Growing evidence suggests that individuals with anxiety disorder have an elevated risk of cardiovascular disease (CVD) but few studies have assessed this association independently of or jointly with depression.We conducted a prospective cohort study using UK Biobank. Diagnoses of anxiety disorder, depression, and CVDs were ascertained through linked hospital admission and mortality data. Individual and joint associations between anxiety disorder and depression and CVD overall, as well as each of myocardial infarction, stroke/transient ischemic attack, and heart failure, were analyzed using Cox proportional hazard models and interaction tests.Among the 431,973 participants, the risk of CVD was higher among those who had been diagnosed with anxiety disorder only , depression only , and both conditions  compared to those without these conditions, respectively. There was very little evidence of multiplicative or additive interaction. Results were similar for myocardial infarction, stroke/transient ischemic attack, and heart failure.Having anxiety is associated with the same magnitude of increased risk of CVD among people who do not have depression and those who do. Anxiety disorder should be considered for inclusion in CVD risk prediction and stratification, in addition to depression. Mental health disorders and cardiovascular disease (CVD) affect more than 600 and 400 million people worldwide, respectively , 2. One However, these studies did not assess the association of anxiety disorder with CVDs independently of and jointly with depression. Existing evidence has shown both that depression is associated with CVD –11 and tTo that end, our study aimed to examine the individual and joint associations of anxiety disorder and co-existing depression with a range of incident CVD  using the UK Biobank population cohort.We conducted a prospective cohort study using data from UK Biobank. UK Biobank recruited over 500,000 participants between 2007 and 2010 from the general population, aged 40 to 69 years. Participants visited one of the 22 assessment centers across England, Scotland, and Wales to provide their information and biological samples. We excluded participants who had experienced CVD, MI, stroke/TIA, or heart failure before the baseline assessment ascertained through either self-report or linkage to medical records and who were first admitted for anxiety disorder or depression after the baseline assessment.The exposures of interest were anxiety disorder and depression diagnosed before the baseline assessment and were obtained through record linkage to hospital admission data: Health Episode Statistics  and Scottish Morbidity Records (Scotland). We defined anxiety disorder as F40–43 and depression as F32–33, using the International Classification of Diseases, 10th revision (ICD-10).The outcomes of interest were incident  CVD, MI, stroke/TIA, and heart failure. The death certificate data were obtained from the National Health Service Information Centre  and the National Health Service Central Register Scotland (Scotland) and were available up to September 2021 in England and Wales, and October 2021 in Scotland. The hospital admission data were available up to September 2021 in England, July 2021 in Scotland, and February 2018 in Wales. Follow-up was censored at the date of relevant hospitalization or date of death, whichever occurred first. We defined CVD as an ICD-code of I20–25, I42.0, I42.6, I42.7, I42.9, I50, I60–64, and I110; MI as I21; stroke/TIA as I60–64 or G45, and heart failure as I42.0, I42.6, I42.7, I42.9, I50, or I110.2; height was measured to the nearest centimeter, using a Seca 202 stadiometer, and body weight was measured to the nearest 0.1 kg, using a Tanita BC-418 body composition analyzer by trained staff.Covariates included sociodemographic  and lifestyle  factors. Age, sex, and ethnic group were self-reported by participants using a touchscreen questionnaire at baseline. Deprivation level was based on tertiles of the Townsend area deprivation index, which was derived from the postcode of residence using aggregated data on unemployment, car and home ownership, and household overcrowding . AlcoholCox proportional hazard models were used to estimate the associations between anxiety disorder and depression and CVD outcomes, and the results expressed as HR and 95% CIs. Proportional hazard assumptions were checked by statistical tests based on Schoenfeld residuals. Separate models were run for each CVD outcome: overall CVD, MI, stroke/TIA, and heart failure. The main analyses comprised two stages. Firstly, the associations of each anxiety disorder and depression with CVD outcomes were analyzed by (1) univariable models, (2) multivariable models adjusted for sociodemographic confounders , and (3) multivariable models adjusted for both sociodemographic confounders and lifestyle factors . Because we could not establish the temporality between exposures and lifestyle factors, which could follow the exposure onset, we used models adjusted for sociodemographic confounders in the following analyses. Secondly, the individual and joint associations of anxiety disorder and depression with each of CVD, MI, stroke/TIA, and heart failure were determined, and multiplicative and additive interactions were tested. CVD outcomes were regressed on anxiety disorder, depression, their product term, and sociodemographic confounders. The HRs of anxiety disorders, depression, and their product term were used to estimate the individual and joint associations. The product term, and the relative excess risk due to interaction (RERI), were used to investigate the presence of multiplicative and additive interactions respectively. Missing values were < 5% and all analyses were complete case analyses.https://biobank.ndph.ox.ac.uk/showcase/refer.cgi?id=592) (Supplementary Table S1). All analyses were conducted using R (version 3.5.3) with packages survival (version 3.2-7) and interactionR (version 0.1.5).Two different sensitivity analyses were performed to assess whether the additional use of self-reported exposures or primary care-diagnosed exposures and outcomes (available for 45% of the participants) affected the results. The case ascertainment in primary care settings was based on the UK Biobank Read codes mapping (UK Biobank was approved by the North-West Multi-Centre Research Ethics Committee (Ref: 11/NW/0382). The investigation conforms to the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study. This work was conducted under the UK Biobank application number 7155.Of the 502,413 UK Biobank participants who had not withdrawn from the study and could be linked to hospital admission/death data, 35,058 were excluded because they had CVD before the baseline assessment and 35,382 were excluded because they developed depression or anxiety disorder after the baseline assessment. Consequently, 431,973 participants were included in the analyses .Figure 1Supplementary Table S2).Overall, 428,296 (99%) had no anxiety disorder or depression, 911 (0.2%) had anxiety disorder only, 2,427 (0.6%) had depression only and 399 (0.1%) had both anxiety disorder and depression . ParticiWhen adjusted for sociodemographic factors, both anxiety disorder and depression were associated with increased risk of CVD, MI, stroke/TIA, and heart failure . AdditioAnxiety disorder was associated with CVD, MI, stroke/TIA, and heart failure independently of and jointly with depression when adjusted for sociodemographic factors . The risSupplementary Table S3). Similarly, the addition of primary care data showed individual and joint associations with MI (Supplementary Table S4).In the sensitivity analysis, the addition of self-reported anxiety disorder and depression attenuated overall associations but there were individual and joint associations of both conditions with overall CVD  using the UK Biobank population cohort. Anxiety disorder and depression were associated with incident CVD independently of each other and their co-existence was associated with a higher risk than either condition in isolation. However, there was no evidence of interaction implying that the sum of their individual associations with CVD was almost identical to their joint association based on RERI. Therefore, having anxiety contributes to the same relative excess risk of CVD regardless of whether depression is also present.Our findings would be consistent with different mechanisms by which anxiety disorder and depression potentially increase CVD risk. This would be biologically plausible based on previous studies suggesting different brain structures between these conditions –22. For Our findings are consistent with previous evidence that has suggested similar individual and joint associations of anxiety disorder and depression with CVD risks , 24 but There are some limitations to our study. First, ascertainment of anxiety disorder and depression using hospital admission may be incomplete and less likely to include people with less severe conditions since they are often treated in primary care settings . HoweverOur findings suggest that anxiety disorder and depression may increase the risk of CVD independently of each other. As we are facing an increasing number of people living with anxiety disorder, their higher risk of CVD should be noted. In recent years, some CVD risk prediction algorithms  have included depression . Given tWe examined the individual and joint associations of anxiety disorder and depression with incident CVD, MI, stroke/TIA, and heart failure among the middle- and old-aged UK population using the linkage of UK Biobank to hospital admission and mortality data. We found a higher risk of CVD among those with anxiety disorder only and depression only and the highest risk among those with both conditions, but no evidence of interaction on multiplicative or additive scales. This implies that the sum of their individual associations with CVD was almost identical to their joint association and therefore having anxiety contributes the same relative excess risk of CVD regardless of the presence of depression. One explanation is the existence of different mechanisms by which anxiety disorder and depression increase the CVD risk and this requires further research. Meanwhile, as has happened with depression, anxiety should be considered for inclusion in CVD risk prediction and stratification.


