of available evidence on the association between aPL and FGR. The aPL refers to three tests including ACA, LA, and with FGR , 37. Apawith FGR . Some rewith FGR , while mwith FGR , emphasiwith FGR .Screening for ACA is most commonly used in clinical practice as one of the criteria for classification of APS. Some studies reported that the incidence of FGR was higher in positive ACA than in negative ACA cases , 48. Theβ2GP1 are rarely the sole antibodies detected in patients with clinical features of APS. However, it is a main target of antiphospholipid antibodies, playing a role in pathogenesis of adverse obstetric outcomes [β2GP1 are the ones associated with the lowest live birth rate and highest incidences of FGR, very preterm FGR, and stillbirth compared with ACA or with LA alone [β2GP1 and FGR  among four cohort studies [β2GP1 may be beneficial to APS patients who have a history of FGR.LA alone . We foun studies , 18, 22.β2GP1 positivity [Data from a case-control study of 2257 pregnancies reported that significantly more women positive for LA had pregnancies complicated by FGR compared with women who were LA negative . Furthersitivity . TherefoCurrently, the treatment strategies to prevent APS-related obstetric complications include antiplatelet (low-dose aspirin) , anticoaOur study is the most comprehensive review evaluating the association between aPL and FGR by the type of aPL. Also, we conducted separate meta-analyses by the types of aPL. Furthermore, we evaluated risk factors for FGR of studies included. Finally, half of the included studies were published after 2010, suggesting a minor effect of publication years. Furthermore, we evaluated risk factors for FGR of studies included. However, our study also has some limitations. Firstly, some included studies had limited number of FGR cases, which might generate spurious associations. Additionally, most patients with FGR were treated with drugs like aspirin and heparin, which might lead to the underestimation of risk. Finally, different definitions of FGR can cause more variations. Therefore, caution is needed when interpreting the results.Recently, a systematic review and meta-analysis evaluated pregnancy outcomes in patients with APS . HoweverOur meta-analysis showed that aPL positivity increased the risk of FGR. Furthermore, the risk of FGR varies with the aPL antibody type. Therefore, it is necessary to measure aPL when FGR occurs. Women who have experienced adverse pregnancy outcomes, particularly severe FGR, should be screened for the presence of aPL. In order to generate the best evidence, we recommend future population-based studies to further investigate the association between aPL and FGR by adopting a prospective cohort study approach with large study populations, carefully selected disease-free controls, good adjustment for potential confounding factors, and longer duration of follow-up through multiple pregnancies.


Post-infectious bronchiolitis obliterans (PIBO) is a long-term sequela after an initial insult to the lower respiratory tract. A comprehensive understanding of the factors that contribute to a high risk of developing PIBO is important to help define therapeutic strategies and improve prognosis.We performed a systematic review of published literature available in the online databases including PubMed, Embase, Web of Science, CNKI, Wan Fang, and VIP, with the last search updated on 27 January 2022. Observational studies and case-control studies that provide sufficient data to examine associations between potential risk factors and PIBO were included. Pooled odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI) and heterogeneity were calculated.p < 0.001). Mechanical ventilation ranked second . Use of γ-globulin, use of glucocorticoids, co-infection of bacteria, a history of wheezing, and being male were other prominent risk factors. The effects of premature birth, allergic rhinitis, and imaging finding  are less clear and require further confirmation. Cases that developing PIBO had a lower age compared with controls . No significant differences were observed in the duration of fever . Children diagnosed with PIBO had higher LDH levels  and duration of hospitalization .A total of 14 risk factors were selected from 9 studies included in the analysis. The strongest risk factors were hypoxemia, mechanical ventilation, tachypnea, and wheezing. Hypoxemia conferred the greatest risk with pooled OR of 21.54 (95% CI: 10–46.36, In this study, we found that the strongest risk factors for PIBO were hypoxemia, mechanical ventilation, tachypnea, and wheezing. Use of glucocorticoids, γ-globulin, co-infection of bacteria, a history of wheezing, and being male may also play a role. The factors discussed above can inform the generation of a clinical prediction model for the developing PIBO in children. There are three forms of bronchiolitis obliterans (BO) seen by pediatricians: post-infectious bronchiolitis obliterans (PIBO); BO post lung transplantation; and BO after bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT) , 2. Of tThe prognosis of PIBO is overall poor, which is related to the late diagnosis, irreversible pulmonary fibrosis, and airway obstruction , 11. To Therefore, it is extremely necessary to identify the risk factors predicting the occurrence of PIBO following lower respiratory tract infections. A better understanding and knowledge of the topic can alert the professionals to the need of designing effective strategic measures to reduce the incidence, take early intervention, and improve the prognosis of PIBO in children. This study aimed to assess the quality of available evidence and present summary estimates of the strength of association between the risk factors and PIBO in children using meta-analysis.This meta-analysis was conducted and reported according to MOOSE guidelines.The PUBMED, EMBASE, Web of Science, and Chinese databases  were systematically searched with the restriction of language only in English and Chinese (last search updated on 27 January 2022). We used the Medical Subject Headings (MeSH): “bronchiolitis Obliterans” as the core search term in case of some unexpected missing of any potentially eligible studies. The references list of each of the initially included studies was also checked for further articles of interest. The final search strategies of PubMed, Web of Science, and Embase are presented in online Criteria for inclusion: (1) case-control study, retrospective or prospective observational study, cross-sectional study, and cohort study; (2) all subjects were children (aged 0–18 years) diagnosed with or without PIBO after lower respiratory tract infections; (3) the definition of PIBO is clear; (4) the effect estimates