The aim of the present study was to evaluate, by means of a meta-analysis approach, whether new available data, appeared on qualified literature, can support the effectiveness of an association of HbA1c variability with the risk of macro- and/or micro-vascular complications in type 2 diabetes mellitus (T2DM).The meta-analysis was conducted according to PRISMA Statement guidelines and considered published studies on T2DM, presenting HbA1c variability as standard deviation (SD) or its derived coefficient of variation (CV). Literature search was performed on PubMed in the time range 2015–July 2022, with no restrictions of language.p < 0.0001) for stroke, 1.30  for transient ischaemic attack/coronary heart disease/myocardial infarction, and 1.32  for peripheral arterial disease. Micro-vascular complications yielded HR 1.29  for nephropathy, 1.03  for neuropathy, and 1.15  for retinopathy. For all-cause mortality, HR was 1.33 , and for cardiovascular mortality 1.25 .Twenty-three selected studies fulfilled the aims of the present investigation. Overall, the analysis of the risk as hazard ratios (HR) indicated a significant association between the HbA1c variability, expressed either as SD or CV, and the complications, except for neuropathy. Macro-vascular complications were all significantly associated with HbA1c variability, with HR 1.40 (95%CI 1.31–1.50, Our meta-analysis on HbA1c variability performed on the most recent published data since 2015 indicates positive association between HbA1c variability and macro-/micro-vascular complications, as well as mortality events, in T2DM, suggesting that this long-term glycaemic parameter merits further attention as a predictive, independent risk factor for T2DM population.The online version contains supplementary material available at 10.1007/s00592-023-02037-8. Glycated haemoglobin HbA1c) is a biomarker with central role in the diagnosis and follow-up of patients with diabetes mellitus, although not a perfect one c is a bi. AmericaResearch has been exploring other parameters that can offer more accurate and individualized disease monitoring. Glycaemic variability can be measured over the short term with continue glucose monitoring (CGM) of interstitial glucose levels both within-day and between-day, and it can also be assessed over the long term (months to years) by the oscillation of fasting plasma glucose or HbA1c levels. Long-term glycaemic variability is most commonly assessed by HbA1c variability , which cTraditional measures of HbA1c variability can include the standard deviation (SD) and its derived coefficient of variation (CV), the latter calculated as SD divided by the mean . HoweverThe systematic review and meta-analysis provided by Gorst et al.  have sugThe aim of the present study was to evaluate, by means of a meta-analysis approach, whether new available data, appeared on qualified literature since 2015, can support the effectiveness of an association of HbA1c variability with the risk of macro- and/or micro-vascular complications in T2DM.The meta-analysis was conducted according to PRISMA Statement guidelines , followiAs anticipated in Introduction, traditional measures of HbA1c variability include the standard deviation (SD) and the derived coefficient of variation (CV), calculated as SD divided by the mean . Since tThe present meta-analysis considered published studies presenting SD and CV, since these parameters are the most commonly available indices for HbA1c variability.Literature search was performed on PubMed in the time range 2015–July 2022, with no restrictions of language, using as search terms the followings:(HbA1c variability OR glycosylated haemoglobin variation OR HbA1c CV OR HbA1c SD OR HbA1c coefficient of variation OR HbA1c standard variation) AND (type 2 diabetes mellitus AND (microvascular complications OR macrovascular complications)).All resulting articles were reviewed by two reviewers (R.C. and G.S.).P: Population: patients (age > 18y) with diagnosis of T2DM;I: Investigated condition: measurement of HbA1c variability, assessed by the SD or CV;C: Comparison condition: logistic or Cox regression analysis for outcome risk prediction;O: Outcome: risk of adverse macro-/micro-vascular complications;S: Study type: any kinds of clinical trials .Eligibility criteria were selected according to the PICOS framework , 20:P: PAll the articles that fulfilled the requirements were considered, without restriction on ages of participants (as long as they were adults). We excluded reviews, editorials, and case reports. Full articles on potentially relevant studies were downloaded and reviewed for inclusion.The main adverse outcomes of interest were all-cause mortality, cardiovascular mortality, and both diabetes macro-complications  and micro-complications . When an article presented more estimates of the HbA1c variability, based on different models, all the proposed data were considered.Meta-analysis was performed using review manager (RevMan) [computer program] version 5.4.1 . Analysis was stratified according to the presence of data regarding HbA1c variability in terms of coefficient of variation (CV) or as standard deviation (SD) and using hazard ratios (HR) or odds ratios (OR) data, as made available by considered studies. Subgroup analyses and overall values were presented. Separate analyses of HR and OR were performed, due to the different nature of the risk parameter meaning. Analysis was performed using the random-effects method , 22. Res2. Heterogeneity was also evaluated by using I2 statistics based on χ2 test [z-distribution and significance results provided [The measure of the extent of variation (heterogeneity) among the effects observed in different studies was quantified by Tau χ2 test  considerprovided .Figure p < 0.0001), with the contributing effect of both HbA1c-CV and HbA1c-SD   for stroke  for transient ischaemic attack/coronary heart disease/myocardial infarction  for peripheral arterial disease  for nephropathy  for neuropathy  for retinopathy  Fig. . Macro-voke Fig. , HR of 1ion Fig. , and 1.3ase Fig. . Considethy Fig.  and HR 1thy Fig. . Since d2 test and I2 statistics), which may affect each relative overall effect.Considering the OR as measure of association between HbA1c variability (expressed either as CV or SD) and risk for each of the outcomes Fig. , most ofIn this meta-analysis, we assessed the association and the potential clinical utility of HbA1c variability in T2DM, focusing on studies published in the last years, from 2015 until present day. The relevance of the issue consists of the fact that HbA1c variability could be a potentially modifiable risk factor and therefore could provide additional information for an optimized management of diabetes mellitus. The present analysis suggests that HbA1c variability (assessed as SD or CV) is significantly associated with the risk (as HR) of macro-vascular complications in T2DM, therefore conditioning also all-cause mortality and specifically cardiovascular mortality. On the other side, HbA1c variability may predict a significant risk of micro-vascular complications only for nephropathy and retinopathy, while the neuropathy risk appears not relevant.These results confirm that individualizing care on the basis of change in glycaemic variability can be an important aspect of precision medicine in diabetes managing , althougThe burden of HbA1c variability found by the present meta-analysis in patients affected by T2DM regarding vascular complications appears to have approximately the same weight as the main detected risk factors, such as age, male sex and history of hypoglycaemia , suggestAs regard neuropathy, the HbA1c variability, assessed in the present analysis according to data on HR Fig. , appeareStill regarding neuropathy, the analysis of data set providing estimates of HbA1c variability in terms of OR Fig.  permitteThe results of the meta-analysis considering the predictive role of HbA1c on various vascular complications and 10 shThe present meta-analysis revealed different performance in defining the risk associated with HbA1c considering either HR or OR. It should be noted that OR indicates the presence of an association between an intervention and related risk, summarizing an overall study, but tends to exaggerate risk; moreover, the OR is a static measure and does not consider rates. Conversely, HR considers rates and indicates how the intervention modifies the rate of experiencing the considered event. HR, generally obtained with the standard Cox regression method, permits to investigate the effect of one or more variables (covariates) on the “time-to-first-event” . TherefoI2 statistics, very often presents a significant value, with ranges also greater than 50%, suggesting substantial/considerable heterogeneity [Regarding the heterogeneity issue for HR data, the considered outcomes present an appreciable variability among studies, since the heterogeneity measure, in particular as ogeneity . Since t2 and I2 parameters, and this fact may influence the overall effect. Moreover, data for neuropathy are influenced greatly by the presence of several values coming from a single study [Concerning OR, the results for two micro-complications (nephropathy and neuropathy) are characterized by a relevant heterogeneity, as suggested by Taule study  obtainedOur meta-analysis on HbA1c variability performed on the most recent published data since 2015 extends the view of previously published study by Gorst et al. [Supplementary file1 (DOCX 19 KB)Below is the link to the electronic supplementary material.