Non-pharmaceutical interventions (NPIs), such as social distancing and hand washing, have been associated with a decline in the preterm birth rate worldwide. We aimed to evaluate whether the preterm birth rate in Korea during the coronavirus disease 2019 lockdown has changed compared to that in previous years.A birth registry from the Korea Statistical Information Service, which is a nationwide official database, was used to include all births claimed to have occurred between 2011 and 2020. Newborns with gestational age (GA) less than 22 weeks and birth weight less than 220 g were excluded. The pre-NPI period was designated as January 2011 to January 2020, and the NPI period was defined as February 2020 to December 2020. We assessed the effect of NPI on the incidence of prematurity per 100 births using an interrupted time-series quasi-experimental design and implementing an autoregressive integrated moving average (ARIMA) model.P < 0.001). The ARIMA model showed that in all singleton and multiple births, except those in July , September , and December , most observed values were within the 95% PI of the expected values and showed an increasing trend.From 2011 to 2020, a total of 3,931,974 live births were registered, among which 11,416 were excluded. Consequently, the final study population included 3,920,558 live births (both singleton and multiple births) among which 275,009 (7.0%) were preterm. The preterm birth rate was significantly higher during the NPI period (8.68%) compared to that in the pre-NPI period (6.92%) (In this nationwide observational study, the trend in premature birth rate did not significantly change due to NPI implementation in Korea, as it had been increasing since 2011. The trend of Korea's birth rate appears to be unaffected by the implementation of NPIs; however, further studies with a longer follow-up period are needed. After the first quarter of 2020, most countries decided to implement non-pharmaceutical interventions (NPIs) to prevent the spread of COVID-19 .Preterm labor is defined as labor that starts before 37 weeks of pregnancy. The estimated global preterm birth rate in 2014 was 10.6%, and this was similar in Asia, where a 10.4% preterm birth rate was reported . SeveralInvestigators in Tennessee first identified an association between NPI and preterm birth after the COVID-19 pandemic . Birth r2.2.1.Birth registry data from the Korean Statistical Information Service  was used to include information on all births between 2011 and 2020 . Parents2.2.This was a retrospective, observational study that evaluated the change in preterm birth rates after the implementation of NPI. After the first confirmed case of COVID-19 in Korea on January 20, 2020, the government imposed mitigation measures, such as social distancing and restricted overseas travel, in February 2020. In this study, the NPI period was defined as January 2011 to January 2020 and the pre-NPI period as February 2020 to December 2020. Although only live births are meant to be registered, we observed 11,416 cases in the categories of gestational age (GA) less than 22 weeks and birth weight less than 220 g . These c2.3.As per the World Health Organization's definition, in this study, preterm birth was defined as births with a GA < 37 weeks . Subgrou2.4.Categorical variables were expressed as frequencies (%) and compared using the Chi-square test. Odds ratios of preterm births by birth types, such as singletons and multiples, and GA subgroups were calculated using multivariable logistic regression analyses between the defined pre-NPI and NPI periods after adjusting for maternal age, sex, maternal education, and birth order.auto.arima in the forecast package in R  and R Statistical Software .We assessed the effect of NPI on preterm birth rates and prematurity incidence per 100 births using an interrupted time-series quasi-experimental design . To accoage in R . Using tAdditionally, to compare the results using different statistical methods, segmented regression analysis was performed for statistical modeling of interrupted time series to evaluate whether the trend changed during the NPI period , 18. The2.5.This research was conducted ethically, in accordance with the World Medical Association and Declaration of Helsinki, and the institutional review board (No. 4-2021-0416) approved the study.3.P < 0.001). Additionally, the proportion of low-birth-weight neonates, with birth weight under 2,500 g, especially in the subcategory of 1,500 g to less than 2,500 g , was higher in the NPI period compared to the pre-NPI period. Detailed demographic features of the study populations for both periods are shown in The final study population included 3,920,558 births, of which 275,009 (7.0%) were preterm . A sligh3.1.The observed and expected preterm birth rates were plotted in 3.2.P < 0.001) and a similar trend was observed in the multivariate analysis . (Preterm births (including both singletons and multiple births) increased in the NPI period when compared to the pre-NPI period (odds ratio (OR) = 1.25, 95% CI, 1.23–1.27,  0.001).  When pre3.3.We summarized and compared the results of previous international studies on whether there was a change in the preterm birth rate due to NPI implementation . Overall4.In this study, we aimed to establish whether a correlation exists between preterm birth rates and the NPI period in Korea in 2020. Our findings showed that the preterm birth rate was increasing in the pre-NPI period, and this continued to increase after the implementation of such measures, suggesting an unclear impact of NPI implementation on the preterm birth rate.Preterm births have been increasing in most developed countries, including South Korea. The percentage of preterm births in the United States increased from 9% in 1981 to 10.5% in 2021 , 32. SimThe etiology of preterm delivery can be broadly categorized into three main groups: (1) spontaneous preterm labor; (2) maternal or fetal infections; and (3) premature preterm rupture of the membranes . EtiologIn contrast to our findings, many international data-based studies supported a negative association between NPI and preterm birth that were investigated up to the first quarter of 2020. In the United States, Gemmill et al. reported a decline in preterm birth rate during the pandemic, especially during the early and late 2020 . Oakley 4.1.Owing to the lack of confirmed etiologies for preterm births, the decline in preterm births during pandemic lockdowns could simply be a coincidence. On the other hand, further investigating this potential association could lead to more effective measures to prevent preterm births. Cohort data from other countries with lockdown periods during the pandemic showed a potential decrease in preterm births during the pandemic; however, they only investigated a short period of time after the NPI, mostly the first three months of 2020. This contrasts with our study, with data collection over a large period, in which we found no significant relationships between NPI implementation and preterm birth. Another limitation to our study is the lack of individual patient data in our database. For instance, the database does not include information on the cause or type of preterm birth, such as an underlying maternal or fetal condition (“indicated preterm birth”) or preterm rupture of membranes or cervical dilatation (“spontaneous preterm birth”). Consequently, it is difficult to correlate NPI with a specific type of preterm birth. However, because NPI could affect the maternal or fetal environment in multifaceted ways, differentiating the type of birth in the analysis may not have necessarily provided additional helpful information. However, to improve the quality of the database, further collection of National Health Insurance Data and the Korean Developmental Survey Data is required in the future. As a result of these limitations, we cannot definitively conclude that a causal relationship between COVID-19 mitigation measures and preterm birth rate exists.5.In conclusion, we were unable to establish a significant relationship between the NPI and pre-NPI preterm birth rates in South Korea. The overall South Korean preterm birth rate continues to increase, and this contributes to the country's disease burden. Future research should ideally aim to investigate whether there are more significant variables that could affect preterm birth rates, as well as how clinicians can reduce these factors and ultimately decrease the rate of preterm births.