of potential risk factors for PIBO are reported; and (5) sufficient data were provided to calculate odds ratio (OR). Exclusion criteria were as follows: (1) case reports, reviews, or unpublished literature; (2)BO caused by lung transplantation, heart-lung transplantation, HSCT, BMT, and Stevens–Johnson Syndrome; (3)Irrelevant reporting topics: such as organizing pneumonia, interstitial lung disease, bronchiectasis, and cystic fibrosis; and (4) adequate information could be obtained for categorical variables and continuous variables.Data were independently extracted by JL and LZ; any inconsistency was resolved by QZ after referring to the original article. The following variables were collected and recorded in an Excel table: the first author, publication year, region, sample size, age, and risk factors were included. When full data cannot be obtained from the study, we tried to contact the corresponding author to obtain all the data.The Newcastle–Ottawa Scale (NOS) for case-control studies was used to assess study quality concerning cases and controls selection (four items), comparability (one item), and exposure (three items). The star system ranges from 0 to 9, with higher scores representing better study quality. JL and DL accomplished this process independently, and disagreements were resolved by QZ.I2 statistic, and I2 > 50% was considered significant. If there was significant heterogeneity, a random-effects model was used, or else, a fixed-effects model. The pooled effect estimates were reported as an OR with 95% confidence intervals (CI) for dichotomous data and mean difference (MD) with 95% CI for continuous outcomes. The significance of the pooled effects was determined by the Z-test, two-tailed p < 0.05 was considered statistically significant.Statistical analysis was performed using the Review Manager 5.4 software . Raw data of continuous variables were converted into mean and standardized difference (SD) when suitable . HeterogThe flowchart of the study selection process is shown in The nine studies included in the qualitative analysis comprised 377 cases and 1,342 controls. The general characteristics were summarized in p = 0.003).Eight studies , were included, comprising 343 cases and 1,237 controls, to study the association between age and PIBO from 1991 to 2020 –20. CaseNine studies  were included, consisting of 377 cases and 1,342 controls, to study the association between being male and PIBO from 1991 to 2020 –21. MetaTwo studies from China were included, comprising 57 cases and 275 controls, to analyze the association between hypoxemia and PIBO from 2011 to 2020 , 18. MetFive studies (three studies from China and one each from Argentina and Chile), were included, comprising 195 cases and 800 controls, to study the association between mechanical ventilation and PIBO from 1991 to 2020 , 20, 21.Three studies (two studies from China and one from Chile) were included, comprising 84 cases and 322 controls, to study the association between tachypnea and PIBO from 1998 to 2020 –18. MetaFour studies were included (three studies from China and one from Chile), consisting of 104 cases and 368 controls, to study the association between wheezing and PIBO from 1998 to 2020 , 16–18. Three studies from China were included, consisting of 58 cases and 681 controls, to study the association between the use of γ-globulin and PIBO from 2011 to 2020 , 20, 21.Four studies (three studies from China and one from Chile) were included, consisting of 86 cases and 701 controls, to study the association between the use of glucocorticoids and PIBO from 1998 to 2020 , 20, 21.Four studies from China were included, consisting of 120 cases and 453 controls, to study the association between co-infection of bacteria and PIBO from 2011 to 2020 , 20, 21.Four studies (six studies from China and one from Chile) were included, consisting of 173 cases and 403 controls, to study the association between a history of wheezing and PIBO from 1998 to 2020 , 18, 19.p = 0.008).Two studies from China were included, comprising 127 cases and 181 controls, to analyze the association between LDH levels and PIBO from 2012 to 2020 , 19. Chip < 0.001).Three studies from China were included, comprising 145 cases and 201 controls, to analyze the association between duration of hospitalization and PIBO from 1998 to 2020 , 17, 19.p = 0.55), atelectasis of 1.25 , pleural effusion of 0.65 . No significant differences were observed in Premature birth  (p = 0.52) (p = 0.06)  , 20, 21, = 0.52) , 16, 17, = 0.06) .This is the first comprehensive systematic review and meta-analysis to date, which attempt to systematically assess the effect of a multitude of possible risk factors on PIBO in children. We identified 14 risk factors in total. This meta-analysis was the first to show that hypoxemia was most strongly associated with PIBO (OR 21.54). Mechanical ventilation was found to confer a significant risk (OR 14.61). Clinical manifestations, such as tachypnea and wheezing, were also observed to be prominent risk factors . Use of γ-globulin (OR 4.77), use of glucocorticoids (OR 4.46), co-infection of bacteria (OR 2.23), a history of wheezing (OR 2.22) and being male (OR 1.52) were other prominent risk factors. The effects of premature birth, allergic rhinitis, duration of fever, and imaging finding  are less clear and require further confirmation. Cases that developing PIBO had a lower age compared with controls . Both LDH levels and duration of hospitalization had a statistically significant association with PIBO . This is the first meta-analysis to examine the association between hypoxemia, mechanical ventilation, tachypnea, and wheezing with PIBO.In this meta-analysis, we found that hypoxemia was the strongest predictor of PIBO, which was a novel finding. Hypoxemia usually occurs earlier than mechanical ventilation, which made it a more sensitive and good early warning indicator than other predictors. No mechanisms have been proposed to explain the adverse effects of hypoxia on the development of PIBO. Based on the limited data shown in animal studies, Matthew and colleagues showed the development of BO and pulmonary fibrosis 1 month after sulfur mustard (SM) inhalation exposure in rats . They foAlthough our meta-analysis found that mechanical ventilation was a significant risk factor for PIBO, our results do not indicate that mechanical ventilation causes injury to the lung that increases the risk of developing PIBO, or as an indicator of disease severity. Further studies are needed to elucidate the relationship between mechanical ventilation and PIBO and to investigate the need for lung-protective strategies in this susceptible population .Hypoxemia and mechanical ventilation were