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Abstract Background Several recent studies reported the potential adverse effects of titanium exposure on glucose homeostasis among the non-pregnant population, but the association of titanium exposure with gestational diabetes mellitus (GDM) is scarce. Methods The present study of 1,449 pregnant women was conducted within the Jiangsu Birth Cohort (JBC) study in China. Urine samples were collected in the early pregnancy, and urinary titanium concentration and non-targeted metabolomics were measured. Poisson regression estimated the association of titanium exposure in the early pregnancy with subsequent risk of GDM. Multiple linear regression screened for titanium-related urine metabolites. Mediation analyses assessed the mediating effects of candidate metabolites and pathways. Results As parameterized in tertiles, titanium showed positive dose–response relationship with GDM risk (P for trend = 0.008), with women at the highest tertile of titanium exposure having 30% increased risk of GDM [relative risk (RR) = 1.30 (95% CI: 1.06, 1.61)] when compared to those exposure at the first tertile level. Meanwhile, we identified the titanium-related metabolites involved in four amino acid metabolic pathways. Notably, the perturbation of the aminoacyl-tRNA biosynthesis and alanine, aspartate and glutamate metabolism mediated 27.1% and 31.0%, respectively, of the relative effect of titanium exposure on GDM. Specifically, three titanium-related metabolites, choline, creatine and L-alanine, demonstrated predominant mediation effects on the association between titanium exposure and GDM risk. Conclusions In this prospective study, we uniquely identified a correlation between early pregnancy titanium exposure and increased GDM risk. We unveiled novel insights into how perturbations in amino acid metabolism may mediate the link between titanium exposure and GDM. Notably, choline, creatine, and L-alanine emerged as key mediators influencing this association. Our findings imply that elevated titanium exposure in early pregnancy can lead to amino acid dysmetabolism, thereby elevating GDM risk. Graphical Abstract

Abstract Background The recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring. Methods Based on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring. Results Compared with “low IPAI” group, offspring with “high IPAI” have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted β were − 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and − 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among “high IPAI” group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72). Conclusions Our results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

Abstract In this multicenter, non-inferiority, randomized trial, we randomly assigned 992 women undergoing in-vitro fertilization (IVF) with a good prognosis (aged 20-40, ≥3 transferrable cleavage-stage embryos) to strategies of blastocyst-stage (n = 497) or cleavage-stage (n = 495) single embryo transfer. Primary outcome was cumulative live-birth rate after up to three transfers. Secondary outcomes were cumulative live-births after all embryo transfers within 1 year of randomization, pregnancy outcomes, obstetric-perinatal complications, and livebirths outcomes. Live-birth rates were 74.8% in blastocyst-stage group versus 66.3% in cleavage-stage group (relative risk 1.13, 95%CI:1.04-1.22; Pnon-inferiority 3 days. Among good prognosis women, a strategy of single blastocyst transfer increases cumulative live-birth rates over single cleavage-stage transfer. Blastocyst transfer resulted in higher preterm birth rates. This information should be used to counsel patients on their choice between cleavage-stage and blastocyst-stage transfer (NCT03152643, https://clinicaltrials.gov/study/NCT03152643 ).

Abstract Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3′-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

Abstract The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10−8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10−14; 543 patients) and 1.80 (P = 1.11 × 10−9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

Aims: To examine the concurrent validity of the Chinese version of Physical Activity Neighborhood Environment Scale (PANES-CHN) among urban adults in regional China. Methods: With multistage sampling approaches, 801 eligible urban adults aged 35–74 years were recruited from Nanjing municipality of China between July and September of 2019. The neighbourhood built environment features were measured subjectively with PANES-CHN and objectively with geographic information system. The concurrent validity of PANES was assessed using Spearman’s correlations (rs). Results: Among the total 801 participants, the mean age was 54.4 (standard deviation = 11.5), while 48.7 % were men. Overall, of all the five objectively-measurable built environment characteristics, the Spearman correlations were examined significant between subjective and objective measurements for commercial facilities (item 2) (rs = 0.19, 95CI%=0.12, 0.25), recreational facilities (item 6) (rs = 0.10, 95CI%=0.02, 0.16), traffic junctions (item 12) (rs = 0.15, 95CI%=0.07, 0.22), medical/education facilities (item 17) (rs = 0.22, 95CI%=0.15, 0.29), but not for public transport stops. Similar scenarios were observed for participants aged 35–60 years, with sufficient physical activity, men or women. The rs value for medical/education facilities (item 17) was significantly higher in participants aged 35–59 years (0.28 vs. 0.13; p = 0.04) than those aged 60 + years. Conclusions: PANES-CHN generally has an acceptable validity for assessing built environment characteristics among urban adults in China, which implies that PANES-CHN can be used to measure built environment attributes in health-related population studies.

Abstract Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.