This meta-analysis aimed to compare the prognostic between lobectomy and sublobar resection in patients with stage I non-small cell lung cancer (NSCLC).We conducted a detailed search in PubMed, Embase, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) comparing the prognosis of lobectomy and sublobar resection for stage I NSCLC, with the primary outcomes being overall survival (OS) and disease-free survival (DFS).A total of 2222 patients were included in the 5 RCTs. The results showed no statistical difference in OS  and DFS  between patients who underwent lobectomy and sublobar resection during the total follow-up period. In terms of dichotomous variables, there were no statistical differences in OS  and DFS  between the two groups during the total follow-up period, as well as 5-year OS  and 5-year DFS . In addition, subgroup analysis showed a better prognosis for non-adenocarcinoma patients with sublobar resection than lobectomy , but also an increased cause of cancer death (not limited to lung cancer) .Our results showed that for stage I NSCLC, lobectomy is usually not a justified operation.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023407301, identifier CRD42023407301. LobectoLiu et al. published a meta-analysis in 2014 comparing OS between lobectomy and sublobar resection in stage IA NSCLC, including 12 studies from 1993 to 2013 and found that OS was not as robust with sublobar resection as with lobectomy . In 20212This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement: an updated guideline for reporting systematic reviews , registe2.1From the time of database establishment to March 2023, two researchers conducted a systematic and exhaustive screening of PubMed, Embase, Web of Science, and the Cochrane Library databases for articles on lobectomy and sublobar resection for NSCLC, using the following keywords:((lobectomy OR lobar resection) AND ((sublobar resection OR limited resection) OR (wedge AND segmentectomy)) AND ((lung cancer OR pulmonary cancer OR carcinoma of lung OR pulmonary carcinoma OR lung carcinoma OR lung neoplasms OR lung adenocarcinoma OR cancer of lung)). In particular, references to relevant literature were manually searched to avoid omitting any potentially relevant studies.2.2According to the PICOS principles, the criteria for inclusion in the studies were as follows: 1) patients were diagnosed with clinical stage I NSCLC , sublobar resection was extended to lobectomy if N1 disease is found during surgery; 2) intervention and control were sublobar resection and lobectomy; 3) outcomes of relevant included but were not limited to OS, DFS, recurrence rate, etc.; and 4) the included studies belong to the RCTs.The exclusion criteria for this study were: 1) the full text of the study was not available; 2) the study data were not available, including the protocol; 3) when updating published articles for the same study cohort, studies that included the most recent or largest population were selected.2.3Data extraction was performed independently by 2 researchers according to a pre-designed form. For eligible studies, the following relevant information was extracted: 1) study characteristics: author, year of publication, country, sample size, and registration number; 2) participant characteristics: including tumor stage, histological typing, age, gender, follow-up time, etc.; and 3) survival outcomes applied for comparison.2.4Two researchers used the Cochrane Collaboration’s tools to assess the quality of RCTs. Three indicators of “high risk”, “low risk”, and “unclear risk” were used to assess random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. Two researchers, after discussion, will discuss and resolve differences in the evaluation, and bring in a third person when necessary.2.52 statistic; I2>75% was considered severe heterogeneity, >50% and <75% high heterogeneity, >25% and <50% moderate heterogeneity, and <25% low heterogeneity. Due to the diversity of the population included in this study, a random-effects model was used uniformly to combine the results with the premise of improving the credibility of the results. A p-value <0.05 in a two-sided test is statistically significant  and 95% confidence interval (CI) were used to evaluate continuous variables, and the relative risk (RR) and 95% CI were used to evaluate dichotomous information. Heterogeneity was calculated with the Inificant , and sen33.16334 records were retrieved across the four databases using the set search strategy and no additional records were retrieved from other sources. After removing duplicates, 3064 records remained, and 2964 irrelevant articles were excluded by reviewing the titles and abstracts of the articles. After browsing the complete text, 95 articles were excluded, of which 88 were not RCTs, 5 due to duplication of data sources, 1 for being a research protocol, and 1 owing to unavailable data. In the finals, 5 RCTs , 11–14 wBetween 1995 and 2023, 5 RCTs compared survival outcomes of patients with stageINSCLC after lobectomy and sublobar resection. Of all patients, 1100 underwent sublobar resection, and the other 1122 underwent lobectomy. In three studies, sublobar resection included both segmental and wedge resection; the remainder included only segmental resection. In addition, all but one of the studies were for stage IA NSCLC with follow-up beyond 5 years and all provided OS and DFS. The characteristics of the studies included in this meta-analysis are outlined in 3.2The quality assessment of the included studies is presented in 3.32 = 75%, p=0.018). Five studies offered 5-year OS, and the results showed no difference in 5-year OS between the two groups  .Three studies reported HR for OS in patients with stage I NSCLC who underwent sublobar resection versus lobectomy throughout the follow-up period, with pooled results indicating no difference in OS  Figure 22 = 0). Moreover, from the perspective of dichotomous variables, there was also no difference in DFS among the two groups at the overall follow-up   Figure 43.4Predefined subgroup analyses were performed, as detailed in 4Our results showed no difference in prognosis between patients with stage I NSCLC who underwent lobectomy and sublobar resection, using OS and DFS as the primary endpoints. Previously, the results of Nakamura et al. showed that the two surgical approaches were comparable in terms of OS , which iSince the publication of the results of the LSCG trial in 1995 , lobectoOur study showed no difference between the lobectomy and sublobar resection in OS and DFS over the total follow-up period in terms of the HR and the dichotomous variable perspective; 5-year OS and 5-year DFS were also comparable in terms of the dichotomous variable perspective. This may be due to the better prognosis of patients with stage I NSCLC, with data showing that the 5-year survival rate of patients with stageINSCLC in the United States was about 70% between 2001 and 2017 . Other sIn addition, the low rate of lymph node metastasis in stage I NSCLC may also be another factor, with the results of related studies showing that the rate of lymph node metastasis in stage I NSCLC ranges from 3.2% to 14.5% –27. An RRegarding the effect of gender on OS after two surgical approaches, the results of Kim et al. showed that gender was not a factor affecting the survival rate of both surgical modalities  and a prConcerning histological staging, our meta-analysis showed that for non-adenocarcinoma in stage I NSCLC, OS was better and statistically significant for sublobar resection than with lobectomy. In contrast, for adenocarcinoma, there was no difference in OS between lobectomy and sublobar resection. This may be attributed to the fact that adenocarcinoma is more often seen in women, and most of its occurrence is not due to tobacco, but more likely to the increased inhalation of oil-based cooking fumes, household pollutants, and industrial dust , and oneRegarding the cause of death, the results of this study showed that the number of cancer deaths (not limited to lung cancer) was higher with sublobar resection than with lobectomy, with statistically significant results. Lung cancer probably accounts for the majority of the deaths. In addition to the possibility that cancer cells remaining at the surgical margin, it is also possible for lung cancer to spread through the air space (STAS). In 2015, the WHO defined “STAS” as the invasion of the airspace around the lung parenchyma by micropapillary, solid nests, or clusters of single cells beyond the tumor margin . Mino-KeBesides, according to WHO statistics in 2019, cardiovascular disease has become the number one cause of death worldwide. Thus, considering competing mortality rates, survival rates for early-stage lung cancer are high, reaching 70% , while mThere are some limitations to this study. A total of 5 RCTs to date were included to compare the prognosis of lobectomy and sublobar resection. The small number of articles makes them more susceptible to chance. More detailed subgroup analyses, such as the effect of race, age, and thoracoscopic surgery on OS, or the differences between the different types of sublobar resection and their indications are difficult to perform because of the limited nature of the data. Large samples of RCTs and more detailed data are still needed for more detailed subgroup analyses of groups, specific staging, and histology for specific surgeries, leading to more specific conclusions. Due to differences in the populations included in the study, there was some heterogeneity in some of the results.In conclusion, this meta-analysis showed that for stage I NSCLC, lobectomy is usually not a justified operation. Gender was not a factor affecting OS for lobectomy and sublobar resection in stage I NSCLC, and sublobar resection in non-adenocarcinoma patients had a better OS, but at the same time, sublobar resection might increase the risk of cancer death (not limited to lung cancer).The original contributions presented in the study are included in the article/GL: Writing – original draft, Conceptualization, Methodology. ZX: Writing – original draft, Methodology, Software. YZ: Data curation, Software, Writing – original draft. SD: Data curation, Methodology, Software, Writing – original draft. FT: Resources, Validation, Writing – original draft. RJ: Data curation, Methodology, Software, Writing – original draft. MD: Data curation, Validation, Writing – original draft. QZ: Resources, Validation, Writing – original draft. DZ: Conceptualization, Supervision, Validation, Writing – review & editing.


