A Manganese-Based Nanodriver Coordinates Tumor Prevention and Suppression through STING Activation in Glioblastoma.

Glioblastoma (GBM), the most prevalent and aggressive primary malignant brain tumor, exhibits profound immunosuppression and demonstrates a low response rate to current immunotherapy strategies. Manganese cations (Mn2+) directly activate the cGAS/STING pathway and induce the unique catalytic synthesis of 2'3'-cGAMP to facilitate type I IFN production, thereby enhancing innate immunity. Here, a telodendrimer and Mn2+-based nanodriver (PLHM) with a small size is developed, which effectively target lymph nodes through the blood circulation and exhibit tumor-preventive effects at low doses of Mn2+ (3.7 mg kg-1). On the other hand, the PLHM nanodriver also exhibits apparent antitumor effects in GBM-bearing mice via inducing in vivo innate immune responses. The combination of PLHM with doxorubicin nanoparticles (PLHM-DOX NPs) results in superior inhibition of tumor growth in GBM-bearing mice due to the synergistic potentiation of STING pathway functionality by Mn2+ and the presence of cytoplasmic DNA. These findings demonstrate that PLHM-DOX NPs effectively stimulate innate immunity, promote dendritic cell maturation, and orchestrate cascaded infiltration of CD8 cytotoxic T lymphocytes within glioblastomas characterized by low immunogenicity. These nanodivers chelated with Mn2+ show promising potential for tumor prevention and antitumor effects on glioblastoma by activating the STING pathway.

Multilocular thymic cysts can be easily misdiagnosed as malignant tumor on computer tomography: A case report.

BACKGROUND: Multilocular thymic cyst (MTC) is a rare mediastinal lesion which is considered to occur in the process of acquired inflammation. It is usually characterized by well-defined cystic density and is filled with transparent liquid. CASE SUMMARY: We report on a 39-year-old male with a cystic-solid mass in the anterior mediastinum. Computer tomography (CT) imaging showed that the mass was irregular with unclear boundaries. After injection of contrast agent, there was a slight enhancement of stripes and nodules. According to CT findings, it was diagnosed as thymic cancer. CONCLUSION: After surgery, MTC accompanied by bleeding and infection was confirmed by pathological examination. The main lesson of this case was that malignant thymic tumor and MTC of the anterior mediastinum sometimes exhibit similar CT findings. Caution is necessary in clinical work to avoid misdiagnosis.

Pre-transplant Use of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma: A Multicenter, Retrospective Cohort Study.

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma (HCC) patients is rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICIs therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICIs therapy during the study period. The median post-LT follow up was 8.1 (interquartile range [IQR] 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) was diagnosed by liver biopsy. Multivariate logistics regression analysis showed that time interval between the last administration of ICIs therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (OR = 0.096, 95%CI 0.026-0.357; P < 0.001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (OS) (HR = 9.960, 95%CI 1.006-98.610; P = 0.043). We conclude that patients who receive a pre-LT ICIs therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with a higher post-LT mortality.

Joint Exposure to Multiple Air Pollutants, Genetic Susceptibility, and Incident Dementia: A Prospective Analysis in the UK Biobank Cohort.

Objectives: This study aimed to evaluate the joint effects of multiple air pollutants including PM2.5, PM10, NO2, and NOx with dementia and examined the modifying effects of genetic susceptibility. Methods: This study included 220,963 UK Biobank participants without dementia at baseline. Weighted air pollution score reflecting the joint exposure to multiple air pollutants were constructed by cross-validation analyses, and inverse-variance weighted meta-analyses were performed to create a pooled effect. The modifying effect of genetic susceptibility on air pollution score was assessed by genetic risk score and APOE ε4 genotype. Results: The HR (95% CI) of dementia for per interquartile range increase of air pollution score was 1.13 (1.07∼1.18). Compared with the lowest quartile (Q1) of air pollution score, the HR (95% CI) of Q4 was 1.26 (1.13∼1.40) (P trend = 2.17 × 10-5). Participants with high air pollution score and high genetic susceptibility had higher risk of dementia compared to those with low air pollution score and low genetic susceptibility. Conclusion: Our study provides evidence that joint exposure to multiple air pollutants substantially increases the risk of dementia, especially among individuals with high genetic susceptibility.

Tailoring raloxifene into single-component molecular crystals possessing multilevel stimuli-responsive room-temperature phosphorescence.