Dear Editor,1 As stated by the authors, these comments and analyses support and strengthen the results of our article.1First of all, we would like to thank the authors for their comments and analyses regarding the results of our article.In similar genetic association studies, DNA samples are usually isolated from peripheral blood. However, the TaqMan allelic discrimination assay used in this study is a very sensitive genotyping method and does not work in any genetic changes that occur in the genotyped DNA sequence. To ensure quality control, genotyping was performed without knowledge of the subjects’ case/control status, and a 15% random sample of cases and controls was genotyped twice by different persons and reproducibility was 100%. Therefore, there cannot be any bias regarding genotyping.1, the G allele of HOTAIR rs1899663 G>T polymorphism has been considered protective in some studies.2 But, there are studies in the literature reporting that the T allele of HOTAIR rs1899663 G>T polymorphism increases the risk of cancer.3 Contrary to these results, Hassanzarei et al4 reported that the T allele of rs1899663 G>T polymorphism of HOTAIR gene was protective against breast cancer in the Iranian population. The basis of HOTAIR rs1899663 G>T polymorphism is the replacement of guanine by thymine at the 12th chromosome at 53967210th position.5HOTAIR rs1899663 G>T polymorphism is located in the intronic region of HOTAIR gene (in the second intron site in 4903 position).5 Many researchers have focused on finding the role of functional intronic polymorphisms because genetic polymorphisms in introns can affect alternative gene splicing and alter the expression of distant genes.6 In silico analysis via HaploReg v4 software shows that the HOTAIR rs1899663 G>T polymorphism has altered the binding affinity of transcription factors such as PAX-4, SOX, SPZ1, and ZFP281.6 However, there is no evidence in the literature regarding the clinical and biological significance of neither the G allele nor the T allele of HOTAIR rs1899663 G>T polymorphism. When the biological significance of the G and T alleles of HOTAIR rs1899663 G>T polymorphism is understood with further analysis (such as reporter gene assays), it will be better understood whether the G allele is protective or the T allele increases risk.As reported in our article


Sex difference exists in the prevalence of dementia and cognitive decline. The impacts of sex-specific reproductive risk factors across the lifespan on the risk of dementia or cognitive decline are still unclear. Herein, we conducted this systemic review and meta-analysis to finely depict the longitudinal associations between sex-specific reproductive factors and dementia or cognitive decline.PubMed, EMBASE, and Cochrane Library were searched up to January 2023. Studies focused on the associations of female- and male-specific reproductive factors with dementia or cognitive decline were included. Multivariable-adjusted effects were pooled via the random effect models. Evidence credibility was scored by the GRADE system. The study protocol was pre-registered in PROSPERO and the registration number is CRD42021278732.A total of 94 studies were identified for evidence synthesis, comprising 9,839,964 females and 3,436,520 males. Among the identified studies, 63 of them were included in the meta-analysis. According to the results, seven female-specific reproductive factors including late menarche (risk increase by 15%), nulliparous (11%), grand parity (32%), bilateral oophorectomy (8%), short reproductive period (14%), early menopause (22%), increased estradiol level (46%), and two male-specific reproductive factors, androgen deprivation therapy (18%), and serum sex hormone–binding globulin (22%) were associated with an elevated risk of dementia or cognitive decline.These findings potentially reflect sex hormone-driven discrepancy in the occurrence of dementia and could help build sex-based precise strategies for preventing dementia.The online version contains supplementary material available at 10.1186/s12916-023-03159-0. Strong evidence shows a sex discrepancy in the incidence of dementia and cognitive decline, and this discrepancy varies with age. A recently conducted study with 29,850 participants from 21 cohorts across 6 continents found that women had a higher incidence of dementia compared to men, especially in low- and lower-middle-income countries . CognitiInvestigating the correlations between sex-specific reproductive characteristics and dementia can provide more convincing insights into sex-related differences in dementia. The life of a woman can be divided into four stages: puberty, latency, peri-menopause, and menopause. The timing of the endocrine transition phases like menarche and menopause, both female-specific and age-related, is crucial for the separation standard. Furthermore, females undergo special biological processes, such as pregnancy and breastfeeding. However, whether these female-specific factors can further influence cognition remains debatable. A cohort study of 4 million participants found that later menarche increased the risk of dementia, while later menopause and longer reproductive period decreased the risk . HoweverMale-specific reproductive factors are less distinct across the lifespan than female-specific factors, and the separation of male phases based on reproductive factors has not been clearly defined. However, emerging studies focusing on the relationship between male-specific hormone-related factors, such as androgen deprivation therapy (ADT) and dementia have yielded contradictory results , 8. HereWe followed the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement’s instructions . SystemaThe inclusion criteria were as follows: (1) Studies were required to be cohort studies, however, for female reproductive factors , besides cohort studies, case–control studies were also included given the expectation of modest recall bias; (2) The measurement of the outcomes had to be described in detail, with cognitive decline assessed using standard and full-scaled cognitive tests, and dementia or AD diagnosed using objective and globalized diagnostic criteria such as Diagnostic and Statistical Manual of Mental Disorders criteria, International Classification of Diseases codes, and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria; and (3) For dose–response analysis, the pooled related factors needed to be separated into at least three levels, with specific or calculable person-years and case numbers within each level.Two researchers independently screened the included studies. If a discrepancy arose, the third author was asked to determine whether to include or exclude the study. When two or more studies originated from the same database, the study with the biggest sample size and/or most detailed information was retained. Additionally, we combed through the bibliographies of qualified studies to avoid overlooking any potentially pertinent studies.Predesigned templates were used to extract data from each article, including first author, publication year, study design, population resource, cognitive status at the baseline, mean age, gender composition, follow-up duration, attrition rate, total sample size for analysis, incident case, type of outcome, outcome measurement, type of exposed factor, measurement of exposed factor, adjusted confounders, and risk estimates. If any required data was not reported in the publication, we contacted the authors to obtain it. Two authors with extensive experience extracted the data, and any disagreements were resolved with assistance from a third reviewer.The Newcastle–Ottawa Scale (NOS) was used to evaluate potential bias. In order to more accurately measure potential bias in studies, a modified version of the NOS was utilized   for a series of risk factors were acquired for further analysis. When odds ratios (ORs) were provided in some articles instead of relative risks (RRs) or hazard ratios (HRs), we used the following algorithm to convert ORs to RRs :P0 represents the incidence of dementia or cognitive decline in the non-exposed group. If P0 cannot be calculated, the overall incidence rate of the entire sample can be used instead.I2 metric [To begin, we specified definitions of exposures to facilitate comparison of pooled data across studies: (a) early menarche was defined as age at menarche ≤ 13 years; (b) late menarche was ≥ 16 years; (c) early menopause was ≤ 45 years; (d) late menopause was ≥ 54 years; (e) short reproductive period was ≤ 34 years; (f) long reproductive period was ≥ 38 years; (g) early childbearing was ≤ 20 years; and (h) late childbearing was ≥ 30 years. The fixed model combined risk estimates of the same category within a study, while the random model pooled estimates across studies [2 metric . For facDose–response analysis for eligible components was undertaken using the inverse variance weighted least squares regression with cluster robust error variances (REMR model) . For stuhttps://community.cochrane.org/help/tools-and-software/gradepro-gdt)  puberty-related factors, (2) latency period-related factors, (3) peri-menopause-related factors, (4) sex hormones in post-menopause, and (5) gynecological operations across the lifespan. Male-specific reproductive factors were sorted into 2 categories: (1) male-specific diseases and related factors and (2) late-life sex hormones. Figure  puberty-I2 = 0%). In the latency period, the pooled RRs were 1.14  for the short reproductive period and 0.91  for the long reproductive period. For parity, increased risks were seen for both nulliparous  and grand parity (≥ 5) , with a 3% increase per parity . One study reported a decreased risk of dementia with infertility  , while late menopause was protective, lowering risk by 7% . Dose–response analysis showed an inverse linear relationship between age at menopause and dementia/cognitive decline (p < 0.0005)  for increased total estradiol. Findings from an individual study suggested that increased free estradiol levels could reduce the risk of cognitive decline . Higher sex hormone–binding globulin (SHBG) levels increased the risk of dementia in one study . For gynecological surgery, five studies on bilateral oophorectomy gave a pooled adjusted RR of 1.08 , while one study on hysterectomy with bilateral oophorectomy had a RR of 0.85 (95% CI = 0.75 to 0.97)  compared to prostate cancer patients not receiving ADT, and 1.17  versus those without prostate cancer. By ADT type, RRs versus prostate cancer controls were 2.03 for antiandrogens  and 1.47 for orchidectomy . Versus healthy controls, RRs were 1.60 for orchidectomy  and 1.15 for gonadotropin-releasing hormone (GnRH) agonists . Subgroup analysis was conducted by race, follow-up time, study quality, and sample size    and benign prostatic hyperplasia (BPH)  were associated with increased risk of dementia. Additionally, higher SHBG levels were linked to an elevated risk of dementia or cognitive decline . For male-specific reproductive factors, 28.5% had divergence > 50%, with ADT being the most disputed result (index S divergence =  − 0.02)  and even each additional birth may impair cognition. Compared to nulliparous women, parous women have approximately 22% lower estrogen levels and shorter menstrual cycle lengths , reflectThird, bilateral oophorectomy can cause a sudden drop in endogenous estrogen, which we found to be associated with an increased risk of dementia or cognitive decline . This alFourth, one study found that increased serum-free estradiol was associated with reduced risk of cognitive decline, while higher SHBG (which binds and decreases free estradiol) increased risk. This supports the findings above. However, we found higher total estradiol was associated with an increased risk of dementia or cognitive decline, aligning with one study concluding higher total estradiol independently predicts incident dementia . FurtherEstrogen plays an important role in the nervous system and benefits cognition. It protects the brain from cognitive decline through several mechanisms, including promoting neurogenesis and reducing β-amyloid (Aβ) and hyperphosphorylated tau, thereby slowing cognitive deterioration . AdditioSimilar to the influence of estrogen on female cognition, androgens appear to play a comparable role in males. Our findings suggest ADT, which suppresses androgen levels to treat prostate cancer, may increase the risk of dementia or cognitive decline. These findings are consistent with previous study . We alsoMoreover, we also found ED associated with an increased risk of dementia versus healthy males, which was coordinated with another cross-sectional study . ED is cOur study has several notable strengths compared to previous studies. First, the key strength of our work is the intensive literature search, screening, and extraction. This study is the first systematic review and meta-analysis focusing on the associations between sex-specific reproductive risk factors and dementia or cognitive decline. Second, risk factors were carefully characterized to unify results across diverse studies with precision. Third, the index S divergence concept was introduced to assess heterogeneity more credibly. Fourth, dose–response relationships were explored for multiple factors. Finally, a multifaceted approach rated the strength of the evidence.This study has some limitations to note. First, while a full range of sex-specific reproductive factors was identified, the number and heterogeneity of studies varied across risk factors. Second, dementia subtypes could not be thoroughly examined due to insufficient studies. Third, included studies encompassed retrospective and case–control designs in addition to prospective cohorts. Further large-scale longitudinal studies are needed to provide more definitive evidence.In summary, this systematic review and meta-analysis comprehensively examined associations between sex-specific reproductive factors and dementia or cognitive decline. The findings support hormone-related mechanisms underlying links between reproductive factors and cognition. Further high-quality research is needed to elucidate the role of individual risk factors and enable precise, personalized approaches to dementia prevention.Additional file 1: Appendix A. Newcastle–Ottawa quality assessment scale-cohort studies. Appendix B. Newcastle–Ottawa quality assessment scale-case control studies. Appendix C. Quality assessment according to the Newcastle–Ottawa Scale of cohort studies and case–control studies. Appendix D. Grading approaches used to assess the credibility of meta-analysis. Appendix E. Characteristics of included studies. Appendix F. Measurement of the outcomes on included studies. Appendix G. Characteristics of studies with cognitive decline, dementia, and AD. Appendix H. Results of dose–response analysis between certain factors and relative risks of dementia or cognitive decline. Appendix I. Results of subgroup analysis on ADT. Appendix J. Detailed GRADE score on credibility of the meta-analysis on dementia or cognitive decline. Appendix K. Results of systemic review. Appendix L. Results of index S divergence.


