Incontinence-associated dermatitis (IAD) is increasingly found among critically ill patients, but the risk factors for IAD in these patients are currently unclear. The purpose of this meta-analysis was to identify the risk factors of IAD in critically ill patients.I2 test was used to estimate the heterogeneity of studies, and Egger's test was used to assess the potential publication bias.Web of Science, PubMed, EMBASE, and Cochrane Library were systemically searched until July 2022. The studies were selected based on inclusion criteria, and data were independently extracted by two researchers. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies. Odds ratios (ORs) and their associated 95% confidence intervals (CIs) were used to identify significant differences in the risk factors. The A total of 7 studies enrolling 1,238 recipients were included in the meta-analysis. Age ≥ 60 , female sex , dialysis , fever , vasoactive agent , PAT score ≥ 7 , frequency of bowel movement > 3times/d , and liquid stool  were the risk factors of IAD among critically ill patients.Many risk factors are related to IAD among critically ill patients. Nursing staff should pay more attention to evaluating the risk of IAD and enhance the care of high-risk groups. The term moisture-associated skin damage (MASD) is defined as inflammation and erosion of the skin caused by prolonged exposure to moisture and its contents, including urine, stool, perspiration, wound exudate, mucus, or saliva. MASD encompasses the four forms of moisture-associated skin damage, which include: 1) incontinence-associated dermatitis (IAD); 2) intertriginous dermatitis (ITD), also called intertrigo; 3) peristomal moisture-associated dermatitis; and 4) periwound moisture-associated dermatitis .The protocol of this systematic review (register number: CRD42022353492) was registered in PROSPERO  studies that addressed the risk factors for IAD in critically ill patients; (2) studies that were cohort studies or case-control studies; (3) studies published in English.The following were the exclusion criteria: (1) case series, duplicate reports, reviews, and conference reports; (2) missing or abnormal data; (3) low quality of literature [Newcastle-Ottawa Scale (NOS) score < 6].Two authors independently screened the retrieved literature in line with the inclusion and exclusion criteria, and the following data information was extracted: name of the first author, country, study type, time of publication, basic characteristics of the included cases, and possible risk factors for IAD in critically ill patients. Discrepancies were discussed and solved by the researchers.The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included literature , and theI2. The fixed-effects model was used when p > 0.1 and I2 < 50%; otherwise, the random-effects model was used. One study was eliminated at a time in the sensitivity analysis. The OR and its 95% CI were calculated for count data, and differences were considered statistically significant at p < 0.05. When there were more than three studies included in the individual risk factor analysis, Egger's test was used to check for publication bias. The results showed P ≥ 0.05, suggesting that the included studies' publication bias was insignificant.Review Manager 5.4 was used for the statistical analysis. The heterogeneity of the included literature was assessed using There were 107 results from the literature search; most studies were excluded because they were not relevant to our study. 39 studies were then excluded because they did not meet the inclusion criteria after the full-text articles were reviewed. Finally, seven studies involving 1,238 recipients (432 cases and 806 controls) were included in this study. The study selection process is shown in The specific characteristics of the studies included in the meta-analysis are presented in The meta-analysis showed that risk factors for IAD in critically ill patients included age ≥ 60 , female sex , dialysis , fever , vasoactive agent , PAT  score ≥ 7 , frequency of bowel movement > 3 times/d , and liquid stool ; sedative was concluded that a protective factor against IAD  . There wI2 = 71% vs. I2 = 1%). Also, “Ma et al. (I2 = 52% vs. I2 = 0%) and liquid stool (I2 = 50% vs. I2 = 0%).Sensitivity analysis manifested that the result of the age, gender, mechanical ventilation, antibiotic, dialysis, diabetes, fever, sedative, vasoactive agent, PAT score, urinary incontinence, and frequency of bowel movement was stable. Nevertheless, “Campbell et al. ” had an a et al. ” was theP > 0.05).Egger's test was conducted to evaluate potential publication bias . The resIAD is a common skin injury in critically ill patients, which greatly affects the quality of life of patients . TherefoIAD was associated with the critically ill patient's general condition, our study showed that the risk of IAD in recipients with age ≥ 60 years was 2.18 times higher than the recipients with age < 60 years, which agreed with the findings of earlier research . The agiOur investigation also discovered that the risk of IAD increased with the fever which agrees with the studies of Demarre et al. . Fever pThe probability of developing IAD was associated with the perineal environment. Patients with PAT ≥ 7 had a 5.32 times higher risk of developing IAD compared with those with PAT < 7 points, Li et al.  supporteThis meta-analysis showed that mechanical ventilation, antibiotic, enteral nutrition, albumin, diabetes, and urinary incontinence were not the risk factors for IAD. This may be related to the small sample size in the literature. Further research is needed in the future.This meta-analysis had several limitations. First, we only included English-language literature from four databases, there may not have been sufficient retrieval. Moreover, some risk factor indicators in this meta-analysis were not combined effectively because of the limited amount of literature, which might have impacted the results.Through this systematic review and meta-analysis, we have found a few risk factors for IAD in critically ill patients, which might provide a basis for clinical prevention. Future large-scale prospective cohort studies will be required to identify further risk factors for IAD in critically ill patients, which will be helpful for IAD care and prevention moving forward.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.HJ designed the study and wrote the first draft of the manuscript. HJ, HL, and JS verified data extraction and data analysis. QX and YL supervised the data acquisition, data analysis, and interpretation. LC reviewed the manuscript. All authors read and approved the final manuscript.


Amyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. The etiology of ALS remains unexplained for over 85% of all cases, suggesting that besides the genetic basis of the disease, various environmental factors are implicated in the pathogenesis of ALS. This study aimed to investigate the contribution of known environmental risk factors of ALS in the Cypriot population.We conducted a case–control study with a total of 56 ALS cases and 56 healthy gender/age-matched controls of Cypriot nationality. Demographic, lifestyle characteristics, medical conditions, and environmental exposures were collected through the use of a detailed questionnaire. Statistical analyses using the R programming language examined the association between the above environmental factors and ALS.p = 0.000461) difference in smoking status between the two groups. In addition, univariate logistic regression analysis showed a statistically significant association between ALS cases for head trauma/injury (p = 0.0398) and exposure to chemicals (p = 0.00128), compared to controls.A chi-square test analysis revealed a statistically significant (This case–control investigation has shed some light on the epidemiological data of ALS in Cyprus, by identifying environmental determinants of ALS, such as smoking, head trauma, and chemical exposure, in the Cypriot population. Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neuromuscular disease, characterized by degenerative changes in both upper and lower motor neurons . ALS is Therefore, this current case–control study aimed to investigate potential environmental risk factors for ALS in the Cypriot population. To the best of our knowledge, this is the first study conducted in Cyprus exploring detailed information regarding environmental exposure to various factors , medical history, lifestyle, and anthropometric data that could be associated with ALS.n = 56) of healthy age/gender-matched controls. A total of 112 eligible participants were recruited into the study  were selected according to the inclusion criteria, and their eligibility to fulfill the interview. According to those 56 ALS participants, we recruited an equal number (he study . All ALSχ2) and the Mann–Whitney–Wilcoxon test are non-parametric tests that were used to compare the demographic data for ALS cases versus age and gender-matched controls. To estimate the odds ratio (ORs) and 95% CIs for associations between ALS and exposure risk factors in Cypriot ALS cases and age/gender-matched controls, univariate logistic regression analysis was performed using the glm function in R studio. The level of significance for all tests was defined as a value of p of <0.05. In univariate logistic regression analysis, Bonferroni correction was applied to control the probability of committing type I error .All statistical analysis was performed using R studio and R statistical packages and scripts, version 4.2.1 . The chi-square test , BMI (p = 0.29), residence (p = 0.47), and place of birth (p = 0.82). A statistically significant difference in smoking status was found between cases and controls (p = 0.000461). In a total of 21 ALS smokers, only two female cases were reported to have a history of smoking (9.5%), with the remaining 90.5% being male smokers. White-collar occupations were predominant in this study, with controls being more involved in such professions (68%) in comparison to cases (57%). However, no statistically significant association (p = 0.33) was observed between the two groups. A number of medical conditions which have been reported by the study population were selected according to prevalence. Both diabetes and high blood pressure were commonly found in controls, with much higher frequency. However, no statistically significant results were found for the medical conditions.As shown in p = 0.0398) difference, exhibiting a high risk of developing ALS if they had a history of head trauma . Electric injury (p = 0.0127) was also found to correlate with ALS. Cases who have been injured by electric shock at least once in their lifetime have a significantly higher risk of developing ALS . Furthermore, given the positive association previously found between lifestyle and/or occupational exposure to chemicals, metals, radiation and fertilizers, and ALS risk, we evaluated this relationship in the Cypriot population. A positive association between exposure to chemical substances (p = 0.00128) and risk for ALS was identified between cases and controls . Half of ALS cases (28 out of 56) had been exposed to chemical substances, of which 20 cases (71%) reported an occupational exposure . All of the ALS risk factors remained statistically significant after Bonferroni correction. Nevertheless, no association was observed between the risk of ALS and occupational or lifestyle exposure to metals , radiation (p = 0.99), use of fertilizers (p = 0.777), and living/working near industrial areas or farms (p = 0.387).As seen in p of 0.0478  with sensitivity analysis. Additionally, the electric injury was no longer significant , and results were confirmed with Bonferroni correction.Since the above risk factors–smoking, head trauma, electric injury, and exposure to chemicals–were found to be statistically significant in this study, a sensitivity analysis excluding all deceased ALS cases and 15 matched controls was performed. Three of the four previously found significant variables, including smoking, head trauma, and exposure to chemicals, remained statistically significant after performing this analysis. Fertilizers, which were not statistically significant in the initial analysis, showed a value of This study investigated environmental exposure risk factors for ALS in Cyprus using detailed epidemiological, demographic, and medical history questionnaires. Interestingly, educational attainment was not correlated with ALS as seen in other studies. For instance, studies have shown that educational attainment is associated with lower odds of ALS , 20–22. Smoking is an additional risk factor, and its role in ALS remains unsolved. It is well known that smoking is considered a major health risk for various diseases and conditions, including coronary heart disease, stroke, chronic obstructive pulmonary disease (COPD), and several types of cancer . Only inThe limitations of this study include those as follows: (i) Small sample size for the analysis of subgroups of certain factors , which results in low study power. In addition, it is generally adequate for very common risk factors and lacks to provide enough power for the detection of rare exposures. However, Cyprus is a small country, and the recruitment of a larger study population is almost impossible, especially for ALS cases who have lost their mobility and speech. (ii) Recall bias is also a concern when using questionnaires, especially if past or long-term information is required, and participants might be unable to remember potential data. We understand that recall bias is an issue in case–control epidemiological studies, but in this case, due to the nature of ALS and the small sample size contributing to the population of Cyprus, it is unavoidable. (iii) In some cases, family members were not willing to complete the questionnaire, while others were not able to provide information.To conclude, our study has demonstrated different environmental predictors for ALS in the Cypriot population. Particularly, results support that smoking, head trauma, and exposure to chemicals are indeed risk factors for ALS and were also confirmed with the performance of sensitivity analysis. Other expected factors, including exposure to metals, exposure to radiation, and residence near industrial areas or farms, were found not to be predisposing factors, and neither BMI nor educational attainment were found to be protective for ALS in the Cypriot population. In spite of that, electric injury and fertilizers showed different statistical results with sensitivity analysis. A possible explanation regarding the differentiation between initial statistical analysis and sensitivity analysis is the rapid decrease in sample size, which consequently affects the expected outcomes. Finally, the results of our study highlight the need for further epidemiological studies as well as studies to explore how such factors may potentially influence ALS pathology at the molecular level.The original contributions presented in the study are included in the article/The studies involving humans were approved by the Cyprus National Bioethics Committee (EEBK/EP/2013/28) and conducted in accordance with the Declaration of Helsinki. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.EM: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft. CC: Conceptualization, Data curation, Formal analysis, Methodology, Software, Writing – review & editing. PN: Conceptualization, Supervision, Writing – review & editing. KC: Conceptualization, Supervision, Writing – review & editing. EZ-P: Conceptualization, Supervision, Writing – review & editing.


