Monomeric Far-red and Near-infrared Fluorescent Biliproteins of Ultrahigh Brightness.

Far-red and near-infrared fluorescent proteins have regions of maximum transmission in most tissues and can be widely used as fluorescent biomarkers. We report that fluorescent phycobiliproteins originating from the phycobilisome core subunit ApcF2 can covalently bind biliverdin, named BDFPs. To further improve BDFPs, we conducted a series of studies. Firstly, we mutated K53Q and T144A of BDFPs to increase their effective brightness up to 190 % in vivo. Secondly, by homochromatic tandem fusion of high-brightness BDFPs to achieve monomerization, which increases the effective brightness by up to 180 % in vivo, and can effectively improve the labeling effect. By combining the above two approaches, the brightness of the tandem BDFPs was much improved compared with that of the previously reported fluorescent proteins in a similar spectral range. The tandem BDFPs were expressed stably while maintaining fluorescence in mammalian cells and Caenorhabditis elegans. They were also photostable and resistant to high temperature, low pH, and chemical denaturation. The tandem BDFPs advantages were proved in applications as biomarkers for imaging in super-resolution microscopy.

Visual identification of three kinds of human decidual tissues from elective termination of pregnancy.

INTRODUCTION: The decidua can be classified into the decidua basalis, decidua capsularis and decidua parietalis. This study aimed to visually identify these three kinds of decidual tissues from fresh samples obtained in early pregnancy based on their macroscopic appearances, which can be discerned visually. METHODS: Decidual samples were collected from 15 pregnant women between 6 and 8 weeks of gestation after elective termination of pregnancy. We identified the three different kinds of fresh decidual tissues in early pregnancy according to their different macroscopic appearances by only the naked eye. H&E staining, in situ immunofluorescence and flow cytometry were performed to confirm the accuracy of this method. RESULTS: We developed a method to discern the three different kinds of decidual tissues according to their individual macroscopic features. We found that the decidua parietalis was a thick tissue with less blood, with one side being intact epidermis and the other side being rough tissue. The decidua basalis had rough surfaces, a dense texture and high blood content. The decidua capsularis was a thin membrane tissue with or without blood clots. CK+/HLA-G+ extravillous trophoblast cells (EVTs) and heme oxygenase-1+ (HMOX1+) decidual macrophages were present in large quantities in the decidua basalis and decidua capsularis but were nearly undetectable in the decidua parietalis. We also found a wide distribution of endovascular extravillous trophoblast cells (enEVTs), which participate in spiral artery remodelling in the decidua basalis. DISCUSSION: We successfully identified three kinds of human decidual tissues from early pregnancy with the naked eye for the first time. This breakthrough method will greatly assist studies related to decidua during early pregnancy.

National Volume-Based Procurement (NVBP) exclusively for insulin: towards affordable access in China and beyond.

Universal access to insulin remains a global public health challenge mainly due to its high price. After unsuccessful healthcare reforms attempting to lower insulin prices over the past several decades, the novel pooled procurement-also known as the national volume-based procurement (NVBP)was initiated exclusively for insulin in China. The NVBP exclusively for insulin represents a unique approach to conquering the challenges in the pooled procurement many low-income and middle-income countries face. In this paper, we described how the pooled procurement mechanism was implemented for insulin in China. Forty-two insulin products from 11 companies were procured, with a median price reduction of 42.08%. The procurement price ranged from US$0.35 to US$1.63 (¥2.35-¥10.97) per defined daily dose (DDD). The median procurement price per DDD was US$$0.54 (¥3.63) for human insulins and US$0.92 (¥6.18) for analogue insulin (p<0.001), respectively. A total of 32 000 medical facilities participated in the procurement, and the pooled demand for insulin was 1.61 billion daily doses, with an estimated saving of US$2.85 billion (¥19 billion) for the first year of the procurement agreement. Insulin affordability and accessibility improved substantially. This study reveals that the NVBP exclusively for insulin could effectively reduce insulin prices and improve access to this essential medicine. Even though the pooled procurement option looks efficient, its long-term impacts on the healthcare system should be closely monitored.

Association of psychological distress, smoking and genetic risk with the incidence of lung cancer: a large prospective population-based cohort study.