Background: Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer. Methods: Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs). Results: Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p

Abstract Pathogenic mutations in mitochondrial DNA cause severe and often lethal multi-system symptoms in primary mitochondrial defects. However, effective therapies for these defects are still lacking. Strategies such as employing mitochondrially targeted restriction enzymes or programmable nucleases to shift the ratio of heteroplasmic mutations and allotopic expression of mitochondrial protein-coding genes have limitations in treating mitochondrial homoplasmic mutations, especially in non-coding genes. Here, we conduct a proof of concept study applying a screened DdCBE pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells derived from a patient with hypertrophic cardiomyopathy. We achieve efficient G4300A correction with limited off-target editing, and successfully restore mitochondrial function in corrected induced pluripotent stem cell clones. Our study demonstrates the feasibility of using DdCBE to treat primary mitochondrial defects caused by homoplasmic pathogenic mitochondrial DNA mutations.

Abstract Background Most lung cancer risk prediction models were developed in European and North‐American cohorts of smokers aged ≥ 55 years, while less is known about risk profiles in Asia, especially for never smokers or individuals aged < 50 years. Hence, we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range. Methods Based on the China Kadoorie Biobank cohort, we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines. Then, we separately developed risk prediction models to construct a lung cancer risk score (LCRS) in 159,715 ever smokers and 336,526 never smokers. The LCRS was further validated in an independent cohort over a median follow‐up of 13.6 years, consisting of 14,153 never smokers and 5,890 ever smokers. Results A total of 13 and 9 routinely available predictors were identified for ever and never smokers, respectively. Of these predictors, cigarettes per day and quit years showed nonlinear associations with lung cancer risk (Pnon‐linear < 0.001). The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day. We also observed that lung cancer risk declined sharply within the first 5 years of quitting, and then continued to decrease but at a slower rate in the subsequent years. The 6‐year area under the receiver operating curve for the ever and never smokers’ models were respectively 0.778 and 0.733 in the derivation cohort, and 0.774 and 0.759 in the validation cohort. In the validation cohort, the 10‐year cumulative incidence of lung cancer was 0.39% and 2.57% for ever smokers with low (< 166.2) and intermediate‐high LCRS (≥ 166.2), respectively. Never smokers with a high LCRS (≥ 21.2) had a higher 10‐year cumulative incidence rate than those with a low LCRS (< 21.2; 1.05% vs. 0.22%). An online risk evaluation tool (LCKEY; http://ccra.njmu.edu.cn/lckey/web) was developed to facilitate the use of LCRS. Conclusions The LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Abstract Background Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. Methods In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40–75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20–80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. Results The GCRS using 11 questionnaire-based variables demonstrated a Harrell’s C-index of 0.754 (95% CI, 0.745–0.762) and 0.736 (95% CI, 0.710–0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. Conclusions The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Federated learning is a new type of distributed learning framework that allows multiple participants to share training results without revealing their data privacy. As data privacy becomes more important, it becomes difficult to collect data from multiple data owners to make machine learning predictions due to the lack of data security. Data is forced to be stored independently between companies, creating “data silos”. With the goal of safeguarding data privacy and security, the federated learning framework greatly expands the amount of training data, effectively improving the shortcomings of traditional machine learning and deep learning, and bringing AI algorithms closer to our reality. In the context of the current international data security issues, federated learning is developing rapidly and has gradually moved from the theoretical to the applied level. The paper first introduces the federated learning framework, analyzes its advantages, reviews the results of federated learning applications in industries such as communication and healthcare, then analyzes the pitfalls of federated learning and discusses the security issues that should be considered in applications, and finally looks into the future of federated learning and the application layer.

Abstract Background Besides featured glucose consumption, recent studies reveal that cancer cells might prefer “addicting” specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear. Methods Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved. Results We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD. Conclusion Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.

Abstract Neonatal heart undergoes metabolic conversion and cell cycle arrest preparing for the increased workload during adulthood. Herein, we report that neonatal ketone body elevation is a critical regulatory factor for postnatal heart development. Through multiomics screening, we found that the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, was transiently induced by colostrum in the neonatal heart. Hmgcs2 knockout caused mitochondrial maturation defects. Meanwhile, postnatal heart development was compromised and cardiomyocytes reacquired proliferation capacity in Hmgcs2 knockout mice. Consequently, over 40% of newborn Hmgcs2 knockout mice died before weaning. The heart function of surviving Hmgcs2 knockout mice was also impaired, which could be rescued by ketone body supplementation during the suckling stage. Mechanistically, ketone body deficiency inhibited β-hydroxybutyrylation but enhanced acetylation of mitochondrial proteins, which might be responsible for the inhibition of the enzyme activity in mitochondria. These observations suggest that ketone body is critical for postnatal heart development through regulating mitochondrial maturation and metabolic reprogramming.

Objective: Although our previous genome-wide association study (GWAS) has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer (NSCLC), the causal variants remain unclear. The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC. Methods: CCK-8, colony formation, EdU incorporation, Transwell, and quantitative real-time polymerase chain reaction assays were applied to examine variant function. The tumor xenograft model was used to examine variant function in vivo. Caspase-8 activity assays, flow cytometry analysis, and co-immunoprecipitation assays were used to explore the molecular mechanism. Results: The missense variant rs3769823 (A > G), which caused the substitution of lysine with arginine at amino acid 14 in caspase-8 (caspase-8K14R), was identified as a potential causal candidate in 2q33.1. Compared with the wild type caspase-8 (caspase-8WT) group, the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8. Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro. Moreover, caspase-8K14R repressed lung cancer cell growth in vivo. Mechanistically, caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD. Conclusions: These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway, leading to a decreased risk of NSCLC.