Diabetes has been related to a higher risk of breast cancer (BC) in women. However, it remains unknown whether the incidence of BC is increased in women with prediabetes. A systematic review and meta-analysis was therefore performed to evaluate the relationship between prediabetes and risk of BC.Observational studies with longitudinal follow-up relevant to the objective were found via searching Medline, Embase, Cochrane Library, and Web of Science. A fixed- or random-effects model was used to pool the results depending on heterogeneity.2 = 3%). Subgroup analyses showed that study characteristics such as study design, menopausal status of the women, follow-up duration, diagnostic criteria for prediabetes, methods for validation of BC cases, and study quality scores did not significantly affect the results .Eight prospective cohort studies and two nest case-control studies were included. A total of 1069079 community women were involved, and 72136 (6.7%) of them had prediabetes at baseline. During a mean duration follow-up of 9.6 years, 9960 (0.93%) patients were diagnosed as BC. Pooled results with a fixed-effects model showed that women with prediabetes were not associated with a higher incidence of BC as compared to those with normoglycemia  with mild heterogeneity (p for Cochrane Q test = 0.42, IWomen with prediabetes may not be associated with an increased risk of BC as compared to women with normoglycemia. Breast cancer (BC) is a highly prevalent malignancy among women worldwide, with approximately 1.4 million new diagnoses annually . EstabliAccumulating evidence suggests that hyperglycemia may have an adverse effect on BC incidence and prognosis , 6. A reThe PRISMA 2020 , 17 statIn order to identify studies that met the meta-analysis’ objectives, the following terms were combined (1): “prediabetes” OR “pre-diabetes” OR “prediabetic” OR “pre-diabetic” OR “prediabetic state” OR “borderline diabetes” OR “impaired fasting glucose” OR “impaired glucose tolerance” OR “IFG” OR “IGT” OR “fasting glucose” OR “HbA1c” (2); “breast”; and (3) “neoplasms” OR “carcinoma” OR “cancer” OR “tumor” OR “malignancy”. In the search, the dates of databases creation and the date of last search  were taken into consideration. Our selection criteria were limited to studies conducted on humans and published in English as full-length papers. Additionally, we manually checked the references of the related original and review articles to identify the original studies that were not included.The PICOS criteria were followed in determining study selection criteria.(1) P (Participants): Women without a known diagnosis of cancer at baseline.(2) I (Intervention): Women with prediabetes at baseline. The diagnosis of prediabetes was in accordance with the criteria used in the original studies.(3) C (Control): Women with normoglycemia at baseline.(4) O (Outcome): The incidence of BC during follow-up durations, compared between women with prediabetes and women with normoglycemia.post-hoc analyses of clinical trials, and nested case-control studies.(5) S (Study design): Observational studies that follow patients over time, including cohort studies, Reviews, meta-analyses, editorials, studies enrolling patients with known cancer at baseline, studies without longitudinal follow-up, studies did not investigate prediabetes as exposure, or studies with no relevant outcomes were excluded.For the purpose of assessing the study quality, the Newcastle–Ottawa Scale (NOS)  was used2 statistic  and 95% confidence intervals (CIs) were used to assess the association between prediabetes and risk of BC. For variance stabilization and normalization, we performed a logarithmical transformation followed by a calculation of the RRs and standard errors (SE) . An evaltatistic . If I2 >was used . Sensitiwas used . The RevAn overview of the database search process is shown in Characteristics of the included studies are displayed in 2 = 3%). Pooled results with a fixed-effects model showed that women with prediabetes were not associated with a higher incidence of BC as compared to those with normoglycemia (RR: 0.99, 95% CI: 0.93 to 1.05, p = 0.72; Since two of the included studies reported data according to the age of the included women, and another two studies according to the menopausal status of the included women separately, these datasets were included in the meta-analysis independently. Overall, 15 datasets from ten studies were available for the meta-analysis –31. MildBased on this meta-analysis, women with prediabetes were shown to be not associated with an increased incidence of BC compared to controls with normoglycemia. Further sensitivity analyses by omitting one study at a time showed consistent results. Subsequent subgroup analyses showed that the results were not significantly by differences of study characteristics such as study design, menopausal status of the women, follow-up durations, definition of prediabetes, methods for the validation of BC cases, or study quality scores. As a result, these results indicate that prediabetes may not be a risk factor of BC in women.Few previous meta-analyses have evaluated the association between prediabetes and risk of BC. Although an early meta-analysis incorporating the evidence from 16 cohort studies that found that overall prediabetes may be associated with an increased risk of cancer, subsequent subgroup analysis showed that the association may be site-specific according to different cancers . As for Although it is shown in recent studies that the global burdens of premenopausal and postmenopausal BC have been both raising in recent decades, the risk factors of premenopausal and postmenopausal BC could be different . In thisIn addition, subgroup analysis also suggested that the difference of the definition of prediabetes did not significantly affect the association between prediabetes and the risk of BC. Nevertheless, the results should be interpreted cautiously because none of the included studies defined prediabetes as IGT in these studies. In a recent meta-analysis, different definitions and diagnostic criteria were found to affect the association of prediabetes with diabetes risk . TherefoThis study also has limitations. First, we could not determine whether the association was consistent across pathological types of BC. In addition, although all selected studies utilized multivariate regression analysis, residual confounding factors could not be excluded, such as the potential influences of dietary and other lifestyle factors that are related to the risk of BC. Finally, as mentioned previously, it remains to determine if difference in menopausal status and definition of prediabetes may affect the results of the meta-analysis.Based on the meta-analysis, prediabetes may not be associated with an increased incidence of BC in women. However, it remains to be investigated if the conclusion is universal in pre and postmenopausal women, and in prediabetes with different definitions and diagnostic criteria.The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.JL designed the study. JL and RT performed literature review, study identification, quality evaluation, and data collection. JL and ZL performed statistical analysis and interpreted the results. JL drafted the manuscript. All authors revised the manuscript. All authors contributed to the article and approved the submitted version.