Simultaneously achieving room-temperature phosphorescence (RTP) and multiple-stimuli responsiveness in a single-component system is of significance but remains challenging. Crystallization has been recognized to be a workable strategy to fulfill the above task. However, how the molecular packing mode affects the intersystem crossing and RTP lifetime concurrently remains unclear so far. Herein, four economic small-molecular compounds, analogues of the famous drug raloxifene (RALO), are facilely synthesized and further explored as neat single-component and stimuli-responsive RTP emitters via crystallization engineering. Thanks to their simple structures and high ease to crystallize, these raloxifene analogues function as models to clarify the important role of molecular packing in the RTP and stimuli-responsiveness properties. Thorough combination of the single-crystal structure analysis and theoretical calculations clearly manifests that the tight antiparallel molecular packing mode is the key point to their RTP behaviors. Interestingly, harnessing the controllable and reversible phase transitions of the two polymorphs of RALO-OAc driven by mechanical force, solvent vapor, and heat, a single-component multilevel stimuli-responsive platform with tunable emission color is established and further exploited for optical information encryption. This work would shed light on the rational design of multi-stimuli responsive RTP systems based on single-component organics.

Incorporating genetic similarity of auxiliary samples into eGene identification under the transfer learning framework.

BACKGROUND: The term eGene has been applied to define a gene whose expression level is affected by at least one independent expression quantitative trait locus (eQTL). It is both theoretically and empirically important to identify eQTLs and eGenes in genomic studies. However, standard eGene detection methods generally focus on individual cis-variants and cannot efficiently leverage useful knowledge acquired from auxiliary samples into target studies. METHODS: We propose a multilocus-based eGene identification method called TLegene by integrating shared genetic similarity information available from auxiliary studies under the statistical framework of transfer learning. We apply TLegene to eGene identification in ten TCGA cancers which have an explicit relevant tissue in the GTEx project, and learn genetic effect of variant in TCGA from GTEx. We also adopt TLegene to the Geuvadis project to evaluate its usefulness in non-cancer studies. RESULTS: We observed substantial genetic effect correlation of cis-variants between TCGA and GTEx for a larger number of genes. Furthermore, consistent with the results of our simulations, we found that TLegene was more powerful than existing methods and thus identified 169 distinct candidate eGenes, which was much larger than the approach that did not consider knowledge transfer across target and auxiliary studies. Previous studies and functional enrichment analyses provided empirical evidence supporting the associations of discovered eGenes, and it also showed evidence of allelic heterogeneity of gene expression. Furthermore, TLegene identified more eGenes in Geuvadis and revealed that these eGenes were mainly enriched in cells EBV transformed lymphocytes tissue. CONCLUSION: Overall, TLegene represents a flexible and powerful statistical method for eGene identification through transfer learning of genetic similarity shared across auxiliary and target studies.

Discovery of a Monoclonal Antibody That Targets Cell-Surface Pseudaminic Acid of Acinetobacter baumannii with Direct Bactericidal Effect.

The therapeutic effects of antibodies include neutralization of pathogens, activation of the host complement system, and facilitation of phagocytosis of pathogens. However, antibody alone has never been shown to exhibit bactericidal activity. In this study, we developed a monoclonal antibody that targets the bacterial cell surface component Pseudaminic acid (Pse). This monoclonal antibody, Pse-MAB1, exhibited direct bactericidal activity on Acinetobacter baumannii strains, even in the absence of the host complements or other immune factors, and was able to confer a protective effect against A. baumannii infections in mice. This study provides new insight into the potential of developing monoclonal antibody-based antimicrobial therapy of multidrug resistant bacterial infections, especially those which occurred among immunocompromised patients.

Substantial decline of organ preservation fluid contamination following adoption of Ischemia-Free liver transplantation：a Post-hoc analysis.