Navigation is a complex cognitive process. CRY2 gene has been proposed to play an important role in navigation behaviors in various non-human animal species. Utilizing a recently developed neuroimaging-transcriptomics approach, the present study reported a tentative link between the CRY2 gene and human navigation. Specifically, we showed a significant pattern similarity between CRY2 gene expression in the human brain and navigation-related neural activation in functional magnetic resonance imaging. To further illuminate the functionality of CRY2 in human navigation, we examined the correlation between CRY2 expression and various cognitive processes underlying navigation, and found high correlation of CRY2 expression with neural activity of multiple cognitive domains, particularly object and shape perception and spatial memory. Further analyses on the relation between the neural activity of human navigation and the expression maps of genes of two CRY2-related pathways, i.e., the magnetoreceptive and circadian-related functions, found a trend of correlation for the CLOCK gene, a core circadian regulator gene, suggesting that CRY2 may modulate human navigation through its role in circadian rhythm. This observation was further confirmed by a behavioral study where individuals with better circadian regularity in daily life showed better sense of direction. Taken together, our study presents the first neural evidence that links CRY2 with human navigation, possibly through the modulation of circadian rhythm. Navigation is of pivotal importance for survival. Previous studies have suggested that spatial navigation is highly inheritable , 2 and gOne candidate is Cryptochromes that are highly conserved across animals and associated with navigation in insects and migratory birds e.g., , 8]. Alt. Alt8)].To do this, we ran an integrative study by combining gene expression data in the human brain, large-scale neuroimaging meta-analysis activation maps, and behavioral test data to examine the potential link between CRY2 and human navigation. Specifically, we examined the pattern similarity of CRY2 expression in human brain and the brain functional activation in navigation-related tasks. A similar approach that combines neuroimaging and gene expression atlas  has successfully linked genes with functional activation patterns , functiohttp://www.brain-map.org) is a publicly available online resource for gene-expression data. The atlas characterizes gene expression  in postmortem human brain based on genome-wide microarray-based measurement, for more than 20,000 genes at ~500 sampling sites distributed over the whole brain , suggesting that the significant correlation could be generalized beyond the six donors. To examine the robustness of the observed correlation, we established a null distribution of inter-donor repetition of gene expression-navigation correlation, that is, the number of donors whose CRY2 expression level significantly  correlated with the activation map of a random sample of fMRI studies. The null distribution was positively skewed . Importantly, we found that the number of repetitions among donors (six out of six) in the CRY2-navigation correlation were among the extreme 3.1% in this distribution, which suggested that this correlation was unlikely to be caused by chance (p = 0.031). In short, regions with a higher level of CRY2 gene expression were more likely to be activated in navigation-related tasks, suggesting a tentative link between the CRY2 gene and human navigation.We first examined the similarity between the expression map of CRY2 in the brain and the map of navigation-related activation  = 7.31, p = 0.001, SD = 0.025, ps < 0.02). Specifically, the standardized expression level of CRY2  entered the resultant models for four out of six donors (ps < 0.045), the standardized expression level of S100B  was accepted for five out of six donors (ps < 0.002), while the interaction term was significant for two out of six donors (ps < 0.009). Pulling together the beta coefficients of all donors, the approximate random effect analysis revealed that the beta coefficient of expression levels of CRY2 was significantly larger than 0  and those of S100B smaller than 0 . In contrast, the beta coefficients of CRY2-S100B interaction term was not significantly different from 0 (p = 0.175). These results together suggested that CRY2 and S100B independently contributed to navigation-related activation.We also found that the expression level of CRY2 across the brain was negatively correlated with that of the navigation-related S100B for each donor [betaTo further explore which component of navigation is associated with CRY2, we examined nine domains  that may be relevant to navigation. Specifically, we examined the correlation between CRY2's expression map with the fMRI activation map of each of these domains extracted from the Neurosynth database . The results were presented in p = 0.006, repeated in five out of six donors; PER2, averaged beta = 0.057, p = 0.045, repeated in four out of six donors; NPAS2: averaged beta = 0.072, p = 0.013, repeated in four out of six donors; TIMELESS: averaged beta = −0.054, p = 0.030, repeated in five out of six donors. The navigation-expression correlation was not significant for the rest core clock component genes  (puncorrecteds > 0.10). Among the genes that showed significant correlation, the CLOCK gene survived FDR correction for the multiple comparison correction (q = 0.05).As for the circadian aspect of CRY2, we focused on a set of circadian regulation genes , including CLOCK, CRY1, ARNTL, PER1, PER2, PER3, CSNK1D, CSNK1E, NPAS2, TIMELESS, and ARNT2 , a core component of navigation, after controlling for sex , presumably due to the close functional relevance between navigation and memory. In contrast, the correlations in perception and social cognition were restricted to subdomains presumably relevant to navigation. For instance, in the domain of Perception, object perception that is related to scene and landmark perception in navigation yielded robust correlation; in contrast, face perception was not robustly correlated with CRY2 expression. In addition, self-referential in the social cognition domain had robust correlation with CRY2, probably due to the involvement of egocentric navigation –41; howeOur study further demonstrated that the association between the CRY2 gene and navigation might be realized through circadian-regulation, not magnetosensing-related, function of CRY2. Previous studies have shown that circadian regulation is a well-established function of human Cryptochromes , 17, andin vivo, possesses the biochemical properties necessary for sensing magnetic field, and might still have the functional potential for this purpose , the Fundamental Research Funds for the Central Universities (2019NTSS27 and 2021XZZX006), Shenzhen Institute of Artificial Intelligence and Robotics for Society (AC01202005022), and the National Basic Research Program of China (2018YFC0810602).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Gastrointestinal (GI) bleeding is a common clinical condition that can be caused by a variety of reasons. Bleeding can occur anywhere in the GI tract, and it usually presents as vomiting of blood, melena or black stools. We herein present a case of a 48-year-old man who was ultimately diagnosed with perforation of the lower ileum, pseudoaneurysm of the right common iliac artery, lower ileum-right common iliac artery fistula, and pelvic abscess caused by accidental ingestion of a toothpick. This case suggests that accidental ingestion of a toothpick may also be the cause of GI bleeding in some patients. For patients with unexplained GI bleeding, especially those with small bowel bleeding, a rational and combined use of gastroduodenoscopy, colonoscopy, unenhanced and contrast-enhanced abdominal CT can help detect the causes of GI bleeding and improve diagnostic accuracy. Gastrointestinal (GI) bleeding is a common clinical condition that includes mainly upper and lower GI bleeding. Bleeding can occur anywhere in the GI tract, whereas bleeding from the small intestine is relatively uncommon, accounting for ~5–10% of all patients with GI bleeding –4. Howev12/L, hemoglobin level of 51 g/L, platelet count of 151 × 109/L, white blood cell count of 7.1 × 109/L. Fecal occult blood tests were positive (+), the results of other laboratory tests were normal. The patient's condition improved after receiving hemostasis, acid suppression, gastric protection therapies, fluid replacement, and infusion of red blood cell suspension (400 mL).A 48-year-old male was presented to our hospital during the Chinese Spring Festival period with the chief complaint of melena for 10 days. He underwent both gastroduodenoscopy and colonoscopy in the local hospital, but no definite bleeding site was identified. He received hemostatic therapy and discharged after his condition improved. One day ago, the patient presented with melena again, and then visited our hospital. He had received surgical treatment for appendicitis 20 years ago and had a 30-year history of alcohol consumption (about 150 g/day). He had no previous history of liver diseases, coagulation disorders, GI bleeding, taking non-steroidal anti-inflammatory drugs (NSAIDs) or familial diseases. On admission, his body temperature was normal, blood pressure was 94/44 mmHg, with a heart rate of 106 beats/min. Physical examination showed an anemic face with pale skin and palpebral conjunctiva, mild tenderness in the lower abdomen, and no rebound pain. Routine blood test demonstrated a red blood cell count of 1.63 × 1012/L, hemoglobin of 45 g/L, platelet count of 129 × 109/L, and white blood cell count of 4.6 × 109/L. The patient's condition was stabilized (blood pressure of 102/56 mmHg and heart rate of 98 beats per minute) after volume expansion therapy, fluid replacement, and infusion of red blood cell suspension (400 mL) and frozen plasma (200 mL).After a day of admission, the patient suddenly had bright red blood in his stool , his blood pressure had dropped to 80/40 mmHg, with a heart rate 115 of beats/min. Routine blood test was performed again and revealed a red blood cell count of 1.55 × 10To further clarify the etiology of the bleeding, unenhanced and contrast-enhanced abdominal computed tomography CT) were performed. Unenhanced abdominal CT revealed encapsulated effusion in the middle part of the pelvic cavity, pelvic abscess was considered  and Web of Science databases using the keywords “Pseudoaneurysm” and “Toothpick” on March 8, 2023, only 2 related published literatures were identified , 11. NevIt is currently difficult to diagnose GI bleeding, and the diagnosis of small bowel bleeding due to foreign body ingestion is even more challenging, because most patients cannot recall a history of foreign body ingestion. Gastroduodenoscopy and colonoscopy are the methods of choice for the initial diagnosis and treatment of GI bleeding in patients . Due to According to the algorithm for suspected small bowel bleeding proposed by a newly published guideline , if signTherefore, for patients with unexplained GI bleeding, when the sites and causes of bleeding are not clearly identified during gastroduodenoscopy and colonoscopy, rational and combined use of VCE, enteroscopy, unenhanced and contrast-enhanced abdominal CT, CTE, MRE, CTA, DSA, and radionuclide methods should be considered by clinicians, and exploratory laparotomy can also be performed if necessary . UnenhanIn our case, the patient was not identified the exact site and etiology of GI bleeding with the initial gastroduodenoscopy and colonoscopy examinations. However, in the subsequent CT examination, it was found to be a foreign body in the patient's small bowel. This indicates that a rational and combined application of gastroduodenoscopy, colonoscopy, and CT can help detect the causes of GI bleeding and improve diagnostic accuracy.In our patient, a portion of the ileum (~30 cm in length) was removed. This was based on the reasons that the toothpick had caused multiple perforations (5 perforation sites) in the lower ileum, and severe inflammatory edema occurred at the sites of perforation, with localized and encapsulated abscess formation. The patient also underwent a stent placement procedure to treat the right common iliac artery pseudoaneurysm. This treatment method was consistent with our previous study . After tIn conclusion, this case suggests that accidental ingestion of a toothpick may also be the cause of GI bleeding in some patients. For patients with unexplained GI bleeding, especially those with small bowel bleeding, a rational and combined application of gastroduodenoscopy, colonoscopy, unenhanced and contrast-enhanced abdominal CT can help detect the causes of GI bleeding and improve diagnostic accuracy. After an accurate diagnosis, appropriate management can be performed.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study was approved by the Institutional Ethics Committee of the Suining Central Hospital. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.YX, JY, and GY participated in the study design and writing of the manuscript. GY, LF, YL, and SH participated in clinical data collection and analysis and carried out the interpretation of the CT images. GY, RL, GT, and BF revised the paper critically for intellectual content. All authors read and approved the final manuscript.