Construction project complexity can be daunting, so both academics and practitioners have been looking for guidance. Previous studies have attempted to reconcile the inconsistencies and complexities in the relationships among project complexity, project success, and project management success. However, such research has failed to establish these clear relationships. Accordingly, the approach of systematic review and meta-analysis is applied in this study to investigate and compare how different project complexity affects project success and project management success by selecting 22 articles and 77 effect sizes. The results indicate that integrational complexity significantly positively affects project success, whereas it is not significantly negatively associated with project management success. Within a technical-organizational-environmental (TOE) framework, effects of organizational, environmental, and technical complexity on project success and project management success are also discussed here. A possible moderator (the national/regional income level) is tested and verified. The findings contribute to the system of knowledge on project complexity and provide guidelines for decision-makers to achieve a balance between project success and project management success in routine operation of construction projects.

IntroductionThis study was conducted to assess the effect of mixed isoacid (MI) supplementation on fermentation characteristics, nutrient apparent digestibility, growth performance, and rumen bacterial community in yaks.MethodsA 72-h in vitro fermentation experiment was performed on an ANKOM RF gas production system. MI was added to five treatments at doses of 0, 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% on the dry matter (DM) basis of substrates using a total of 26 bottles (4 bottles per treatment and 2 bottles as the blank). Cumulative gas production was measured at 4, 8, 16, 24, 36, 48, and 72 h. Fermentation characteristics including pH, the concentration of volatile fatty acids (VFAs), ammonia nitrogen (NH3-N), microbial proteins (MCP), and the disappearance rate of dry matter (DMD), neutral detergent fiber (NDFD), and acid detergent fiber (ADFD) were measured after a 72-h in vitro fermentation to determine an optimal MI dose. Fourteen Maiwa male yaks (180–220 kg, 3–4 years old of age) were randomly assigned to the control group (without MI, n = 7) and the supplemented MI group (n = 7, supplemented with 0.3% MI on DM basis) for the 85-d animal experiment. Growth performance, nutrient apparent digestibility, rumen fermentation parameters, and rumen bacterial diversity were measured.ResultsSupplementation with 0.3% MI achieved the greatest propionate and butyrate content, NDFD and ADFD compared with other groups (P < 0.05). Therefore, 0.3% was used for the animal experiment. Supplementation with 0.3% MI significantly increased the apparent digestibility of NDF and ADF (P < 0.05), and the average daily weight gain of yaks (P < 0.05) without affecting the ruminal concentration of NH3-N, MCP, and VFAs. 0.3% MI induced rumen bacteria to form significantly different communities when compared to the control group (P < 0.05). g__norank_f__Bacteroidales_BS11_gut_group, g__norank_f__Muribaculaceae, g__Veillonellaceae_UCG-001, g__Ruminococcus_gauvreauii_group, g__norank_f__norank_o__RF39 and g__Flexilinea were identified as the biomarker taxa in responding to supplementation with 0.3% MI. Meanwhile, the abundance of g__Flexilinea and g__norank_f__norank_o__RF39 were significantly positively correlated with the NDF digestibility (P < 0.05).ConclusionIn conclusion, supplementation with 0.3% MI improved the in vitro rumen fermentation characteristics, feed fiber digestibility, and growth performance in yaks, which was associated with changes of the abundance of g__Flexilinea and g__norank_f__norank_o__RF39.

Abstract Background Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6‐methyladenosine (m6A) RNA modification regulates gene expression and cell fate. However, the reasons for activation of KIAA1429 (also known as VIRMA, an RNA methyltransferase) and its underlying mechanism in lung adenocarcinoma (LUAD) remain largely unexplored. In this study, we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD. Methods Whole‐genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase. The in vitro and in vivo functions of KIAA1429 were investigated. Transcriptome sequencing, methylated RNA immunoprecipitation sequencing (MeRIP‐seq), m6A dot blot assays and RNA immunoprecipitation (RIP) were performed to confirm the modified gene mediated by KIAA1429. RNA stability assays were used to detect the half‐life of the target gene. Results Copy number amplification drove higher expression of KIAA1429 in LUAD, which was correlated with poor overall survival. Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD. Mechanistically, the target genes of KIAA1429‐mediated m6A modification were confirmed by transcriptome sequencing and MeRIP‐seq assays. We also revealed that KIAA1429 could regulate BTG2 expression in an m6A‐dependent manner. Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2, the m6A “reader”)‐dependent BTG2 mRNA stability and promoted the expression of BTG2; thus, participating in the tumorigenesis of LUAD. Conclusions Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis, which may provide a novel view on the targeted molecular therapy of LUAD.