INTRODUCTION: Preservation fluid (PF) contaminations are common in conventional liver transplantation (CLT) and presumably originate from organ or PF exposures to the external environment in a non-strict sterile manner. Such exposures and PF contamination may be avoided in ischemia-free liver transplantation (IFLT) because of the strict sterile surgical procedures. In this study, we evaluated the impact of IFLT on organ PF contamination. METHODS: A post-hoc analysis using data from the first randomized controlled trial of IFLT was performed to compare the incidence, pathogenic spectrum of PF contamination, and incidence of early recipient infection between IFLT and CLT. Multivariable logistic regression was used to explore risk factors for PF contamination. RESULTS: Of the 68 cases recruited in the trial, 64 were included in this post-hoc analysis. The incidence of culture-positive PF was 9.4% (3/32) in the IFLT group versus 78.1% (25/32) in the CLT group (P<0.001). Three microorganisms were isolated from PF in the IFLT group, while 43 were isolated in the CLT group. The recipient infection rate within postoperative day 14 was 3.1% (1/32) in the IFLT group vs 15.6% (5/32) in the CLT group, although this difference did not reach statistical significance (P=0.196). Multivariate analysis revealed that adopting IFLT is an independent protective factor for culture-positive PF. CONCLUSION: PF contamination is substantially decreased in IFLT, and IFLT application is an independent protective factor for PF contamination. Using rigorous sterile measures and effective antibiotic therapy during IFLT may decrease PF contamination.

The Application of Membrane Separation Technology in the Pharmaceutical Industry.

With the advancement in membrane technology, membrane separation technology has been found increasingly widespread applications in the pharmaceutical industry. It is utilized in drug separation and purification, wastewater treatment, and the recycling of wastewater resources. This study summarizes the application history of membrane technology in the pharmaceutical industry, presents practical engineering examples of its applications, analyzes the various types of membrane technologies employed in the pharmaceutical sector, and finally, highlights the application cases of renowned international and Chinese membrane technology companies in the pharmaceutical field.

Sodium, potassium intake, and all-cause mortality: confusion and new findings.

BACKGROUND: The World Health Organization (WHO) has established recommended daily intakes for sodium and potassium. However, there is currently some controversy regarding the association between sodium intake, potassium intake, the sodium-to-potassium ratio, and overall mortality. To assess the correlations between sodium intake, potassium intake, the sodium-to-potassium ratio, and overall mortality, as well as the potential differences in sodium and potassium intake thresholds among different population groups, we analyzed data from NHANES 2003-2018. METHODS: NHANES is an observational cohort study that estimates sodium and potassium intake through one or two 24-h dietary recalls. Hazard ratios (HR) for overall mortality were calculated using multivariable adjusted Cox models accounting for sampling design. A total of 13855 out of 26288 participants were included in the final analysis. Restricted cubic spline analyses were used to examine the relationship between sodium intake, potassium intake, and overall mortality. If non-linearity was detected, we employed a recursive algorithm to calculate inflection points. RESULTS: Based on one or two 24-h dietary recalls, the sample consisted of 13,855 participants, representing a non-institutionalized population aged 40-80 years, totaling 11,348,771 person-months of mean follow-up 99.395 months. Daily sodium intake and daily potassium intake were inversely associated with all-cause mortality. Restrictive cubic spline analysis showed non-linear relationships between daily sodium intake, potassium intake, sodium-potassium ratio, and total mortality. The inflection point for daily sodium intake was 3133 mg/d, and the inflection point for daily potassium intake was 3501 mg/d, and the inflection point for daily sodium-potassium ratio intake was 1.203 mg/mg/d. In subgroup analyses, a significant interaction was found between age and high sodium intake, which was further confirmed by the smooth curves that showed a U-shaped relationship between sodium intake and all-cause mortality in the elderly population, with a inflection point of 3634 mg/d. CONCLUSION: Nonlinear associations of daily sodium intake, daily potassium intake and daily sodium-potassium ratio intake with all-cause mortality were observed in American individuals. The inflection point for daily sodium intake was 3133 mg/d. And the inflection point for daily sodium intake was 3634 mg/d in elderly population. The inflection point for daily potassium intake was 3501 mg/d. The inflection point for daily sodium-potassium ratio intake was 1.203 mg/mg/d, respectively, A healthy diet should be based on reasonable sodium intake and include an appropriate sodium-to-potassium ratio.

Evaluating causal influence of maternal educational attainment on offspring birthweight via observational study and Mendelian randomization analyses.