Background: Emerging evidence suggests a potential link between psychological distress (anxiety and depression) and lung cancer risk, however, it is unclear whether other factors such as tobacco smoking and genetic susceptibility modify the association. Methods: We included 405,892 UK Biobank participants free of cancer at baseline. Psychological distress was measured using the Patient Health Questionnaire-4 (PHQ-4). A polygenic risk score (PRS) was calculated using 18 lung cancer-associated genetic loci. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 7.13 years, 1754 lung cancer cases were documented. The higher score of psychological distress was associated with an increased risk of lung cancer (HRper 1-SD= 1.07, 95% CI: 1.02-1.11) after adjustment for smoking and other confounders. Mediation analysis revealed that 16.8% (95% CI: 13.0%-20.6%) of the distress-lung cancer association was mediated by smoking. Compared with never smokers with no distress, participants with heavy smoking and high distress had the highest risk of lung cancer (HR=18.57, 95% CI: 14.51-23.76). Both multiplicative and additive interactions were observed between smoking and psychological distress in lung cancer. Furthermore, the greatest relative increase in risk was observed among those with high genetic risk and high distress (HR=1.87, 95%CI: 1.50-2.33), and there was a significant additive interaction between the PRS and psychological distress. Conclusion: Our results indicate that psychological distress was associated with an elevated risk of incident lung cancer, and such relation was modified by tobacco smoking and genetic susceptibility.

Target capture sequencing for the first Nigerian genotype I ASFV genome.

African swine fever (ASF) is a contagious viral disease that affects domestic pigs and wild boars, causing significant economic losses globally. After the first Nigerian outbreak in 1997, there have been frequent reports of ASF in pig-producing regions in the country. To facilitate control, it is important to understand the genotype and phylogenetic relationship of ASF viruses (ASFVs). Recent genetic analysis of Nigerian ASFV isolates has revealed the presence of both genotypes I and II; this is based on analysis of a few selected genes. Phylogenetic analysis of ASFV whole genomes highlights virus origins and evolution in greater depth. However, there is currently no information on the ASFV genome from Nigerian isolates. Two ASFV-positive samples were detected during a random survey of 150 Nigerian indigenous pig samples collected in 2016. We assembled near-complete genomes of the two ASFV-positive samples using in-solution hybrid capture sequencing. The genome-wide phylogenetic tree assigned these two genomes into p72 genotype I, particularly close to the virulent Benin 97/1 strain. The two ASFVs share 99.94 and 99.92 % genomic sequence identity to Benin97/1. This provides insight into the origin and relationship of ASFV strains from Nigeria and Italy. The study reports for the first time the determination of near-complete genomes of ASFV using in-solution hybrid capture sequencing, which represents an important advance in understanding the global evolutionary landscape of ASFVs.

Effects of Alzheimer's disease and related dementias on dental care usage and economic burden in older adults: a cross-sectional study.

AIM: Distinct subtypes of Alzheimer's disease (AD) and related dementias (RD) might have different effects on dental care usage and economic burden. To determine the effects of AD and RD on specific types of dental care usage (preventive and treatment visits) and dental care costs from different payers (total and out-of-pocket costs). METHODS: A cross-sectional study was conducted using the Medicare Current Beneficiary Survey in 2016. This study identified 4268 community dwelling older adults with and without Alzheimer's disease and related dementias (ADRD) from a nationally representative sample of Medicare beneficiaries. Dental care usage and costs are based on self-reported data. Preventive dental events included preventive and diagnosis events. Treatment dental events included restorative, oral surgery and other events. RESULTS: This study identified 4268 (weighted N=30 423 885) older adults, including 94.48% without ADRD, 1.90% with AD and 3.63% with RD. Compared with older adults without ADRD, those with AD had similar dental care usage, but those with RD were 38% less likely to have treatment visit (OR: 0.62; 95% CI: 0.41 to 0.94) and had a 40% reduced number of total treatment visits (incidence rate ratio: 0.60; 95% CI: 0.37 to 0.98). RD was not associated with dental care costs, but AD was associated with higher total costs (ß: 1.08; 95% CI: 0.14 to 2.01) and higher out-of-pocket costs (ß: 1.25; 95% CI: 0.17 to 2.32). CONCLUSIONS: Patients with ADRD were more likely to have adverse dental care outcomes. Specifically, RD was associated with lower treatment dental care usage and AD was associated with higher total and out-of-pocket dental care costs. Effective patient-centred strategies should be used to improve dental care outcomes in patients with distinct subtypes of ADRD.

Identifying a dynamic transcriptomic landscape of the cynomolgus macaque placenta during pregnancy at single-cell resolution.