associated with severe lung injury. Based on the results of the meta-analysis, we speculated that predictors of PIBO showed that factors representing acute pulmonary insult severity were correlated with PIBO development, and it seemed that the more severe the episode of initial pneumonia, the higher the incidence of PIBO.Most patients with PIBO are younger than 3 years of age at onset. Huang calculated that the median age of the 56 children with PIBO was 17.71 (7–91) months . Hong KoIn our study, specific clinical manifestations such as tachypnea and wheezing were significant risk factors of PIBO. The patient usually presents wheezing, tachypnea, dyspnea, and persistent cough for weeks or months after the initial infection –27. YazaOur analysis also confirms that the association between several initial imaging factors and PIBO has a very small effect. These include pulmonary consolidation, atelectasis, and pleural effusion. The most common HRCT finding is the mosaic pattern in children with PIBO –33. It iOur study also found that a history of wheezing was significantly associated with developing PIBO compared with allergic rhinitis. The number of studies included was small, and we did not assess the relationship between atopic dermatitis, history of eczema, allergic sensitization early in life, allergic sensitization early in life, tobacco, and PIBO. It appears that more well-designed clinical studies are needed to identify risk factors of PIBO.Although this study has summarized the major risk factors for the development of PIBO, our systematic review has also limitations. The timing of assessment of the clinical manifestations and treatment of disease was generally not available. The definition and method of summarizing risk factors, the method of analysis, and the method of reporting results were heterogeneous. Given the limited number of studies included in the analysis, the findings from our meta-analysis should be confirmed in future research. One aim of the study was to precisely quantify the risk associated with these factors by combining center estimates in a meta-analysis. To pursue this aim, an agreement to supply and combine common data from many centers is required. This might be achieved through a special working group in the provision of the relevant data to central registries for analysis. Fortunately, since 2016, an international consortium of experts consisting of pediatric pulmonologists, radiologists, pathologists, physical therapists, psychologists, basic scientists, and statisticians has gathered regularly for a workshop on PIBO in Geisenheim, Germany . FurtherIn future studies, additional analyses are required to test other factors that may also be predictive of PIBO in children. Furthermore, studies should investigate the role of hypoxemia and another possible case mechanism by studying larger samples and by more careful measurement and analysis of possible confounding factors. Further multicenter prospective trials are required to understand the complexity of the disease and to define risk factors.In conclusion, this systematic review and meta-analysis have found hypoxemia to be the most significant risk factor for PIBO, followed by mechanical ventilation, tachypnea, and wheezing. Use of glucocorticoids, use of γ-globulin, co-infection of bacteria, a history of wheezing, and being male may also play a role. The factors identified by our meta-analysis can inform the generation of a clinical prediction model for the developing PIBO in children. Further investigation is required to verify this relationship and explore other aspects of the aetiopathogenesis of PIBO.The original contributions presented in the study are included in the article/DL, JL, and QZ designed the study. JL contributed to the literature search, data collection, statistical analysis, and drafting of the manuscript. DL, LZ, and YC contributed to the literature search and data collection. QZ performed the manuscript review. All authors have read and approved the content of the final manuscript.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.


It is unknown whether clinically indicated replacement of peripheral intravenous catheters (PIVCs) increases the risks of PIVC-associated complications and infections compared to routine replacement of PIVCs.Clinicaltrials.gov for randomized controlled trials (RCTs) that compare the safety outcomes of routine replacement and clinically indicated replacement of PIVCs were included for meta-analysis. The primary outcome was the incidence of phlebitis, and secondary outcomes included the risks of occlusion, local infection, infiltration, catheter-related bloodstream infection (CRBSI), and accidental removal of the PIVC.We searched PubMed, the Web of Science, the Cochrane Library, Ovid MEDLINE, and P = 0.04, 2I = 49%]. In addition, the study group was associated with a higher risk of occlusion  and infiltration (fluid leaks)  than the control group. However, no significant differences were observed in the risks of local infection  and CRBSI  between the study and control groups.A total of 9 RCTs involving 10 973 patients were included in this meta-analysis, of whom 5,546 and 5,527 were assigned to the study group  and control group (routine replacement of PIVCs every 72–96 h), respectively. The incidence of phlebitis in the study group was significantly higher than that in the control group , identifier [CRD42022302021].[ Peripheral intravenous catheter (PIVC) placement is one of the most common invasive procedures performed in acute care hospitals. More than 70% of hospitalized patients undergo placement of a PIVC to provide access for the intravenous administration of fluids, drugs, and nutrition –3. AlthoP < 0.001], but no significant difference was observed in the reversion period   , 13, howClinicaltrials.gov for RCTs published before January 31, 2022 were performed. The following search terms were used: “catheter,” “vascular access device,” “catheterization,” “clinically indicated replacement,” and “routine replacement.” We only included RCTs that investigated the safety outcomes of clinically indicated or routine replacement of PIVCs. The inclusion criteria were: (1) clinically indicated replacement of PIVCs as the intervention group; (2) routine replacement of PIVCs every 72–96 h as the control group; (3) adult patients; (4) designed as a RCT; and (5) data regarding the clinical outcomes of interest were available. We excluded case reports, case series, observational studies, and retrospective cohort studies. Two investigators (CYC and WCC) independently screened and reviewed each study. In case of any disagreement, a third investigator (YFW) made the final decision. For each included study, we extracted the following data: publication year, study design, study site, and the incidence of complications. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines  along with 95% CIs for outcome analyses.We used the Cochrane risk-of-bias tool  to assesThe search of the online databases yielded a total of 1,431 studies after excluding 229 duplicates. In addition, 1,372 studies were judged to be irrelevant after screening the titles, abstracts, and publications with no full text available. Furthermore, 50 studies were excluded after the full text of 59 articles was screened. Finally, 9 RCTs , 20–23 wSeven of the RCTs , 21–23 wP = 0.04, 2I = 49%)   . The res2 = 86%) .P = 0.01, 2I = 82%] , occlusion , infiltration , and accidental dislodgement  (P = 0.002) in comparisons of a clinically indicated group and routine replacement group . The difference between the present study and Webster’s study could be explained by the addition of two recent trials  and CRBSI  based on the analysis of 7 trials involving 7,323 patients. These findings suggest that clinically indicated replacement does not increase the risk of catheter-associated infections compared to routine replacement.The risk of PIVC-associated infections, including local infections and CRBSIs, was not different between the clinically indicated and routine replacement groups in the present study. These findings are consistent with a previous study , in whicP = 0.04, I2 = 99%, This study has several limitations. First, several outcomes were analyzed based on data with heterogeneity, which may be due to various catheter devices, insertion sites, medical care, infusion medications, definitions of the complications, study facility, patients’ local , other lines placed at the same time, the demographic features of included patients . Second, the timing of routine replacement of PIVCs was not consistent, even though we performed subgroup analysis  to minimize the time and measure differences , and selection bias could still exist between studies. Third, compared with routine replacement, clinically indicated replacement of PIVCs may reduce costs, prolong the indwelling time of PIVCs, reduce the workload of staff, and improve patient discomfort. As expected, we found that pooled analysis showed that the study group  had longer indwelling time per catheter than control group (routine replacement of PIVCs every 72–96 h) (mean difference: 21.17 h; 95% CI, 0.62–41.73, The results of this meta-analysis indicated that clinically indicated replacement of PIVCs was associated with increased risks of PIVC-associated phlebitis, infiltration, and occlusion compared to routine replacement. However, the risk of PIVC-associated infections, including local infections and CRBSIs, was not different between the two groups. Based on these findings, we suggest that routine replacement of PIVCs every 72–96 h maybe a preferred option than clinically indicated replacement in the clinical care of patients. Further large studies are still needed to verify these findings.The original contributions presented in this study are included in the article/C-YC, W-CC, C-CL, and Y-FW: conceptualization and methodology. C-YC, W-CC, J-YC, and C-CL: software. C-CL and Y-FW: validation. C-YC and W-CC: formal analysis and writing—original draft preparation. J-YC and W-CC: investigation. C-YC, W-CC, and J-YC: resources and data curation. J-YC, C-CL, and Y-FW: supervision and writing—review and editing. C-YC, W-CC, J-YC, C-CL, and Y-FW: visualization. All authors contributed to the article and approved the submitted version.


The risk of Congenital Heart Defects (CHD) is greatly influenced by variants within the genes involved in folate-homocysteine metabolism. Polymorphism in MTHFR (C677T and G1793A) and MS/MTR (A2756G) genes increases the risk of developing CHD risk, but results are controversial. Therefore, we conducted a case–control association pilot study followed by an up-dated meta-analysis with trial sequential analysis (TSA) to obtain more precise estimate of the associations of these two gene variants with the CHD risk.MTHFR C677T 3450 CHD patients and 4447 controls whereas for MS A2756G 697 CHD patients and 777 controls.For case–control study, we enrolled 50 CHD patients and 100 unrelated healthy controls. Genotyping was done by PCR–RFLP method and meta-analysis was performed by MetaGenyo online Statistical Analysis System software. For meta-analysis total number of individuals was as follows: for MTHFR C677T and MS A2756G polymorphism with risk of CHD whereas MTHFR G1793A was significantly associated with the disease. On performing meta-analysis, a significant association was observed with MTHFR C677T polymorphism but not with MS A2756G. Trial sequential Analysis also confirmed the sufficient sample size requirement for findings of meta-analysis.Results of the original pilot study suggested lack of association for MTHFR in increased risk of CHD.The results of the meta-analysis suggested a significant role of  MTHFR gene at nucleotide position 1793 G to A transition in exon 11 (rs2274976) which results an arginine-to-glutamine change at codon 594 and modifies enzyme activity . Statistical heterogeneity between studies was assessed by Cochran’s Q test and I-square  which can be due to dispersed data and repeated significance testing. Bias from low trial with low methodological qualities, publication bias and small trial bias may result in false analysis .(PDA: 8%) and least for endocardial cushion defect (6%). The frequency of complex CHD forms (more than one CHD condition) were as follows: 4% for ASD with PDA, 2% for VSD with AV-canal defect, 4% for VSD with pulmonary arterial hypertension (VSD-PAH) and 2% for endocardial cushion defect along with dextrocardia.Based on echocardiography reports, the different CHD phenotypes were categorised Table . The obsThe genotypic and allelic frequencies along with Chi square values for Hardy–Weinberg calculations for the all the three polymorphisms in study participants are depicted in Table In order to investigate the possible association of these three polymorphisms with susceptibility of CHD, ORs with 95% confidentiality intervals was calculated for different genetic models which are presented in Table MTHFR C677T and MS A2756G polymorphisms, we observed that even though the values calculated for ORs under different models were above 1, but none of the values reached statistical significance level (p > 0.05). The present study proclaimed lack of association of MTHFR C677T and MS A2756G gene polymorphism with the risk of CHD in our population. Furthermore, the GA vs GG genotype depicted a strong significant association of MTHFR G1793A gene polymorphism. The G vs A frequency showed