Background: Although extensive discussions on the influence of maternal educational attainment on offspring birthweight, the conclusion remains controversial, and it is challenging to comprehensively assess the causal association between them. Methods: To estimate effect of maternal educational attainment on the birthweight of first child, we first conducted an individual-level analysis with UK Biobank participants of white ancestry (n = 208,162). We then implemented Mendelian randomization (MR) methods including inverse variance weighted (IVW) MR and multivariable MR to assess the causal relation between maternal education and maternal-specific birthweight. Finally, using the UK Biobank parent-offspring trio data (n = 618), we performed a polygenic score based MR to simultaneously adjust for confounding effects of fetal-specific birthweight and paternal educational attainment. We also conducted simulations for power evaluation and sensitivity analyses for horizontal pleiotropy of instruments. Results: We observed that birthweight of first child was positively influenced by maternal education, with 7 years of maternal education as the reference, adjusted effect = 44.8 (95%CIs 38.0-51.6, P = 6.15 × 10-38), 54.9 (95%CIs 47.6-62.2, P = 4.21 × 10-128), and 89.4 (95%CIs 82.1-96.7, P = 4.28 × 10-34) for 10, 15 and 20 years of maternal educational attainment, respectively. A causal relation between maternal education and offspring birthweight was revealed by IVW MR (estimated effect = 0.074 for one standard deviation increase in maternal education years, 95%CIs 0.054-0.093, P = 2.56 × 10-13) and by complementary MR methods. This connection was not substantially affected by paternal education or horizontal pleiotropy. Further, we found a positive but insignificant causal association (adjusted effect = 24.0, 95%CIs -150.1-198.1, P = 0.787) between maternal education and offspring birthweight after simultaneously controlling for fetal genome and paternal education; this null causality was largely due to limited power of small sample sizes of parent-offspring trios. Conclusion: This study offers supportive evidence for a causal association between maternal education and offspring birthweight, highlighting the significance of enhancing maternal education to prevent low birthweight.

Storage stability of lysostaphin solution and its pulmonary delivery.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading causative pathogen of nosocomial pneumonia with an alarming in-hospital mortality rate of 30%. Last resort antibiotic, vancomycin, has been increasingly used to treat MRSA infections, but the rapid emergence of vancomycin-resistant strains urges the development of alternative treatment strategies against MRSA-associated pneumonia. The bacteriolytic enzyme, lysostaphin, targeting the cell wall peptidoglycan of S. aureus, has been considered as a promising alternative for MRSA infections. Its proteinaceous nature is likely benefit from direct delivery to the lungs, but the challenges for successful pulmonary delivery of lysostaphin lying on a suitable inhalation device and a formulation with sufficient storage stability. In this study, the applicability of a vibrating mesh nebulizer (Aerogen Solo®) and a soft mist inhaler (Respimat®) was investigated. Both devices were capable of aerosolizing lysostaphin solution into inhalable droplets and caused minimum antibacterial activity loss. In addition, lysostaphin stabilized with phosphate-buffered saline and 0.1% Tween 80 was proved to have acceptable stability for at least 12 months when stored at 4 °C. These promising data encourage further clinical development of lysostaphin for management of MRSA-associated lung infections.

A target-triggered fluorescence-SERS dual-signal nano-system for real-time imaging of intracellular telomerase activity.

Telomerase (TE) is a promising diagnostic and prognostic biomarker for many cancers. Quantification of TE activity in living cells is of great significance in biomedical and clinical research. Conventional fluorescence-based sensors for quantification of intracellular TE may suffer from problems of fast photobleaching and auto-fluorescence of some endogenous molecules, and hence are liable to produce false negative or positive results. To address this issue, a fluorescence-SERS dual-signal nano-system for real-time imaging of intracellular TE was designed by functionalizing a bimetallic Au@Ag nanostructure with 4-p-mercaptobenzoic acid (internal standard SERS tag) and a DNA hybrid complex consisted of a telomerase primer strand and its partially complimentary strand modified with Rhodamine 6G. The bimetallic Au@Ag nanostructure serves as an excellent SERS-enhancing and fluorescence-quenching substrate. Intracellular TE will trigger the extension of the primer strand and cause the shedding of Rhodamine 6G-modified complimentary strand from the nano-system through intramolecular DNA strand displacement, resulting in the recovery of the fluorescence of Rhodamine 6G and decrease in its SERS signal. Both the fluorescence of R6G and the ratio between the SERS signals of 4-p-mercaptobenzoic acid and Rhodamine 6G can be used for in situ imaging of intracellular TE. Experimental results showed that the proposed nano-system was featured with low background, excellent cell internalization efficiency, good biocompatibility, high sensitivity, good selectivity, and robustness to false positive results. It can be used to distinguish cancer cells from normal ones, identify different types of cancer cells, as well as perform absolute quantification of intracellular TE, which endows it with great potential in clinical diagnosis, target therapy and prognosis of cancer patients.