Previous cohort studies have found an association between Bacillus Calmette–Guérin (BCG) administration and incident dementia. In the systematic review and meta-analysis, we aimed to summarize the current evidence of the effect of BCG use on the risk of developing dementia.We searched six databases until 20 May 2023 for studies investigating the risk of dementia and BCG administration. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were pooled in the meta-analysis. Meta-regression, subgroup, and sensitivity analysis were conducted as well.2 = 84.5%, p < 0.001) was observed, the pooled HR was 0.55 (0.42–0.73), indicating that BCG exposure or treatment reduced the risk of incident dementia by 45%. Moreover, the sensitivity analysis showed good robustness of the overall effect with no serious publication bias.Of the 4,043 records initially evaluated, five articles were included for final analysis, with a total of 45,407 bladder cancer (BC) patients. All five studies were evaluated and rated as with high quality, and a low possibility of publication bias was indicated. A significant association between BCG and the incidence of dementia in BC patients was found in all five studies. Although a high heterogeneity (IBCG administration is associated with a significantly lower risk of developing dementia. However, an epidemiological cohort is needed to establish a relationship between BCG use and incident dementia in the normal population. Once the relationship is confirmed, more people may benefit from the association.identifier: CRD42023428317. Alzheimer's disease (AD) is the most common form of dementia, accounting for two-thirds of all dementia diagnoses  plaques and neurofibrillary tangles (hyperphosphorylated tau protein) . Numerous meta-analyses have proved its efficacy  is a live attenuated form of Recently, some trials suggested that, in bladder cancer (BC) patients, BCG users have a decreased incidence of AD. However, these studies have some limitations, such as different diagnostic codes . This meta-analysis was reported following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines , insufficient data, unavailable full text, animal studies, and bench studies.Duplicates were removed by automated processing in EndNote. Then, two authors (CH and YL-C) screened titles and abstracts independently to identify relevant studies. Finally, the available full texts were systematically examined to evaluate compliance with our inclusion and exclusion criteria (CH and YL-C). When there were disagreements, a third reviewer (JW) made the final decision.Data were extracted from eligible studies by two independent investigators (CH and YL-C). Any disagreements were resolved through consultation with a third investigator (JW), if necessary. The following information was extracted from the included studies: first author, year of publication, study design, study period, region, sample size, gender, age, follow-up period, BCG interventions, dementia subjects, effect size (such as HR), and corresponding 95% confidence intervals (CIs).The quality of the included studies was assessed using the Newcastle–Ottawa Scale (NOS) by two independent authors (CH and YL-C), and disagreements were resolved through a third reviewer (JW). The NOS assigns a maximum of 9 points based on the following items: selection, comparability, and outcome. Subsequently, the bias risk of each study was rated as high (≤4), medium (5–6), and low (7–9), respectively.2. If the heterogeneity is considered significant (I2 > 50% or P < 0.05), a random effects model would be employed. Otherwise, the fixed-effect model would be adopted. Subgroup analyses stratified by region, age, gender, race/ethnicity, dose, follow-up period, and outcome were performed to examine subgroup differences and potential heterogeneity sources. Sensitivity analyses were performed to assess the robustness of the primary results. Moreover, the results of the fixed effects and random effects models were compared to check the stability of the pooled results. The Harbord test and Egger's test were used to evaluate potential publication bias. All statistical analysis was performed using STATA . A p < 0.05 was considered to be statistically significant.We calculated the pooled effect size (HR) and the corresponding 95% CIs for incident dementia in the BCG group compared with the non-BCG group. The heterogeneity was quantified using the Q test and In = 1,735), 2,308 records were left. Of them, 714 records were further excluded due to reviews (n = 326), book chapters (n = 44), conference abstracts (n = 154), non-English literature (n = 129), and letters or editorials (n = 61). Then, 1,583 records were excluded after screening titles and abstracts. Eight studies were further excluded because of the following reasons: animal studies (n = 3), no effect size (n = 1), no full text (n = 1), and duplicates (n = 3). Finally, five eligible articles were included in this meta-analysis.A total of 4,043 records were initially retrieved using our search strategy. As shown in n = 5) are summarized in n = 2) or the USA (n = 3), respectively. The study period (duration from study entry date to study end) of each study ranged from 6 to 52 years, and the mean/median follow-up period varied from 3 to 8 years. All participants  in these studies were BC patients receiving BCG induction or maintenance, while AD or other dementia patients were defined according to diagnostic codes and/or drugs prescribed. Among them, three studies considered incident AD as the outcome, and another two studies considered dementia (including AD) as the outcome. All studies were rated with the maximum score according to the NOS, indicating a high quality  was observed, so the random effects model was used. All studies showed a significant association between BCG and the incidence of dementia in BC patients, and the pooled HR was 0.55 , indicating that BCG exposure or treatment reduced the risk of incident dementia by 45%.p = 0.041), the USA , age , dose , follow-up period , and AD . Therefore, BC patients with such characteristics  may have a low risk of incident dementia.Subgroup analyses were performed stratified by region, age, gender, race/ethnicity, dose, follow-up period, and outcome . The stup-values were 0.108 and 0.052, respectively. The results indicated a low possibility of publication bias. Then, the stability of the meta-analysis results was assessed using the sensitivity analysis (leave-one-out method). When excluding any single study, there was no significant change in the pooled HR, indicating a robust result  was observed, a pooled HR was estimated at 0.55 (0.42–0.73), which indicated that BCG use could reduce the risk of incident dementia in BC patients. Moreover, according to meta-regression results, patients have the following characteristics, such as from Israel, old age, high dosage, short follow-up period, and AD as outcomes appear to have a reduced incidence of dementia after BCG vaccine treatment. Regarding the management of dementia, a dose-response relationship should be considered in practice, and BCG treatment may be more effective for AD than other types of dementia.In this systematic review and meta-analysis, the association between BCG use and incident dementia was investigated. Since only BC patients were included, the study overcame the health patient bias, which is a serious concern for most studies of vaccination and dementia risk. Our data demonstrated that patients not treated with BCG had a significantly higher risk of developing dementia. Although a significant heterogeneity  intravesical BCG instillation may increase the immunosuppressive Treg population by IL-2 cytokines (Baek et al., Chlamydia pneumoniae, human herpesvirus-6, Epstein-Barr virus, Herpes simplex virus-1, and the Herpesviridae family were found to be associated with a higher risk of AD (Ou et al., Recently, similar studies were evaluated for other vaccinations [such as influenza vaccination (Wiemken et al., The interpretation of this systematic review and meta-analysis must be considered within its limitations. First, all studies have a retrospective nature. Therefore, selection bias cannot be ruled out. Second, BC patients are indicated for BCG administration, and most BC patients have a good prognosis and long-term follow-up. The two key elements support testing the hypothesis in BC patients. However, the role of BCG administration remains unclear in the normal population, and further cohort studies are required. Third, although meta-regression results support the dose-dependent relationship between BCG use and the risk of dementia, the relationship was not evaluated in the study. Moreover, there was a lack of competing risk assessments. These were due to the limited availability of data from included studies. Finally, caution is required for the interpretation since a high heterogeneity exists in the analysis.In conclusion, the present systematic review and meta-analysis indicates that BCG administration is associated with a decreased risk of dementia in BC patients. The findings suggest that the BCG administration may also have a preventive role in dementia. However, more epidemiological studies are needed to clarify the association between BCG use and decreased dementia risk in the normal population. In addition, further bench studies are needed to better understand the mechanisms linking BCG and incident dementia.The original contributions presented in the study are included in the article/M-SW and Y-AZ designed the study and drafted the initial manuscript. CH and Y-LC performed the screening and collected data. JW and C-PG supervised data collection. All authors approved the final version of the report.


Completeness of reporting was high, but more than half were considered subject to potential bias. The trend synthesis showed that half (n = 7) of the included publications demonstrated a higher risk of testicular cancer in the sons of mothers exposed to cigarette smoke during pregnancy. The meta-analysis generated an overall summary risk estimate of 1.00  (n = 10 publications), with a lower risk for seminoma  and nonseminoma  (n = 4 publications). Conclusions: This systematic review did not provide evidence of an association between maternal exposure to cigarette smoke and risk of testicular cancer in offspring. An overall positive trend was suggested, but it had low statistical precision. The methodological limitations across publications encourage further research based on valid exposure data.Background: Maternal exposure to cigarette smoke in pregnancy may play a role in the development of testicular cancer in offspring. An updated and comprehensive systematic review of the available evidence is needed. Objective: To identify and evaluate current evidence on maternal exposure to cigarette smoke during pregnancy and testicular cancer in offspring. Methods: A systematic search of English peer-reviewed original literature in PubMed through a block search approach. Publications were considered if assessing maternal exposure to cigarette smoke and the risk of testicular cancer in offspring. Results: Among the 636 identified records, 14 publications were eligible for review and 10 for meta-analysis. Quality assessment of the publications was conducted. Most included publications were case-control studies ( Maternal exposure to cigarette smoke during pregnancy proposes a significant health risk to the mother and fetus and is a plausible risk factor for cancers . The chein utero .,23.22,23Completeness of reporting was assessed in the following nine areas: (1) study design, (2) sampling frame and procedures, (3) inclusion and exclusion, (4) population characteristics of exposed/unexposed or cases/referents, (5) response rate reported or implicitly given, (6) methods for exposure measurement, (7) method for outcome ascertainment, (8) statistical analysis, and (9) exposure–response. The nine areas were equally weighted with a value of 1 given for adequate reporting and a value 0 for inadequate reporting. We considered a sum score of ≥6 points as a sufficient completeness of reporting.Potential sources of bias were evaluated in a total of eight areas, of which the following five areas were considered the most critical sources of bias and were included for final