Serum creatinine is associated with cardiovascular risk and cardiovascular events, however, the relationship between serum creatinine levels and cardiovascular risk is not well established in hypertensive population in Jiangsu Province. We aimed to evaluate the association of serum creatinine levels with traditional cardiovascular risk factors and 10-year cardiovascular risk in a Chinese hypertensive population.Participants were patients with hypertension registered and enrolled in health service centers in 5 counties or districts from January 2019 to May 2020 in Jiangsu Province of China followed strict inclusion and exclusion criteria, demographics as well as clinical indicators and disease history and lifestyle were collected. Participants were divided into four groups according to quartiles of serum creatinine levels, then the China-PAR model was used to calculate 10-year cardiovascular risk for each individual.P < 0.05). Multivariable logistic regression showed that serum creatinine in the Q4 group compared with that in the Q1 group was positively associated with overweight and obesity , while negatively associated with physical activity , and so on. Multiple linear regression showed 10-year cardiovascular risk is positively associated with serum creatinine levels after adjusting for multiple risk factors .A total of 9978 participants were enrolled in this study, 4173(41.82%) were males. The blood pressure level and prevalence of dyslipidemia, elderly, current smokers and drinking as well as obesity were higher in the Q4 group than the Q1 group (all Serum creatinine was associated with several traditional cardiovascular risk factors and the 10-year cardiovascular risk in hypertensive patients. Creatinine-reduction and kidney-sparing therapy are essential for patients with hypertension to optimize control of cardiovascular risk. In clinPrevious studies have shown that slight changes in serum creatinine incrementally associated with increased risk for CVD such as coronary heart disease and heart failure , 7, but The prediction model for atherosclerotic cardiovascular disease (ASCVD) risk in China (China-PAR) has been validated in several Chinese population cohort, which is considered to be a suitable cardiovascular risk prediction model for Asians –12. BaseTherefore, the aim of our study is to estimate the association between serum creatinine levels and traditional cardiovascular risk factors and 10-year cardiovascular risk based on data from a hypertensive population in Jiangsu Province of China, in order to provide references for the prevention of CVD in hypertensive patients with higher creatinine levels.22.1Five representative counties or districts in Jiangsu province were selected by multistage stratified random sampling method according to the characteristics of regional economic development , population distribution and lifestyle to ensure the representativeness of research participants. Participants with essential hypertension were registered and enrolled from 50 towns or communities (10 towns or communities were randomly selected according the Random number table method from each counties or districts) in health service centers from January 2019 to May 2020 in Jiangsu Province of China followed strict inclusion and exclusion criteria. Participants aged 40-70 years old, continued residence in registration location for more than half a year, and voluntarily signed informed consent were included. The exclusion criteria were lacking of basic information, diagnosed with secondary hypertension or coronary heart disease, stroke and heart failure and other CVD, used serum creatinine-lowering agents or other drugs that may affect creatinine levels and inability or unwillingness to participate in the survey. A total of 9978 participants with essential hypertension were included in the final analysis Figure 12.2The participants are required to control diet and not to over eat meat or do strenuous exercise within three days prior to the measurement. Blood samples were obtained from an antecubital vein after fasting for at least 8 hours and then aliquoted within 2 hours and frozen at −80°C, then transported in dry ice to the central laboratory in Jiangsu Province Center for Disease Control and Prevention, which was certificated by The National Laboratory Certification of China. The serum creatinine was measured by automatic biochemical analyzer  within one week, and the whole process of laboratory testing was strictly controlled by professionals.2.32 as the underweight group; 18.5–23.9 as the normal group; 24.0–27.9 as the overweight group; ≥28.0 kg/m2 as the obesity group  ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg or with anti-hypertensive treatment or participants had a reported history of hypertension . Hypertety group , 17. Smoty group .2.4https://www.cvdrisk.com.cn/ASCVD/ Articles/Index/52). The China-PAR risk score included sex, age, SBP, WC, smoking, diabetes, geographic region, urbanization, family history of CVD, and treatment for hypertension. Based on the calculated risk score, the participants were divided into three risk categories: <5% as low risk group, 5-9.9% as moderate risk group, and ≥10% as high risk group , and two-sided P values of <0.05 were considered statistically significant.Continuous variables meeting the normal distribution were expressed using the mean ± standard deviation (SD) and use F-test. Categorical variables are expressed as counts and percentages and were compared using 33.1P<0.05).The general characteristics of the 9978 participants enrolled in this study by serum creatinine levels are presented in 3.2P<0.001), 1.432, 1.336, 0.189 and 0.727 in the Q4 group compared with that in the Q1 group respectively, which suggests that serum creatinine levels are positively correlated with age, obesity and alcohol consumption, but negatively correlated with fruits and vegetables intake.Multivariable logistic regression was performed to study the relationship between serum creatinine and cardiovascular risk factors, as shown in 3.3P < 0.05), 1.385, 0.194 in the Q4 group compared with that in the Q1 group in men, respectively.Results further analyzed according to gender stratification was shown in P < 0.05), 1.310, 0.258, 0.704 in the Q4 group compared with that in the Q1 group, respectively. The results showed that serum creatinine was positively associated with age, while negatively associated with physical activity in both genders.As for women, the OR for age, hypertension treatment, physical exercise and intake of vegetables and fruits was 1.492. The mean risk of CVD in Q1 and Q4 groups were 13.56% and 15.53% in men, and 9.76% and 11.07% in women, respectively .The 10-year predicted cardiovascular risk according to quartiles of serum creatinine is shown in 3.5P < 0.001). After grouping by gender, the proportions of individuals at high risk in Q1 and Q4 groups were 80.07% and 86.42% in males, and 47.21% and 58.70% in females, respectively .The distribution of cardiovascular risk classes according to quartiles of serum creatinine is shown in 3.6P<0.001). Comparing by gender, cardiovascular risk was positively correlated with serum creatinine level in men , although no statistical significance has been found in women.The results of the multiple linear regression are shown in 3.7P< 0.001), especially in men . In addition, serum creatinine is positively correlated with cardiovascular risk in hypertensive patients without diabetes  in Model 3, comparing by gender, serum creatinine and 10-year cardiovascular risk are positively correlated in both men  and women , respectively.In order to exclude the confounding effects of hypertension treatment and diabetes on serum creatinine, we conducted sensitivity analysis and excluded hypertension patients with hypertension treatment or diabetes, as shown in 4The morbidity and mortality of CVD have been increasing gradually in China, partly attributed to the increased exposure and aggregation of multiple cardiovascular risk factors . PreviouThe results have important clinical significance. Firstly, we used a relatively novel risk prediction model to evaluate individual cardiovascular risk and provided reference for the control of hypertensive patients with high creatinine level to reduce cardiovascular risk. Secondly, serum creatinine is a relatively convenient biochemical index, and serum creatinine in addition to traditional CVD risk factors should be taken into account when evaluating risk for development of CVD in hypertensive patients, especially in male.Based on the China-PAR project, the China-PAR risk score has good internal consistency and has been proved to be a suitable method for predicting 10-year cardiovascular risk in Chinese population . In our The rationale for the positive association between serum creatinine and cardiovascular risk remains to be fully clarified. Serum creatinine refers to endogenous serum creatinine, which is the product of human muscle metabolism and the surrogate of renal function . Its levAlthough this study highlights the association between serum creatinine levels and cardiovascular risk factors and 10-year risk of CVD in patients with hypertension in Jiangsu province of China, there are several limitations. The participants with hypertension were recruited from a single province in China, so extrapolation to other populations should be cautious. In addition, our study is a cross-sectional study, and prospective studies are needed for further verification. Finally, other factors that may affect creatinine levels and cardiovascular risk factors such as urea nitrogen and uric acid were missing in this study, and the number and type of antihypertensive drugs were not considered in the study, but we conducted a sensitivity analysis to reduce part of the confounding effect.5In conclusion, serum creatinine was associated with several cardiovascular risk factors in a hypertensive population in Jiangsu province. The 10-year cardiovascular risk was higher in hypertensive patients with higher serum creatinine levels, especially in men. Creatinine-reduction and kidney-sparing therapy is essential for patients with hypertension to optimize control of cardiovascular risk factors and reduce cardiovascular risk.