Cervical cancer (CC) is one of the most common gynecologic tumors among women around the world. Although the etiological role of human papillomavirus (HPV) in CC is well established, other factors in CC carcinogenesis remains unclear. Here, we performed a systematic review and meta-analysis to explore the association between infections of human herpesvirus (HHVs) and CC risk.Embase and PubMed databases were utilized to search the relevant studies. The revised JBI Critical Appraisal Tool was used to assess the quality of the included studies. Prevalence and odds ratios (ORs) with 95% confidence intervals (CI) were calculated to evaluate the association between viral infection and CC or precancerous cervical lesions (PCL).Totally 67 eligible studies involving 7 different HHVs were included in meta-analysis. We found an increased risk of CC or PCL that was associated with the overall infection of HHVs . Subgroup analysis showed a trend towards positive correlations between herpes simplex virus type 2 (HSV-2) infection and CC  or PCL , and the same is true between Epstein-Barr virus (EBV) infection and CC  or PCL . However, for HSV-1 and cytomegalovirus (HCMV), there was no association between viral infection and CC or PCL. By contrast, the roles of HHV-6, HHV-7, and Kaposi sarcoma–associated herpesvirus (KSHV) in cervical lesions were unclear due to the limited number of studies.This study provided evidence that HHVs infection as a whole increase the risk of CC incidence. In addition, some types of HHVs such as EBV and HSV-2 may serve as potential targets in the development of new interventions or therapeutic strategies for cervical lesions.The online version contains supplementary material available at 10.1186/s12985-023-02234-5. Cervical cancer (CC) is one of the most common gynecologic tumors among women around the world. Despite CC could have been prevented through HPV vaccination , screeniHuman herpesviruses (HHVs) are a family of DNA viruses including herpes simplex virus type 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (HCMV), human herpesvirus 6 and 7 (HHV-6 and HHV-7), and Kaposi sarcoma–associated herpesvirus (KSHV). Like HPV, HHVs causatively linked to a spectrum of human sexually transmitted diseases. Infections of HHVs are usually asymptomatic but more likely to establish a lifelong persistent infection . Except Science [HSV-1 and HSV-2 are historically associated with oral and genital herpes, respectively, however, HSV-1 infection in genital tract continues to increase with the changes in sexual practices in recent years . In 1968Science . Later oScience –18, and Science , 18. HowScience , 21. Of Science ; on one Science ; on the Science . In addiScience .Despite the correlations described above, the roles of HHVs in HPV-related CC remains incompletely understood. In the current study, we conducted a systematic review and meta-analysis to elucidate the potential roles of HHVs as a whole in the development of CC. The association between CC and the individual herpesvirus, i.e., HSV-1, HSV-2, HCMV, and EBV, was also investigated. Additionally, the effects of the possible influencing factors on the primary outcomes including virus detection methods, specimen type, stage of the disease, and different regions divided by the human development index (HDI)  were incThis study was registered in the International Prospective Register of Systmactic Reviews database (CRD42022314073) and followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guideline.We searched Embase and PubMed using Medical Subject Headings (MeSH) terms and “search terms” (as listed in the Supplementary Methods). The most recent search was done on September 16, 2023. We applied no date or language restrictions. The reference list of identified papers was manually checked for additional relevant articles.Studies meeting the following criteria were included. First, the participants were women with cervical lesions  and women with normal cervix. Meanwhile, cervical lesions include CC and/or precancerous cervical lesions (PCL). Second, the detections of HHVs antigens or antibodies were performed in all participants. Third, studies reported prevalence of HHVs infections or addressed the adjusted odds ratio (OR) for the association between cervical lesions and HHVs.The exclusion criteria were as follows: (1) studies that included participants with CC or PCL combined with other genital malignancies; (2) methods for viral detections without detailed descriptions, such as “manufacturer information”, “detection of targets”, or “performed as the manufacturer’s guidelines”; (3) detection of viral infection using lymphocytes immune responses to viral antigens; (4) studies that lacked a control group; (5) studies that were published as abstracts, letters, case reports, or reviews; (6) studies that were repeated research results.A preconceived and standardized form was used for data collection. Extracted information included: (1) authors and year of publication; (2) countries where the research was conducted; (3) population investigated ; (4) specimen type; (5) method for viral detection; (6) relevant findings: number of individuals with cervical lesions and /or herpesviruses infections; (7) the adjusted OR values and their corresponding 95% confidence interval (CI), if applicable. Two authors (Yuan Xia and Yangxuan Lin) independently conducted study selection and data extraction, and all extracted data were cross checked by the third and fourth author (Shunli Cai and Han Zhang). Disagreements were resolved through consensus.We assessed study quality using the revised JBI Critical Appraisal Tools of 8 items (Supplementary Methods). Studies with at least seven “yes” scores were considered to be of high methodology quality, those with between four and six “yes” scores to be of moderate quality and those with less than four “yes” scores to be of low methodological quality. Three authors  performed this evaluation independently and disagreement was resolved through consensus and discussion.We analyzed the results by the pooled prevalence and odds ratio (OR). In the primary analysis, we first studied the overall association between HHVs and CC or PCL. Then, we studied individual HHV in cervical lesions of the pooled prevalence and OR value. For 9 studies that related to HSV-2 and reported adjusted effect estimates, we also conducted meta-analysis to pool the adjusted estimates.Subsequently, univariable and multivariable random effects meta-regression analyses were performed to investigate factors associated with OR values, as well as to explain interstudy heterogeneity. According to the results of meta-analysis and mete regression, we further performed subgroup analysis for HSV-2 and EBV by different stages of disease , viral detection methods, and different HDI regions. In addition, we also assessed the OR value of EBV in specimen types.The GRADE  tool was used to assess the quality of evidence of the primary outcome . The eviAll statistical analyses were conducted using R statistical software version 4.2.0. Random effects model was used to calculate the pooled results and 95% CI. Heterogeneity was assessed using the I² statistic. Forest plots were generated to visualize the study-specific effect sizes along with 95% CI. We assessed publication bias using Peters test. All p values were two-sided. A p value of less than 0.05 was considered to be significant.Totally 2233 publications were yielded after removal of duplicates, and 353 articles were left for full-text reading after excluding 1880 irrelevant records based on the screening of title and abstract. After full-text screening, 67 eligible publications –84 were In all selected studies, the overall pooled prevalence of HHV among women with CC was 56% (95% CI 48–63%), whereas a significantly lower pooled proportion of 34% (95% CI 27–42%) was indicated in individuals with normal cervix  Tables . SimilarSeven different herpesviruses including HSV-1, HSV-2, HCMV, EBV, HHV-6, HHV-7, and KSHV were included in this review. The numbers of studies and individuals used to evaluate the association between CC or PCL were summarized in Table For HSV-1 and HCMV, there was no association between viral infection and CC or PCL Tables -3. By coIn addition, a small number of studies elucidate the presence of HHV-6, HHV-7 and KSHV in cervical samples. One study  from ItaThe results of meta-regression are shown in Table According to the different stages of disease, results of subgroup analysis showed that HSV-2 was identified as a risk factor for CC  and CIN2/3  except for CIN1  Tables A. MoreovFor EBV, regardless of the different stages of disease progression, subgroup analysis revealed an association of EBV infection and cervical lesions Tables A. The poWe include five outcomes in the GRADE assessment: the associations between HHVs, HSV-1, HSV-2, HCMV or EBV infection and CC or PCL. We assessed the quality of evidence from ‘very low’ to ‘moderate’ for theses outcomes Table .By using the Peters test, we did not find publication bias in HSV-1 (P = 0.7324), HCMV (P = 0.5436) and EBV (P = 0.7702), except for HSV-2 (P = 0.0036).CC is the frequently occurring cancer of the female genital tract, and HPV infection is an established cause of CC. Other than HPV, the association between other viruses such as HHV and the risk of CC remains unclear. Therefore, it is of particularly necessary to perform this meta-analysis and systematic review. Based on our analyses, we found that the pooled prevalence of HHVs among CC or PCL patients are significantly higher than normal controls, suggesting that HHVs infections are very likely to increase the risk of cervical lesions. We also conducted four meta-analyses to explore the roles of HSV-1, HSV-2, HCMV, and EBV in cervical lesions, respectively. The results showed a trend towards a positive correlation between HSV-2 or EBV infections and cervical lesions, but there is no association between HSV-1 or HCMV and cervical lesions.As one of the most common pathogens of sexually transmitted infection, HSV-2 was shown to be a risk factor for CC  and PCL  in the present study. Actually, the association between HSV-2 and CC has been debated for a long time. One meta-analysis  of longiMoreover, we provided strong evidence that the incidence of CC is increased approximately 5-fold upon exposure to EBV, and the incidence of PCL is also increased upon EBV infection, in line with a previous meta-analysis  that shoAnother interesting finding of our meta-analysis is that the risk of cervical lesions with HSV-2 or EBV infections negatively correlated to HDI distribution Fig. C. For inLastly, there are several limitations of this study. First, HPV infection is the main cause of CC, but the most studies in our analysis did not provide the data of HHVs and HPV co-infection. Thus, we failed to take the HPV infection into account in the subgroup analysis. Second, although we performed analyses in terms of different means of detection among studies, more detailed factors were not included in our analysis. For example, immunological tests for HSV-2 specific serum antibodies include ELISA, neutralization, complement fixation tests, radioimmunoassay, etc. In addition, different type of antibodies (IgA or IgG) with different cut-off values were applied. Thus, we cannot exclude the impacts of the above factors on the results.Collectively, our results revealed the effects of HHVs infections on CC or PCL. We found a robust positive correlation between EBV infection and CC risk. Although the individual HHV-6, HHV-7, or KSHV was not independently analyzed, their potential roles in CC require further investigations. Importantly, our findings suggest HHVs  as potential targets in the development of new interventions or therapeutic strategies, including but not limited to vaccines and microbicides, for cervical lesions.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3