assessment: (i) reporting of tested hypotheses, (ii) selection bias from loss of follow-up or lack of representativeness in a population sample, (iii) information bias related to exposure ascertainment, (iv) information bias related to outcome ascertainment, and (v) accounting for confounding. Each of the five areas were either rated as high risk (score = 2), uncertain risk (score = 1), or low risk (score = 0). Individual publications were considered at high risk if the sum risk of bias score ≥ 8.The assigned quality assessment scores for completeness of reporting and risk of bias for individual publications are presented in Descriptive characteristics were extracted from each included publication, hereunder author and publication year; study design, period, and population; country of population origin; ascertainment of both exposure and outcome; and whether the study assessed the histological subtype of testicular cancer.To provide an overview of the direction of the association between maternal exposure to cigarette smoke during pregnancy and testicular cancer in offspring, a qualitative trend synthesis was conducted, illustrated by arrows: a downwards arrow indicating lower risk of testicular cancer in offspring (estimate below 1.00); upward arrow indicating higher risk of testicular cancer in offspring (estimate above 1.00); and a horizontal arrow indicating no association found . An asterisk was added if the estimates were statistically significant.Publications were deemed eligible for the meta-analysis if they provided a comparable risk estimate  and 95% confidence interval (CI) between exposure and outcome. In the case of the sole report of several levels of exposure with no overall estimate provided, the highest level versus the reference category was chosen for further analysis. In the case of publications presenting both crude and confounder adjusted estimates, the latter was selected.I2) statistics were calculated to evaluate in-between study variation and 25% was considered to be the threshold for importance of chance. A funnel plot by the standard error to the logarithm of the risk estimate was furthermore generated to assess sources of publication bias using the Egger’s regression-based test [A forest plot for the meta-analysis was performed in Review Manager  by utilizing an inverse-variance random-effects model to calculate an overall risk estimate. Heterogeneity (sed test .n = 8 publications) in offspring are presented in n = 11), while the remaining were ecological studies (n = 3).Selected characteristics of the 14 included publications reporting on the association between maternal exposure to cigarette smoke and risk of testicular cancer  and interviews (n = 4), which were either ascertained retrospectively post-birth (n = 8) or during the first half of pregnancy (n = 2). Most case-control studies utilized binary exposures of ever/never having smoked during pregnancy (n = 7), while one study utilized a binary exposure with the cut-off point of seven cigarettes . The last two case-control studies utilized exposure levels with number of cigarettes smoked during pregnancy  (n = 1) or a combination of binary exposures and exposure levels (n = 1). Of the three included ecological studies, two used tobacco-related lung cancers among the maternal generation as a proxy for smoke exposure, while the remaining ecological study utilized population level smoking behavior data of the presumed maternal generation (n = 1). The ecological studies ascertained smoking exposure through cancer registries (n = 2) and survey data (n = 1).Ascertainment of maternal exposure to cigarette smoke varied across the publications. Of the 11 case-control studies, one study measured cotinine concentrations in maternal serum collected during pregnancy, while the remaining 10 case-control studies based their ascertainment on self-report, hereunder self-administered questionnaires (n = 9) and through patient enrollment at cancer centers (n = 2) or cancer surveillance programs (n = 2). A combination of extracting information from both cancer registries and cancer centers was used in a single publication (n = 1).Diagnoses of testicular cancer in offspring were mainly extracted from national/regional cancer registries (n = 12), and more than half of the publications were considered to have a high risk of bias (n = 8), according to our predefined criteria  demonstrated a trend toward a higher risk of testicular cancer in offspring whose mothers were exposed to cigarette smoke during their pregnancy compared with mothers who were not or who were less exposed. The remaining publications reported either a reduced risk (n = 3) or null estimates (n = 4) for associations with cigarette smoke during pregnancy.The results from the qualitative trend synthesis are presented in n = 11). A mix of both positive, negative, and no associations were observed across the included case-control studies, of which none reported statistical significance. Tuomisto et al. (2009) demonstrated that women with cotinine concentrations in the serum equivalent to that of a smoker (defined as ≥15 ng/mL) had a 32% lower risk of having a son with testicular cancer in comparison with women with non-smoker levels of cotinine (defined as <5 ng/mL) [Case-control studies (5 ng/mL) . The cas5 ng/mL)  and Brow5 ng/mL)  reported5 ng/mL)  and Møll5 ng/mL)  observed5 ng/mL)  found no5 ng/mL) , McGlynn5 ng/mL) , Sonke e5 ng/mL) , and Swe5 ng/mL)  reportedn = 3). All three ecological studies showed a trend toward a higher risk of testicular cancer according to proxies of maternal exposure to cigarette smoking in pregnancy. Hemminki et al. (2005) [Ecological studies (. (2005)  observed. (2005)  reported. (2005)  observedn = 4) generated estimates below unity for both seminoma  and nonseminoma testicular cancer   .Begg’s Rank Correlation = 0.357).A funnel plot of all publications included in the meta-analyses assessing maternal exposure to cigarette smoke and testicular cancer in offspring indicated no publication bias , confirmIn this systematic review, we conducted a meta-analysis of available human epidemiological evidence on the association between maternal exposure to cigarette smoke and testicular cancer in offspring, while assessing study quality and providing summary estimates of associations. On balance, a positive association was consistently observed in large ecological studies, while smaller case-control studies reported inconsistent associations and were hampered by a lack of statistical precision. Only one small case-control study quantified cotinine in maternal serum during pregnancy. Completeness of reporting of outcomes was high, but over 50% of the included publications were at potential risk of bias, specifically information and confounding bias.The qualitative trend synthesis provided some indication of a trend toward a higher risk of testicular cancer if mothers were exposed to cigarette smoking during their pregnancy, but the overall pattern was largely inconsistent and only half of the publications demonstrated a risk estimate above 1.00, with most estimates being relatively close to unity and not statistically significant. Considering only the case-control studies, the results were particularly inconsistent with a mix of both positive, negative, and null associations, challenging the overall interpretation of findings. In contrast, all ecological cohort studies reported positive associations, with two detecting statistical significance. However, the ecological studies reporting statistical significance utilized maternal lung cancer and the smoking habits of the assumed maternal generation as a proxy for maternal cigarette smoking, thus cautious interpretation of these results is encouraged. On balance, the inconsistency in findings and general lack of statistical significance across the included publications subsequently impeded this current review from providing substantial conclusion.seminoma/nonseminoma: 380/461)  .The included publications generally had a high completeness of reporting, but more than half of the publications were considered at a high risk of bias. These publications were particularly prone to information and residual confounding bias, with the latter being due to not accounting for confounders at all. As testicular cancer ascertainment was relatively comparable across the publications, the primary sources to information bias were identified through methods for exposure ascertainment. Most publications ascertained maternal cigarette smoking through self-reporting, with a large number of case-control studies relying on data collected at the time of the son’s testicular cancer diagnosis, thus after the occurrence of exposure, which is not necessarily a reliable measure due to the risk of recall bias. Given this, we expect the self-report of exposure will bias the estimate away from the null above 1. Similarly, cigarette smoking is recognized to be notoriously underreported, particularly by pregnant women, likely due to fear of stigmatization . Importarange: 4586–12,592), implying statistical precision. However, they utilized all lung cancer as a proxy for maternal exposure to cigarette smoking, and although tobacco smoking is indeed a predominant risk factor of lung cancer with about 90% of lung cancer cases being attributed to tobacco use [The ecological studies were all large (nacco use , not allacco use . Thus, tIn contrast, the case-control study design was considered methodologically adequate for studying rare diseases and outcomes ; howeverAlthough our systematic review did not provide substantial evidence into an association between maternal exposure to cigarette smoking during pregnancy and testicular cancer, it remains uncertain whether our overall results are due to a lack of an association or perhaps due to the methodological limitations consistently observed across the included publications. Intriguingly, previous studies have found a link between maternal smoking during pregnancy and a higher risk of other parameters of male reproductive health, hereunder cryptorchidism ,44, reduThe main strength of our systematic review is the extensive and transparent literature search followed by the application of predefined eligibility and quality assessment tools. On balance, the present review provides an updated and deepened understanding about the available evidence on smoking during pregnancy and testicular cancer. Considering the prevalent behavior of active smoking during pregnancy  and the A limitation of our review includes the confined number of included publications. Our a priori aim was to provide an updated review given that the latest review was published almost a decade ago. To our surprise, no original research has been conducted since 2009, but in our opinion, this only emphasizes the need for further research using more optimal data and illuminating the methodological limitations previously highlighted. The lack of an association in the current systematic review calls for further research based on valid exposure data to provide substantial inference. Ideally, we sought to solely include publications utilizing the gold standard of cotinine measurements, but we were compelled to widen our review by including various proxies of exposure. Prospective cohort studies utilizing biological sampling are of a stronger design; however, such studies are difficult to implement. Finally, the evaluation of bias may potentially be prone to subjectivity, but this was to the best of our abilities avoided by involving two researchers who independently evaluated the publications, with any discrepancies resolved by a third researcher.In this systematic review and meta-analysis, we did not find evidence of an association between maternal exposure to cigarette smoke and risk of testicular cancer in offspring. The qualitative trend synthesis suggested an overall positive trend but was hampered by statistical power and not confirmed in the meta-analysis. It is evident that there is a gap in studies assessing prenatal exposure to cigarette smoke utilizing more direct and precise methods. Given the mixed quality of the included publications and their methodological limitations, further original research based on valid exposure data is needed to fully establish the association.