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Review Board of Jiangsu Center for Disease Control and Prevention (SL2015-B004-01). The patients/participants provided their written informed consent to participate in this study.Study concept and design: QX, YuZ, YoZ, YQ, XC; Acquisition of data: XC, DW, HJ, JL, YQ, QX; Analysis and interpretation of data: XC, DW, HJ, JL, YQ, YoZ, QX; Drafting of the manuscript: XC, DW, JL, YQ, QX; Critical revision of the manuscript for important intellectual content: QX, YQ, YuZ; Statistical analysis: XC, DW, JL, YQ, QX; Obtained funding: QX; Technical, or material support: YQ, YoZ, YuZ, QX; Study supervision: QX. All authors contributed to the article and approved the submitted version.


This study presents the clinical phenotypes and genetic analysis of seven patients with benign familial infantile epilepsy (BFIE) diagnosed by whole-exome sequencing.The clinical data of seven children with BFIE diagnosed at the Department of Neurology, Children’s Hospital Affiliated to Zhengzhou University between December 2017 and April 2022 were retrospectively analyzed. Whole-exome sequencing was used to identify the genetic causes, and the variants were verified by Sanger sequencing in other family members.de novo frameshift variant c.397delG (p.E133Nfs*43) in the proline-rich transmembrane protein 2 (PRRT2) gene while case 2 had a nonsense variant c.46G > T (p.Glu16*) inherited from the father, and cases 3–7 carried a heterozygous frameshift variant c.649dup (p.R217Pfs*8) in the same gene. In cases 3 and 4, the frameshift variant was de novo, while in cases 5–7, the variant was paternally inherited. The c.397delG (p.E133Nfs*43) variant is previously unreported.The seven patients with BFIE included two males and five females ranging in age between 3 and 7 months old. The main clinical phenotype of the seven affected children was the presence of focal or generalized tonic–clonic seizures, which was well controlled by anti-seizure medication. Cases 1 and 5 exhibited predominantly generalized tonic–clonic seizures accompanied by focal seizures while cases 2, 3, and 7 displayed generalized tonic–clonic seizures, and cases 4 and 6 had focal seizures. The grandmother and father of cases 2, 6, and 7 had histories of seizures. However, there was no family history of seizures in the remaining cases. Case 1 carried a PRRT2 gene that causes BFIE, expanding the mutation spectrum of PRRT2.This study demonstrated the effectiveness of whole-exome sequencing in the diagnosis of BFIE. Moreover, our findings revealed a novel pathogenic variant c.397delG (p.E133Nfs*43) in the  Benign familial infantile epilepsy  is a benign familial neurological disorder with an incidence of 1 in 10,000 , 3.PRRT2 gene, encoding proline-rich transmembrane protein 2, is a major causative gene for BFIE. PRRT2 located on the short arm 11.2 of chromosome 16, is mainly expressed in the nervous system, especially in the cerebral cortex, hippocampus, basal ganglia, and cerebellum  # 605751], paroxysmal kinesigenic dyskinesia , and infantile convulsions and choreoathetosis . Other genetic mutations, including mutations in SCN2A, KCNQ2, SCN8A, and ATP1A2, have also been found to cause BFIE , imaging tests included cranial computed tomography (CT), and magnetic resonance imaging (MRI), and electrophysiological tests included long-range video electroencephalogram monitoring.After obtaining informed consent from the children’s guardians, 2 mL of peripheral venous blood was collected from each child and the parents into ethylenediaminetetraacetic acid tubes. Whole-exome sequencing was performed on the three members of each family and the suspected variants with clinical significance were verified in the family members using Sanger sequencing. Genetic sequencing was performed by the Beijing Zhiyin Oriental Translational Medicine Research Center Co., Ltd., and the relevant data analysis was conducted by Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases in our hospital.All the children experienced seizures of varying severity during infancy; details of the clinical manifestations of the children are listed in Cranial MRI showed varying degrees of cerebral white matter hemi-oval central myelin hypoplasia at 6 months old in cases 1 and 4, indicating a delay in neuronal development. On the other hand, the cranial MRI showed varying degrees of frontotemporal subarachnoid widening in cases 1, 2, and 6 . No devePRRT2 (NM_145239.2) gene in the seven children. Whole-exome sequencing analysis showed that among the seven probands, cases 2, 5, 6, and 7 carried variants inherited from the father, while the variants in cases 1, 3, and 4 were de novo. Case 1 carried a de novo frameshift shift variant c.397delG , and all the variants in cases 5, 6, and 7 were frameshift variants c.649dup (p.R217Pfs*8). The c.397delG (p.E133Nfs*43) frameshift variant was novel and has not been reported previously. The evidence for the pathogenicity of c.397delG (p.E133Nfs*43) included PVS1, PS2, PM2, and PP3. The variant was predicted to be deleterious by multiple software programs including SIFT, Polyphen-2, and MutationTaster. According to the standards and guidelines of the ACMG , nearly 100 variants have been reported in the of cases . In thisof cases  reportedPRRT2 are associated with a variety of neurological disorders, such as BFIE, paroxysmal kinesigenic dyskinesia, and infantile convulsions and choreoathetosis, which account for more than 90% of all cases , with a prevalence estimated at 1:150,000, characterized by recurrent episodes, transient chorea, dystonia, and/or ballismus  is representative of a number of disorders, often with devastating and persistent adverse consequences. Many brain malformations and inborn metabolic disorders are caused by genetic factors, such as ion channel disease, which may be associated with abnormalities in brain structure. Most children with neurometabolic disorders show some signs of disordered metabolism, which can be differentially diagnosed by genetic testing. When the diagnostic criteria are unclear, genetic testing may be the most effective means of diagnosing these diseases. Moreover, genetic testing can also guide the application of appropriate antiepileptic drugs and clinical management , 34. In PRRT2 is a major causative gene of BFIE, with mutations in the gene showing an expanding clinical spectrum and incomplete penetrance. Genetic testing is critical for the diagnosis and clinical management of BFIE patients and is beneficial for prognostic prediction. Moreover, the current study identified a novel BFIE-associated variant, c.397delG (p.E133Nfs*43), in the PRRT2 gene, thereby expanding the genetic spectrum of BFIE.In summary, BFIE is a genetic epilepsy with onset in the first year of life. https://www.ncbi.nlm.nih.gov/, SCV002760034.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.YG, DM, YZ, XW, AM, and JK contributed to the study conception and design and performed material preparation and data collection and analysis. The first draft of the manuscript was written by YG, DM, and YZ. XW and YZ critically revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by Joint Construction Project of Henan Medical Science and Technology Project , Scientific and Technological Project of Henan , Henan Engineering Research Center of Childhood Neurodevelopment Open Project (SG201907), and National Natural Science Foundation of China (81901387).