Supporting healthy pregnancy outcomes requires a comprehensive understanding of the cellular hierarchy and underlying molecular mechanisms in the primate placenta during gestation. Here, we present a single-cell transcriptome-wide view of the cynomolgus macaque placenta throughout gestation. Bioinformatics analyses and multiple validation experiments suggested that placental trophoblast cells exhibited stage-specific differences across gestation. Interactions between trophoblast cells and decidual cells also showed gestational stage-dependent differences. The trajectories of the villous core cells indicated that placental mesenchymal cells were derived from extraembryonic mesoderm (ExE.Meso) 1, whereas placental Hofbauer cells, erythrocytes, and endothelial cells were derived from ExE.Meso2. Comparative analyses of human and macaque placentas uncovered conserved features of placentation across species, and the discrepancies of extravillous trophoblast cells (EVTs) between human and macaque correlated to their differences in invasion patterns and maternal-fetal interactions. Our study provides a groundwork for elucidating the cellular basis of primate placentation.

A differentiation roadmap of murine placentation at single-cell resolution.

The placenta is one of the most important yet least understood organs. Due to the limitations of conventional research approaches, we are still far from a comprehensive understanding of mouse placentation, especially regarding the differentiation of trophoblast lineages at the early developmental stage. To decipher cell compositions and developmental processes, we systematically profile the single-cell transcriptomes of trophoblast cells from extraembryonic tissues (embryonic day 7.5 (E7.5) and E8.5) and placentae (E9.5-E14.5) at one-day intervals. We identify distinct trophoblast cell types during mouse placentation, including unreported progenitor cells and intermediate precursor cells. An updated differentiation roadmap of mouse trophoblast lineages is presented following systematic transcriptome analyses. Based on transcriptomic regulatory network inference, we specify transcription factors responsible for the regulation of dynamic developmental processes during lineage diversification. We map lineage differentiation trajectories and find that sinusoid trophoblast giant cells arise from the subpopulation of ectoplacental cone cells. We provide a comprehensive single-cell data resource to shed light on future mechanistic studies of the gene regulatory networks governing hemochorial placentation.

Primate gastrulation and early organogenesis at single-cell resolution.

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.

Dissecting the fate of Foxl2-expressing cells in fetal ovary using lineage tracing and single-cell transcriptomics.

Gonad somatic cells acquire sex-specific fates during sex determination. In XX gonad, a subset of somatic cells expresses Foxl2 after sex determination which is considered the progenitor of granulosa cells. However, whether these cells also contribute to other cell types at later developmental stages is unknown. In the present study, the cell fate of Foxl2-expressing cells in fetal ovaries was analyzed by lineage tracing and single-cell transcriptomics. We found that Foxl2-expressing cells gave rise to three cell types at later developmental stages, including granulosa cells, theca-interstitial cells, and stromal cells. Series single-cell RNA sequencing revealed FOXL2-positive cells were divided into two clusters at P0. One group further differentiated into granulosa cells and Theca-G (Theca-interstitial cells derived from granulosa) at P14. Another group was classified as stromal cell lineage, then a small portion of them further differentiated into 3ß-HSD-positive Theca-S (Theca-interstitial cells derived from stroma). Cyp17a1 was expressed in Theca-S, but not in Theca-G. This study demonstrated that Folx2-expressing cells in XX gonad after sex determination are multipotent and theca-interstitial cells are derived from different progenitors. Our data provided an important resource, at single-cell resolution, for a better understanding of somatic cell differentiation in ovary development.

Association of MC1R variation and plumage color diversity of Nigerian domestic pigeon (Columba livia domestica).