Background: Bronchopulmonary dysplasia (BPD) is the most common serious pulmonary morbidity in preterm infants with high disability and mortality rates. Early identification and treatment of BPD is critical. Objective: This study aimed to develop and validate a risk scoring tool for early identification of preterm infants that are at high-risk for developing BPD. Methods: The derivation cohort was derived from a systematic review and meta-analysis of risk factors for BPD. The statistically significant risk factors with their corresponding odds ratios were utilized to construct a logistic regression risk prediction model. By scoring the weights of each risk factor, a risk scoring tool was established and the risk stratification was divided. External verification was carried out by a validation cohort from China. Results: Approximately 83,034 preterm infants with gestational age < 32 weeks and/or birth weight < 1500 g were screened in this meta-analysis, and the cumulative incidence of BPD was about 30.37%. The nine predictors of this model were Chorioamnionitis, Gestational age, Birth weight, Sex, Small for gestational age, 5 min Apgar score, Delivery room intubation, and Surfactant and Respiratory distress syndrome. Based on the weight of each risk factor, we translated it into a simple clinical scoring tool with a total score ranging from 0 to 64. External validation showed that the tool had good discrimination, the area under the curve was 0.907, and that the Hosmer–Lemeshow test showed a good fit (p = 0.3572). In addition, the results of the calibration curve and decision curve analysis suggested that the tool showed significant conformity and net benefit. When the optimal cut-off value was 25.5, the sensitivity and specificity were 0.897 and 0.873, respectively. The resulting risk scoring tool classified the population of preterm infants into low-risk, low-intermediate, high-intermediate, and high-risk groups. This BPD risk scoring tool is suitable for preterm infants with gestational age < 32 weeks and/or birth weight < 1500 g. Conclusions: An effective risk prediction scoring tool based on a systematic review and meta-analysis was developed and validated. This simple tool may play an important role in establishing a screening strategy for BPD in preterm infants and potentially guide early intervention. Bronchopulmonary dysplasia (BPD), also known as chronic lung disease (CLD), is one of the most common complications in preterm infants . Since 1BPD is an abnormal development of the lungs and pulmonary vasculature caused by multiple prenatal and postnatal risk factors. Although several individual risk factors have been identified, the interaction between these factors and their relationship are controversial . MoreoveIn recent years, many scholars have devoted themselves to exploring and establishing suitable risk prediction models for BPD . Most ofThis study was strictly performed in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines  and the PubMed, Web of Science, Embase and Cochrane Library were comprehensively searched to obtain relevant original English literature on risk factors for BPD from January 1990 to May 2022. Search strategies used combinations of the following search terms:  OR  AND (bronchopulmonary dysplasia [MeSH] OR bpd [tw] OR chronic lung disease [tw]) AND (Risk Factors [MeSH] OR predictive factors [tw] OR dangerous factors [tw]). All relevant free search terms were searched for potential articles and used the snowball method to track references included in this meta-analysis. Two researchers (Z.Y. and M.Z.) screened the literature independently in strict accordance with the inclusion and exclusion criteria. Any differences in the search process were fully discussed with the third researcher (A.L.) until consensus was reached.Inclusion criteria: (1) preterm infants with gestational age (GA) < 32 weeks and/or birth weight (BW) < 1500 g; (2) studies were case-control or cohort studies based on original data; (3) the odds ratio (OR) and 95% confidence interval (95% CI) of the risk factor could be obtained directly or through data transformation; (4) the outcome was BPD; (5) articles published in English; (6) the study was published in a peer-reviewed journal.Exclusion criteria: (1) the original study was not available; (2) the definition of BPD was unclear; (3) the outcomes were BPD or death, and data from separate categories of BPD ; (4) studies limited to gene polymorphisms; (5) the research types were animal studies, reviews, commentaries, editorials, case reports or republished articles.Data extraction: Two researchers (Y.X. and Z.Y.) independently extracted data from relevant studies using a pre-determined data extraction form, and entered these into an Excel spreadsheet after a third researcher (Y.W.) checked data extraction for accuracy and completeness. The following information was extracted: (1) basic information includes first author, published year, country, number of centers, research time, study design, and (2) baseline characteristics include BW and GA, the number of case groups and control groups, and definition of BPD.Quality assessment: The Newcastle Ottawa Scale (NOS)  was used2 statistic. When the heterogeneity test indicated no significant , a fixed-effects model was applied; otherwise, a random-effects model was used. Sensitivity analysis and subgroup analysis were performed to test the stability of the results and explore the source of heterogeneity, respectively. Begg’s test and Egger’s test were used to investigate publication bias. A 2-tailed p < 0.05 was considered statistically significant.The statistical analysis of the data was conducted using the statistical software “STATA17.0”. In order to ensure the stability of meta-analysis results, the risk factors were not analyzed if less than 3 articles were included. OR with corresponding 95% CI was calculated to estimate the statistical outcomes. Statistical heterogeneity was assessed and quantified using the Cochran Q statistic and Iβ-coefficient, and the formula nth risk factor, and nth risk factor. To develop a simple risk scoring tool, we calculated the corresponding score by dividing each regression coefficient We developed a prediction scoring tool based on a systematic review and meta-analysis. The appropriate OR with 95% CI of each risk factor in the model was used to calculate the corresponding The validation cohort was from a population retrospective cohort of preterm infants hospitalized in NICU, the First Affiliated Hospital of Anhui Medical University, between 1 June 2017 and 1 June 2022. Preterm infants included in this cohort must meet the following criteria: (1) GA at birth < 32 weeks and/or BW < 1500 g; (2) admission to NICU within 24 h after birth; and (3) survival time ≥ 28 days. The following preterm infants were excluded: (1) complicated congenital heart disease, genetic metabolic disease, diaphragmatic hernia or congenital respiratory malformation; (2) missing or incomplete data; or (3) death before fulfilling the BPD definition. The study protocol was approved by the Committee of the First Affiliated Hospital of Anhui Medical University (No. Quick-PJ2022-08-31). Due to the retrospective nature of this study, informed consent was waived.(1)2) for ≥3 consecutive days to maintain arterial oxygen saturation in the 90–95% range.The diagnosis of BPD was acquired according to the 2018 definition proposed by NICHD , preterm(2)Maternal hypertensive disorders (MHD) included chronic hypertension , gestational hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg occurring after 20 weeks’ gestation), preeclampsia  and eclampsia .(3)Chorioamnionitis (CA) was defined as clinical CA with or without histological proven CA .(4)The administration of antenatal steroids was defined as a single course of 4 doses of 6 mg of dexamethasone given intramuscularly 12 h apart.(5)Small for gestational age (SGA) was defined as a BW below the 10th percentile or 2 standard deviations below the mean weight for the same GA .(6)Respiratory distress syndrome (RDS) was defined as a clinical symptom  consistent with chest X-ray findings .(7)Surfactant treatment was given as early as possible according to the neonatal respiratory condition after birth combined with evidence of RDS .(8)Sepsis was defined as an infection that can be proven by the culture of pathogenic bacteria (including bacteria and fungi) in blood, cerebrospinal fluid, or other sterile cavities under the premise of abnormal clinical signs and symptoms . Based oThe definition criteria of some clinical indicators in the validation cohort were shown as follows:p > 0.05 was considered to show good model consistency. The classification of the model was evaluated using a decision curve analysis (DCA), reflecting the net benefit of the model to patients.The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the prediction power of the model. The value of AUC ranges from 0.5 to 1.0, and the greater the value, the better the prediction accuracy. The calibration curve was drawn by bootstrapping with 1000 resamples. The Hosmer−Lemeshow test was used to evaluate the goodness-of-fit of the model, and p < 0.05 was considered statistically significant. Patients were divided into low, low-intermediate, high-intermediate, and high groups based on the obtained frequencies of BPD using different risk scores. Statistical analyses were performed with SPSS 26.0 software and R version 4.1.2 software.Youden’s J statistic (Youden’s index = sensitivity + specificity − 1) was used to calculate the cut-off points, and A total of 12,915 potentially relevant studies were initially identified. By eliminating duplicate articles and screening titles and abstracts, 58 studies ,78,79,80A total of 58 studies ,78,79,80After listing the risk factors for BPD presented in the 58 studies ,78,79,80The 12 risk factors assessed by the Begg’s test and Egger’s test suggested publication or selection bias. The results were: CA, GA, Sex, DRI, MV, Days of MV, Surfactant, PDA, RDS, Sepsis, NEC, Pulmonary air leak. Details of publication bias for all risk factors are presented in The derivation cohort was derived from 58 studies ,78,79,80n = 21), admission exceeding 24 h after birth (n = 5), and death before fulfilling the BPD definition (n = 83) were excluded. Finally, 767 preterm infants were included in the validation cohort  were males. In total, 49.9% of the mothers were treated with antenatal steroids, 15.5% had CA, 43.5% of infants were treated with surfactants after delivery, the mean GA was 30.14 ± 1.79 weeks, the mean BW was 1306.04 ± 314.28 g, and the mean 5 min Apgar score was 8.63 ± 1.89. There were 185 cases of BPD, and the cumulative incidence of BPD was 24.12%. Detailed basic characteristics of preterm infants in the validation cohort are shown in p ≥ 0.05, the following five risk factors were excluded: MHD, Antenatal steroids, PROM, Caesarean section and ROP. Due to heterogeneity, partial results were selected from appropriate subgroup analyses or sensitivity analyses. To identify early preterm infants that are at high-risk of developing BPD, the following nine risk factors were included: CA, GA, BW, Sex, SGA, 5 min Apgar score, DRI, Surfactant, RDS. Forest plots are presented in p = 0.000); GA per 1 week increase ; BW per 100 g increase ; Sex ; SGA ; 5 min Apgar score per 1 point increase ; DRI ; Surfactant ; RDS . The risk score was calculated as follows:A total of 24 risk factors were identified through a systematic review and meta-analysis. Due to +6 = 2, 30–30+6 = 4, 29–29+6 = 6, 28–28+6 = 8, 27–27+6 = 10, 26–26+6 = 12, 25–25+6 = 14, 24–24+6 = 16, <24 = 18); BW ; Sex ; SGA ; 5 min Apgar score ; DRI ; Surfactant ; RDS  ; GA  .p = 0.3572), and the calibration curve showed excellent agreement between the predicted and actual observations, indicating that the tool had good consistency  predicted by combined indicator , sensitivity was 0.897, and specificity was 0.873 . The ROCsistency . Furthersistency .p = 0.000),  and , respectively , which usually occurs in the third trimester. Therefore, incomplete differentiation of AT2 cells in preterm infants results in insufficient pulmonary surfactant, which contributes to the pathogenesis of RDS . For yeaAt present, a number prediction models for BPD in preterm infants have been proposed. However, almost all existing models were based on observational studies, and there are no evidence-based studies. Most were developed in specific centers and populations, while lacking independent external validation. The predictive models tended to perform well in modeled data, but their accuracy was significantly reduced when other external validations were performed, so generalizability was limited ,18. The The present study has certain limitations. First, the 58 articles included came from different regions and races, which inevitably displayed some heterogeneity. Although we conducted subgroup analysis and sensitivity analysis, the sources of heterogeneity of some risk factors could not be determined. Second, every risk factor included ≥ 3 studies, and although the stability of the results was guaranteed to a certain extent, other clinical indicators cannot be included in the analysis. Third, due to the different risk factors for different outcomes in the meta-analysis, we excluded the outcomes BPD or death, and severity of BPD . Finally, the derivation cohort of this study came from populations from different countries, while the validation cohort was only from preterm infants from one hospital in China, which may be an issue in applying data generated from mainly Caucasian populations. However, ethnic and genetic differences in the prediction of BPD cannot be ignored, the large data set may provide an important opportunity to evaluate outcome differences in Caucasian vs. Asian cohorts. In the future, we hope to continue to update our model, including adding outcomes that predict the severity of BPD, and conduct multi-center external validation to further provide a scientific and objective reference tool for early clinical identification and prevention of BPD.We have provided and validated an easy-to-use, low-cost, early predicting-capabilities and accurate BPD risk-scoring tool based on a systematic review and meta-analysis to identify and stratify high-risk preterm infants for BPD. This tool may play an important role in clinical practice and generating targeted screening strategies for BPD in preterm infants.