The occurrence of orofacial Clefts (OFCs) is a congenital disease caused by many factors. According to recent studies, air pollution has a strong correlation with the occurrence of OFCs. However, there are still some controversies about the current research results, and there is no relevant research to review the latest results in recent years.In this paper, the authors conducted a systematic review and meta-analysis to explore the correlation between ambient air pollution and the occurrence of neonatal OFCs deformity.We searched Pubmed, Web of science, and Embase databases from the establishment of the database to May 2023. We included observational studies on the relationship between prenatal exposure to fine particulate matter 2.5 (PM2.5), fine particulate matter 10 (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO) and the risk of cleft lip (CL), cleft palate (CP), cleft lip with or without palate (CL/P). the Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate the quality of the literature. Funnel plot and Egger’s regression were used to verify the publication bias. Random effect model or fixed effect model was used to estimate the combined relative risk (RR) and 95% confidence interval (95%CI).2.5 was positively correlated with CL and CP, with a combined RR and 95%CI of 1.287 and 1.267 . Two studies reported a positive correlation between O3 and CL, with a combined RR and 95%CI of 1.132. Two studies reported a positive correlation between PM10 and CL, with a combined RR and 95%CI of 1.108 . No association was found between SO2, CO, NO2 exposure during pregnancy and the risk of OFCs.A total of eleven studies were included in this study, including four cohort studies and seven case-control studies, including 22,453 cases of OFCs. Ten studies had low risk of bias and only one study had high risk of bias. Three studies reported that PM10, PM2.5, O3 and the risk of OFCs in the second month of pregnancy. Exposure assessment, research methods and mechanisms need to be further explored.The results of this study showed that there was a significant statistical correlation between exposure to PMThe online version contains supplementary material available at 10.1186/s12884-023-06104-4. Birth defects, also known as congenital malformations or congenital diseases, are due to external environmental factors, genetic factors or both leading to structural, functional and metabolic abnormalities in the process of growth and differentiation . OFCs isThe incidence of OFCs is very different in countries around the world. From 2006 to 2018, a cross-sectional study of 5.74 million live births in South Korea found that the incidence of OFCs was 19.6/10,000 . From 203 exposure dose, the risk of aortic valve defect, pulmonary valve malformation and conotruncal defect increased in a dose-response relationship [Children with OFCs will have many complications due to oral structure problems, such as difficulty in breastfeeding, increased incidence of anemia, and language development disorders , 8. Comptionship .3 increase in PM2.5 concentration in the first month of pregnancy, the OR and 95%CI of birth defects were 1.09  [2.5, PM10, CO and OFCs, and conducted systematic review and meta-analysis to explore the possible correlation between common environmental air pollution and the occurrence of neonatal OFCs.A retrospective control study in Ohio, USA, showed that for every 10 µg/m01,1.18) . Studies01,1.18) , 13. In According to the Preferred Reporting Items for Systematic review and Meta-analysis (PRISMA) , PubMed,10, PM2.5, SO2 and other common air pollutants during pregnancy; [Studies were selected according to the following criteria:  The studegnancy; . The stuegnancy; . All theTwo authors extracted the following information from the retrieved literature: first author, study design method, publication year, study location, study duration, sample size, exposure time, exposure method, related covariates, OR, RR and 95%CI. The Newcastle-Ottawa quality assessment scale (NOS) was used by two authors to independently evaluate the quality of the literature, with a total score of 9 points. There were three main evaluation criteria: selection of subjects, comparability between groups, and measurement of exposure factors . If at lP < 0.1 indicated that there was publication bias. Secondly, when extracting the RR value, we chose the RR value in the single pollutant model, because not all studies have adjusted other pollutants as covariates, and there is a certain collinearity between multiple pollutants [I2. When P > 0.1 and I2 ≤ 40, the fixed effect model was used to evaluate the RR value. Otherwise, we use the random effects model [I2 > 40) and no publication bias for sensitivity analysis.First, we used the funnel plot and Egger’s test to verify the publication bias, and llutants . Heterogts model . FinallyP < 0.05 indicated that the difference was statistically significant.In addition, the literature we included has the problem of different exposure time. Excluding the potential impact of exposure time, we chose the most critical period of facial partialization and development. The 5–10 weeks of gestation and the second month of gestation mentioned in the most literature are the most critical period for the differentiation and development of OFCs. We use these periods as an exposure period , 21. AllBy searching the database, we retrieved 353 articles, deleted 95 duplicate articles, read the titles and abstracts of the remaining 258 articles, and deleted 194 articles according to the criteria set above. The remaining 64 articles were further evaluated. After full-text reading, 53 articles that did not meet the requirements were excluded, including 22 articles on animal experiments, 28 articles on reviews, conferences, and case reports, and 3 articles on lack of data evaluation. Finally, 11 articles were included in the study , 22–31. PM2.5 was positively correlated with CL and CP, with RR and 95%CI were 1.287 and 1.267 . O3 was positively correlated with CL, RR and 95%CI were 1.132. There was no significant correlation between residual air pollutants and CL, CP, CL/P ) [I2 = 44.3%), (Table P = 0.652). In the study of the association between PM10 and the risk of CL/P, no significant association between PM10 and the risk of CL/P was found.Among the four studies reporting the association between PM0,1.23)) . The poo2.5 exposure during pregnancy and the risk of OFCs. Two of the five articles studied the relationship between PM2.5 exposure during pregnancy and the incidence of CL. Five studies studied the relationship between PM2.5 exposure during pregnancy and CP, CL/P.Five studies reported the correlation between PM2.5 exposure during pregnancy and the risk of CL, Zhao J et al. observed a significant positive correlation between PM2.5 exposure during pregnancy and the risk of CL, with RR = 1.29, 95%CI= , and the combined RR = 1.287, 95%CI=  [2.5 during pregnancy and the risk of CP, Zhao et al., Zhu et al., Zhou et al. observed a significant positive correlation between PM2.5 and the risk of CP [3 increase in PM2.5 exposure in the second month of pregnancy, the risk increased by 26.7%, 95%CI=  and the heterogeneity was high(I2 = 72.4%), Egger ‘s test did not detect publication bias (P = 0.704) , heterogeneity decreased, and no publication bias was detected. In the association study between PM2.5 and the risk of CL/P, no significant association was found between PM2.5 and the occurrence of CL/P.In the literature on the association between PM4,1.411) . Similarsk of CP , 27, 28.2 during pregnancy and the risk of OFCs. Four of the eight articles studied the relationship between exposure to SO2 during pregnancy and the incidence of CL. Six of the eight articles studied the relationship between SO2 and CP, CL/P.Eight studies reported the correlation between exposure to SO2 exposure during pregnancy and the risk of CL/P, Jiang W et al. observed a significant positive correlation between SO2 exposure during pregnancy and the risk of CL/P, with RR = 1.350, 95%CI=, and the remaining correlation was found in the remaining five articles [2 and the risk of CL/P, no significant association was found between SO2 and the occurrence of CL/P  and , respectively. The combined RR of the three studies was 1.132, 95%CI= , and the heterogeneity was moderate(I2 = 67.9%), Egger ‘s test (P = 0.793) did not detect publication bias , and no significant correlation was found in the remaining articles [In the literature on the association between CO exposure during pregnancy and the risk of CL, Zhao J et al. observed a significant positive correlation between CO exposure during pregnancy and the risk of CL, with RR = 1.240, 95%CI=  [articles . The com2 exposure during pregnancy and the risk of OFCs. Two of the seven articles studied the relationship between NO2 exposure during pregnancy and the incidence of CL. Six and five studies studied the relationship with CP, CL/P, respectively.Seven studies reported the correlation between NO2 exposure during pregnancy and the risk of CP, three articles reported a significant positive association, and the other reported an insignificant association. The combined RR = 1.201, 95%CI=  was not statistically significant. Jiang W et al. observed a significant positive correlation between NO2 exposure during pregnancy and the risk of CL/P, with RR = 1.48, 