Objectives: Domestic pigeons (Columba livia domestica) have diverse plumage pigmentations. Melanocortin 1 receptor (MC1R) gene variation has been correlated with color traits. The association between MC1R and plumage coloration in African domestic pigeons is yet to be investigated. Materials and Methods: Herein, we report the relationships between single nucleotide polymorphisms (SNPs) in MC1R and plumage of 35 domestic pigeons from Nigeria with 4 different plumage phenotypes plus 37 published MC1R sequences from France (n = 14) and Russia (n = 11). Results: We obtained 14 SNP sites among 72 individuals. Missense mutations C206T (Ser69Leu) and G253A (Val85Met) were observed in 16 and 8 Nigerian pigeons, respectively. The chi-squared test (p < 0.05) for C206T, G253A, and A520G has the advantage of homozygous genotypes CC, GG, and AA, respectively. The association of C206T loci showed the advantage of CC genotype in ash-red, spread, and white pigeons, and TT in blue-bar, spread, and white feather pigeons. For G253A and A520G loci, GG and AA were dominant in all plumages except for genotype AA in G253A, which was prominent in ash-red, spread, and white plumages. The three SNPs were assigned to seven haplotypes. The median-joining network revealed 20 haplotypes, including 5 in Nigeria and 2 shared. Conclusion: This study provides an insight into the association of MC1R variation and plumage diversity in Nigerian domestic pigeons. However, due to the limitation of the current data, we could not make further conclusions; this necessitates the need for more genomics studies on Nigerian pigeons.

Impact of Alzheimer's disease and related dementias on colorectal cancer screening utilization, knowledge, and associated health disparities.

Background: Colorectal cancer screening can detect colorectal cancer at an early stage and reduce mortality. None of the existing clinical practice guidelines provide specific recommendations for colorectal cancer screening in patients with Alzheimer's disease and related dementias (ADRD). Limited studies have assessed the impacts of ADRD on colorectal cancer screening use and knowledge, and no studies have focused on the associated health disparities. Objectives: To examine the utilization, knowledge, and associated health disparities of colorectal cancer screening in older adults with ADRD. Methods: This study used the Medicare Current Beneficiary Survey from 2015 to 2018. Two types of colorectal cancer screening, including fecal occult blood test (FOBT) and colonoscopy/sigmoidoscopy, were measured. The colorectal cancer screening knowledge was evaluated by asking if the participants have heard of two screening methods and whether they knew Medicare pays for colorectal cancer screenings. Logistic regression models were used to examine the impact of ADRD diagnosis on the utilization and knowledge of colorectal cancer screening. Results: The overall colorectal cancer screening rate in older adults increased from 86.4% to 88.96% from 2015 to 2018. Patients with AD were 39% (OR: 0.61; 95% CI: 0.50-0.76) less likely and those with RD were 25% (OR: 0.75; 95% CI: 0.62-0.91) less likely to use any colorectal cancer screening when compared to older adults without ADRD. The rate of knowledge of colonoscopy/sigmoidoscopy remained high between 84.23% and 84.57% while the knowledge of FOBT increased from 64.32% to 78.69% during the study period. Compared to older adults without ADRD, those with AD were 77% (OR: 1.77; 95% CI: 1.12-2.81) more likely to hear of colonoscopy/sigmoidoscopy. The rate of knowledge of Medicare pay for colorectal cancer screening increased from 42.19% to 45.27% during the study period. Compared to older adults without ADRD, those with AD were 19% (OR: 0.81; 95% CI: 0.70-0.94) less likely to know that Medicare pays for colorectal cancer screening. Conclusion: ADRD was significantly associated with colorectal cancer screening utilization and knowledge. In addition, this study identified health disparities in race/ethnicity, gender, and urban/rural residence in colorectal cancer screening use and knowledge.

New Far-Red and Near-Infrared Fluorescent Phycobiliproteins with Excellent Brightness and Photostability.

Far-red and near-infrared fluorescent proteins can be used as fluorescence biomarkers in the region of maximal transmission of most tissues and facilitate multiplexing. Recently, we reported the generation and properties of far-red and near-infrared fluorescent phycobiliproteins, termed BeiDou Fluorescent Proteins (BDFPs), which can covalently bind the more readily accessible biliverdin. Far-red BDFPs maximally fluoresce at ∼670 nm, while near-infrared BDFPs fluoresce at ∼710 nm. In this work, we molecularly evolved BDFPs as follows: (a) mutations L58Q, S68R and M81K of BDFPs, which can maximally enhance the effective brightness in vivo by 350 %; (b) minimization and monomerization of far-red BDFPs 2.1, 2.2, 2.3, and near-infrared BDFPs 2.4, 2.5 and 2.6. These newly developed BDFPs are remarkably brighter than the formerly reported far-red and near-infrared fluorescent proteins. Their advantages are demonstrated by biolabeling in mammalian cells using super-resolution microscopy.

A Single-Cell Characterization of Human Post-implantation Embryos Cultured In Vitro Delineates Morphogenesis in Primary Syncytialization.