Schizophrenia is a highly heritable, severe psychiatric disorder that involves dysfunctions in thinking, emotions, and behavior, with a profound impact on a person’s ability to function normally in their daily life. Research efforts continue to focus on elucidating possible genetic underlying mechanisms of the disorder. Although the genetic loci identified to date to be significantly associated with schizophrenia risk do not represent disease-causing factors, each one of them could be seen as a possible incremental contributor. Considering the importance of finding new and more efficient pharmacological approaches to target the complex symptomatology of this disorder, in this scoping review, we are focusing on the most recent findings in studies aiming to elucidate the contribution of one of the genetic factors involved – the BDNF gene Val66Met polymorphisms. Here we performed a systematic search in Pubmed, Embase, and Web of Science databases with the search terms: (BDNF gene polymorphism) AND (schizophrenia) for articles published in the last 5 years. To be selected for this review, articles had to report on studies where genotyping for the BDNF Val66Met polymorphism was performed in participants diagnosed with schizophrenia (or schizophrenia spectrum disorders or first-episode psychosis). The search provided 35 results from Pubmed, 134 results from Embase, and 118 results from the Web of Science database. Twenty-two articles were selected to be included in this review, all reporting on studies where an implication of the BDNF Val66Met polymorphisms in the disorder’s pathophysiology was sought to be elucidated. These studies looked at BDNF gene Val66Met polymorphism variants, their interactions with other genes of interest, and different facets of the illness. The Met/Met genotype was found to be associated with higher PANSS positive scores. Furthermore, Met/Met homozygous individuals appear to present with worse cognitive function and lower levels of serum BDNF. In the Val/Val genotype carriers, increased BDNF levels were found to correlate with weight gain under Risperidone treatment. However, due to heterogeneous results, the diversity in study populations and studies’ small sample sizes, generalizations cannot be made. Our findings emphasize the need for further research dedicated to clarifying the role of gene polymorphisms in antipsychotic treatment to enhance specificity and efficacy in the treatment of schizophrenia. Schizophrenia is a severe, chronic mental illness involving thinking, emotions, and behavior dysfunctions, resulting in impaired perception, social withdrawal, and loss of touch with reality. Individuals with schizophrenia often experience hallucinations, delusions, disorganized speech, and abnormal movements or behaviors. Pharmacological treatments available for schizophrenia vary in efficacy, with an estimated 34% of patients meeting the criteria for treatment resistance . ConsideThe brain-derived neurotrophic factor (BDNF) is one of the most studied members of the neurotrophin family, which includes neural growth factor (NGF) and neurotrophins 3 and 4, among others . The BDNAlterations in BDNF at both the gene and protein levels during brain development have been implicated in the myriad of abnormalities found in the brains of individuals with schizophrenia . The genIn this review, we aim to capture the current consensus and divergence in findings relating to the implication of the BDNF Val66Met polymorphisms in the clinical presentation of individuals who have schizophrenia. Data supporting the hypothesis that peripheric BDNF gene expression and protein levels reflect those in the brain hints at possible avenues of finding applicability of genetic polymorphism determination for prognosis, therapy monitoring and therapeutic response in schizophrenia .Our team systematically searched Pubmed, Embase, and Web of Science databases with the search terms: (BDNF gene polymorphism) AND (schizophrenia) for articles published in the last 5 years. The search provided 35 results from Pubmed, 134 results from Embase, and 118 results from the Web of Science database. To be selected for this review, articles had to report on studies where genotyping for the BDNF Val66Met polymorphism was performed in participants diagnosed with schizophrenia or schizophrenia spectrum disorders or first-episode psychosis. In addition, these studies also had to aim at analyzing for associations between the Val66Met polymorphism and risk for schizophrenia or with the clinical presentation of participants. After reading abstracts and removing articles that did not fit the criteria, 22 articles were selected to be included in this review seen in the PRISMA diagram .Twenty-two articles were selected for this scoping review, all reporting on studies involving participants with a schizophrenia or schizophrenia-related disorder, where an implication of the BDNF Val66Met polymorphisms in the disorder’s pathophysiology was sought to be elucidated. These studies looked not only at different polymorphism variants but also their interactions with other genes of interest and at different facets of the illness, in some instances highlighting associations with its most difficult symptoms – the negative ones. Since the first study announcing the isolation of BDNF as a new neurotrophic factor in the pig brain in 1982 , a consiRecent findings also suggest that gender and age impact how the BDNF Val66Met polymorphism contributes to neurodegenerative disease . The stun = 50 in kumar , as well as ethnicity, in-depth exploration of associations between the BDNF Val66Met polymorphism, its TrkB receptor and immune factors as well as peripheral levels of BDNF, and all this taking into account morphologic changes depicted through imaging investigations as well as the diurnal, seasonal and hormonal BDNF variations, medication interactions, metabolic and lifestyle factors. Identifying BDNF gene variants that lead to effective antipsychotic drug response could have crucial implications for patients and the clinical sector associated costs.The current review covered a wide range of studies exploring the implications of the BDNF geneVal66Met polymorphism in schizophrenia, published in the last 5 years. The Met/Met genotype was found to be associated with higher PANSS positive scores, the PANSS global scores in these cases also reflecting greater severity of illness. It was also associated with a history of suicide attempts. Consistent with previous studies, Met/Met homozygous individuals present with worse cognitive function and lower levels of serum BDNF.In the Val/Val genotype carriers, increased BDNF levels were correlated with weight gain under Risperidone treatment. However, due to the study’s small sample size depicting this, generalizations cannot be made. Future studies may take on the challenge of delineating genetic markers that could allow prediction for treatment response in schizophrenia.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Investigating factors associated with benign convulsions with mild gastroenteritis (CwG) is important for early detection and treatment. In previous studies, uric acid (UA) has been reported to be associated with CwG. However, the association between CwG and abnormal laboratory values remains inconclusive. We performed a meta-analysis of recent reports to determine the association between CwG and laboratory findings, including UA, in patients with acute gastroenteritis without convulsions.We conducted electronic searches of three databases  and one scholarly search engine ) up to February 2023 for studies on CwG. Eligible studies were observational studies that assessed patients with CwG, reported laboratory data, and stated the presence or absence of convulsions during illness episodes. Patients were children with mild gastroenteritis, with the exposure group developing convulsions and the control group not. The outcome was a comparison of laboratory data between the two groups. The effect size was calculated using the standardized mean difference (SMD), and random-effects models were used for the analysis because of high heterogeneity.2 = 81.68%, p= 0.002). The optimal serum UA cutoff value was 7.21 mg/dL, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.827 ).In total, 148 articles were included in this study. After the screening, nine studies, including 8,367 patients, were selected for the meta-analysis. The most prevalent laboratory finding was an increased serum UA level, with an SMD of 1.42 : ; Z = 9.242, p< 0.001; I This meta-analysis suggests that CwG is strongly associated with increased serum UA levels. These results demonstrate that more attention should be paid when interpreting laboratory findings in pediatric patients with acute gastroenteritis. Benign convulsions with mild gastroenteritis (CwGs) were first reported by Morooka  in 1982.Although the prognosis is good, repeated seizures cause panic in parents, and the child often requires hospitalization and acute care . FurtherOne characteristic of CwG is the absence of abnormal findings on clinical examination. No blood test result abnormalities have been reported -7. HowevInvestigating the factors associated with CwG is important for its early detection and treatment. However, the association between CwG and abnormal laboratory values remains inconclusive. We performed a meta-analysis to determine the association between CwG and laboratory findings in patients with acute gastroenteritis without convulsions and further validate the association between UA and CwG from previous papers.Material and methodsData SourcesEthical approval was not required as this was a retrospective analysis of previously published data. This study was conducted in accordance with the standard guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . Two autStudy SelectionPediatric patients diagnosed with acute gastroenteritis were included in this study. The exposure was CwG. We included participants with acute gastroenteritis without convulsions as study controls. The principal outcome of this analysis was the difference in blood test results between children with gastroenteritis, with or without convulsions.Data ExtractionData were extracted independently by two authors. The extracted variables were the author’s name, article title, journal name, publication year, study location, study design, sample size, and mean and standard deviation (SD) of laboratory data for acute gastroenteritis. The following keywords were used in our search strategies: (“convulsions with mild gastroenteritis” or “CwG”) and . Potentially eligible articles were assessed using inclusion and exclusion criteria. Studies that met all the following criteria were included: (1) observational studies reporting on patients with CwG, (2) studies reporting laboratory data, and (3) studies reporting the presence or absence of convulsions during an illness episode. Studies that met any one of the following criteria were excluded: (1) conference papers, (2) abstracts, (3) commentaries, (4) letters, and (5) insufficient or inaccurate information. We aimed to identify all relevant studies, regardless of their language or publication status (published or preprinted). Two authors independently assessed the risk of bias in the included studies using the Newcastle-Ottawa Scale (NOS) .Statistical Analysishttp://pymeta.com/). Cohen’s classification was used to interpret the magnitude of the effect size of the laboratory findings. SMD > 0.8 was considered large [I2 statistic, with heterogeneity estimates of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively [I2 statistic. IfI2 > 50%, a random-effects model was used. A standard method for detecting outliers defines a study as an outlier if its CI does not overlap with the pooled effect. Sensitivity analysis was performed to assess the possible causes of heterogeneity. All analyses were performed using R version 4.2.2.The pooled effect estimate was the standardized mean difference (SMD). All statistical analyses and figures were prepared in R language (the “meta” and “metafor” packages) and PyMeta  count, and Na and calcium (Ca) levels, on the final result.Subgroup AnalysisWe also conducted subgroup analyses to evaluate the etiology of the heterogeneity. Subgroup analyses were performed according to country.Publication BiasTo assess reporting bias, if at least 10 trials were available for a single intervention, we used funnel plots to examine the reporting bias for the primary outcome. However, the