95%CI= [2 and the risk of CL.In the literature on the association between NO0,1.750) . The com2.5, PM10, O3 in the second month of pregnancy and the risk of CL/P. Among them, PM10 was associated with an increased risk of CL/P. This is consistent with the results of Rao A et al. ‘s previous meta-analysis that O3 increases the risk of OFCs [Our results showed that there was a significant positive correlation between exposure to PM of OFCs .In 2016, the results of the global death factor survey showed that air pollutants were the sixth leading cause of death, and 7.5% of global deaths were attributed to ambient air pollution. The countries with higher deaths included China and India . PM can 3) is a photochemical environmental pollutant affected by climate. It is easy to form when the temperature fluctuates greatly [2.5, PM10, O3 and the risk of OFCs during the critical period of pregnancy.Ozone (O greatly . Studies greatly –42. ThisThere are many reasons for the occurrence of OFCs, including genetics, environment and their combined effects. The combination of genetics and environment is called “epigenetics” . RelatedWhether the address change during pregnancy will affect the accuracy of the results, many scientists have studied it. Two cohort studies in the United States have shown that the address registered at birth can well replace the residential address during pregnancy. The exposure concentration of air pollutants will not be significantly different due to the difference between the registration address at birth and the residence address during pregnancy , 49. ButOur study has several advantages. First, we conducted a systematic review and meta-analysis. Compared with individual studies, the evidence level of systematic reviews and meta-analysis is relatively high. Second, we divided OFCs into CL, CP, CL/P and analyzed them with air pollutants respectively. Finally, among the 11 articles we included, 10 studies were low risk of bias and only 1 study was high risk of bias. After adjusting for them, we found that the heterogeneity was lower than before.There are some limitations in our research. First of all, we study the high heterogeneity between some literatures, which is related to the limited number of literatures, different geographical locations, different exposure methods, and large research time span. Secondly, there may be differences in the diagnosis of diseases in different studies. There are no trained nurses to inquire about prenatal exposure factors, and professional doctors use relevant scales to classify and evaluate diseases , 53. Thi2.5, PM10, O3 and OFCs, and there is no statistical significance between residual air pollutants and OFCs. However, this association may be affected by the study area and research-related exposure methods, which are important factors causing heterogeneity, and further large-scale cohort studies are needed to verify this association. It is recommended that future public health work should minimize exposure of pregnant women to related air pollutants.In conclusion, the results of this study show that there is a positive correlation between PMBelow is the link to the electronic supplementary material.Supplementary Material 1


The benefits of vitamin E (VE) for multiple health outcomes have been well evaluated in many recent studies.The purpose of this umbrella review was to conduct a systematic evaluation of the possible associations between VE intake and various health outcomes.We systematically searched various databases, such as PubMed, Embase, and the Web of Science, to identify related meta-analyses of observational studies and randomized trials. We estimated the effect size of each association by using the random or fixed effects models and the 95% confidence intervals. We used standard approaches to evaluate the quality of the articles (AMSTAR) and classified the evidence into different levels of quality (GRADE).A total of 1,974 review articles were searched, and 27 articles with 28 health outcomes were yielded according to our exclusion criteria. The intake of VE was inversely associated with the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, cervical neoplasms, cardiovascular disease, Parkinson's disease, depression, age-related cataracts, metabolic syndrome, and fracture. Overall, most of the quality of the evidence was low or very low. Three outcomes  were identified as having a “moderate” level of quality. The AMSTAR scores for all health outcomes ranged from 5 to 10.Our study revealed that VE intake is beneficially related to multiple health outcomes. However, future studies on recommended doses and recommended populations of VE are also needed.http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022339571. Vitamin E (VE), a fat-soluble antioxidant, is composed of tocopherol and tocotrienol α, β, δ, γ subtypes . PreviouWe systematically searched, organized, and evaluated existing evidence from numerous systematic reviews and meta-analyses on multiple health outcomes associated with VE intake . We inclWe searched systematic reviews and meta-analyses of observational studies and randomized trials from PubMed, Embase, and Web of Science databases from inception to March 2022. The search strategy we used was as follows: ((((((vitamin E[Title/Abstract]) OR (Tocopherol[Title/Abstract])) OR ) OR (beta-Tocopherol[Title/Abstract])) OR (gamma-Tocopherol[Title/Abstract])) OR (Tocotrienol[Title/Abstract])) AND (((systematic review[Title/Abstract]) OR ) OR (systematic overview[Title/Abstract])). Meta-analyses and systematic reviews with meta-analyses of observational (cohort and case-control) and interventional  studies that evaluated VE intake and health outcomes in humans were included regardless of the race, gender, country, or region of participants. If two or more health outcomes existed in a single article, data for each outcome were extracted separately. If two or more meta-analyses revealed the same association, we chose the largest one to avoid duplicate assessments. Furthermore, articles reporting VE intake with therapeutic utilities were excluded only if nontherapeutic intake was also reported. Articles written in languages other than English and not involving humans were also excluded.P-value and publication bias by Egger's test. Any difference was resolved by the third investigator.The following information was extracted independently by two investigators: (1) name of the first author, (2) cancer outcomes and non-cancer outcomes, (3) year of publication, (4) category of exposure (dietary and supplement VE), (5) the number of included studies, (6) the number of events and total participants in each study, (7) study design , (8) type of comparisons (highest v lowest dose reduction of any dietary and supplement VE), (9) the estimated summary effect  and corresponding 95% confidence intervals (CIs), (10) type of effect model (fixed or random model), and (11) The AMSTAR items  were used to evaluate the quality of the included articles . In our 2 statistics and Cochran's Q test were used to estimate the heterogeneity between studies  and 18% , respectively . The higHigher dietary VE was also related to lower esophageal cancer risk , especially for esophageal squamous cell carcinoma (ESCC) . A slightly linear dose–response relationship was detected between a 3 mg/day increment of dietary VE and the risk of esophageal cancer  . FurtherAn analysis of the highest vs. lowest VE intake revealed that the intake of VE played a protective role in bladder cancer progression . Moreover, a potential linear association was also detected between VE intake and bladder cancer risk . A signiNo significant association was observed between VE consumption and the risks of glioma , thyroidA higher intake of VE supplements was associated with a significant reduction in the risk of cardiovascular disease  . CompareDietary VE intake was not associated with the risk of all-cause mortality while comparing the highest group with the lowest group , even in the further subgroup analysis . Higher P < 0.10. One meta-analysis did not report the I2 statistic. A very high level of heterogeneity (I2>70%) was observed in three meta-analyses, and eight meta-analyses reported moderate-to-high levels of heterogeneity (I2 50%−70%). Sixteen meta-analyses reported low levels of heterogeneity (I2 < 50%).Among the 28 non-overlapping meta-analyses, 13 meta-analyses reported a Q test The quality of the evidence by GRADE was low (47.1%) or very low (44.1%) . Three oThe associations between VE and multiple health outcomes have been reported by a large number of studies and integrated into many meta-analyses. Overall, 27 meta-analyses involving 28 unique outcomes of the correlation between VE intake and multiple health outcomes were included in this umbrella review. The results indicated that the intake of VE was related to a lower risk of subsequent cancer outcomes  and non-cancer outcomes . Given that most of the evidence was from observational studies, compelling evidence for VE and multiple health outcomes does not seem to exist.There is some discrepancy in subgroup analyses based on the study type of several outcomes . Some of the potential reasons are mentioned below. First, the development of some diseases, such as age-related cataracts, is a long process for healthy individuals, and it may take a decade to manifest the protective effect of VE intake . The lenThe results of this study suggested that higher VE intake is negatively associated with the risk of cancer outcomes  and non-cancer outcomes . The protective effect of higher VE intake on these outcomes may be explained by the oxidative properties of VE. A possible mechanism might be that, as an antioxidant, VE can prevent DNA from being damaged by scavenging lipid hydrogen peroxide radicals , 46, 47.For the safety of VE supplements, healthy individuals should not use more than 1,000 mg of VE per day. A daily intake of VE of up to 800 IU appears safe and beneficial . When thNotably, this is the first comprehensive review of available evidence on VE intake and multiple health outcomes. Standard tools were used to assess the quality of the methods in the included literature (AMSTAR) and the strength of the evidence (GRADE). To avoid possible selection bias, the study was conducted by two researchers. However, our study has several limitations. First, most of the meta-analyses included were based on retrospective studies, and the overall GRADE quality was low. Second, considering that the most common source of VE is dietary intake, it is difficult to obtain VE as the only antioxidant or key nutrient. Third, the results of the study have a large deviation, and there are more confounding factors. Micronutrient combinations have also been frequently used in studies where the interaction between multivitamins is not further elucidated, and not all meta-analyses have a subgroup analysis of these factors. Finally, the definitions of maximum and minimum intakes were not clearly and uniformly quantified, making it difficult to determine the magnitude of the correlation and the impact of standardized baselines, and dose–response analyses were performed in less than half of the included meta-analyses.In conclusion, we concluded that the intake of VE was related to a lower risk of multiple types of cancer and other diseases of diverse systems. Thus, VE intake at a safe dose is recommended to gain protect against certain diseases. However, further high-quality studies on recommended doses and recommended populations of VE are also needed. For specific populations  who are taking medication, additional vitamin E supplementation needs to be evaluated by a specialist before use.The original contributions presented in the study are included in the article/JA and TZ conceived the project and drafted the manuscript. TZ, XY, JL, and XZ performed the screening and extraction. DL and HX performed the statistical analysis. JA revised the manuscript. All authors contributed to the article and approved the submitted version.