that the allele ‘A’ is adding a significant risk of approximately 5.7 folds in the development of CHD in the studied population. Distribution of MTHFR haplotypes in cases & controls and their association towards CHD susceptibility is depicted in Table For both p = 2.71e‐006) and C-G was significantly involved in protection against CHD development  in the population under reference. By analysing LD scores in two study groups it was observed that the MTHFR variants were in complete LD in both patients  and controls .The frequency of C-G haplotype was higher in both cases and controls (0.690 & 0.895 respectively). There was complete absence of T-A haplotype in both study groups. The haplotype combination C-A was significantly associated with CHD risk  as shown in Table We found 26 eligible studies having 3450 cases and 4447 controls with reference to MS polymorphism, none of the applied genetic models found association with CHD in overall population or even after subgrouping  in the genes controlling this pathway may be the genetic risk factors for these disorders . Therefo workers –38. Regapulation , 40. Xu MTHFR C677T with risk of CHD, as it was a pilot study and carried on limited number of samples. But after performing meta-analysis, the results suggested a positive association of MTHFR C677T with the risk of CHD. The results of the overall analysis depicted an increased risk of CHD with the presence of MTHFR 677 T- allele in fetus. The putative risk allele-677 T had a 1.33 folds increased risk of CHD against the C-allele. From the subgroup analysis, the increased risk of the T-allele was widely detected in Asians but not in Caucasians. Our results are compatible with the previous Meta analyses that investigated the association of the MTHFR C677T polymorphism in CHD [Genetic association studies have been a powerful approach for identifying susceptibility genes for common diseases but it has been experienced that most of the initial positive associations were not reproduced in the subsequent replication studies because of small sample size or false-positive reports , 42. Metm in CHD , 43. Furm in CHD . The finIn conclusion, the results of meta-analysis and TSA support the role of MTHFR C677T gene polymorphism as susceptibility factor for Congenital Heart Defects. For MTHFR G1793A and MS A2756G gene polymorphisms, there is need to perform large number of homogenous studies to evaluate these crude results further.


The rs10166942 CT genotype was associated with increased migraine risk  and increased MO risk . No association was detected for the rs11172113. The rs2651899 and the rs10166942 have an effect on migraine. Larger studies are needed to dissect the role of these variants in migraine.The genetic basis of migraine is rather complex. The rs2651899 in the PR/SET domain 16 (PRDM16) gene, the rs10166942 near the transient receptor potential cation channel subfamily M member 8 (TRPM8) gene, and the rs11172113 in the LDL receptor-related protein 1 (LRP1) gene, have been associated with migraine in a genome-wide association study (GWAS). However, data from subsequent studies examining the role of these variants and their relationship with migraine remain inconclusive. The aim of the present study was to meta-analyze the published data assessing the role of these polymorphisms in migraine, migraine with aura (MA), and migraine without aura (MO). We performed a search in the PubMed, Scopus, Web of Science, and Public Health Genomics and Precision Health Knowledge Base (v7.7) databases. In total, eight, six, and six studies were included in the quantitative analysis, for the rs2651899, rs10166942, and rs11172113, respectively. Cochran’s Q and I2 tests were used to calculate the heterogeneity. The random effects (RE) model was applied when high heterogeneity was observed; otherwise, the fixed effects (FE) model was applied. The odds ratios (ORs) and the respective 95% confidence intervals (CIs) were calculated to estimate the effect of each variant on migraine. Funnel plots were created to graphically assess publication bias. A significant association was revealed for the CC genotype of the rs2651899, with the overall migraine group (RE model OR: 1.32; 95% CI: 1.02–1.73;  Migraine is a complex disorder of the brain, with great variety in its pathogenesis, clinical presentation, genetic make-up, and therapeutic approach . It is tPhenotypically, migraine manifests with recurrent episodes characterized by pulsating intense pain in the head unilaterally . AdditioFrom a pathophysiological perspective, several theories including various molecular mechanisms have been connected to migraine risk, such as the release of vasoactive neuropeptides vascular dysfunction, vasodilation, defective function of brain networks, plasma protein extravasation, cortical spreading depression (CSD), and “neurogenic inflammation” ,8. MoreoWhile the pathophysiological pathways via which the previously referred mechanisms can lead to the migraine are not fully understood , there a+/K+ Transporting Subunit Alpha 2 (ATP1A2), encoding the sodium–potassium- transporting ATPase, in Sodium Voltage-Gated Channel Alpha Subunit 1 (SCN1A) encoding a voltage- gated sodium channel subunit, can all lead to FHM [The genetic architecture of migraine is complex, as migraine is considered a polygenic disease, where a few genetic factors are implicated in its appearance and phenotypic traits ,23,24. Td to FHM ,27. AddiApart from FHM and monogenic migraine with aura syndromes, there are polymorphisms  that have been further found to be associated with migraine ,30,31,32In view of the former considerations, the aim of the present study was to retrieve, review, and meta-analyze the available published data assessing the role of the PRDM16 rs2651899, the rs10166942 near the TRPM8 gene, and the LPR1 rs11172113 polymorphisms on migraine. Additionally, we attempted to assess the role of these variants on the risk of the main migraine endophenotypes, namely the MA and the MO.The Preferred Reporting items Systematic Reviews and Meta-Analyses (PRISMA) guidelines  were appWe searched through the PubMed, Scopus, Web of Science, and Public Health Genomics and Precision Health Knowledge Base (v7.7) databases for eligible articles examining the relationship between migraine and the PRDM16 rs2651899, the rs10166942 near the TRPM8 gene, and the LPR1 rs11172113 polymorphisms (the last search was performed on 18 March 2022). The search for each variant was performed separately. We used the term “migraine” in combination with either “rs2651899”, or “rs10166942”, or “rs11172113”, as free words. The PubMed algorithm of the literature search for the present meta-analysis is presented at We initially checked