Cholangiocarcinoma is a heterogenous group of cancers, with large genetic variation seen within subtypes. Here, the authors find 12 significantly mutated genes and 5 focal CNA regions were found in perihilar cholangiocarcinoma, and identified METTL14 to have a potential tumour suppressive role.

Abstract Background Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown. Methods Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk. Results Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10−16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (P sPRS= 0.863 and P wPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10−6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, P interaction = 1.01×10−7), rs2336652 (3p22.3, near CLASP2, P interaction = 3.92×10−7), rs16018 (19p13.2, in CACNA1A, P interaction = 3.92×10−7), and rs4726760 (7q34, near BRAF, P interaction = 9.19×10−7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation. Conclusions Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC. Trial registration http://www.clinicaltrials.gov , NCT01696968 .

BackgroundChina has the largest burden of esophageal cancer (EC). Prediction models can be used to identify high-risk individuals for intensive lifestyle interventions and endoscopy screening. However, the current prediction models are limited by small sample size and a lack of external validation, and none of them can be embedded into the booming electronic health records (EHRs) in China. ObjectiveThis study aims to develop and validate absolute risk prediction models for EC in the Chinese population. In particular, we assessed whether models that contain only EHR-available predictors performed well. MethodsA prospective cohort recruiting 510,145 participants free of cancer from both high EC-risk and low EC-risk areas in China was used to develop EC models. Another prospective cohort of 18,441 participants was used for validation. A flexible parametric model was used to develop a 10-year absolute risk model by considering the competing risks (full model). The full model was then abbreviated by keeping only EHR-available predictors. We internally and externally validated the models by using the area under the receiver operating characteristic curve (AUC) and calibration plots and compared them based on classification measures. ResultsDuring a median of 11.1 years of follow-up, we observed 2550 EC incident cases. The models consisted of age, sex, regional EC-risk level (high-risk areas: 2 study regions; low-risk areas: 8 regions), education, family history of cancer (simple model), smoking, alcohol use, BMI (intermediate model), physical activity, hot tea consumption, and fresh fruit consumption (full model). The performance was only slightly compromised after the abbreviation. The simple and intermediate models showed good calibration and excellent discriminating ability with AUCs (95% CIs) of 0.822 (0.783-0.861) and 0.830 (0.792-0.867) in the external validation and 0.871 (0.858-0.884) and 0.879 (0.867-0.892) in the internal validation, respectively. ConclusionsThree nested 10-year EC absolute risk prediction models for Chinese adults aged 30-79 years were developed and validated, which may be particularly useful for populations in low EC-risk areas. Even the simple model with only 5 predictors available from EHRs had excellent discrimination and good calibration, indicating its potential for broader use in tailored EC prevention. The simple and intermediate models have the potential to be widely used for both primary and secondary prevention of EC.

Summary: Chronological age only represents the passage of time, whereas biological age reflects the physiology states and the susceptibility to morbidity and mortality. The association between biological age and lung cancer risk remains controversial. Hence, we conducted a prospective analysis in the UK Biobank study and two-sample Mendelian randomization analysis to investigate this association. Biological aging was evaluated by PhenoAgeAccel, derived from routine clinical biomarkers. Independent of chronological age, PhenoAgeAccel was positively associated with the risk of overall and histological subtypes of lung cancer. There was a joint effect of PhenoAgeAccel and genetics in lung cancer incidence. In Mendelian randomization analysis, the genetically predicted PhenoAgeAccel was associated with the increased risk of overall lung cancer, small cell, and squamous cell carcinoma. Our findings suggest PhenoAgeAccel is an independent risk factor for lung cancer, which could be incorporated with polygenic risk score to identify high-risk individuals for lung cancer.

Polygenic Risk Scores (PRS) show promise for facilitating cancer risk stratification. Here, the authors performed a large genome-wide association study and develop a PRS for nasopharyngeal carcinoma, which could improve risk stratification and personalized screening.

Abstract To study the combustion process of fuel in the microwave plasma torch, we designed a butane microwave plasma device exploiting a tungsten rod as an electrode. Through analysis of the image record by high-speed camera, we found that the discharge of butane microwave plasma torch is a cyclic process at atmospheric pressure at a frequency of around 100 Hz. During the discharge, the active particles continuously diffuse from the electrode to the outside like the bloom of the flower. Then, the variation of plasma torch of jet height and temperature with microwave power is obtained. In addition, we studied the effects of different butane flow rates on the plasma torch. The results illustrate that excessive butane will lead to carbon deposition on the electrode. All in all, this work provides a new understanding of the combustion of the microwave plasma torch, which is conducive to the further development of microwave plasma in the fields of waste gas treatment, fuel combustion, and plasma engine.

Abstract Background Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS. Methods Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family. Results Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls. Conclusion LRP2 is a novel candidate genetic cause of non-syndromic familial CS.