PARP inhibitors (PARPi) have a well-established role in platinum-sensitive ovarian cancer (PSOC), in BRCA mutant (BRCAm), and homologous recombination deficiency (HRD) population. However, their role in wild type and homologous recombination proficient population is still not clear.A meta-analysis of hazard ratios (HR) of randomized control trials (RCTs) was conducted to study the role of PARPi. The published RCTs comparing the efficacy of PARP inhibitors alone or in combination with chemotherapy and/or target therapies versus placebo/chemotherapy alone/target therapy alone in primary or recurrent ovarian cancer settings were selected. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints.A total of 14 primary studies and 5 updated studies are considered, consisting of 5363 patients. Overall, HR for PFS was 0.50 [95% CI 0.40–0.62]. HR of PFS was 0.94 [95% CI 0.76–1.15] in the PROC group, 0.41 [95% CI 0.29–0.60] was in HRD with BRCA unknown (BRCAuk), 0.38 [95% CI 0.26–0.57] in HRD with BRCAm, and 0.52 [95% CI 0.38–0.71] in HRD with BRCAwt. In the HRP group, overall HR for PFS was 0.67 [95% CI 0.56–0.80], 0.61 [95% CI 0.38–0.99] in HRD unknown with BRCA wt, and 0.40 [95% CI 0.29–0.55] in BRCAm HR for PFS. Overall, HR for OS was 0.86 [95% CI 0.73–1.031].The results suggest that PARPi have a meaningful clinical benefit in PSOC, HRD, BRACm, and also in HRP and PROC; however, the evidence is not sufficient to recommend their routine use and further studies are needed to expand their role in the HRP and PROC groups.The online version contains supplementary material available at 10.1186/s12957-023-03027-4. Epithelial cancer of the ovary ranks fifth in cancer death among women and is the seventh most frequent cancer diagnosed worldwide. According to the American Cancer Society, about 19,880 women will receive a new diagnosis of ovarian cancer and about 12,810 women will die from ovarian cancer in the USA in 2022 . If the There are numbers of randomized controlled trial and meta-analysis which had shown the importance of PARP inhibitors in advanced platinum-sensitive ovarian cancer in BRCA-mutant cohort and HRD population in first-line maintenance settings, in recurrent maintenance settings, and in treatment of refractory ovarian cancer after failure of 2nd or 3rd lines of platinum-based chemotherapy –8. The qWe conducted this meta-analysis of hazard ratios of randomized control trials to study the role of PARP inhibitors in epithelial cancer of the ovary in platinum-resistant and HRP patients with ovarian cancer.Meta-analysis of phase 2 or 3 randomized controlled trials was performed, and the results are presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Articles published between 1987 and June 2022 were considered.A systematic literature search of PubMed, Embase, and Cochrane library was carried out to identify all published phase 2/3, RCT using the following search strings:  or "poly adp ribose polymerase inhibitors"[All Fields] or ("parp"[All Fields] and "inhibitors"[All Fields]) or "parp inhibitors"[All Fields]) and ("ovarian neoplasms"[MeSH Terms] or ("ovarian"[All Fields] and "neoplasms"[All Fields]) or "ovarian neoplasms"[All Fields] or ("ovarian"[All Fields] and "cancer"[All Fields]) OR "ovarian cancer"[All Fields])), and . The last search was performed in June 2022.Out of 66 studies retrieved, 14 studies were considered for quantitative analysis after the elimination of duplicates and exclusion, and 5 additional studies obtained through hand search were also considered which were updated analysis from the previous studies , 9–25. MAll randomized trials that compared the efficacy of PARP inhibitors alone or in combination with chemotherapy and/or target therapies versus placebo/chemotherapy alone/target therapy alone in primary or recurrent ovarian cancer setting are the inclusion criteria.All non-randomized studies, retrospective studies, review articles, cohort, observational studies, non-published literature, and abstract presented as part of meetings are the xclusion criteria.Two authors (RP and TK) independently scanned all the abstracts and shortlisted the studies meeting the above inclusion criteria, and the data was entered in predefined proforma on an Excel sheet, the following values were recorded: first author information, publication year, clinical trial acronym, country, base line characteristics, study design, inclusion and exclusion criteria, sample size, HRD and BRCA-mutated status, progression-free survival, overall survival, time to first subsequent therapy or death, time to second subsequent therapy, and adverse event.I2. Random effect models were used when heterogeneity was high. Forest and funnel plot were prepared. Publication bias was assessed.Any discrepancies were settled after discussion with the third author (MP). Quality assessment was performed using Jadad’s score Table  26], an, an26], As variables evaluated in different studies were different, only the variables common between various studies were considered for the final analysis.For the final analysis, two primary endpoints were considered, progression-free survival (PFS) and overall survival (OS). The secondary endpoints were PFS 2, TFST, and TSST. The OS was defined as the time from the date of recruitment to death, and PFS was defined as the time from recruitment to the progression of the disease as described in the studies. PFS 2 was the time from randomization to the second progression of the disease, TFST from randomization to the first subsequent therapy or death, and TSST the time to the second subsequent therapy or death.As the data for individual patients were not available, meta-analysis of hazard ratio was carried out as described by Tierney et al. . The pacThe manuscript is presented following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , and theA total of 14 primary studies were considered for final quantitative analysis Fig. . In the Subgroup meta-analysis of data in HRD cohort and BRCA-mutant cohort was carried out by making a total of 6 subgroups in platinum-sensitive ovarian cancer . BRCA mutation group includes both BRCA 1 and BRCA 2 mutation detection on germline and/or somatic testing. HRD group includes high LOH group. On analysis, HR of PFS in HRD with BRCA unknown status was found to be 0.37 [95% CI 0.27–0.49]  HR was 0.85 [95% CI 0.74–0.99] , HR was 0.65 [95% CI 0.48–0.88] . In HRD cohort and in BRCA mutation cohort, there is a significant improvement in PFS as shown by many randomised control trials , 38, andOn subgroup analysis, in non-BRCA-related HRD population, an improvement in PFS like that in PRIMA trial was seen . ClinicaIn HRP group, where DNA repair mechanisms are intact, PARP inhibitors have a role in prolonging progression-free survival as seen in various studies. In HR-proficient pathway, the mechanism of synthetic lethality which is described in BRCA mutated and BRCAness population does not happen because of intact DNA repair pathway ; hence, P = 0.05). In platinum-sensitive ovarian cancer in primary settings, González-Martín et al. [Overall survival data is mature for very few studies; in SOLO 2  trial inn et al.  showed pn et al. , the proIn the SOLO series, it was seen that second progression was subsequently prolonged after Olaparib either in the first-line maintenance, recurrent maintenance, or in treatment with Olaparib in platinum refractory cancer, suggesting that Olaparib did not disable another chance for the patient to benefit from subsequent therapy , 19, 21,TFST and TSST are clinically meaningful endpoints in assessment of disease recurrence and restarting of the first and second subsequent therapy, suggesting sustained PFS benefit and thus is a signature for overall survival benefit . In thisThe strength of this meta-analysis is that it is the first meta-analysis of its kind providing pooled survival data analysis for HRP population and BRCA wildtype population. We have also analyzed the survival data for use of PARP inhibitors in platinum-resistant ovarian cancer which was also not mentioned in previous published meta-analysis. Analysis of overall survival data was also unique for our study as it was not provided by any previous clinical trials. We have also analyzed the PFS data as given by updated randomized control studies.The limitations of our study are that the analysis was done on study level data rather than individual patient data. We have not provided separate data for PARP inhibitors in the first line and recurrent settings, but this type of analysis is already done in the previously published meta-analysis . The rolThe results of this meta-analysis suggest that PARP inhibitors have a role in epithelial cancers of ovary, both in the platinum-sensitive and platinum-resistant ovarian cancers in the first line as well in the recurrence. The results further suggest that in the future, PARP inhibitors can be used in epithelial ovarian cancer without HR and BRCA testing as they provide meaningful clinical benefits in terms of improved PFS in all the subgroups.Additional file 1. Supplement file 1- Cochrane risk of bias tool for the included studies.Additional file 2. Package meta R used for data analysis.Additional file 3. PRISMA checklist for reporting of meta analysis.