titles and abstracts of identified articles for relevance. From the articles that passed the initial screening, full texts were retrieved. Additionally, the reference lists of the identified articles were scanned for supplementary eligible studies.Studies that met the following criteria were included: (1) written in the English language, (2) publication before the 18 March 2022, and (3) the absolute genotype numbers for the examined variants were available for controls and patients with migraine. Data from GWASs and studies containing irrelevant data were not included.The following data from each eligible study were extracted when possible: (1) author, (2) year of publication, (3) ethnicity/location of the examined population, (4) numbers (n) of cases with migraine and controls, (5) age at onset of migraine, (6) mean age of the participants during examination, (7) number of males and females in patients with migraine and controls, (8) criteria applied to the assessment of the diagnosis of migraine, (9) test of the Hardy–Weinberg Equilibrium (HWE) principle, (10) applied method for correction for multiple comparisons, (11) genotype absolute numbers, and (12) main results.https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download, accessed on 16 December 2021). The odds ratios (ORs) and the respective 95% confidence intervals (CIs) were calculated in order for the effect of each variant on migraine to be estimated. The following effects were calculated: (a) homozygosity for the variant allele genotype, (b) heterozygosity, and (c) homozygosity for the wild-type allele. Three phenotypic traits were considered as outcomes: (a) migraine, (b) MA, and (c) MO. Statistically significant values were considered those with values lower than 0.05 (p < 0.05).Statistical analyses were performed with Review Manager (RevMan) Version 5.4 (Q < 0.10 and/or I2 > 75%) [Cochran’s Q and I2 tests were used to calculate the heterogeneity. The random effects (RE) model was applied when high heterogeneity was observed (P2 > 75%) ; otherwi2 > 75%) . Funnel The search of the databases  yielded 14 articles, published between 2011 and 2021. After the initial evaluation of titles and abstracts, three articles were excluded as review articles. Consequently 11 full texts were examined for eligibility. Four articles ,38,45,46The search of the databases (after the remove of duplicate records) yielded 14 articles, published between 2011 and 2021. After the initial evaluation of titles and abstracts, three articles were excluded (no genetic studies or review articles). Consequently 11 full texts were examined for eligibility. Five articles ,46,52,53The search of the databases (after the remove of duplicate records) yielded 18 articles, published between 2011 and 2022. After the initial evaluation of titles and abstracts, four articles were excluded (no genetic studies or review articles). Consequently 14 full texts were examined for eligibility. Eight articles ,55,56,57p-value = 0.04). The forest plots can be accessed in A significant association was revealed between the PRDM16 rs2651899 and the overall migraine group for the CC genotype  and a marginal trend for a protective effect of the AA genotype . The forest plots can be accessed in A significant association revealed between the PRDM16 rs2651899 and the MA subgroup group for the CC genotype  and for the TT genotype . On the contrary, the heterozygosity CT was associated with increased migraine risk . The forest plots can be accessed in A significant association for a protective effect was revealed between the rs10166942 and the overall migraine group for the CC genotype  while the heterozygosity CT was associated with increased MO risk . A marginal protective effect against MO was found for the TT genotype . The forest plots can be accessed in A significant association, with a protective effect was revealed between the rs10166942 and the overall migraine group for the CC genotype . The forest plots can be accessed in Only a marginal trend for association was revealed between the LPR1 rs11172113 and migraine for the CT genotype  on the risk of migraine, as well as on the risk of the main migraine phenotypes, namely the MA and the MO. Our study detected a significant influence of the PRDM16 rs2651899 on the risk of overall migraine and MA. Moreover, we detected a significant association between the rs10166942 (near the TRPM8 gene) CT genotype and increased migraine risk and MO risk, while the homozygosities appear to confer a protective effect. Finally, we did not detect any association between the LRP1 rs11172113 and any of the migraine phenotypes.The PRDM16 gene encodes a zinc finger transcription factor, which contains an N-terminal PR domain ,60. The The PRDM16 rs2651899 polymorphism is an intronic variant located at chromosome 1:3167148. This variant polymorphism may alter PRDM16 gene splicing or may have an effect on downstream regulatory elements, influencing the expression of PRDM16 mRNA . The varTRPM8 proteins are cold-sensitive channels responding to a great variety of ligands . They arThe rs10166942 is an upstream gene variant located at Chromosome 2:233916448, near the TRPM8 gene. Interestingly, carriers of the rs10166942 C allele appeared to have decreased TRPM8 expression and reduced sensitivity to cold stimuli . MoreoveThe third examined polymorphism in our study is the intronic rs11172113 located at Chromosome 12:57133500 of the LRP1 gene. The LRP1 gene is expressed in the brain, vasculature and, many other human tissues . It is iThe fact that none of the examined polymorphisms has been associated with both MA and MO subgroups could be attributed to several reasons. Firstly, despite the similarities in genetic architecture between MA and MO, a few differences also exist . MoreoveMigraine causes severe impairment, influencing the quality of life, and the patients are unable to be productive in their daily activities ,80; consIn conclusion, based on our findings the PRDM16 rs2651899 is associated with migraine and MA, and the rs10166942 (near the TRPM8 gene) CT genotype is associated with increased migraine risk and MO risk, while the homozygosities appear to confer a protective effect. Additionally, we did not detect any association between the LRP1 rs11172113 and any of the migraine phenotypes. In any case, considering that therapeutic approaches for migraine are often ineffective, it will be interesting to observe whether a personalized treatment based on the genetic architecture of each individual could be applied in the future. Future larger collaborative studies are needed, in cohorts with multiethnic backgrounds, for the role of these variants in migraine to be more accurately elucidated.