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Permeable pavements can decrease the volume of stormwater, thereby mitigating the risk of flooding and reducing the urban heat island effect. This study investigated the influence of incorporating granulated blast-furnace slag (GBFS), hydroxypropyl methylcellulose (HPMC), and polypropylene plastic textile fiber (PPTF) on the mechanical properties and water permeability of pervious concrete. Orthogonal tests were employed to conduct the analysis. The findings indicate that the pervious concrete with GBFS, HPMC, and PPTF (termed GBFS-HPMC/fiber pervious concrete) exhibited the highest cubic compressive strength, ultimate tensile strength, and flexural strength. These values were 25.22 MPa, 3.36 MPa, and 5.39 MPa, respectively. The standard deviations for cubic compressive strength, split tensile strength, flexural strength, water permeability coefficient, and porosity, as calculated using SPSS, were 1.57, 0.1, 1.17, 0.35, and 0.4, respectively. Scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) were used to analyze the microstructure and compositional combinations of the pervious concrete. The analyses revealed that the calcium-silicate-hydrate (C-S-H) gel, produced by GBFS hydration, enhanced the bonding within the interfacial transition zone (ITZ) and between the fibers and aggregates. Additionally, the anchoring and supporting effects of the PPTF in the matrix contributed to stabilizing the overall matrix structure. Lastly, a gray correlation analysis was applied to optimize the admixture. The findings indicate that following the optimization, the cubic compressive strength increased by 7.2%, splitting tensile strength by 2.1%, and flexural strength by 2.5%. In summary, the mechanical properties of pervious concrete improved after optimizing the admixture. In recent years, the expansion of urban regions and the concentration of populations has resulted in the reduction of vegetated areas and natural habitats due to the construction of residential buildings and traditional concrete pavements. This situation hinders the natural infiltration of rainwater into the soil. During intense precipitation episodes, drainage systems cannot expel water rapidly, leading to waterlogging events in low-lying urban zones ,2,3. ConPervious concrete serves as a sustainable paving material that effectively addresses the shortcomings of traditional concrete pavements. This material consists of a mortar layer enveloped by coarse aggregate, which is bonded to form a porous, honeycomb-like structure. This structure offers the advantages of both water permeability and acoustic noise reduction ,9,10. ThWith the promotion of China’s “dual-carbon” initiative, reducing carbon emissions to address climate change is the focal point of achieving overall energy-efficient and environmentally friendly development . As a keSlag can induce the “volcanic ash effect”, reacting with calcium hydroxide produced by cement hydration to form hydrated calcium silicate , hydrateThe preparation of pervious concrete necessitates less gelling material, resulting in weaker bonding. However, the inclusion of hydroxypropyl methylcellulose can extend the mixing and forming time, enhancing the cohesion of the mix to prevent segregation. This compound boasts exceptional thickening and water retention properties, effectively enhancing the bond between the gelling material and aggregates, thus improving mechanical properties . When ceIncorporating fibers can reduce the high brittleness and poor resistance to bending and deformation inherent in pervious concrete, thus, enhancing its mechanical properties. Polypropylene plastic textile fibers, known for their ease of dispersion, acid and alkali resistance, and high toughness, are a suitable reinforcement for pervious concrete, effectively inhibiting crack formation and propagation ,29,30. R4) orthogonal experiment with the objective of exploring the influence of the slag replacement rate, cellulose additive, and PPTF additive on the mechanical and water permeability properties of pervious concrete. The study examined the compressive strength, tensile strength, flexural strength, permeability coefficient, and porosity of GBFS-HPMC/fiber-reinforced concrete. Gray correlation analysis and principal component analysis were employed to determine the optimal GBFS replacement rate, HPMC admixture, and PPTF admixture to enhance the mechanical properties of GBFS-HPMC/fiber-reinforced concrete. To promote the usage of GBFS-HPMC/fiber pervious concrete in real-world projects, it is essential to provide a reference.Significant advancements have been made in the research of pervious concrete, both at the domestic and international levels. However, the constrained strength of pervious concrete limits its range of applications. Consequently, the current research focus centered on enhancing its mechanical properties while simultaneously considering the water permeability performance. Unlike previous studies that primarily examined individual materials, this paper presents a novel approach. This study devised a three-tier, four-variable L9  orthogonal table. The PPTF dosages were 1%, 0.3%, and 0.5%. This experiment employed an orthogonal test to study three influential factors: GBFS substitution rate (A), HPMC dosage (B), and PPTF dosage (C). The GBFS substitution rate was 15%, 20%, and 25%; the HPMC dosage was 0.1%, 0.15%, and 0.2% of the cementitious material; and the PPTF dosage was 0.1%, 0.3%, and 0.5%. The orthogonal design of the test is shown in In the process of specimen preparation, first coarse aggregate, sand, PPTF, and part of the water were added and mixed for 30 s, then GBFS and cement were added and mixed for 60 s. Finally, HPMC reinforcement was added, followed by the addition of the remaining water, and the mixture was mixed for an additional 120 s. Subsequently, a combination of manual pounding and static compression molding techniques was employed. For each group of specimen molding, twelve specimens measuring 100 mm × 100 mm × 100 mm and three nonstandard specimens measuring 100 mm × 100 mm × 400 mm were prepared. In total, 150 specimens were prepared. Following the removal from molds, a total of 150 specimens were obtained, which encompassed 12 nonstandard specimens measuring 100 mm × 100 mm × 400 mm. These specimens were allowed to undergo natural conservation for a duration of 28 days, commencing from the 24th hour. The process of specimen preparation and molding is depicted in Upon completion of the curing period, the cubic compressive strength, splitting tensile strength, and flexural strength were measured. A YAW-50000J compression–shear testing machine was used for loading. Tests for the porosity and water permeability coefficient were performed following the procedures outlined earlier.2), and The specimen was placed at the center of the bearing plate on the press, and a continuous and uniform load was applied with a loading speed of 0.5 MPa/s. The calculation formula is provided in Equation (1). As per the guidelines specified in GB/T50081-2019, titled “Concrete physical and mechanical properties test method standard” , the tes2), and The split compressive strength specimen was placed on the press support, and a continuous and stable load was applied at a rate of 0.015 MPa/s. The maximum load was recorded after the specimen fractured. The calculation formula is presented in Equation (2). In accordance with the standards outlined in GB/T50081-2019, “Concrete physical and mechanical properties test method standard” , the tesThe flexural strength specimen was placed on the press support and loaded at a rate of 0.05 MPa/s. The maximum load was recorded when the specimen fractured. The calculation formula is given in Equation (3). As specified in GB/T50081-2019, titled “Concrete physical and mechanical properties test method standard” , the tes2), Once the specimen reached the age of 27 days, it was immersed in water for 24 h. After 28 days of aging, the permeability coefficient test was conducted. The calculation formula is presented in Equation (4), and the testing equipment for permeability coefficient is shown in −3), and The specimen was placed in a container with water, ensuring the water level was more than 20 cm higher than the specimen size. An electronic scale was used to measure the suspended mass of the specimen in water, denoted as −1 to a minimum value of 4.98 mm·s−1. Similarly, the maximum and minimum porosity values recorded were 14.62% and 13.65%, respectively. After the incorporation of GBFS, HPMC, and PPTF, a notable decrease in the permeability coefficient and porosity was observed. Despite this reduction, the values remained higher than those of the control group, which had a permeability coefficient of 6.35 mm·s−1 and a porosity of 14.89%. Nevertheless, all test groups met the stipulated specification requirements.The outcomes of the tests for the cubic compressive strength, split tensile strength, flexural strength, permeability coefficient, and porosity in the pervious concrete for both the test group and the control group are presented in The results of the permeability coefficient, cubic compressive strength, and splitting tensile strength tests were subjected to ANOVA and extreme variance analysis using SPSS. The results are presented in The analysis of variance revealed that both GBFS and PPTF had a significant impact on the pervious concrete, whereas HPMC showed no significant effect. The magnitude of influence of the three factors on the cubic compressive strength was ranked by