Identifying risk loci for obsessive-compulsive disorder and shared genetic component with schizophrenia: A large-scale multi-trait association analysis with summary statistics.

Due to limited samples, no genetic loci have been identified for obsessive-compulsive disorder (OCD) in genome-wide association studies. Additionally, although co-morbidities between OCD and schizophrenia (SCZ) were observed, their common genetic etiology was not completely known. Here, we conducted a comprehensive investigation regarding the genetic architecture of OCD and the common genetic foundation shared by OCD and SCZ using summary statistics data (2688 cases and 7037 controls for OCD; 53,386 cases and 77,258 controls for SCZ). We discovered significant genetic correlation between OCD and SCZ (r̂g=0.296, P = 2.82 × 10-11). We then performed two multi-trait association analyses to detect OCD-associated loci and colocalization analysis to detect causal variants. Parallel gene-level analyses were also implemented. We identified 323 OCD-relevant variants located within 12 loci, with four loci shared the same causal variants between OCD and SCZ. Further, the gene-level analyses discovered 8 OCD-associated genes. Finally, multiple functional analyses at both SNP and gene levels showed that these genetic association signals had significant enrichments in the regions of left ventricle and anterior cingulate cortex, and suggested an important role of pathways involving regulation of telomere maintenance, histone phosphorylation, and GnRH secretion. Overall, this study identified new genetic loci for OCD and provided substantial evidence supporting common genetic foundation underlying OCD and SCZ. The findings advanced our understanding of genetic architecture and pathophysiology of OCD as well as shedding light on shared genetic etiology of the two disorders.

Identifying risk loci for FTD and shared genetic component with ALS: A large-scale multitrait association analysis.

Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆg = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22.1, 5q35.1, 9p21.2, 19p13.11, and 20q13.13). Among these, ALS and FTD had causal variants in 9p21.2 and 19p13.11. Moreover, MOBP (3p22.1), C9orf72 (9p21.2), MOB3B (9p21.2), UNC13A (19p13.11), SLC9A8 (20q13.13), SNAI1 (20q13.13), and SPATA2 (20q13.13) were discovered by both SNP- and gene-level analyses, which together discovered 15 FTD-associated genes, with 10 not detected before (IFNK, RNF114, SLC9A8, SPATA2, SNAI1, SCFD1, POLDIP2, TMEM97, G2E3, and PIGW). Functional analyses showed these genes were enriched in heart left ventricle, kidney cortex, and some brain regions. Overall, this study provides insights into genetic determinants of FTD and shared genetic etiology underlying FTD and ALS.

Mitigation of Anti-Drug Antibody Production for Augmenting Anticancer Efficacy of Therapeutic Protein via Co-Injection of Nano-Rapamycin.

The induction of anti-drug antibody (ADA) is a formidable challenge for protein-based therapy. Trichosanthin (TCS) as a class of ribosome-inactivating proteins is widely studied in tumor treatment. However, the immunogenicity can induce the formation of ADA, which can cause hypersensitivity reactions and neutralize the efficacy of TCS, thus limiting its clinical application in cancer therapy. Here, a promising solution to this issue is presented by co-administration of the rapamycin nanoparticles and TCS. PEGylated rapamycin amphiphilic molecule is designed and synthesized as a prodrug and a delivery carrier, which can self-assemble into a nanoparticle system with encapsulation of free rapamycin, a hydrophobic drug. It is found that co-injection of the PEGylated rapamycin nanoparticles and TCS could mitigate the formation of anti-TCS antibody via inducing durable immunological tolerance. Importantly, the combination of TCS and the rapamycin nanoparticles has an enhanced effect on inhibit the growth of breast cancer. This work provides a promising approach for protein toxin-based anticancer therapy and for promoting the clinical translation.

Prediction of 19F NMR chemical shifts for organic compounds with ORCA.