limited number of trials for each intervention precluded the use of this test.ResultLiterature Search and Study SelectionFigure Meta-AnalysisI2 = 86.32%, p < 0.001) , decreased chlorine (Cl) level ; Z = -3.989, p < 0.001; I2 = 57.44%, p = 0.052), and decreased WBC level ; Z = -6.217, p < 0.001; I2 = 0.00%, p = 0.428). Apart from this, minor significant differences were confirmed in the laboratory findings, including decreased hydrogen carbonate (HCO3- ) level ; Z = -5.053, p < 0.001; I2 = 0.00%, p = 0.504), increased aspartate transaminase (AST) level ; Z = 3.635, p < 0.001; I2 = 46.90%, p = 0.052), and decreased blood urea nitrogen (BUN) level ; Z = -2.859, p = 0.004;I2 = 0.00%, p = 0.887). No significant differences were observed in the C-reactive protein (CRP), potassium (K), Ca, glucose (Glu), alanine aminotransferase (ALT), and creatinine (Cre) levels. In particular, for UA, where the effect size was quantified as large (SMD > 0.8), a physiologically significant difference was considered to exist and subsequently analyzed , resulting in a percentage variation of approximately 5% in I2 ; Z = 7.258, p < 0.001; , 1.62; ZSensitivity analysis after removing the outlier verified no significant change in the pooled SMD Figure . TherefoMeta-Regression and Subgroup AnalysisHigh heterogeneity indicated unreliability; therefore, we performed further meta-regression analysis for numerical variables and subgroup analysis for categorical variables. The results of the univariate meta-regression analysis between effect size and possible contributors to heterogeneity were insignificant Table .For subgroup analysis, we classified the data into two subgroups by country. One was the Korean group, and the other was the Chinese group. We found heterogeneity between the Korean and Chinese subgroups (p = 0.012) Figure , suggestReceiver Operating Characteristic Curve (ROC)Moreover, we searched for the thresholds of serum UA levels that caused CwG in five articles that excluded the outlier. As shown in Figure Discussion3-, and BUN. UA had the highest SMD among these laboratory findings. Therefore, focusing especially on UA as a predictor of the onset of convulsions in CwG, we concluded that a serum UA level could be a useful marker .Our study is the first meta-analysis to examine laboratory findings using CwG as an exposure group. In this meta-analysis, the laboratory findings associated with CwG included increased levels of UA and AST, and decreased levels of Na, Cl, WBC, HCO3- levels [The association between abnormalities of blood test results and CwG is a controversial topic. Some studies have reported no blood test result abnormalities associated with CwG -7. Howev- levels  in CwG c- levels  reported- levels  reported- levels . Althoug- levels ,22, in a- levels . Hence, 3- [Hyperuricemia primarily results from underexcretion, which occurs via two primary pathways, the kidney (70%) and the intestine (30%) . Dehydra3- . In our Regarding the intestinal pathway, acute gastroenteritis can also cause hyperuricemia . A studyThis meta-analysis included papers from Japan, Korea, and China, primarily involving individuals of Asian descent -16. The The relationship between seizures and UA suggests that UA may contribute to seizure susceptibility ,31. ReseThe strength of our study is that it was the first meta-analysis to investigate the relationship between CwG and UA levels. In addition, we used sensitivity analysis to evaluate the evidence and identify specific reference values to predict CwG. However, this study has some limitations. First, all studies included were retrospective. This may have introduced several biases that could have affected the results. Second, a high degree of heterogeneity was observed among the studies. Third, articles from non-indexed and unpublished journals were not included, which may have resulted in publication bias. Fourth, this study has not been able to completely rule out other factors that may cause elevated UA, such as dehydration.Our results suggest that the most prevalent laboratory finding was an increased serum UA level with a large effect, and the optimal serum UA cutoff value was 7.21 mg/dL with moderate accuracy. Our report strongly supports the known finding of elevated UA levels in CwGs. This meta-analysis also showed that increased serum UA levels were significantly associated with CwG. As for the causal role of hyperuricemia in CwG, larger prospective studies with exposure to hyperuricemia and outcomes of CwG are needed.


Previous studies have not established potential causal associations between coffee and caffeine consumption in endometrial cancer (EC) and its subgroups. Therefore, we used a two-sample MR method to assess the causal association between coffee and caffeine consumption and EC risk. We also evaluated the association between these genetically predicted exposures and EC prognosis.p < 5 × 10–8. The EC Association Consortium (ECAC) performed a genome-wide association study (GWAS) analysis of 12,906 cases and 108,979 controls. FinnGen Consortium performed a GWAS analysis of 1,967 EC cases and 167,189 controls. The primary technique we employed was inverse-variance weighted, followed by the weighted median, MR-Egger regression, and MR robust adjusted profile score methods. We used the MR pleiotropy residual sum, Outlier test, and MR-Egger regression to assess Outlier and pleiotropic variants. We also conducted a sensitivity analysis through the leave-one-out method.This study used 12 and two independent single-nucleotide polymorphisms (SNPs) associated with coffee and caffeine consumption as instrumental variables at a genome-wide significance level of Genetically predicted coffee consumption was not associated with EC and its subgroups in the ECAC, and the association was consistent in the FinnGen consortium. After excluding eight SNPs with confounding factors, the study performed sensitivity analyses, delivering consistent results. We also observed that caffeine consumption was not correlated with EC risk. As confirmed by MR analysis, selected SNPs determined that most do not significantly impact the likelihood of developing EC.Our study indicated no convincing evidence supports coffee and caffeine consumption causing EC or impacting its prognosis. More studies are needed to validate the results. Endometrial cancer (EC) is one of the most common gynecologic malignancies. Its incidence was rising globally, with approximately 417,000 new cases in 2020  is a technique for assessing if an exposure factor has a causal effect on an outcome . MR streIn this investigation, we evaluated the causal association of coffee and caffeine consumption with the risk of EC and its subgroups using a two-sample MR approach. We also assessed the correlation between the prognosis for EC and these genetically indicated exposures.Genetic variations serve as instrumental variables (IVs) in MR analyses to establish the causal link between exposure and outcome . MR analP < 5 × 10–8) and independently   (P < 0.05 to ensure that IVs were not associated with the outcome (The 15 single-nucleotide polymorphisms (SNPs) correlated with coffee consumption, derived from a meta-analysis of four large-scale genome-wide association studies (GWASs), involved 375,833 individuals (UK Biobank and three US cohorts) of European descent  Supplem. The GWA,000 kb) , 18 assotrength) . To fulftrength) , 20. Fin outcome . In the  outcome .P < 5 × 10–8, independent, and strongly correlated with the F-statistic, and were used to perform MR analyses. Detailed information on SNPs related to coffee and caffeine consumption is shown in The two variants associated with caffeine consumption came from a meta-analysis of 6 GWAS and included 9,876 individuals of European ancestry  Supplem. A self-Endometrial cancer-related data were obtained from the Endometrial Cancer Association Consortium (ECAC) and the FinnGen Consortium. ECAC performed a GWAS analysis of 12,906 cases and 108,979 controls . To avoi1 consortium, which included 681,275 Europeans  was used as the primary statistical method. We used IVW with random effects to assess the relationships for genetically predicted coffee consumption. IVW fixed-effects models  were used to estimate the interactions between genetic prediction and caffeine consumption. We also performed the weighted median (WM) and MR-Egger regression methods . The IVWvalidity . We applvalidity . We also2), by the framework of MR analysis based on the Multi-Organomics Database of SUrvival-Related Cancers  and caffeine (the per 80-mg increase) in this study were 159 and 67, indicating that the IVs had sufficient instrumental strength. Furthermore, MR-PRESSO did not detect abnormal SNPs in preliminary and sensitivity analyses. We did not detect heterogeneity by IVW and MR-Egger regression.p < 0.05) in the causal relationship between two data sets and coffee consumption by MR-Egger: endometrioid endometrial carcinoma (EEC) in the ECAC consortium and EC in the FinnGen consortium (p > 0.05). Additionally, we performed random-effects IVW analyses on the ECAC data and FinnGen consortium data, resulting in no significant differences from the preliminary analyses . We also performed subgroup analyses, which showed that caffeine consumption was not a factor in the pathogenesis of EEC  and NEC . In the FinnGen Consortium data analysis, we also observed that caffeine consumption was not correlated with EC risk  .The study also performed a leave-one-out analysis, which excluded the effect of individual SNPs on the overall causal estimate by removing each SNP stepwise and repeating the MR analysis. The leave-one-out analysis showed relatively stable results after removing each SNP –4.P = 0.036) linked to coffee consumption, while the SNPs rs4410790  had the opposite effect. Additionally, coffee- and caffeine-consumption-associated SNPs rs4410790  and caffeine-consumption-associated SNPs rs73073176  were also identified to be associated with shorter cancer-specific survival (CSS)  in EC was positively associated with the SNPs rs1956218  .Our study did not find genetically predicted associations between coffee and caffeine consumption regarding the risk of EC and its subgroups. No outlier SNPs were detected, although preliminary analyses detected pleiotropy in individual groups. Leave-one-out analyses also showed relatively stable results. After excluding SNPs with confounding factors, the study performed sensitivity analyses that did not detect pleiotropy or heterogeneity, delivering consistent results. Furthermore, we found that most SNPs were not associated with EC prognosis by MR analysis.P = 0.297]. Moreover, a large prospective study (Previous research has been controversial regarding the association between coffee or caffeine consumption and the risk of EC. In recent times, a cross-sectional study  demonstrve study  investigve study . Meanwhive study , an incrve study , Lafrancve study  and Lukive study . DespiteRecently, there have been large-scale Mendelian randomization studies on coffee consumption and overall cancers, including EC, reported no causal relationship , 43. NevThe study also has several disadvantages. Individual groups had horizontal pleiotropy in preliminary analyses, yet after excluding SNPs with potential confounders, we performed sensitivity analyses with generally consistent results. Second, most studies on coffee and caffeine used self-report methodologies, which were prone to bias. In addition, in this study, we did not stratify the menopausal status of EC patients, which might have led to the effect of coffee and caffeine intake on the risk of OC being influenced by menopausal status. Our studies were based on European populations and may need to be more generalizable to others.Our MR investigation found no persuasive evidence to indicate a causal relationship between coffee and caffeine consumption and the risk of EC, and it was found to be largely irrelevant to the prognosis of EC. In the future, more clinical and basic studies are still needed to validate our results.The original contributions presented in this study are included in this article/ZC: Conceptualization, Data curation, Investigation, Methodology, Software, Validation, Writing—original draft. CL: Investigation, Methodology, Software, Supervision, Validation, Writing—original draft. JW: Conceptualization, Investigation, Validation, Visualization, Writing—original draft. FK: Formal analysis, Methodology, Project administration, Resources, Writing—review and editing.