Abstract Inner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. However, the genetic causes and molecular mechanisms in the IDAs need further exploration. Here we identified two loss-of-function variants of WDR63 in both MMAF and non-obstructive azoospermia (NOA) affected cohorts. WDR63 encodes an IDA-associated protein that is dominantly expressed in testis. We next generated Wdr63-knockout (Wdr63-KO) mice through the CRISPR-Cas9 technology. Remarkably, Wdr63-KO induced decreased sperm number, abnormal flagellar morphology and male infertility. In addition, transmission electron microscopy assay showed severely disorganized “9 + 2” axoneme and absent inner dynein arms in the spermatozoa from Wdr63-KO male mice. Mechanistically, we found that WDR63 interacted with WDR78 mainly via WD40-repeat domain and is necessary for IDA assembly. Furthermore, WDR63-associated male infertility in human and mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. In conclusion, the present study demonstrates that bi-allelic variants of WDR63 cause male infertility via abnormal inner dynein arms assembly and flagella formation and can be used as a genetic diagnostic indicator for infertility males.

Abstract Background Psychological distress may exert a negative influence on reproductive function of couples at reproductive age. Couples seeking assisted reproductive technology (ART) treatment may have a higher prevalence of psychological distress than fertile couples. However, whether psychological distress is associated with the outcome of ART treatment remains unknown. We aimed to investigate the association of pre-treatment psychological distress and clinical pregnancy rate among infertility couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Methods This nested case-control study was conducted based on women who underwent their first fresh IVF or ICSI cycle in the Jiangsu Birth Cohort Study (JBC) between November 2015 and January 2019. A total of 150 women who did not obtain clinical pregnancy after first IVF or ICSI fresh embryo transfer were identified as cases, and a total of 300 age matched women who obtained clinical pregnancy were identified as controls. Conditional logistic regression analyses were used to investigate the association between psychological distress and the outcome of first IVF or ICSI treatment, adjusting for multiple potential confounders. Results No statistically significant association was observed between score of maternal symptoms of psychological distress and clinical pregnancy. Adjusted ORs of logistic regression were 1.00 (95% CI 0.97-1.03) for anxiety, 0.98 (95% CI 0.95-1.02) for depression, and 0.98 (95% CI 0.95-1.01) for perceived stress, respectively. When treat depression and anxiety as categorical variables, 62 (13.8%) were classified as clinical depression, 11 (2.4%) were classified as clinical anxiety, among 450 women in the present study. Psychological distress symptoms were also not associated with clinical pregnancy rate. Adjusted ORs of logistic regression were 0.27 (95% CI 0.03-2.33) for anxiety, 0.88 (95% CI 0.46-1.68) for depression, respectively. Conclusions Our findings firstly indicated that psychological distress experienced prior to IVF/ICSI treatment was not associated with clinical pregnancy.

Dietary pattern is excellent in reflecting an individual's eating conditions. Longitudinal data on fetal growth can reflect the process of intrauterine growth. We aimed to evaluate the associations between maternal dietary patterns and intrauterine parameters in middle and late pregnancy. The present study was conducted within Jiangsu Birth Cohort (JBC) study. Dietary information was assessed with a food frequency questionnaire (FFQ) in the second and third trimester of gestation. B-ultrasound scans were performed to obtain fetal intrauterine parameters, including head circumference (HC), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW). Exploratory factor analysis was used to extract dietary patterns. Multiple linear regression and linear mixed-effects model (LMM) were used to investigate the association between maternal dietary patterns and fetal growth. A total of 1,936 pregnant women were eligible for the study. We observed inverse associations of maternal “Vegetables and fish” and “Snack and less eggs” patterns during mid-pregnancy with fetal HC Z-score, respectively (“Vegetables and fish”: β = −0.09, 95% CI −0.12, −0.06; “Snack and less eggs”: β = −0.05, 95% CI −0.08, −0.02). On the contrary, “Animal internal organs, thallophyte and shellfish” pattern in the second trimester was associated with increased HC Z-scores (β = 0.04, 95% CI 0.02, 0.06). Consistently, score increase in “Vegetables and fish” pattern in the third trimester was inversely associated with the Z-scores of HC (β = −0.05, 95% CI −0.09, −0.02), while “Meat and less nuts” pattern was positively correlated with the Z-scores of HC (β = 0.04, 95% CI 0.02, 0.07). As compared to the fetus whose mothers at the lowest tertile of “Snack and less eggs” pattern in both trimesters, those whose mothers at the highest tertile demonstrated 1.08 fold (RR = 2.10, 95% CI 1.34–3.28) increased risk of small HC for gestational age (GA). No correlation was observed between maternal dietary patterns and other intrauterine parameters. Our results suggested the effects of maternal dietary patterns on fetal growth, particularly HC. These findings highlighted the adverse impact of unhealthy dietary pattern on fetal growth, might provide evidence for strategies to prevent intrauterine dysplasia and dietary guidelines during pregnancy.

Since supervised learning intrusion detection models rely on manually labeled data, the process often requires a lot of time and effort. To make full use of unlabeled network traffic data and improve intrusion detection, this paper proposes an intrusion detection method for industrial control systems based on improved comparative learning SimCLR. Firstly, a feature extraction network is trained on SimCLR using unlabeled data; a linear classification layer is added to the trained feature extraction network model; and a small amount of labeled data is used for supervised training and fine-tuning of the model parameters. The trained model is simulated on the Secure Water Treatment (SWaT) dataset and the publicly available industrial control dataset from Mississippi State University, and the results show that the method has better results in all evaluation metrics compared with the deep learning algorithm using supervised learning directly, and the comparative learning has research value in industrial control system intrusion detection.