Existing evidence indicates that exposure to per- and polyfluoroalkyl substances (PFASs) may increase the risk of hypertension, but the findings are inconsistent. Therefore, we aimed to explore the relationship between PFASs and hypertension through this systematic review and meta-analysis.We searched PubMed, Embase, and the Web of Science databases for articles published in English that examined the relationship between PFASs and hypertension before 13 August 2022. The random effects model was used to aggregate the evaluation using Stata 15.0 for Windows. We also conducted subgroup analyses by region and hypertension definition. In addition, a sensitivity analysis was carried out to determine the robustness of the findings.The meta-analysis comprised 15 studies in total with 69,949 individuals. The risk of hypertension was substantially and positively correlated with exposure to perfluorooctane sulfonate (PFOS) , perfluorooctanoic acid (PFOA) , and perfluorohexane sulfonate (PFHxS) . However, perfluorononanoic acid (PFNA) exposure and hypertension were not significantly associated .We evaluated the link between PFASs exposure and hypertension and discovered that higher levels of PFOS, PFOA, and PFHxS were correlated with an increased risk of hypertension. However, further high-quality population-based and pathophysiological investigations are required to shed light on the possible mechanism and demonstrate causation because of the considerable variability.https://www.crd.york.ac.uk/prospero/ PROSPERO, registration number: CRD 42022358142.  Since the 1940s, per- and polyfluoroalkyl substances (PFASs) have been extensively used because of their surfactant and stability qualities in industrial processes and goods such as aerospace and military, automotive, aviation, textiles, leather, clothing, construction and household goods, electronics, fire protection, food processing, and medical supplies . PersistAccording to the data from the World Burden of Disease (GBD), the increasing incidence of hypertension has emerged as a major contributor to global mortality –17. HypeA systematic review and meta-analysis were conducted to  review thttps://www.crd.york.ac.uk/prospero/), which was conducted under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement   observational study design, such as case–control studies, cohort studies, and cross-sectional studies; (2) at least one type of PFASs exposure  is observed; (3) hypertension results; (4) a risk assessment is provided, including a 95% confidence interval (CI), ORs, RRs, or HRs. Exclusion criteria included studies that (1) are not full-text; (2) have pregnant women as participants; (3) have repetitive data; (4) take the form of laboratory research, non-human animal research, a letter, or a review; and (5) are of low quality.Lv and An separately extracted data and evaluated the quality of each research project. Disagreements were discussed and resolved amicably. We retrieved the following data from every qualifying study: first author; publication year; research design; population characteristics ; sample size; categories of PFASs; definition and diagnostic criteria of hypertension; maximum adjusted ORs, RRs, or HRs, 95% CI  correspoThe Newcastle–Ottawa Scale (NOS) was used in order to assess the level of methodological rigor present in case–control studies and cohort studies . The stuThe NTP/OHAT Risk of Bias Rating was also used to assess the quality of the included studies . Seven mThe Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guideline was used to assess the confidence in the body of evidence , which e2) , otherwise, a random effect model was employed  . Heterogemployed .To determine the cause of the variation, a subgroup analysis was performed, stratified by geographic area and hypertension threshold. To evaluate the impact of missing studies and to identify the source and size of any heterogeneity in the results, sensitivity analyses were conducted by eliminating studies one by one from the analysis. Publication bias was evaluated using funnel plots, and the predicted findings were confirmed using Egger's test . The metFollowing the search strategy, a total of 6,784 articles from these three online resources were reviewed. After removing the duplicates, we were left with 4,276 research articles. After evaluating the titles and abstracts, 34 articles were chosen for further consideration. Researchers discarded 19 articles because they did not meet the inclusion or exclusion criteria. These included one review, 10 studies without an applicable exposure or result, four studies conducted on pregnant women, and four studies that simply replicated previous findings. A total of 15 publications were included in the meta-analysis, as shown in The term “hypertension” alone has a wide range of interpretations. The majority of studies (10 of 15 included studies) use a blood pressure reading of 140/90 mm Hg as the diagnostic threshold for hypertension , 35–37, The quality of the 15 studies that were suitable for inclusion was analyzed. The results showed that 11 of the cross-sectional studies were of high- or medium-quality –36, 38, The results of the risk of bias assessment are shown in Based on cross-sectional and case–control studies, the overall strength of evidence for the association between PFASs and hypertension was “limited”, and the direction of effect was inconsistent across most studies. However, for PFASs combined with hypertension events, we rated the overall strength of evidence as “moderate”. The majority of PFASs–hypertension combinations assessed exhibited consistent statistically significant positive evidence of an association, and all studies included in the meta-analysis were “moderate.” These results provide some epidemiologic proof that PFASs may increase the risk of hypertension.To determine whether PFASs exposure was associated with hypertension, 15 studies were analyzed, as shown in I2 = 94.6%, P < 0.05), as shown in The association between PFOS exposure and hypertension was investigated in 13 studies . A combined OR estimate of 1.31  was calculated. We employed a random effects model to examine the connection between PFOS exposure and hypertension due to the significant heterogeneity of the studies , as shown in In total, 11 cross-sectional studies, one case–control study, and three cohort studies were retrieved to examine the correlation between PFOA exposure and hypertension. The overall findings revealed that being exposed to PFOA increased the risk of hypertension . A random effects model was used due to the significant heterogeneity of the included studies , as shown in No statistically significant association between PFNA exposure and hypertension was found in six cross-sectional studies, one case–control study, and two cohort studies. As a whole, we found a merged evaluation of 1.08 . In addition, a random effects model was adopted since the studies had high heterogeneity , as shown in The association between PFHxS exposure and hypertension risk was examined in seven cross-sectional investigations, one case–control study, and two cohort studies. A positive relationship  was found between PFHxS exposure and the risk of hypertension with a random effect model because of high heterogeneity  for Non-American region and 1.15  for American region. Then, the pooled estimate OR of PFNA and hypertension was 1.11  for non-America and 1.05  for America. In addition, a subgroup analysis by hypertension threshold revealed a positive association between PFOS and PFOA exposure and the development of hypertension  for 140/90 mmHg, but no statistically significant association  for non-140/90 mmHg. All results are shown in P = 0.26 for PFOA, P = 0.56 for PFNA, P = 0.67 for PFHxS). However, publication bias was present in the meta-analysis evaluating the association between PFOS and hypertension (P = 0.028). A sensitivity analysis was conducted by eliminating specific articles one by one to assess the stability of the findings and establish that any research did not influence them. The results for PFOA, PFNA, and PFHxS are consistent to some degree. The odds ratio (OR) between PFOS exposure and hypertension increased but remained positively associated , except for the research by Christensen et al.  and PFOS  exposure and the risk of hypertension. Our findings are consistent with the nine previously published studies , 35–37 tThe association between hypertension and any PFASs   was reported in a cohort-based study based on electronic health records . Higher N = 3; PFOA, N = 2; PFNA, N = 1; PFHxS, N = 2). Studies were categorized by country in order to identify regional variations in the association between PFASs exposure and hypertension. Notably, PFOA, PFNA, and PFHxS were not associated with hypertension in the United States. Regional differences in lifestyle, socioeconomic level, local diets, the local incidence of hypertension, average blood pressure, and ethnic adaptability to PFASs exposure may obscure the association between PFASs exposure and hypertension.It was shown that in the further stratified analysis, grouping according to the hypertension threshold, PFASs exposure, and hypertension were not significantly correlated with the non-140/90 group, which may be due to the lack of studies in the non-140/90 group  and found that the possible relationship could be completely recognized. However, there is a lack of research on “surrogate PFASs”, or polyfluoroalkyl compounds such as F-53B and OBS, which results in a high degree of variability or a hampered capacity to discover possible correlations. Therefore, the lack of association we observed calls for a thorough explanation and further research. At the same time, PFASs exposure occurs worldwide but differs from country to country due to the wide variety of potential sources and routes of exposure. In addition, because each study's population, models, statistical techniques, and adjustments for numerous confounding variables are unique, each study's conclusions may differ. Finally, a recent study highlighted the importance of PFASs isomers and enantiomers . Due to Our understanding of the relationship between PFASs exposure and hypertension has been strengthened by this meta-analysis, which demonstrates a positive association between PFOS, PFOA, and PFHxS exposure and hypertension but no relationship between PFNA and hypertension. In order to manage hypertension and further lower the prevalence of cardiovascular disease and stroke, people should seriously consider reducing environmental PFASs pollution and PFASs exposure. To further understand these mechanisms, further research should be encouraged.Publicly available datasets were analyzed in this study. This data can be found here: Pubmed, Embase, and Web Of Science.FX and XS: integrity of the data, the accuracy of the data analysis, and study concept and design. FX, ZA, and JL: data extraction and analysis. FX: drafting of the manuscript. ZA and JL: study supervision. HG, XL, ZA, JL, XS, HS, and YL: critical revision. All authors reviewed and revised the manuscript, approved the final version for publication, and accepted responsibility for all aspects of the manuscript.