Colorectal cancer (CRC) risk is linked to serum and dietary retinol and carotenoids, according to clinical and epidemiological research. However, the findings are not consistent. As a result, we did this meta-analysis to determine the link between them.From 2000 through 2022, the PubMed, Web of Science, and Embase databases, as well as pertinent article references, were searched and filtered based on inclusion and exclusion criteria and literature quality ratings. High and low intake were used as controls, and OR (odds ratio) or RR (relative risk) and 95% confidence interval were extracted. The extracted data were plotted and analyzed using Stata12.0 software.A total of 22 relevant studies were included, including 18 studies related to diet and 4 studies related to serum. For high and low intake or concentration controls, the pooled OR was as follows: β-carotene , α-carotene , lycopene , lutein/zeaxanthin , β-cryptoxanthin , total carotenoids , retinol , serum carotenoids , serum retinol . Subgroup analysis was performed according to tumor type, study type and sex.Total carotenoid intake and Lutein/Zeaxanthin intake were not associated with CRC risk. High β-carotene, α-carotene, lycopene, and β-cryptoxanthin all tended to reduce CRC risk. Serum carotenoid concentrations were significantly inversely associated with CRC risk. In recent years, the incidence and mortality of malignant tumors have been increasing year by year, even exceeding other chronic diseases, becoming a veritable human health killer . AlthougFruits and vegetables are among the daily foods required for good health since they include high levels of minerals, vitamins, carbs, proteins, dietary fiber, and different substances with nutritional medicinal value that can help prevent a variety of ailments . Many stOver the last two decades, researchers have conducted substantial research on the link between nutrition and cancer. Epidemiological studies have found a link between food and cancer incidence and aggressiveness . A high Two writers (Xiaoyong Han and Rangyin Zhao) separately conducted a literature search for the association between retinol, carotenoids, and related derivatives and the risk of CRC in humans using the PubMed, Web of Science and Embase databases. The following keywords were used in the search: “retinol” or “carotenoids” or “carotene” or α-carotene or “β-carotene” or “cryptoxanthin” or “lycopene” or “lutein” or “zeaxanthin” combined with “colorectal cancer” or “colon cancer” or “rectal cancer.” All relevant literature was searched from 2000 to April 2022. In addition, we performed a manual search of the reference lists of reviews, meta-analyses, and other relevant publications to prevent potentially missed articles. The language of included articles was limited to English.Studies were included according to the following criteria: (1) patients were diagnosed with colon or rectal cancer; (2) observational studies, including cohort or case-control studies; (3) The associations of interest are about the association of serum or dietary retinol or carotenoids with CRC risk, and there are comparisons of high and low content.; (4) Included studies contained relative risks (RR) or odds ratios (OR) with 95% confidence intervals for CRC. The following exclusion criteria were used: (1) reviews or conferences or abstracts or letters to the editor; (2) duplicate study populations; (3) animal studies; (4) other cancer studies; (5) lack of RR or OR data; (6) other vitamin supplement studies.All included papers were examined and relevant data were retrieved independently by two researchers. Inclusion basic information included: name of first author, date of publication, country, type of study, vitamin type, cancer type, sample size of cases and controls, RR or OR and 95% CI for cancer, covariate correction. The disagreement between these two researchers was decided jointly by a third author. The quality of the included studies was assessed using the NOS scoring criteria (0–9 points), and those with a score > 6 were included in the meta-analysis.Q-test and I2 statistic. Q-test (PQ) p-value < 0.1 and I2 > 50% indicated that there was significant statistical heterogeneity between studies, and the results were analyzed using a random-effects model. Otherwise, a fixed effects model was used. We used forest plots to present the meta-analysis results and used Begg’s test as well as Begg’s funnel plots to assess publication bias. In addition, by eliminating each study one by one, a sensitivity analysis was performed to check the stability of the results. Analyses were performed using Stata12.0 for Windows  and p < 0.05 was considered statistically significant.RR or OR with 95% confidence intervals were extracted from each study to assess the association of high retinol or carotenoids intake with cancer risk. The results generally combined in cohort studies are RR values, and the results generally combined in case-control studies are OR values. In order to better calculate and combine the results of studies, the difference between the two is negligible, and all the results are expressed as OR values. In addition, heterogeneity among studies was assessed by n = 235), Web of Science (n = 218), Embase (n = 173). After de-duplication (n = 376), the titles and abstracts of the remaining articles (n = 250) were examined and evaluated. A total of 193 articles were rejected for purpose, article type , or irrelevant findings. Fifty-seven full-text articles were downloaded, of which 35 studies were rejected after initial analysis due to lack of important data or unsatisfactory quality of NOS scores. Finally, the meta-analysis comprised 22 papers that fully fulfilled the inclusion criteria and quality evaluation. The relevant literatures were searched in three main English databases according to the search strategy: PubMed (tp = 0.113), and due to significant heterogeneity , we used a random-effects model for pooled analysis. According to subgroup analysis by tumor type, it can be seen that there is no significant correlation between dietary intake and the risk of colon cancer , and due to significant heterogeneity , we used a random-effects model for pooled analysis. Subgroup analysis by tumor type showed that dietary intake was not significantly associated with the risk of colon cancer , reduced CRC risk. Due to significant heterogeneity , pooling was performed with a random-effects model. Subgroup analysis was performed according to tumor type, study type and gender. Colon cancer  association