Abstract Background In recent years, births to older mothers and multiparous mothers have increased rapidly with the change of birth policy in China. And mothers of advanced age are more likely to have maternal complications and poor birth outcomes. We aimed to estimate the recent trends and underlying risk factors of maternal mortality. Methods In this systematic assessment, we used data from the National Maternal and Child Health Routine Reporting System (2013–2018), Jiangsu Provincial Maternal Mortality Surveillance System (2017–2018), the Integrated National Mortality Surveillance System (2018), City Statistical Yearbooks (2018), City Health Statistical Yearbooks (2018). The factors associated with maternal mortality ratio (MMR) were explored using the stepwise regression analysis and cluster analysis. Results The MMR maintained at low levels between 2013 and 2016 and there was a slight increase in maternal mortality after 2016 in Jiangsu province. With the implementation of the China’s universal two child policies, the percentage of multiparous mothers ascended from 34.2% (95% confidence interval (CI) = 34.1–34.3%) in 2013 to 51.4% (95% CI = 51.3–51.6%) in 2018 (beta = 3.88, P

Background: Prenatal exposures to neurotoxic metals and trace elements are associated with early childhood neurodevelopmental outcomes. However, consequences of simultaneous exposure to mixtures of elements remain unclear. Objective: To examine individual and joint effects of prenatal trace element exposure on early childhood neurodevelopment. Methods: Using a well-established Bangladesh prospective birth cohort (2008–2011), we measured concentrations of 52 trace elements in umbilical cord serum of 569 mother–infant pairs using inductively coupled plasma mass spectrometry. Neurodevelopment was evaluated at 20–40 months of age using Bayley Scales of Infant and Toddler Development, Third Edition. Stability elastic net (ENET) was used to screen elements individually associated with the outcome; candidate exposures were combined by weighted linear combination to form a risk score representing their mixture effect on early childhood neurodevelopment. Results: Stability ENET identified 15 trace elements associated with cognitive composite score and 14 associated with motor composite score, which were linearly combined to form the element risk score (ERS). Children with higher ERScognitive had lower probability of cognitive developmental delay (ORhighest vs lowest: 0.21; 95 %CI: 0.10, 0.40; P

AimsTo evaluate the clinical efficiency of on-table extubation (OTE) versus delayed extubation in patients aged over 60 years that underwent minimally invasive mitral or aortic valve replacement surgery and evaluate the factors associated with successful OTE implementation.MaterialsPatients over 60 years with mitral or aortic valve disease who received minimally invasive mitral or aortic valve replacement surgery from October 2020 to October 2021 were selected retrospectively. We divided patients into the on-table extubated (OTE) group (n = 71) and the delayed extubation (DE) group (n = 22). Preoperative, intraoperative, and postoperative clinical variables were compared between the two groups.ResultsPatients in the DE group underwent longer surgery time, longer aortic occlusion clamping time and longer cardiopulmonary bypass time than those in the OTE group(217.48 ± 27.83 vs 275.91 ± 77.22, p = 0.002; 76.49 ± 16.00 vs 126.55 ± 54.85, p = 0.001; 112.87 ± 18.91 vs 160.77 ± 52.17, p = 0.001). Patients in the OTE group had shorter postoperative mechanical ventilation time (min), shorter ICU time, shorter postoperative hospital length of stay and lower total cost and medication cost (p

ObjectivesAdequate maternal thyroid hormone availability is crucial for fetal neurodevelopment, but the role of maternal mild hypothyroidism is not clear. We aim to investigate the association of maternal mild hypothyroidism with neurodevelopment in infants at 1 year of age among TPOAb-negative women.MethodsThe present study was conducted within the Jiangsu Birth Cohort. A total of 793 mother–infant pairs were eligible for the present study. Maternal thyroid function was assessed by measuring serum thyroid-stimulating hormone, free thyroxine, and thyroid peroxidase antibodies. Neurodevelopment of infants was assessed by using the Bayley Scales of Infant and Toddler Development third edition screening test (Bayley-III screening test).ResultsIn the multivariate adjusted linear regression analyses, infants of women with subclinical hypothyroidism and isolated hypothyroxinemia were associated with decreased receptive communication scores (β = −0.68, p = 0.034) and decreased gross motor scores (β = −0.83, p = 0.008), respectively. Moreover, infants of women with high-normal TSH concentrations (3.0–4.0 mIU/L) and low FT4 concentrations were significantly associated with lower gross motor scores (β = −1.19, p = 0.032), while no differences were observed in infants when the mothers had a high-normal TSH concentration and normal FT4 levels.ConclusionsMaternal subclinical hypothyroidism is associated with decreased receptive communication scores in infants at 1 year of age. In addition, maternal TSH concentration greater than 4.0 mIU/L and maternal isolated hypothyroxinemia are associated with impaired gross motor ability of infants, especially in infants of women with high-normal TSH concentrations (3.0–4.0 mIU/L).