Inflammation is a risk factor for cardiovascular disease (CVD), and particular inflammatory parameters can be used to predict the incidence of CVD. The aim of this study was to assess the association between fibrinogen (FIB), interleukin-6 (IL-6), C-reactive protein (CRP) and galectin-3  and the risk of cardiovascular disease using meta-analysis.PubMed, Embase, Scopus, and Web of Science databases were searched with the appropriate strategies to identify observational studies relevant to this meta-analysis. A random-effects model was used to combine inflammation factor-associated outcomes and cardiovascular disease outcomes, except in the case of galectin-3, where a fixed-effects model was used because of less heterogeneity. Location, age, type of cardiovascular disease, and sample size factors were used to explore heterogeneity in stratification and metaregression for subgroup analysis. A case-by-case literature exclusion approach was used for sensitivity analysis. The funnel plot and Begg's test were combined to assess publication bias.P < 0.001; HR: 1.04, 95% CI: 1.00–1.07, P < 0.05), IL-6 , CRP  and Gal-3 . Location factors help explain the source of heterogeneity, and there is publication bias in the Gal-3 related literature.Thirty-three papers out of 11,456 were screened for inclusion in the analysis. Four inflammation biomarkers were significantly associated with the development of CVD: FIB (OR: 1.21, 95% CI: 1.15–1.27, Taken together, the current research evidence suggests that high levels of fibrinogen, interleukin-6, C-reactive protein and galectin-3 are risk factors for cardiovascular disease and can be used as biomarkers to predict the development of cardiovascular disease to some extent.https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42023391844. Cardiovascular disease (CVD) is the leading cause of death and disability worldwide . PrevaleEpidemiological studies have revealed an independent positive link between elevated plasma fibrinogen (FIB) levels and CVD, as well as a positive relationship with several established CVD risk factors , 5. In ahttps://www.crd.york.ac.uk/PROSPERO) with the registration ID CRD42023391844. In databases (EMBASE) , PubMed , Web of Science (topic), and Scopus , the search strategy “((FIB) OR (fibrinogen) OR (IL-6) OR (interleukin-6) OR (CRP) OR (c reactive protein) OR  OR ) AND (incidence rate) AND (cardiovascular disease)” was used to search for all publications included up to 30 May 2023. The search does not use any filters or restrictions. References of related articles were also manually indexed to ensure maximum comprehensiveness for literature inclusion. All citations were imported into NoteExpress 3.7.0 to remove duplicates.This meta-analysis is registered on PROSPERO  and the incidence of common CVD  selected according to the following specific inclusion and exclusion criteria.The inclusion criteria were (1) observational studies ; (2) Inflammation factors investigated included one or more of FIB, IL-6, CRP, Gal-3, and an endpoint of first cardiovascular disease; and (3) study data contained hazard ratio (HR)/relative risk (RR)/odds ratio (OR) with 95% confidence intervals (CI) per standard deviation (SD) increase in log-transformed biomarker level.The exclusion criteria were (1) non-English works of literature; (2) generally nonhealthy adult population (based on history of certain diseases and current diseases or population treated with interventions such as surgery); (3) sample size <500; and (4) when multiple studies assessed identical factors and endpoints across the same group of participants, only the latest was included.The extraction of crucial data and the quality assessment of the study were performed independently by two investigators to ensure that data collection was as accurate and objective as possible. Any disagreements were resolved through further deliberation and intervention efforts involving a third investigator. The results of the maximum adjustment model were used for the selection of the ending indicator. The details and characteristics derived and recorded among all eligible full texts are listed below: (1) study location; (2) participant characteristics ; (3) study period; (4) study cohort; (5) type of cardiovascular disease; (6) OR/RR/HR with 95% CI; (7) covariates in the maximum-adjusted model. The Newcastle Ottawa Scale (NOS), developed for case‒control and cohort studies, was used to evaluate quality; the scale ranges from 0 to 9, with 7 and above indicating very good quality, 4–6 indicating fairly good quality, and 4 and below indicating poor quality , 24.I2 statistic and the Cochran Q test, where a P-value of <0.05 was considered significant for heterogeneity. Pooled results were calculated using random-effects models if I2 > 50%, which indicated a substantial degree of heterogeneity across studies, or using a fixed-effects model otherwise .FIB  could help explain heterogeneity in investigations of the biomarker FIB.We performed subgroup analysis based on predefined classification criteria, and the results are shown in P < 0.05).The pooled results of this meta-analysis showed that FIB, IL-6, CRP, and Gal-3 are risk factors for the development of CVD. A juxtaposition of the results showed that the pooled results of the four inflammatory factors were similar and that IL-6 had the best homogeneity of relevant studies. Location helps explain the heterogeneity of the included studies. Sensitivity analysis showed relatively stable combined results.A number of biomarkers have become a major focus for improving methods of scoring CVD risk. The use of these biomarkers is attractive because they integrate signals from multiple pathophysiologic pathways and have some combined predictive utility . The resA variety of factors can influence the predictive role of inflammation biomarkers of CVD development, including but not limited to those addressed in the exploration of heterogeneity above. Regarding age factors, observational studies on people aged 85 years indicate that a few of the classical risk factors, such as age, sex, systolic blood pressure, total lipoprotein cholesterol, diabetes, and smoking, become blurred or even play an inverse role in predicting cardiovascular disease under the influence of advanced age factors , 75. MarGiven modern developments, biomarkers are economical and convenient to measure, so the exploration of biomarkers has strong practical importance. As mentioned earlier, these predictive inflammation biomarkers help identify people at risk for CVD and assess the magnitude of an individual's future CVD risk. Appropriate use can be effective for CVD prevention in the general population. In populations already suffering from CVD, these factors can assist in diagnosis and predict disease prognosis. Nowadays, with the continuous development of anti-inflammatory drugs, certain factors are even indicators for the evaluation of anti-inflammatory effects and targets for treatment. For example, IL-6 has been rapidly gaining attention as a key targeted by the atherosclerosis research community . The antThis study involved pooling evidence from high-quality studies with long durations, large sample sizes, and cardiovascular disease occurrence as an endpoint; furthermore, most of the included studies adjusting for important confounders, including age, sex, BMI, smoking and alcohol consumption, and cholesterol. Multiple inflammatory factors were investigated in this study, and the use of these inflammatory markers in conjunction with each other or in combination with other risk factors may be a way forward in future CVD prediction. For example, in one of the studies, patients in the highest tertile with respect to a specific set of 3 inflammatory markers exhibited an extremely high risk of CVD . HoweverIn conclusion, FIB, IL-6, CRP, and Gal-3 are positively associated with the development of CVD in the general adult population and are risk factors for CVD. Combined consideration of the levels of these inflammatory factor can help in the prediction of future cardiovascular disease.