Accurate assignment of 19F NMR has long been a challenge, and quantum chemical methods are possible solutions. Herein we reported a scaling method for the prediction of 19F NMR chemical shift with freely available ORCA program package. Performance of 31 DFT functionals coupled with 11 basis sets were evaluated and influence of geometry optimization was also studied with five functionals coupled with three basis sets. The significance of geometry was further examined through the execution of relaxed surface scans of seven flexible compounds, and averaged shieldings of obtained conformers yielded notable improvement of the correlation between calculated isotropic shielidings and experimental chemical shifts. Utilization of the best scaling factor obtained successfully assigned of fluorine atoms in multifluorinated molecules with different conformations. The method reported here was computationally inexpensive, easily available with acceptable accuracy.

Doing housework and having regular daily routine standing out as factors associate with physical function in the older people.

Background and objectives: Nationwide data were used to explore factors associated with physical function in order to identify interventions that could improve and maintain physical function in the older people. Methods: The physical function was assessed by gait speed (GS). We selected 2,677 male and 2,668 female older adults (aged ≥60) who could perform the GS test as study subjects. GS was measured by having subjects walk across and back a 10-m course. A gait speed less than 20% that of a reference population (<0.7 m/s) was used as the definition of slow gait speed (SGS). Co-morbidity, polypharmacy, medical expenses, need for care, and hospitalization were used to evaluate health status. A stepwise logistic regression model was used to determine factors associated with SGS. Results: SGS was associated with poorer health status, higher medical cost, lower ranking on the Geriatric Depression Scale (GDS) and decreased Mini-mental State Examination (MMSE). Co-morbidity (OR = 1.81, 1.58-2.07), polypharmacy (OR = 1.47, 1.25-1.74), MMSE <24 (OR = 1.85, 1.54-2.22), and GDS ≥ 11 (OR = 1.40, 1.18-1.65) were associated with SGS. In contrast, doing housework (DHW, OR = 0.43, 0.38-0.49), having a regular daily routine (RDR, OR = 0.64, 0.45-0.91), and current alcohol consumption (OR = 0.74, 0.62-0.90) were inversely associated with SGS. DHW plus having RDR could greatly reduce the risk of SGS (OR = 0.29, 0.19-0.43). Conclusion: Poor physical function is associated with poorer health status in Chinese older people. Maintaining a regular daily routine and doing some housework may be important factors that can help older people preserve their physical function.

Co-exposure to multiple air pollutants, genetic susceptibility, and the risk of myocardial infarction onset: A cohort analysis of the UK Biobank participants.

AIMS: The relationship between the long-term joint exposure to ambient air pollution and incidence of myocardial infarction (MI), and modification by genetic susceptibility remain inconclusive. METHODS: We analyzed 329,189 UK Biobank participants without MI at baseline. Exposure concentrations to particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOx) were obtained. Air pollution score assessing the joint exposure were calculated, and its association with MI was evaluated via Cox model under the P-value aggregation framework. Genetic susceptibility to MI was evaluated by incorporating polygenic risk score (PRS) into models. Risk prediction models were also established. RESULTS: During a median follow-up of 13.4 years, 9,993 participants developed MI. Per interquartile range increase of PM2.5, PM10, NO2, and NOx resulted in 74% (95% confidence intervals [CIs] 69%∼79%), 67% (63%∼72%), 46% (42%∼49%), and 38% (35%∼41%) higher risk of MI. Compared with the lowest quartile (Q1) of air pollution score, the multivariable adjusted hazard ratio (HR) (95%CIs) of Q4 (the highest cumulative air pollution) was 3.50 (3.29∼3.72) for MI. Participants with the highest PRS and air pollution score possessed the highest risk of incident MI (HR=4.88, 95%CIs 4.35∼5.47). Integrating PRS, air pollution exposure and traditional factors substantially improved risk prediction of MI. CONCLUSIONS: Long-term joint exposure to air pollutants including PM2.5, PM10, NO2, and NOx is substantially associated with increased risk of MI. Genetic susceptibility to MI strengthens such adverse joint association. Air pollutions together genetic and traditional factors enhances the accuracy of MI risk prediction.

Our study aimed to analyze the relationship between the long-term joint exposure to four ambient air pollutants and incidence of myocardial infarction (MI), and the modification role of genetic susceptibility. Four air pollutants (PM2.5, PM10, NO2, and NOx) were adversely associated with the incidence of MI as well as with its two subtypes including STEMI and NSTEMI. Air pollution score representing co-exposure to multiple air pollutants was related to increased risk of incident MI, STEMI and NSTEMI. Genetic susceptibility to MI strengthened the adverse association of co-exposure to air pollution with the risk of MI, STEMI and NSTEMI.