Abstract The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 TNS3 at 7p12.3 (P = 3.90 × 10−9) and rs1143149 SEPT7 at 7p14.2 (P = 9.75 × 10−9), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819 TNS3 : P interaction = 8.0 × 10−4; rs1143149 SEPT7 : P interaction = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.

Abstract N6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.

Objective: The newly defined cancer-testis (CT) gene, MEIOB, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs). Methods: The Cancer Genome Atlas database was used to quantify the expression of MEIOB. Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro. Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors. Results: We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16–2.06); TNBCs: HR = 7.05 (1.16–41.80)]. In addition, we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that MEIOB participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models. Conclusions: MEIOB played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors, so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.

Abstract Background Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown. Methods We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses’ Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P

Abstract Background The World Health Organization (WHO) in 2015 stated that every effort should be made to provide cesarean delivery (CD) for women in need. In China, the two-child policy largely prompts the number of advanced age childbirth, which raises the possibility of an increasing number of women who need a c-section. The aim of this study was to assess the trends in the overall and medical indication-classified CD rates in the era of the two-child policy in Jiangsu, China. Methods A retrospective cross-sectional study of 291,448 women who delivered in 11 hospitals in Jiangsu province between 2012 and 2019 was conducted. Medical cesarean indication for each woman was ascertained by manually reviewing the medical records. The 291,448 women were divided into two subgroups according to the presence of the indications: the indicated group (7.80%) and the non-indicated group (92.20%). We then fitted joinpoint regression and log-binomial regression models to estimate trends in the CD rates across the study period. Results The overall CD rate was observed with a declining trend from 52.51% in 2012–2015 to 49.76% in 2016–2019 (adjusted RR, 0.92; 95% CI, 0.91–0.93; P

Invasive early stage lung adenocarcinoma has a heterogeneous prognosis. Here, the authors microdissect malignant pulmonary nodules to invasive and preinvasive components and study the mutations that are common or private between the lesions, allowing them to understand the evolutionary path of the tumours.

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder. To enhance the understanding of the gut microbiota structure in ASD children at different ages as well as the relationship between gut microbiota and fecal metabolites, we first used the 16S rRNA sequencing to evaluate the gut microbial population in a cohort of 143 children aged 2–13 years old. We found that the α-diversity of ASD group showed no significant change with age, while the TD group showed increased α-diversity with age, which indicates that the compositional development of the gut microbiota in ASD varies at different ages in ways that are not consistent with TD group. Recent studies have shown that chronic constipation is one of the most commonly obvious gastrointestinal (GI) symptoms along with ASD core symptoms. To further investigate the potential interaction effects between ASD and GI symptoms, the 30 C-ASD and their aged-matched TD were picked out to perform metagenomics analysis. We observed that C-ASD group displayed decreased diversity, depletion of species of Sutterella, Prevotella, and Bacteroides as well as dysregulation of associated metabolism activities, which may involve in the pathogenesis of C-ASD. Consistent with metagenomic analysis, liquid chromatography-mass spectrometry (LC/MS) revealed some of the differential metabolites between C-ASD and TD group were involved in the metabolic network of neurotransmitters including serotonin, dopamine, histidine, and GABA. Furthermore, we found these differences in metabolites were associated with altered abundance of specific bacteria. The study suggested possible future modalities for ASD intervention through targeting the specific bacteria associated with neurotransmitter metabolism.

Abstract Background Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles. Methods We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR). Results The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61–1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023). Conclusions This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1–2 fresh cleavage-stage embryos.

Purpose: To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. Methods: We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. Results: A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01, HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. Conclusions: Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified.

Abstract Background Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors. Long noncoding RNAs play critical roles in tumorigenesis. Methods Real‐time quantitative PCR arrays were used to evaluate the expression levels of cytoskeleton regulator RNA (CYTOR) in NPC tissues and cells. Cell counting kit‐8 and colony formation analyses were used to test the NPC cell viability, while wound healing and transwell assays were employed to detect cell invasion and migration ability. Luciferase reporter assay and Western blot analyses were employed to explore the relationships among CYTOR, miR‐613, and ANXA2. Results We found that CYTOR expression was elevated both in NPC tissues and cells. Functional assays revealed that CYTOR promoted the invasion and migration of NPC cells. The established spontaneous lymph node metastasis model also confirmed that CYTOR promoted NPC cell metastasis in vivo. Mechanically, we found that the subcellular localization of CYTOR mostly occurred in the cell cytoplasm. Luciferase reporter and RIP assays confirmed that CYTOR functioned as the molecular sponge of miR‐613. Subsequent experiments confirmed that ANXA2 was directly targeted by miR‐613. Gain‐ and loss‐of‐function studies further confirmed that CYTOR induced the upregulation of ANXA2 by competitively binding to miR‐613, thus leading to NPC metastasis. Conclusion Our results highlight the importance of CYTOR in NPC development and provide new insights into potential therapeutic targets for NPC.