extreme variance analysis as follows: PPTF (2.89 MPa) > GBFS (1.75 MPa) > HPMC (0.52 MPa), consistent with the variance analysis results. The trend of the GBFS substitution rate, HPMC admixture, and PPTF fiber admixture effects on the cubic compressive strength of the GBFS-HPMC/fiber permeable concrete is illustrated in 2 generated by cement hydration and accelerates the cement hydration process [As depicted in  process ,38. ThisThe cubic compressive strength increases initially with the increase in the HPMC dosage, reaching a maximum strength of 23.41 MPa at a dosage of 0.15%. During the mixing process, the -OH groups in HPMC react with water, forming hydrogen bonds. The molecules become entangled, creating a mesh structure . This stThe compressive strength gradually increased with the rise in the PPTF dosage, exhibiting increments of 6.51%, 12.22%, and 20.12% compared to the control group. The slope of the curve for an increase in the PPTF dosage from 0.3% to 0.5% was steeper than that for the increase in the fiber dosage from 0.1% to 0.3%. This observation confirms that a dosage of 0.5% PPTF significantly enhances the strength of pervious concrete. The fibers contribute to the overall densification of the pervious concrete and impede the propagation of cracks at the interface between the cementitious material and bonded aggregates . The speThe analysis of variance determined that PPTF is a significant factor, whereas GBFS and HPMC were found to be insignificant factors. Extreme variance analysis indicated the strength of influence on splitting tensile strength was PPTF (0.17 MPa) > GBFS (0.13 MPa) > HPMC (0.05 MPa). The trend of each factor’s influence on the splitting tensile strength is shown in As seen in The analysis of variance revealed both GBFS and PPTF as highly significant factors, while HPMC was found to be insignificant. The extreme variance analysis aligned with the variance results, demonstrating the strength of influence on the flexural strength as PPTF (0.31 MPa) > GBFS (0.21 MPa) > HPMC (0.09 MPa). The influence of each factor on flexural strength is illustrated in As observed in The analysis of variance revealed HPMC as a highly significant factor, GBFS as a significant factor, and PPTF as a nonsignificant factor in the permeability coefficient analysis. Similar results were obtained from the ANOVA based on porosity. The extreme variance analysis indicated the strength of influence on the permeability coefficient of the pervious concrete to be HPMC (0.58 mm/s) > GBFS (0.43 mm/s) > PPTF (0.28 mm/s). The influence on porosity followed the same order: HPMC (0.66%) > GBFS (0.57%) > PPTF (0.21%). The influence of each factor on the permeability coefficient and porosity is depicted in As illustrated in The micromorphologies of the C-0 and GHP-3 groups were observed through scanning electron microscopy (SEM), as depicted in 2. The internal structure was not dense enough due to the usage of only cement as the cementitious material. This resulted in more holes and cracks, as shown in 2, formed by the hydration of cement, along with the alkaline environment, leads to a secondary hydration reaction between GBFS and OH−. This resulted in the formation of part of AFt and AFm, as well as a substantial amount of C-S-H gel inside the permeable concrete. This gel reinforces the interface, resulting in a more compact structure that greatly improves the structural strength of permeable concrete, as shown in In the control group, the hydration products of the cement consisted of a small amount of acicular calcium alumina (AFt) and a large amount of flaky Ca(OH)The EDS energy spectrum analysis located hit points and depicted energy spectra, as shown in 2, AFt, and some AFm. GHP-3’s hydration product constituent elements in both regions were Ca, O, Al, and Si. The Si, Al, and Mg levels were higher than in C-0, with CaO, Al2O3, SiO2, and MgO indicating the presence of Ca(OH)2, AFt, and some AFm. This suggests the existence of AFt and a significant amount of C-S-H gel in this region.Hydration products in the control group’s constituent elements in both regions were Ca, O, and S. The O and Ca elements were predominant, with CaO, MgO, etc., indicating the presence of Ca(OH)The design of the orthogonal experiments effectively reduces the number of experimental groups, thereby significantly reducing the workload. Nevertheless, the results of the remaining experimental data remain unknown. Gray correlation analysis provides a quantitative method to describe and predict performance indicators across the entire system . The corThe calculation of the gray correlation coefficient is shown in Equation (6):Next, the performance indicators are subjected to SPSS factor analysis. The coefficients of each factor in the composite score model are normalized to obtain the weights. The weight calculation is shown in Equation (7):Gray correlation analysis  and prinThe weighting coefficients for the cubic compressive strength, splitting tensile strength, flexural strength, water permeability, and porosity were calculated as Gray correlation measures the strength of the correlation between different influencing factors and reference objects. A higher gray correlation indicates a stronger alignment between the trends in test results and the ideal experimental outcomes. This implies better overall performance within the experimental group. Based on these considerations, GHP-3 is determined to be the best experimental scheme for comprehensive performance indexes.The dosage combination yielding the best combined performance index was analyzed by comparing the mean gray correlation for each dosage of every factor, as shown in The GHP-10 test group, consisting of GBFS-HPMC/fiber pervious concrete with the optimal GBFS replacement rate of 20%, HPMC admixture of 0.20%, and PPTF admixture of 0.5% was chosen to evaluate the comprehensive performance indexes. New pervious concrete specimens were prepared using the best admixture determined through gray correlation analysis for both the GHP-10 and GHP-3 test groups. These specimens were then measured for five performance indices: cubic compressive strength, tensile strength, flexural strength, water permeability coefficient, and porosity. The final optimal admixture formulation was derived from these measurements. The data from both sets of programs are presented in This experiment explored the effects of GBFS, HPMC, and PPTF on pervious concrete’s mechanical properties from macrostructural and micromorphological perspectives. The 28-day cubic compressive strength, splitting tensile strength, and flexural strength of GBFS-HPMC/fiber pervious concrete reached the highest values of 25.22 MPa, 3.36 MPa, and 5.39 MPa, respectively. These values exceeded those of the control group by 25.29%, 11.26%, and 16.41%, respectively. Furthermore, the water permeability coefficient and porosity met specifications.The analysis of variance on mechanical properties revealed that PPTF exerted the most substantial influence, followed by GBFS, whereas HPMC had negligible effects. Conversely, the analysis of variance regarding water permeability properties emphasized HPMC as a significant influencing factor, while GBFS and PPTF had minor effects. This observation aligns with the results obtained from the extreme variance analysis. Based on comprehensive analysis, the optimal dosages for GBFS, HPMC, and PPTF to enhance compressive strength are 15%, 0.15%, and 0.5%, respectively. For split tensile strength and flexural strength, the recommended dosages of GBFS, HPMC, and PPTF are 20%, 0.15%, and 0.5%, respectively. To enhance water permeability, the recommended dosages of GBFS, HPMC, and PPTF are 15%, 0.2%, and 0.1%, respectively. SEM microstructure analysis has demonstrated that incorporating GBFS enhances the stability and compactness of the pervious concrete structure. This enhancement is attributed to the secondary hydration of GBFS, which results in the formation of C-S-H gel. This gel fills the pores and reinforces the fiber–aggregate interfacial transition zone. Energy spectroscopy analysis validated the effectiveness of the fibers by detecting the presence of AFt and a substantial amount of C-S-H gel in the GHP-3 test group.Finally, through gray correlation analysis and SPSS factor dimensionality reduction for admixture optimization, we obtained the optimal admixture proportions for GBFS-HPMC/fiber permeable concrete: a GBFS replacement rate of 20%, an HPMC volume admixture of 0.20%, and a fiber volume admixture of 0.5%. As a consequence of this optimization, the GBFS-HPMC/fiber pervious concrete exhibited a 7.2% increase in cubic compressive strength, a 2.1% increase in split tensile strength, and a 2.5% increase in flexural strength. Additionally, the permeability coefficient decreased by 5.5%, and porosity decreased by 3.6%. Notably, the optimized water permeability still complies with the specified requirements, thereby enhancing the material’s mechanical properties. These findings establish a theoretical foundation for the promotion and application of pervious concrete.