between high lutein/zeaxanthin , which was summarized using a fixed-effect model. Subgroup analysis was performed according to tumor type, study type and gender. Colon cancer . High heterogeneity was found , which was combined using the random-effects model. Subgroup analysis was performed according to tumor type, study type, and gender. Colon cancer  association between high carotenoids , which was combined using the random-effects model. Subgroup analysis was performed according to tumor type, study type and gender. Colon cancer  association between high retinol , and fixed effect model was used for combination. Subgroup analysis was performed according to tumor type, study type and gender. Colon cancer  negatively associated with CRC risk. The results showed significant heterogeneity , which was combined using the random-effects model. The subgroup analysis was performed according to the type of nutrients. Serum α-carotene . The results showed significant heterogeneity , and random effects model was used for combination. Subgroup analysis were also performed according to study type. Cohort studies  and carotenoids are widely present in a variety of vegetables and fruits, many people still lack the intake of these nutrients. Therefore, the impact of retinol and carotenoids intake on CRC risk has important public health implications. We included a total of 22 studies that pooled clinical studies on dietary and serum retinol and carotenoids and CRC risk. Subgroup analysis was performed according to tumor type, study category and sex.The results showed that dietary β-carotene intake was not significantly negatively correlated with CRC risk, but β-carotene could significantly lower CRC risk in the male population, showing a protective and preventive effect. The consumption of α-carotene lowered the risk of CRC, however, the link was not statistically significant. A high lycopene consumption lowered CRC risk marginally but not dramatically. There was no link seen between high lutein/zeaxanthin consumption and CRC risk. High intake of β-cryptoxanthin was able to non-significantly reduce the risk of CRC. There was no link found between high total carotenoids consumption and CRC risk. High retinol consumption had no significant connection with CRC risk, and although it appeared to protect women and reduce CRC risk by 21%, high retinol intake was able to significantly increase the risk of CRC for men, and this difference was very important and could guide dietary matching. In summary, high β-carotene, α-carotene, lycopene, and β-cryptoxanthin all have a tendency to reduce CRC risk, which is more pronounced in the male population, but there is uncertainty that must be explored. Total carotenoids intake and Lutein/Zeaxanthin intake were not associated with CRC risk. Beta-carotene has a preventive effect on CRC in men and retinol seems to have a preventive effect in women and a carcinogenic effect in men, and this difference has led us to new ideas about adjusting the diet by sex.In addition to focusing on the risk of dietary retinol and carotenoids on CRC, we also focused on serological aspects of the study. A significant inverse association was found between serum carotenoids concentrations and CRC risk. Serum β-carotene was shown to have a substantial negative relationship with CRC risk. Other carotenoids, while adversely associated, were not significant. Case-control studies have found a substantial negative link between serum retinol and CRC risk, while cohort studies have found no significant relationship, hence the relationship between serum retinol and CRC remains unknown and must be confirmed by large prospective investigations. Most previous studies have focused on dietary carotenoids, but in recent years attention has gradually shifted to serum carotenoids, possibly due to the development of serum detection techniques and more stable and accurate quantitative assessment of serum. Serum carotenoids are widely studied, in addition to CRC , 29, but2 macrophages and activated fibroblasts  to clarify the preventive effect. On the other hand, rigorous animal experiments and tumor cell experiments can be designed to determine the preventive effect, as well as to clarify the preventive mechanism. If validated by multicenter RCT and cell and animal experiments, recipes for relevant populations can be developed and corresponding supplements can be manufactured for promotion and application. Vitamins are one of the essential nutrients for human beings, which contain a wide variety and have different physiological functions and have an important relationship with many diseases. While exploring retinol and carotenoids, we can also try to explore the preventive effects of vitamin B, vitamin C, vitamin D, vitamin E, and folic acid on different cancers. In addition to exploring the value of vitamins in the prevention of cancer, the value of survival and prognosis was explored. In addition, we found that most of the vitamins belong to antioxidants, and in addition to studying the value of vitamins in cancer, the relationship between other antioxidants and cancer can be explored, such as melatonin, anthocyanins, astaxanthin, and quercetin. Finally, it should be noted that excessive use of vitamins will produce corresponding toxic side effects, such as excessive intake of carotenoids will cause loss of appetite, yellow skin, poor sleep, affecting female ovulation and so on –52. TherTotal carotenoids intake and Lutein/Zeaxanthin intake were not associated with CRC risk. High β-carotene, α-carotene, lycopene, and β-cryptoxanthin all tended to reduce CRC risk, with a more pronounced effect in the male population. In addition, β-carotene had a significant preventive effect on CRC in men. In the female population, high dietary retinol intake can reduce CRC risk, while it has carcinogenic effects in men. On the other hand, serum carotenoids concentrations were significantly and inversely associated with CRC risk. Finally, due to the limitations, large prospective studies with adequate sample size, well-controlled confounders, and long-term follow-up are needed for further exploration.The original contributions presented in this study are included in the article/XH and RZ conceived the study and wrote the draft. GZ and YJ performed the literature search. DW and YW extracted the required data. XH performed the statistical analyses. HC reviewed the manuscript. All authors viewed and gave permission to publish this manuscript.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.