In this paper, some recent results on the distributed filtering, estimation and fusion algorithms for nonlinear systems with communication constraints are reviewed. First, some network-induced phenomena and communication protocols in the networked environment are recalled. Second, the recent advances of distributed fusion algorithms for nonlinear systems are discussed, which include distributed fusion extended Kalman filtering, distributed fusion unscented Kalman filtering, distributed fusion cubature Kalman filtering, distributed fusion particle filtering. Subsequently, some new distributed filtering, estimation and fusion algorithms for nonlinear systems subject to communication constraints are summarized and discussed. Finally, conclusion is given and several possible research topics on distributed filtering, estimation and fusion for nonlinear networked systems are pointed out.

BackgroundIt remains undetermined whether neuroticism affects the risk of lung cancer. Therefore, we performed complementary observational and Mendelian randomization (MR) analyses to investigate the association between neuroticism and lung cancer risk.MethodsWe included 364,451 UK Biobank participants free of cancer at baseline. Neuroticism was ascertained using the 12-item of Eysenck Personality Inventory Neuroticism Scale. Multivariable Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Two-sample MR analysis was carried out with summary genetic data from UK Biobank (374,323 individuals) and International Lung Cancer Consortium (29,266 lung cancer cases and 56,450 controls). Furthermore, we calculated a polygenic risk score of lung cancer, and examined the joint-effect and interaction between neuroticism and genetic susceptibility on lung cancer risk.ResultsDuring a median follow-up of 7.13 years, 1573 lung cancer cases were documented. After adjusting for smoking and other confounders, higher neuroticism was associated with an increased risk of lung cancer (HR per 1 SD=1.07, 95% CI: 1.02-1.12). Consistently, MR analysis suggested a causal effect of neuroticism on lung cancer risk (OR IVW=1.10, 95% CI: 1.03-1.17). Compared to individuals with low neuroticism and low PRS, those with both high neuroticism and high PRS had the greatest risk of lung cancer (HR=1.82, 95%CI: 1.51-2.20). Furthermore, there was a positive additive but no multiplicative interaction between neuroticism and genetic risk.ConclusionsOur findings suggest that neuroticism is associated with an elevated risk of incident lung cancer, which is strengthened by the genetic susceptibility to lung cancer. Further studies are necessary to elucidate underlying mechanisms.

Obesity is a leading contributor to colorectal cancer (CRC) risk, but the metabolic mechanisms linking obesity to CRC are not fully understood. We leveraged untargeted metabolomics data from two 1:1 matched, nested case–control studies for CRC, including 223 pairs from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 190 pairs from a prospective Chinese cohort. We explored serum metabolites related to body mass index (BMI), constructed a metabolomic signature of obesity, and examined the association between the signature and CRC risk. In total, 72 of 278 named metabolites were correlated with BMI after multiple testing corrections (p FDR < 0.05). The metabolomic signature was calculated by including 39 metabolites that were independently associated with BMI. There was a linear positive association between the signature and CRC risk in both cohorts (p for linear < 0.05). Per 1-SD increment of the signature was associated with 38% (95% CI: 9–75%) and 28% (95% CI: 2–62%) higher risks of CRC in the US and Chinese cohorts, respectively. In conclusion, we identified a metabolomic signature for obesity and demonstrated the association between the signature and CRC risk. The findings offer new insights into the underlying mechanisms of CRC, which is critical for improved CRC prevention.

Abstract Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse‐variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81‐2.78, P = 1.18 × 10−13). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11‐3.42, P = 7.20 × 10−16); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01‐2.10, P = .047). Nonlinear analysis suggested a log‐linear dose‐response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.

ABSTRACT To assess the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies produced by natural infection and describe the serological characteristics over 7 months after symptom onset among coronavirus disease 2019 (COVID-19) patients by age and severity group, we followed up COVID-19 convalescent patients confirmed from 1 January to 20 March 2020 in Jiangsu, China and collected serum samples for testing IgM/IgG and neutralizing antibodies against SARS-CoV-2 between 26 August and 28 October 2020. In total, 284 recovered participants with COVID-19 were enrolled in our study. Patients had a mean age of 46.72 years (standard deviation [SD], 17.09), and 138 (48.59%) were male. The median follow-up time after symptom onset was 225.5 (interquartile range [IQR], 219 to 232) days. During the follow-up period (162 to 282 days after symptom onset), the seropositive rate of IgM fluctuated around 25.70% (95% confidence interval [CI], 20.72% to 31.20%) and that of IgG fluctuated around 79.93% (95% CI, 74.79% to 84.43%). Of the 284 patients, 64 participants were tested when discharged from hospital. Compared with that at the acute phase, the IgM/IgG antibody levels and IgM seropositivity have decreased; however, the seropositivity of IgG was not significantly lower at this follow-up (78.13% versus 82.81%). Fifty percent inhibitory dilution (ID50) titers of neutralizing antibody for samples when discharged from hospital (geometric mean titer [GMT], 82; 95% CI, 56 to 121) were significantly higher than those at 6 to 7 months after discharge (GMT, 47; 95% CI, 35 to 63) (P