Implantation of the human blastocyst is a milestone event in embryonic development. The trophoblast is the first cell lineage to differentiate during implantation. Failures in trophoblast differentiation during implantation are correlated to the defects of pregnancy and embryonic growth. However, many gaps remain in the knowledge of human embryonic development, especially regarding trophoblast morphogenesis and function. Herein, we performed single-cell RNA sequencing (scRNA-seq) analysis on human post-implantation embryos cultured in vitro. A hierarchical model was established, which was characterized by the sequential development of two primitive cytotrophoblast cell (pCTB) subtypes, two primitive syncytiotrophoblast subtypes, and migrative trophoblast cells (MTB) after the trophectoderm . Further analysis characterized cytoskeleton transition of trophoblast cells and morphogenesis, such as irregular nuclei, cell cycle arrest, and cellular aging during implantation. Moreover, we found syncytialization of hTSCs could mimic the morphogenesis, serving as a powerful tool for further understanding of the mechanism during the implantation stage of pregnancy. Our work allows for the reconstruction of trophoblast cell transcriptional transition and morphogenesis during implantation and provides a valuable resource to study pathologies in early pregnancy, such as recurrent implantation failure.

Evidence of Chinese Herbal Medicine Use From an Economic Perspective: A Systematic Review of Pharmacoeconomics Studies Over Two Decades.

Objectives: Pharmacoeconomics evaluation (PE) is increasingly used in the healthcare decision-making process in China. Little is known about PE conducted in Chinese Herbal Medicines (CHMs). We aimed to systematically review trends, characteristics, and quality of PE of CHMS. Methods: We systematically searched both Chinese (CNKI, WanFang, and VIP) and English (Pubmed) databases. Studies were included if they were PE studies comparing both costs and outcomes between two or more interventions published in Chinese or English. Assessment of the quality of studies was conducted using the Quality of Health Economic Analyses (QHES) instrument. T-test and Chi-square tests were used to compare the studies before and after the first edition of China Guidelines for PE published in 2011, and between studies published in Chinese and English. Results: A total of 201 articles were included. There was an increasing trend of PE studies on CHMs during the study period. The top three studied diseases were central nervous system (CNS), mental, and behavioral disorders; cardiovascular diseases; and blood, immune and endocrine diseases. The average QHES score for the included studies was 63.37. Cost-effectiveness analysis (CEA) accounted for the majority (76.6%) of the included studies. Only a quarter of the articles (27.4%) were funded, and there were significantly more studies funded after the publication of China guidelines for PE. About 96.5% of studies did not specify evaluation perspectives and 89.6% of studies had a sample size of less than 300. Around half of the studies (55%) used incremental analysis, but only a few of them considered using a threshold. Half of the studies lacked sensitivity analysis. There was no significant improvement in the quality of studies published after the publication of China Guidelines for PE, and English articles had significantly higher quality than Chinese articles. Conclusion: This study identified several problems in PE studies on CHMs, including having small sample sizes, lacking necessary research elements, and using single evaluation methods. The quality of PE studies on CHMs was not sufficient. Researchers need to understand the standardized way to conduct PE studies and improve the quality and level of PE studies on CHMs.

Functional characterization and clinical significance of super-enhancers in lung adenocarcinoma.

Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration) and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy.

LMNA Determines Nuclear Morphology During Syncytialization of Human Trophoblast Stem Cells.

Upon implantation, the trophectoderm differentiates into the multi-nucleated primitive syncytiotrophoblast (pSTB) through a process called primary syncytialization to facilitate maternal-fetal interactions and to establish a pregnancy. However, ethical issues and limited access to human embryos around the time of embryo implantation hinder the investigation of the detailed molecular mechanisms underpinning this event in humans. Here we established human trophoblast stem cells (hTSCs) from human blastocysts. We characterized nuclear enlargement in STB differentiated from hTSCs, which recapitulate morphological nuclear features of pSTB in human embryos. Specifically, we revealed that CRISPR/Cas9-mediated LMNA disruption perturbated nuclear volume during hTSCs syncytialization. Overall, our results not only provide an interesting insight into mechanisms underlying nuclear enlargement during primary syncytialization but highlight the hTSCs as an indispensable model in understanding human trophoblast differentiation during implantation.

Association Between Neuroticism and Risk of Lung Cancer: Results From Observational and Mendelian Randomization Analyses.

BACKGROUND: It 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. METHODS: We 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. RESULTS: During 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. CONCLUSIONS: Our 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.