However, rs966221 was not found to be correlated with IS risk in the populations of North, Central, South, and East China. Our meta-analysis demonstrated that the PDE4D rs966221 variant is significantly associated with IS risk in some regional Chinese populations.In published research that includes genome-wide association studies and meta-analyses, the phosphodiesterase 4D (PDE4D) rs966221 variant has been identified as a risk factor in ischemic stroke (IS) in the Caucasian population. Several studies have investigated the relationship between rs966221 and IS susceptibility in Chinese populations over the years but have not provided consistently conclusive results. Therefore, our team performed a new meta-analysis of 5973 IS patients and 6204 controls from qualified studies. We observed no significant link between the PDE4D rs966221 variant and IS in any of the regional Chinese populations. Thus, we performed a subgroup analysis by the geographical distribution of China. Notably, significant associations were observed between rs96622 and the susceptibility of IS in the Northeast Chinese populations ( Stroke is the second most important cause of death and the third most common cause of disability worldwide. According to the global statistics of stroke, ischemic stroke (IS) accounts for 62.4% of all types of stroke . BecausePhosphodiesterase 4D (PDE4D) is one of the proteins of the phosphodiesterase family and participates in the hydrolyzation of cyclic adenosine monophosphate (cAMP) . ResearcThe PDE4D rs966221 variant was first identified as a risk locus of IS in the Caucasian population in a genome-wide association study (GWAS) ,16. In tGiven these contradictory results, the relationship between rs966221 and IS in the Chinese population requires more study. To investigate the association between the frequency of the rs966221 genotype and the susceptibility of IS in the Chinese population, we performed a meta-analysis by combining data from previous case-control cohorts.http://www.ncbi.nlm.nih.gov/pubmed (accessed on 6 May 2023)), Google Scholar (https://scholar.google.com/pubmed (accessed on 6 May 2023)), the China National Knowledge Infrastructure (http://www.cnki.net/pubmed (accessed on 6 May 2023)), and the Wanfang Medicine database (http://www.wanfangdata.com.cn/pubmed (accessed on 6 May 2023)). We browsed all relevant studies using the following terms: “ischemic stroke”, “PDE4D”, and “Chinese or China”. Literature published before 15 October 2022 was selected for this study. As a first step, we performed a systematic literature search using information from four databases: PubMed  were human case-control studies, (2) included analyses of the association between the rs966221 variation and IS, and (3) provided sufficient information to allow calculation of an odds ratio (OR) and a 95% confidence interval (CI) for the rs966221 genotype. Studies not meeting these requirements were excluded.Third, the following data were independently extracted from studies by two investigators: (1) the name of the first author; (2) the year of publication; (3) the study population; (4) the number of IS cases and controls; (5) the genotype distribution of rs966221 in cases and controls; and (6) the OR with the 95% CI or the data used to calculate the OR and the 95% CI.p < 0.001. Finally, several statistical analyses were conducted. The chi-squared test was used to calculate the Hardy–Weinberg equilibrium of rs966221 in each study to prove that there is no difference in theoretical genotype frequencies and actual genotype frequencies. The significance level was established at The relationship between PDE4D rs966221 and IS was estimated using the additive genetic model . 2 statistic to conduct a heterogeneity test [χ2 distribution, with k signifying the number of studies selected in the calculation. A Cochran’s Q test p-value of less than 0.1 indicates significant heterogeneity between studies. The statistic I2 (I2 = (Q − (k − 1))/Q × 100%) indicates the percentage of variation across studies caused by heterogeneity. I2 ranges between 0 and 100% , with a higher percentage indicating a higher level of heterogeneity [We used Cochran’s Q test and the Iity test . The Q sogeneity ,28. p < 0.1 of the Q statistic and I2 > 50%), and a fixed effect model was utilized in the remaining cases. The statistical significance of the OR was examined using the Z test, and a p-value < 0.05 was deemed significant.A random effect model was employed for meta-analysis when heterogeneity was high ).Subgroup analyses were performed according to the seven geographical distributions of the Chinese population . The genetic clustering in different populations has a strong correlation with their geographical distribution, ethnicity, and family of languages . A sensip-value . A funnep-value . The sigUsing a systematic literature search process, we selected 37 articles from four databases. The search flow is shown in p = 0.115, OR = 1.15, 95% CI = 0.96–1.37).Because of the high heterogeneity of the rs966221 polymorphism within the studies, we used a random effects model to compute pooled ORs and 95% CIs. The meta-analysis results showed no significant relationship between PDE4D rs966221 and IS (2 = 98.6%) and East Chinese (I2 = 53.4%) populations. The remaining two regional populations did not show significant heterogeneity (I2 = 0%) and were, therefore, assessed using a fixed effect model. In Northeast Chinese populations, the results suggested significant associations between rs96622 and IS . However, no significant association was observed between rs966221 and IS in East Chinese , South Chinese , and Central Chinese  populations. Given that the 14 studies included in the meta-analysis were from different regions in China, we performed a subgroup analysis by region. In terms of the seven official geographic regions of China , we excluded a subgroup with multiple populations from North, Southwest, and Northwest China. Subgroups were populations from North, Central, South, East, and Northeast China. Data on populations in North China were insufficient to calculate the OR and 95% CI. We utilized a random effects model for calculation because of the high heterogeneity in the Central Chinese .A funnel plot was used to calculate the publication bias of the included studies. The funnel plot had an inverted, symmetrical shape, as shown in A member of the cAMP-specific PDE4 subfamily, PDE4D is reported to be distributed in a variety of cells, including vascular smooth muscle and immune cells . In the For the global population, the association between rs966221 and IS has not yielded consistent results, and the differences in different research results may be related to experimental design, sample size, ethnic differences, and environmental factors. In the Chinese population, the relationship between rs966221 and IS susceptibility has been reported in many studies. A study by Zhang et al. (2019) of 1,773 participants  from West China supported that PDE4D rs966221 was associated with a higher risk of IS . In a stLimitationFor further investigation, we screened previous articles and performed a new meta-analysis that included 5,973 IS patients and 6,204 controls from 14 studies in which seven studies had the conclusion that rs966221 was correlated with IS risk, whereas others reached opposite conclusions. Computed using a random effect model, the meta-analysis reported no significant association between PDE4D rs966221 and IS in the Chinese populations. Notably, we conducted a subgroup analysis by seven geographical regions of China and identified a significant association between rs96622 and IS observed in the Northeast Chinese population. In 2017, the team of Wang performed a population-based large-scale national survey of stroke, including 480 687 individuals in 31 provinces from seven official geographic regions in China, and researchers demonstrated that Northeast China had the highest incidence and mortality of stroke and ranked second in prevalence . For theAlthough we conducted meta-analyses that are effective studies of the association between rs96622 and IS in regional China, our study has several limitations. First, after the strict screening, the amount of original literature included in this meta-analysis is slightly insufficient. Furthermore, the cities involved in the original studies were limited to regional China. If possible, we will integrate more comprehensive and larger data based on the geographical distribution of China to further reveal the relation between rs96622 and IS susceptibility.In sum, our meta-analysis offers reliable evidence of the association between the PDE4D rs966221 variant and vulnerability to IS in regional Chinese populations and provides a new thought for early disease prevention.